Clinical trial NCT03633227
Conditions: Liver Cirrhosis, Biliary
Keywords: Primary Biliary Cholangitis Primary Biliary Cirrhosis PBC Hepatic Impairment Cirrhosis Liver
Sponsor: Intercept Pharmaceuticals
Start date: 2018-06-22; Completion date: 2021-07-09
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the pharmacokinetics (PK) and safety of OCA treatment in participants with PBC and moderate to severe hepatic impairment over a 48-week treatment period. Participants who have completed their 48-week double blind treatment period will continue double-blind treatment until all randomized participants have completed their 48-week treatment period and the database for that period is locked. An open-label extension study in which all participants receive OCA will be considered following review of blinded safety and PK data.

Detailed description:

Arms: arm 1: Participants will initiate treatment with OCA 5 milligrams (mg) tablets orally once weekly. At Week 12, if there are no safety concerns, the dose will be up-titrated to OCA 5 mg twice weekly. Every 6 weeks thereafter, based on tolerability assessments, further up-titration of dose will be considered. At each titration visit, the participants will start the higher dose regimen no earlier than 2 days after the prior dose. The maximum dose titration will be OCA 10 mg twice weekly at least 3 days apart. The minimum treatment duration will be 48-weeks. Participants, who complete their 48-week treatment, can continue the treatment until all randomized participants complete their 48-week treatment period and the database for that period is locked (total duration: approximately up to 3 years). arm 2: Participants will receive OCA matching placebo orally once weekly or twice weekly for the duration of at least 48-weeks. Participants, who complete their 48-week treatment, can continue the treatment until all randomized participants complete their 48-week treatment period and the database for that period is locked (total duration: approximately up to 3 years).
Interventions: intervention 1: Obeticholic Acid (OCA) intervention 2: Placebo
Intervention descriptions: intervention 1: OCA will be administered per dose and schedule specified in the arm description. intervention 2: OCA matching placebo will be administered per the schedule specified in the arm description.

Protocol documents:
Prot_000.pdf: 
1. 
TITLE PAGE 
 
 
Clinical Study Protocol 747-401 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Pharmacokinetics and Safety of Obeticholic Acid in Patients with Primary 
Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
 
EudraCT Number: 2017-001762-13  
ClinicalTrials.gov Identifier: NCT03633227 
 
 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
305 Madison Avenue 
Morristown, NJ 07960 
USA 
 
 
 
 
 
CONFIDENTIAL 
The information contained herein is the property of Intercept Pharmaceuticals, Inc. and may not 
be reproduced, published, or disclosed to others without written authorization of Intercept 
Pharmaceuticals, Inc. 


Clinical Study Report 747-401 
16.1.1 Protocol and Protocol Amendments 
Page 1
Confidential and Proprietary 
16.1.1 
PROTOCOL AND AMENDMENTS 
Protocol 747-401, Version 1, dated 20 Dec 2016 
Protocol 747-401, Version 2, dated 22 May 2017 
Protocol 747-401, Version 3, dated 04 Jan 2018 
Protocol 747-401, Version 4, dated 15 Feb 2019 
Protocol Addendums 
Addendum 1 to Protocol 747-401, dated 19 May 2020  
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1. 
TITLE PAGE 
 
 
Clinical Study Protocol 747-401 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Study Evaluating 
the Pharmacokinetics and Safety of Obeticholic Acid in Patients with Primary 
Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
 
 
Version 1:  20 December 2016 
 
(For FDA Review Only) 
 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
USA 
 
TEL:  
 
 
CONFIDENTIAL 
The information contained herein is the property of Intercept Pharmaceuticals, Inc. and may not 
be reproduced, published, or disclosed to others without written authorization of Intercept 
Pharmaceuticals, Inc. 
 
 
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INVESTIGATOR’S AGREEMENT 
 
I have received and read the current version of the Investigator’s Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-401.  Having fully considered all the information available, 
I agree that it is ethically justifiable to give OCA to selected patients according to this protocol. 
I understand that all information concerning OCA supplied to me by the Sponsor, Intercept 
Pharmaceuticals, Inc., and/or its agents in connection with this study and not previously 
published is confidential information.  This includes the IB, clinical study protocol, case report 
forms (CRF), and any other preclinical and clinical data provided by the Sponsor. 
I understand that no data are to be made public or published without prior knowledge and written 
approval by the Sponsor. 
By my signature below, I hereby attest that I have read, understood and agreed to abide by all the 
conditions, instructions and restrictions contained in Protocol 747-401 and in accordance with 
Good Clinical Practice (CPMP/ICH/135/95), the Declaration of Helsinki, and all regulatory 
requirements for protection of human patients in clinical studies and privacy requirements for the 
protection of individual and company data. 
I acknowledge that the Sponsor of the study has the right to discontinue the study at any time. 
 
 
 
 
 
 
Investigator’s Name (Printed) 
 
 
 
 
 
 
Investigator’s Signature 
 
Date 
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STUDY PERSONNEL CONTACT INFORMATION 
Emergency Contact Information 
Medical Monitor - 24-hour Emergency Reporting 
Contact: 
 MD, Medical Director, Drug Safety,  
Intercept Pharmaceuticals, Inc. 
Mobile: 
  
Telephone: 
  
Email: 
 
 
Or if Not Available: 
Contact: 
 MD, PhD,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Email: 
 
 
 
SAE Contact Information 
SAE Fax: 
 
SAE email address 
 
Telephone 
 
 
Clinical Operations and Project Management 
Contact: 
 VP, Clinical Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 
 
 
 
 
 
 
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Protocol 747-401 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product: 
Obeticholic Acid 
Name of Active Ingredient: 
Obeticholic acid (OCA); 6α-ethyl-chenodeoxycholic acid; (6-ECDCA); INT-747; DSP-1747 
Title of Study:  
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Study Evaluating the Pharmacokinetics and Safety 
of Obeticholic Acid in Patients with Primary Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
Investigators and/or Study Center(s):  
The study is planned to have approximately 20 investigational sites, globally. 
Studied Period: The study will include a 14-day screening period 
and a 48-week double-blind primary treatment period.  Following 
completion of the Week 48 visit, patients will remain on blinded 
investigational product and be seen at regular intervals until all 
patients complete the primary treatment period at which point all 
patients will transition to an open-label long-term safety extension 
(LTSE).  
Phase of Development:   
Phase 4 
 
Objectives:  In patients with Moderate to Severe PBC:  
Primary Objective: 
 
To evaluate the pharmacokinetics (PK) of OCA and its conjugates, glyco-OCA, tauro-OCA, and OCA 
glucuronide 
 
To evaluate the safety and tolerability of OCA treatment compared with placebo 
Secondary Objectives:  
 
To evaluate the effect of OCA treatment compared to placebo on:  
 
The model of end stage liver disease (MELD) score and its components 
 
Child-Pugh (CP) score and its components 
 
Liver biochemistry including bilirubin, alkaline phosphatase (ALP), and aminotransferases (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], and gamma glutamyl transaminase [GGT]) 
 
Biomarkers of bile acid synthesis and homeostasis including fibroblast growth factor 19 (FGF-19), 
7α-hydroxy-4-cholesten-3-one (C4), and plasma and fecal bile acids 
Additional Objectives: 
 
To evaluate the effect of OCA treatment compared to placebo on: 
 
Markers of inflammation 
 
Noninvasive markers of liver fibrosis (Enhanced Liver Fibrosis [ELF] score) 
  
Noninvasive measurement of liver stiffness (transient elastography [TE]) 
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 
To assess clinical outcomes consistent with end-stage liver disease (eg, liver -related events resulting in 
death, hepatic failure leading to liver transplant, variceal bleed, hepatic encephalopathy, spontaneous 
bacterial peritonitis, ascites, hepatocellular carcinoma) 
 
To assess the PK/Pharmacodynamic (PD) relationship of OCA on: 
 
 ALP, total bilirubin, and aminotransferases 
 
Bile acid homeostasis 
 
Safety and tolerability (eg pruritus) 
Methodology:  This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the PK and 
safety of OCA treatment in patients with PBC with moderate to severe hepatic impairment defined as Child-
Pugh B (CP-B) (moderate) and Child-Pugh C (CP-C) (severe) including a broad distribution of MELD scores 
(ranging from 6 to 24).  Approximately 50 patients (including at least 20% of patients with CP-C) will be 
enrolled in the study.  Patients will be screened for up to ≤14 days prior to entering the study (Day 1).  Patients 
who meet all eligibility requirements will be randomized in a 1:1 ratio to one of two treatment groups:  Placebo 
or OCA.  Randomization will be stratified by CP class.  Baseline MELD scores will be monitored on an 
ongoing basis to ensure adequate distribution of MELD scores.   
Following completion of safety assessments and laboratory specimen collection, blinded investigational product 
will be dispensed with instruction to begin dosing the same day (Day 1) at OCA 5 mg or placebo once weekly.  
Double-Blind Primary Treatment Period:  During the primary treatment period (ie, Day 1 through Week 48), 
clinic visits will occur approximately every 6 weeks for the assessment of safety, tolerability, PK, and PD 
(trough).  At each visit, trough PK assessments will be performed in all patients participating in the study.  
Serial PK sampling will be performed at Week 12 and only after a patient uptitrates.  Following completion of 
the Week-48 visit, patients will remain on blinded investigational product and be seen at regular visits every 
3 months until all patients complete the 48-week primary treatment period.  
Long -term Open Label Extension Phase: Once all patients have completed the double-blind 48-week primary 
treatment period, patients will have the option to continue into an open-label long-term safety extension and all 
patients will receive OCA.  Visits in the LTSE will occur every 3 months for up to 5 years.  Patients on placebo 
during the primary treatment period will initiate study medication at 5-mg OCA once weekly and follow the 
dosing regimen based on their CP score.  Patients on OCA during the primary treatment period will continue the 
dose that they are on once unblinded. 
Study Design Diagram 
 
EOS = end of study; EOT = end of treatment, OCA = obeticholic acid 
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*Initial dose titration of investigational product may occur at the Week 12 Visit, or any study visit thereafter for patients on 
all dosing regimens, based on tolerability and safety laboratory tests from the previous visit.  Subsequent dose titration(s) 
may occur no earlier than 6 weeks after the previous dose titration and will be based on tolerability and CP score. 
 
Dosing Regimen:   
All patients will initiate investigational product once weekly with 5-mg OCA or matching placebo.  Starting at 
Week 12, safety and tolerability of investigational product will be evaluated and, if tolerated, the patient can 
increase the dose to the next dose level as described below: 
 
At Week 12, if investigational product is tolerated and laboratory assessments from the Week 6 
visit do not indicate a safety concern, the patient will change the dosing frequency to 5 mg twice 
weekly, at least 3 days apart.   
 
Following an additional 6 weeks of treatment, if investigational product is tolerated, patients may 
be up-titrated to OCA 10 mg twice weekly at least 3 days apart, the maximum dose for patients 
with CP-C.  
 
Following an additional 6 weeks of treatment, if tolerated, patients with CP-B may titrate to a 
maximum dose of OCA 5 mg once daily, the maximum dose for patients with CP-B.  
 
If, during the course of the study, a patient transitions from CP- B to CP-C, or vice versa, the 
maximal dose for the new CP classification would apply.  
Planned OCA or Matching Placebo Dosing Regimen by Child-Pugh Score 
 
Child-Pugh B 
(Moderate Hepatic Impairment) 
Child-Pugh C 
(Severe Hepatic Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting Dose a (Day 1) 
5 mg once 
weekly 
matching placebo 
5 mg once weekly 
matching placebo 
Titration 1b (≥Week 12) 
5 mg twice 
weeklyc 
matching placebo 
5 mg twice 
weeklyc 
matching placebo 
Titration 2b (≥6 weeks 
after Titration 1) 
10 mg twice 
weeklyc 
matching placebo 
10 mg twice 
weeklyc 
matching placebo 
Titration 3b (≥6 weeks 
after Titration 2) 
5 mg once daily 
matching placebo 
NA 
matching placebo 
a Starting dose based on patient’s Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on patient tolerability 
and/or changes in Child-Pugh Score at any time during the study. 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
Number of Patients (planned):  Approximately 50 patients will be enrolled in this study. 
Diagnosis and Main Criteria for Inclusion: 
Key Inclusion Criteria 
1. A definite or probable diagnosis of PBC (consistent with American Association for the Study of Liver 
Diseases [AASLD] and European Association for the Study of the Liver [EASL] Practice Guidelines, 
defined as having ≥2 of the following 3 diagnostic factors: 
 
History of elevated ALP levels for at least 6 months 
 
Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer (<1:80), PBC-specific 
antibodies (anti-GP210 and/or anti-SP100) and/or antibodies against the major M2 components 
(PDC-E2, 2-oxo-glutaric acid dehydrogenase complex)  
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 
Liver biopsy consistent with PBC (collected at any time prior to Screening) 
2. Evidence of cirrhosis including at least one of the following: 
 Biopsy indicating cirrhosis or a medical history with histological evidence of cirrhosis  
 Clinical evidence consistent with cirrhosis including: esophageal varices, ascites, encephalopathy, or 
portal hypertension 
  Liver stiffness as assessed by TE of >16.9kPa 
3. Satisfy the criteria of the modified CP classification for hepatic impairment during Screening (ie, within 
14 days before the first dose of investigational product): 
 
Moderate:  CP-B (Scores 7 to 9) or 
 
Severe:  CP-C (Scores 10 to12) 
4. MELD score of 6 to 24 at Screening 
5. Age ≥18 years 
6. Taking UDCA for at least 12 months (stable dose for ≥3 months) prior to Day 1, or unable to tolerate 
UDCA (no UDCA for ≥3 months)  
7. Contraception:  Female patients must be postmenopausal, surgically sterile, or if premenopausal (and not 
surgically sterile), be prepared to use ≥1 effective method of contraception during the study and for 30 days 
after the end of treatment visit.  Effective methods of contraception are considered to be those listed below: 
 
Barrier method, ie, (a) condom (male or female) with spermicide or (b) diaphragm, with spermicide; or 
 
Intrauterine device; or  
 
Vasectomy (partner), or  
 
Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection, or 
 
Abstinence, if in line with the preferred and usual lifestyle of the patient (where abstinence is defined as 
refraining from heterosexual intercourse) 
8. Must provide written informed consent and agree to comply with the study protocol. 
Key Exclusion Criteria 
1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6) 
2. History of liver transplant, organ transplant 
3. History of alcohol or drug abuse within 12 months prior to Screening 
4. History or presence of other concomitant liver diseases including: 
 
Hepatitis C virus infection, RNA positive 
 
Active hepatitis B infection; however, patients who have seroconverted (hepatitis B surface antigen and 
hepatitis B e antigen negative) may be included in this study after consultation with the medical 
monitor 
 
Primary sclerosing cholangitis 
 
Alcoholic liver disease 
 
Definite autoimmune liver disease or overlap hepatitis 
 
Gilbert's Syndrome 
5. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function during the Screening 
period 
6. Patients with history or presence of hepatorenal or hepatopulmonary syndrome 
7. Patients with significant active infection (ie spontaneous bacterial peritonitis) 
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8. Patients with known or suspected hepatocellular carcinoma 
9. History of known or suspected clinically significant hypersensitivity to OCA or any of its components 
10. Participation in another investigational product, biologic, or medical device study within 30 days prior to 
Screening.  Participation in a previous study of OCA is allowed with 3 months washout prior to enrollment 
in this study 
11. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant 
with the study is uncertain 
12. UDCA naïve (unless contraindicated). 
Investigational Product, Dosage and Mode of Administration:  
OCA 5 mg or OCA 10 mg tablets, oral administration 
Placebo tablets, matched in size and appearance to OCA tablets, oral administration 
Duration of Treatment:  The study will include a 14-day screening period and a 48-week double-blind primary 
treatment period.   Following completion of the Week 48 visit, patients will remain on blinded investigational 
product and be seen at regular visits every 3 months until all patients complete the double-blind 48-week 
primary treatment period.  Hence, depending on the rate of patient enrollment, patients will be exposed to 
investigational product for a minimum of 1 year up to approximately 2 years during the blinded period.  
Following completion of the blinded period, patients will have the option to continue into an extension during 
which they will receive open-label treatment and be seen at regular visits every 3 months for up to 5 years.   
Criteria for Evaluation: 
Primary Objectives 
Assessments 
PK parameters 
OCA and its conjugates, glyco-OCA, tauro-OCA, and 
OCA glucuronide 
Safety and tolerability  
SAEs and TEAEs, physical exam, ECG, vital signs, 
clinical laboratory assessments, discontinuations, 
pruritus and fatigue 
Secondary Objectives 
Assessments 
Changes in Risk Scores 
Changes in MELD and CP Score components  
Changes in liver biochemistry and hepatobiliary 
damage  
Total and direct bilirubin, ALP, ALT, AST, GGT, INR, 
creatinine, albumin, platelets  
PD parameters 
FGF-19, C4, and plasma, fecal bile acids 
Additional Objectives 
Assessments 
Markers of inflammation 
IL-6, hs-CRP, TNF-α, IgM, IgA, IgG, CK-18-M30, and 
others as determined during course of study.   
Noninvasive measurements of liver fibrosis, liver 
stiffness and cirrhosis 
Transient Elastography and ELF (including HA, P3NP, 
and TIMP-1) 
PK/PD relationship of OCA and liver 
biochemistry 
OCA and its conjugates, glyco-OCA tauro-OCA; and 
OCA glucuronide 
PK/PD relationship of OCA and bile acid 
homeostasis 
Bile acids 
Patient reported outcomes 
Pruritus VAS, PBC-40, EQ-5D-5L, CLDQ 
PK/PD relationship of OCA:  Markers of safety 
and tolerability 
Pruritus and fatigue 
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Clinical outcomes 
Incidence and time to first occurrence of any of the 
following:  all-cause mortality, liver-related events 
resulting in death, hepatic failure leading to liver 
transplant, variceal bleed, hepatic encephalopathy, 
spontaneous bacterial peritonitis, ascites, hepatocellular 
carcinoma 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
C4 = 7α-hydroxy-4-cholesten-3-one; CK-18-M30 = cytokeratin-18 neoepitope; CLDQ = Chronic Liver Disease 
Questionnaire; CP = Child-Pugh; ECG = electrocardiogram; ELF = enhanced liver fibrosis; FGF-19 = fibroblast 
growth factor-19; GGT = gamma-glutamyl transferase; HA = hyaluronic acid; HDL = high density lipoprotein; 
hs-CRP = high-sensitivity C-reactive protein; IgA = immunoglobulin; A IgG = immunoglobulin G; IgM = 
immunoglobulin M; INR = international normalized ratio; MACE = Major Adverse Cardiovascular Events; 
MELD = Model End Stage Liver Disease; OCA = obeticholic acid; P3NP = procollagen 3 N-terminal peptide; 
PD = pharmacodynamic; PK = pharmacokinetic; TEAE = treatment emergent adverse events; TIMP-1 = tissue 
inhibitor of metalloproteinase 1; SAE = serious adverse event; TNF-α = tumor necrosis factor-α, VAS = visual 
analog scale 
Statistical Methods: 
Analysis Populations: 
The following patient populations will be evaluated and used for presentation and analysis of the data: 
 
The Intent-to-Treat (ITT) Population will include all randomized patients who receive any amount of 
investigational product (OCA or placebo). The ITT Population will be the primary population used for 
summarizing efficacy assessments.  
 
The Safety Population will include all patients who received at least one dose of investigational product 
(placebo or OCA). The Safety Population will be the primary population used for safety analyses.  
 
The PK Population will include all patients receiving OCA who have adequate concentration-time 
profiles to characterize OCA and its conjugates and must not have any major protocol deviations that 
potentially affect exposure levels.   
Pharmacokinetic Analyses: 
The PK Population will be used for analysis of PK parameters, which include plasma OCA (parent) and its 
conjugates (glyco-OCA and tauro-OCA), total OCA, OCA glucuronide and potentially other conjugates or 
metabolites not yet identified. 
PK analysis will based on the PK population.  Values will be calculated using non-compartmental methods.  The 
values will be summarized by active treatment group using descriptive statistics.  
Safety Analyses: 
Safety analyses will be conducted using the Safety population.  Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results will be summarized by treatment group.  The treatment-
emergent AEs (TEAEs) and serious AEs (SAEs) will be tabulated by system organ class and preferred term for 
each treatment group, and similarly by severity and relationship to treatment.  Laboratory parameters, physical 
examinations including vital signs, and electrocardiograms will be summarized by treatment group using 
descriptive statistics at Baseline and at each scheduled post-Baseline visit.  The absolute change from baseline 
will also be summarized.  No inferential comparison of safety endpoints will be performed. 
Efficacy Analyses: 
This study does not plan to test a formal hypothesis for any efficacy endpoint.   
The endpoints of efficacy assessments are change in bilirubin, INR, creatinine, albumin, platelets, ALT, AST, 
and GGT from baseline to Week 48 (end of the study), change from baseline to Week 48 in CP score and 
components of the CP score, and change from baseline to Week 48 in MELD and components of the MELD 
score.  Analyses of change from Baseline to Week 48 (end of study) will be modelled between treatment groups 
using ANCOVA model with change from Baseline as the dependent variable, treatment group and 
randomization stratification factor as fixed effects and the baseline value as a covariate.  The same analysis will 
be carried out using percentage change from Baseline as the dependent variable. 
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Additional Efficacy Analyses 
Analyses of changes in liver stiffness and ELF, cytokeratin-and TIMP-1, and markers of inflammation will be 
summarized and analyzed using the same methodology specified for the secondary analyses of change in 
bilirubin. 
The following clinical outcomes will be captured in the study: 
 
All-cause mortality 
 
Liver related death 
 
Liver transplant 
 
Variceal bleed 
 
Hepatic encephalopathy 
 
Bacterial peritonitis 
 
Ascites 
 
Hepatocellular carcinoma 
The incidence and time to first occurrence of any of the above listed clinical outcomes will be summarized by 
treatment group using the log rank test stratified by the randomization stratification factor.  Kaplan-Meier (KM) 
estimates of the distribution of the time-to-event will be tabulated and graphed by treatment group.  The 
tabulation will include the KM estimate of the medians and corresponding 95% confidence intervals (CIs), if the 
medians can be estimated.  The number and percent of subjects censored and with events will be presented.  The 
hazard ratio and 95% CI will be estimated based on a Cox regression model stratified by randomization strata.  
In addition, the time to each of the above outcomes will be summarized by treatment group using the same 
methods as defined above. 
Sample Size Justification: 
To reasonably characterize the PK of OCA in patients with hepatic impairment, a simulation-based approach 
estimated a requirement of approximately 20 patients per OCA treatment group assuming a 15% discontinuation 
rate.  Ten patients on placebo will be included as a comparator.  The assessment was based on 80% powering 
for the 90% confidence interval of the geometric mean ratio of Total OCA (sum of OCA, glyco OCA, and tauro 
OCA). 
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................18 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Overview of Disease State and OCA ..........................................................................21 
5.2. 
Clinical Development of Obeticholic Acid ................................................................21 
5.2.1. 
Rationale for Study Design .........................................................................................22 
5.2.2. 
Rationale for Obeticholic Acid Dose and Duration ....................................................23 
5.2.3. 
Rationale for Population Chosen ................................................................................24 
5.2.4. 
Rationale for Control Group .......................................................................................24 
5.3. 
Summary of Known Potential Risks with Investigational Product ............................24 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
6.1. 
Primary Objectives .....................................................................................................25 
6.2. 
Secondary Objectives .................................................................................................25 
6.3. 
Additional Objectives .................................................................................................25 
7. 
INVESTIGATIONAL PLAN .....................................................................................26 
7.1. 
Overall Study Design ..................................................................................................26 
7.1.1. 
Study Design Diagram ................................................................................................27 
7.1.2. 
Schedule of Study Procedures ....................................................................................28 
7.1.3. 
Study Duration ............................................................................................................31 
7.2. 
Number of Patients .....................................................................................................31 
7.3. 
Planned Dosing Regimen ...........................................................................................31 
7.4. 
Dose Adjustment Criteria ...........................................................................................32 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements .................................................33 
7.4.2. 
Safety Criteria for Adjustment or Stopping Doses .....................................................33 
7.5. 
Criteria for Study Termination ...................................................................................34 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................34 
8.1. 
Patient Population .......................................................................................................34 
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8.2. 
Patient Inclusion Criteria ............................................................................................34 
8.3. 
Patient Exclusion Criteria ...........................................................................................35 
8.4. 
Patient Withdrawal Criteria ........................................................................................36 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product ..........................36 
8.4.1.1. 
Pregnancy ...................................................................................................................37 
8.4.2. 
Other Reasons for Discontinuation of Investigational Product or Study 
Termination .................................................................................................................37 
8.4.2.1. 
Withdrawal of Consent ...............................................................................................37 
8.4.2.2. 
Lost to Follow-Up .......................................................................................................37 
8.4.2.3. 
Elevated Liver Enzymes .............................................................................................38 
8.4.3. 
Patient Discontinuation Notification ..........................................................................38 
9. 
TREATMENT OF PATIENTS ..................................................................................38 
9.1. 
Investigational Product Treatment Regimen ..............................................................38 
9.2. 
Concomitant Medications ...........................................................................................39 
9.2.1. 
Drug Interactions ........................................................................................................39 
9.2.2. 
Prohibited Medications ...............................................................................................40 
9.3. 
Treatment Compliance ................................................................................................40 
9.4. 
Randomization and Blinding ......................................................................................40 
9.4.1. 
Methods of Assigning Patients to Treatment Groups .................................................40 
9.4.2. 
Blinding ......................................................................................................................40 
9.4.3. 
Emergency Unblinding Procedures ............................................................................41 
9.5. 
Assignment of Site and Patient Numbers ...................................................................41 
9.5.1. 
Site Numbers ..............................................................................................................41 
9.5.2. 
Patient Numbers ..........................................................................................................41 
9.6. 
Restrictions .................................................................................................................41 
9.6.1. 
Fasting Requirement at Study Visits ..........................................................................42 
9.7. 
Visit Procedures ..........................................................................................................42 
9.7.1. 
Visit Windows ............................................................................................................42 
9.7.2. 
Informed Consent Procedures .....................................................................................42 
9.7.3. 
Assessing Cirrhosis .....................................................................................................42 
9.7.4. 
Screening Procedures (-1 day to 14 days prior to Day 1) ...........................................43 
9.7.5. 
Day 1 Procedures (Randomization) ............................................................................44 
9.7.6. 
Week 3 (Safety Contact) .............................................................................................45 
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9.7.7. 
Week 6 Procedures .....................................................................................................45 
9.7.8. 
Week 12 Procedures ...................................................................................................46 
9.7.9. 
Week 18 and Week 30 Procedures .............................................................................48 
9.7.10. 
Weeks 24 Procedures ..................................................................................................49 
9.7.11. 
Week 36 Procedures ...................................................................................................51 
9.7.12. 
Week 48 Procedures ...................................................................................................52 
9.7.13. 
Every 3 Months after Week 48 ...................................................................................53 
9.7.14. 
End of Treatment/Early Termination Procedures for Patients that Withdraw 
from Investigational Product or Withdraw Consent ...................................................54 
9.7.15. 
Unscheduled Safety Visit ...........................................................................................55 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............55 
10.1. 
Investigational Product ...............................................................................................55 
10.2. 
Investigational Product Packaging and Labeling .......................................................56 
10.3. 
Investigational Product Storage ..................................................................................56 
10.4. 
Investigational Product Administration ......................................................................56 
10.5. 
Investigational Product Accountability and Disposal .................................................56 
11. 
OVERVIEW OF ASSESSMENTS ............................................................................56 
12. 
CLINICAL PHARMACOKINETIC ASSESSMENTS .............................................57 
12.1. 
Pharmacokinetic Blood Sampling ..............................................................................58 
12.2. 
Processing and Handling of Pharmacokinetic Samples ..............................................59 
12.3. 
Bioanalysis ..................................................................................................................59 
13. 
ASSESSMENT OF SAFETY .....................................................................................59 
13.1. 
Adverse Events and Serious Adverse Events .............................................................60 
13.1.1. 
Definitions of Adverse Events ....................................................................................60 
13.1.1.1. 
Adverse Event .............................................................................................................60 
13.1.1.2. 
Treatment-Emergent Adverse Event ..........................................................................60 
13.1.1.3. 
Serious Adverse Event ................................................................................................60 
13.1.2. 
Relationship to Investigational Product ......................................................................61 
13.1.3. 
Recording Adverse Event Severity .............................................................................61 
13.1.3.1. 
Severity of Pruritus (as an Adverse Event) .................................................................62 
13.1.4. 
Reporting of Adverse Events and Serious Adverse Events ........................................62 
13.1.4.1. 
Reporting of Adverse Events ......................................................................................62 
13.1.4.2. 
Reporting of Serious Adverse Events .........................................................................63 
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13.1.5. 
Suspected Liver-Related Clinical Outcome Events ....................................................64 
13.1.5.1. 
Potential Clinical Outcome Events .............................................................................64 
13.1.6. 
Additional Investigator Responsibilities for SAEs .....................................................64 
13.1.7. 
Notification of Post-Study SAEs ................................................................................65 
13.1.8. 
Notification of Post-Treatment SAEs for Subjects Who Continue in the 
Study ...........................................................................................................................65 
13.1.9. 
Follow-Up of AEs and SAEs ......................................................................................65 
13.1.10. 
Pregnancy and Follow-Up ..........................................................................................65 
13.2. 
Other Safety Parameters .............................................................................................66 
13.2.1. 
Medical History/Demographics ..................................................................................66 
13.2.2. 
Physical Examination .................................................................................................66 
13.2.3. 
Vital Signs ..................................................................................................................66 
13.2.4. 
Electrocardiogram .......................................................................................................66 
13.2.5. 
Laboratory Assessments .............................................................................................66 
13.2.6. 
Patient-Reported Outcomes and Healthcare Resource Use ........................................68 
14. 
EFFICACY ASSESSMENTS ....................................................................................69 
14.1.1. 
Child-Pugh Score ........................................................................................................69 
14.1.2. 
Model of End Stage Liver Disease Score ...................................................................69 
14.1.3. 
Changes in Liver Biochemistry and Hepatobiliary Damage ......................................70 
14.2. 
Additional Assessments ..............................................................................................70 
14.2.1. 
Markers of Inflammation, Apoptosis and Necrosis ....................................................70 
14.2.2. 
Noninvasive Measurements of Liver Stiffness and Fibrosis ......................................70 
14.2.3. 
Markers of FXR activation .........................................................................................70 
14.2.4. 
Potential Clinical Outcome Events .............................................................................70 
15. 
STATISTICAL METHODS AND ANALYSES .......................................................71 
15.1. 
Analysis Populations ..................................................................................................71 
15.2. 
Determination of Sample Size ....................................................................................72 
15.3. 
Pharmacokinetic Analyses ..........................................................................................72 
15.4. 
Safety Analyses ..........................................................................................................72 
15.4.1. 
Adverse Events ...........................................................................................................72 
15.4.2. 
Clinical Laboratory Evaluations .................................................................................73 
15.4.3. 
Adverse Events of Special Interest .............................................................................74 
15.5. 
Efficacy Analyses .......................................................................................................76 
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15.6. 
Additional Efficacy Analyses .....................................................................................77 
15.7. 
Handling of Missing Data ...........................................................................................77 
15.8. 
Data Monitoring Committee .......................................................................................78 
15.9. 
Adjudication Committees ...........................................................................................78 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................79 
16.1. 
Study Monitoring ........................................................................................................79 
16.2. 
Audits and Inspections ................................................................................................80 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................80 
18. 
ETHICS ......................................................................................................................80 
18.1. 
Ethics Review .............................................................................................................80 
18.2. 
Ethical Conduct of the Study ......................................................................................81 
18.3. 
Written Informed Consent ..........................................................................................81 
18.4. 
Patient Confidentiality and Data Protection ...............................................................81 
19. 
INVESTIGATOR OBLIGATIONS ...........................................................................81 
19.1. 
Adverse Event Reporting ............................................................................................82 
19.2. 
Protocol Deviations ....................................................................................................82 
19.3. 
Regulatory Documentation .........................................................................................82 
19.4. 
Ethics Review (IRB/IEC) ...........................................................................................82 
19.5. 
Archiving and Record Retention ................................................................................82 
20. 
PUBLICATION POLICY ..........................................................................................83 
21. 
LIST OF REFERENCES ............................................................................................85 
APPENDIX A.  LIST OF STUDY 747-401 OUTCOME EVENTS ...........................................86 
 
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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures (Double-Blind Treatment Period) ..............................28 
Table 2: 
Planned OCA or Matching Placebo Dosing Regimen by Child-Pugh Score .............32 
Table 3: 
Changes in Dosing Regimen Due to Changes in Child Pugh Score ...........................33 
Table 4: 
Early Discontinuation Scenarios .................................................................................55 
Table 5: 
Table of Assessments .................................................................................................57 
Table 6: 
Acceptable Windows for Pharmacokinetic Sample Collection ..................................58 
Table 7: 
Pharmacokinetic Sampling Schedule .........................................................................59 
Table 8: 
Relationship of Adverse Events to Investigational Product .......................................61 
Table 9: 
Severity of Adverse Events ........................................................................................62 
Table 10:  Severity of Pruritus .....................................................................................................62 
Table 11:  List of Laboratory Analytes to be Tested ...................................................................67 
Table 12:  Child-Pugh Scoring System ........................................................................................69 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................27 
  
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this protocol. 
Abbreviation or Specialist Term 
Explanation 
6-ECDCA 
6α-ethyl chenodeoxycholic acid (also known as INT-747) 
AASLD 
American Association for the Study of Liver Diseases  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
antimitochondrial antibody 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
β-hCG 
beta human chorionic gonadotropin 
BAS 
bile acid sequestrants 
BP 
blood pressure 
C4 
7α-hydroxy-4-cholesten-3-one 
CAC 
Cardiovascular Adjudication Committee 
CI 
confidence interval 
CK-18-M30 
cytokeratin-18 neoepitope M30 
CLDQ 
Chronic Liver Disease Questionnaire 
CRA 
Clinical Research Associate 
eCRF 
electronic case report form 
Hs-CRP 
high sensitivity C-reactive protein 
CP 
Child-Pugh 
DDI 
Drug-drug interaction 
DMC 
Data Monitoring Committee 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
enhanced liver fibrosis 
EOS 
end of study 
EOT 
end of treatment 
ET 
Early termination 
FDA 
Food and Drug Administration 
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Abbreviation or Specialist Term 
Explanation 
FGF-19 
fibroblast growth factor-19 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
glyco-OCA 
glycine 6α-ethyl chenodeoxycholic acid 
HCP 
Health care professional 
HDLc 
high density lipoprotein 
IB 
Investigational Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
INR 
international normalized ratio  
IRB 
Institutional Review Board 
ISF 
Investigator site file 
ITT 
intent-to-treat  
IWRS 
interactive web response system 
KM 
Kaplan-Meier 
LDLc 
low density lipoprotein 
LTSE 
Long-term safety extension 
LS 
Least squares 
MACE 
Major adverse cardiovascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model of end stage liver disease  
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cholangitis (also known as primary biliary 
cirrhosis) 
PIS 
patient information sheet 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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Abbreviation or Specialist Term 
Explanation 
SAR 
suspected adverse reaction 
SD 
standard deviation 
SI 
standard international system of units 
SOC 
System organ class 
SUSAR 
suspected unexpected serious adverse reaction 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
the Sponsor 
Intercept Pharmaceuticals, Inc. 
TNF-α 
tumor necrosis factor-alpha 
UDCA 
ursodeoxycholic acid 
UK 
United Kingdom  
ULN 
upper limit of normal 
US 
United States (of America) 
VAS 
Visual Analogue Scale 
VLDL 
very low density lipoprotein 
 
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5. 
INTRODUCTION 
5.1. 
Overview of Disease State and OCA 
Primary Biliary Cholangitis, (PBC, also known as primary biliary cirrhosis [Beuers 2015a, 
Beuers 2015b, Beuers 2015c]) is a serious, life-threatening, cholestatic liver disease of unknown 
etiology that, without treatment, frequently progresses to hepatic fibrosis and eventual cirrhosis, 
hepatic decompensation, and necessitates liver transplantation or results in death.  PBC is a rare 
disease with reported prevalence in the US of 40.2/100,000 (Kim 2000).  PBC disproportionately 
affects women approximately 10:1 and is typically diagnosed in patients between 40 to 60 years 
of age.   
Ursodeoxycholic acid (UDCA), a physiological constituent of human bile, was approved in 2004 
for treatment of PBC (Lindor 2009).  While UDCA therapy had a marked effect on the treatment 
of PBC, up to 50% of patients showed a suboptimal response or no response to UDCA.  Such 
patients were at significantly increased risk of a poor clinical outcome due to PBC disease 
progression.  Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist and modified bile 
acid is derived from the primary human bile acid chenodeoxycholic acid (CDCA), was 
developed for the treatment of PBC and to provide patients with an inadequate response to or 
poor tolerance of UDCA a novel treatment option that was safe and effective.  In May 2016, the 
United States Food and Drug Administration granted accelerated approval for OCA (marketed as 
OCALIVA®), for the treatment of patients with PBC in combination with UDCA in adults with 
an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA.  In 
December 2016, the European Commission granted conditional approval for OCALIVA® for 
the same indication. 
5.2. 
Clinical Development of Obeticholic Acid 
As of 31 Jan 2016, approximately 1726 patients have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 458 patients had PBC, 330 patients had nonalcoholic 
steatohepatitis, 41 patients had diabetes mellitus/ nonalcoholic fatty liver disease, 33 patients had 
alcoholic cirrhosis/portal hypertension, and 20 patients had primary sclerosing cholangitis (PSC).  
Overall, the pharmacokinetic (PK) profile of OCA is consistent with that expected of a bile acid.  
Phase 1 studies demonstrated that OCA is rapidly absorbed and extensively conjugated with 
glycine and taurine to form glyco-OCA and tauro-OCA, respectively.  OCA and its conjugates 
are primarily eliminated via biliary excretion, and plasma concentration time profiles 
demonstrated multiple peaking with prolonged exposure, indicative of enterohepatic circulation.  
Plasma concentrations of OCA and its conjugates spike shortly after meals, consistent with gall 
bladder emptying into the duodenum as expected of a bile acid. 
The OCA clinical development program was based on a wide range of studies in PBC patients 
and healthy volunteers.  The clinical pharmacology studies supported the proposed dosing 
regimen:  10-mg fixed dose and a titration regimen starting at OCA 5 mg with titration to 10 mg 
based on clinical and biochemical response.  The clinical program included a pivotal Phase 3 
clinical study (747-301) and 2 Phase 2 clinical studies (747-201 and 747-202), which formed the 
primary basis of approval of OCA. 
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Study 747-201 (59 patients) evaluated 2 doses of OCA (10 mg and 50 mg) given as monotherapy 
versus placebo.  Statistically significant and clinically relevant relative and absolute reductions 
from Baseline in alkaline phosphatase (ALP) were achieved with both doses of OCA versus 
placebo (p <0.0001).  Mean relative ALP reductions were 44.5% (OCA 10 mg) and 37.6% (OCA 
50 mg) compared to an increase of 0.4% with placebo.  Further, significant improvements in 
gamma-glutamyl transferase (GGT) and in conjugated bilirubin were observed with both doses 
compared with placebo (p <0.05).  OCA also resulted in decreased circulating alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) levels. 
Study 747-202 (165 patients) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in patients on a stable therapeutic dose of UDCA.  Overall, the data from 747-202 were 
consistent with Study 747-201.  Statistically significant and clinically meaningful relative and 
absolute reductions in ALP were achieved with all 3 doses of OCA versus placebo (p <0.0001).  
Mean ALP reductions from baseline ranged from 21% to 25% compared to 3% with placebo.  
Improvements were also seen in GGT and ALT levels and in conjugated bilirubin levels. 
Study 747-301 (216 patients) was a Phase 3, double-blind, placebo-controlled, parallel-group 
study followed by a long-term safety extension (LTSE) using OCA in patients with PBC.  The 
primary endpoint for Study 747 301 was a composite endpoint based on the proportion of 
patients reaching specific criteria for ALP and bilirubin (ALP <1.67x upper limit of normal 
[ULN] with a ≥15% reduction and bilirubin ≤ULN).  Both OCA treatment groups met the 
primary endpoint of achieving a reduction in ALP to <1.67x ULN with a ≥15% reduction from 
baseline and a normal bilirubin level after 12 months of therapy.  The placebo group experienced 
a mean decrease in ALP from baseline of 5%, compared to a significant mean decrease of 39% 
in the OCA 10 mg dose group and 33% in the OCA titration group (both OCA dose groups 
p<0.0001 versus placebo). 
The LTSE phases of both Phase 2 studies and the Phase 3 study support the long-term safety of 
OCA and demonstrate a durable therapeutic response.   
Study 747-302 is an ongoing randomized, double-blind, placebo-controlled clinical outcomes 
study, designed to confirm the clinical benefit of OCA treatment in patients with PBC.  This 
study is inclusive of patients with early to advanced stage PBC. 
5.2.1. 
Rationale for Study Design 
There are limited clinical data available to support the use of OCA in patients with PBC with 
moderate to severe hepatic impairment.  The current recommended dosing of such patients is 
based on modeled systemic and hepatic concentrations.  Therefore, Study 747-401 is specifically 
designed to characterize the PK, safety, and efficacy effect of OCA in this patient population. 
PK and safety parameters will be evaluated as the primary objectives and efficacy parameters 
will be evaluated as secondary and additional objectives.  While the prognostic utility of ALP 
has been established by the Global PBC study group, increasing levels of bilirubin is more 
relevant to understanding the progression of end stage liver disease.  Consistently, bilirubin is a 
key marker of advancing disease as characterized by the Global PBC study group as well as its 
incorporation into MELD, Child-Pugh (CP) and Mayo risk scores.  As such, the potential of 
OCA to stabilize bilirubin levels will be evaluated. 
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In order to generate data for the patient population in a timely fashion, Study 747-401 is 
designed with a relatively short-term, 1-year double-blind treatment period to gather primarily 
PK and safety data.  Therefore, the study will not formally test the long-term efficacy of OCA on 
clinical outcomes.   
Although Study 747-401 is not designed to formally evaluate clinical outcomes, these data will 
be collected and assessed as an additional objective.  Given the importance of evaluating clinical 
outcomes in patients with the most advanced form of the disease, these events will be 
prospectively adjudicated consistent with the procedures implemented in Study 747-302.  This 
will allow for a more robust meta-evaluation of clinical outcomes in patients with moderate to 
severe hepatic impairment following the completion of both studies.  
Patients with moderate or severe hepatic impairment (Child Pugh B or C) will constitute 
approximately 20% of the patients included in the ongoing clinical outcomes Study 747-302 
which was specifically designed to confirm clinical benefit across the spectrum of disease 
including patients with hepatic impairment.  Data collected from Study 747-401 will serve as a 
bridge between the two studies. 
Taken together, data from this study will complement the data from Study 747-302 and offer the 
opportunity to better inform the benefit risk profile and appropriate treatment of 
hepatically-impaired patients.  
5.2.2. 
Rationale for Obeticholic Acid Dose and Duration 
Results from the hepatic impairment study (747-103) indicate that plasma exposure increases, in 
comparison to subjects with normal liver function, with increasing severity of impairment as 
classified by Child Pugh A (CP-A), CP-B or Child Pugh C (CP-C) scores by 1.4-, 8.0-, and 
13-fold, respectively.  No apparent impact on the overall safety profiles were observed in this 
study.  Liver exposure, however, modestly increased by 1.1-, 1.5, and 1.7-fold, respectively, as 
shown in simulations using a physiologic PK model developed to characterize OCA and its 
conjugates.  Together, the results from these analyses suggest that the doses of OCA 
administered to patients with moderate or severe hepatic impairment should be modestly lower 
than those for patients with normal hepatic function to achieve similar hepatic exposure.    
Therefore, a modified dosing regimen is recommended for OCA in patients with moderate and 
severe hepatic impairment that is designed to initiate doses to achieve plasma exposures levels of 
OCA similar to those without hepatic impairment or CP-A.  After which, subjects may then 
titrate their doses upwards to achieve liver exposures that would be similar in both patient 
populations.  This modified dosing regimen was selected based on the established safety and 
tolerability of OCA in subjects with PBC, along with PK/PD modeling and simulations.  
Patients will initiate dosing at OCA 5 mg once weekly.  Starting at Week 12, if the prior dose 
regimen was tolerated, the patients will increase the dosing frequency to 5 mg twice weekly (at 
least 3 days apart).  After 6 weeks, a second titration may occur to OCA 10 mg twice weekly as 
long as tolerated.  Patients classified as CP-B may further titrate their dose upwards to OCA 
5 mg once daily after 6 weeks on the OCA 10 mg twice weekly regimen. 
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5.2.3. 
Rationale for Population Chosen 
Patients with PBC and moderate or severe hepatic impairment, based on Child-Pugh score and 
varying levels of MELD (Model of End-stage Liver Disease), are the targeted population for this 
study as OCA has been studied primarily in early to moderate stages of liver disease in patients 
with PBC.  There is a great need to extend therapies to PBC patients with more advanced liver 
disease.  Given the unmet medical need and observed efficacy, safety and tolerability profile of 
OCA in early and moderate PBC, evaluating the effects of OCA in a late stage population is 
warranted. 
5.2.4. 
Rationale for Control Group  
Placebo Control Group 
The use of a randomized placebo control group added to established standard of care provides 
the best scientific evidence of efficacy and safety.  The use of a placebo control provides a 
concurrent comparator group, accounting for not only a placebo effect but continued standard of 
care.  The use of a placebo control is critical to assess the safety and tolerability of OCA but also 
as a comparator for the high rate of clinical outcomes events which are expected in this advanced 
population.  
5.3. 
Summary of Known Potential Risks with Investigational Product 
The primary AE shown to be related to OCA is pruritus.  Pruritus has also been observed in 
clinical studies with OCA in other indications, as well as in healthy patients, but with a much 
lower frequency than that observed in patients with PBC. 
Consistent with the dose-limiting hepatic toxicities observed in the non-clinical studies and the 
chemical characteristics of OCA as a bile acid and detergent, dose-related but reversible and 
asymptomatic increases in ALT and AST were observed in healthy volunteers treated with 
multiple doses of OCA starting at the 100 mg dose (Study 747-102).   
In patients with chronic liver disease such as PBC, hepatobiliary findings including increased 
transaminases and bilirubin and signs or symptoms of hepatic decompensation such as 
development of jaundice were observed.  These findings were seen more frequently with doses 
of OCA 10 mg once daily to OCA 50 mg once daily (up to 5x the highest recommended dose).  
In addition, cholecystitis, including acute cholecystitis, was reported in association with 
treatment with OCA. 
Lipoprotein changes have also been observed with OCA dosing, including a decrease in high 
density lipoprotein (HDLc) and an increase in low density lipoprotein (LDLc).  Notably, in 
patients with PBC, the decrease in mean HDLc levels occurred early and stabilized within 
3 months after which time levels generally remained constant over the course of treatment.  The 
average levels of HDLc remained within normal limits. Commensurate with decreases in HDLc, 
decreases in total cholesterol were observed in patients with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA treated patients with the exception of a 
modest transient and early rise after initiation of treatment. 
Based on Studies 747-103 and 747-204 in subjects with hepatic impairment, increased systemic 
exposure was not associated with an apparent change in the safety profile of OCA as assessed by 
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the incidence and severity of AEs or by changes in clinical laboratory tests.  Hepatotoxicity has 
been associated with increased liver concentrations of OCA.  Hepatic impairment does not affect 
the ability of OCA to activate FXR in the intestine and the liver. 
Refer to the Investigator’s Brochure (IB) for additional information regarding the known 
potential risks with the investigational product. 
6. 
STUDY OBJECTIVES AND PURPOSE 
The study will be conducted in patients with PBC with moderate to severe hepatic impairment 
defined as CP-B (moderate) and CP-C (severe) with MELD scores ranging from 6 to 24. 
6.1. 
Primary Objectives 
 To evaluate the PK of OCA and its conjugates glyco-OCA, tauro-OCA, and OCA 
glucuronide 
 To evaluate the safety and tolerability of OCA treatment compared with placebo 
6.2. 
Secondary Objectives 
 To evaluate the effect of OCA treatment compared to placebo on:  
 The MELD score and its components 
 CP score and its components 
 Liver biochemistry including bilirubin, ALP, and aminotransferases (ALT, AST, 
and GGT) 
 Biomarkers of bile acid synthesis and homeostasis including fibroblast growth 
factor 19 (FGF-19), 7α-hydroxy-4-cholesten-3-one (C4), and plasma and fecal 
bile acids 
6.3. 
Additional Objectives 
 To evaluate the effect of OCA treatment compared to placebo on: 
 Markers of inflammation 
 Noninvasive markers of liver fibrosis (Enhanced Liver Fibrosis [ELF]™score) 
 Noninvasive measurement of liver stiffness (transient elastography [TE]) 
 To assess clinical outcomes consistent with end-stage liver disease (eg, liver-related 
events resulting in death, hepatic failure leading to liver transplant, variceal bleed, hepatic 
encephalopathy, spontaneous bacterial peritonitis, ascites, hepatocellular carcinoma) 
 The PK/Pharmacodynamic (PD) relationship of OCA on: 
 Liver biochemistry including ALP, total bilirubin, and aminotransferases 
 Bile acid homeostasis 
 Safety and tolerability (eg pruritus) 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the PK and 
safety of OCA treatment in patients with PBC with moderate to severe hepatic impairment 
defined as Child-Pugh B (CP-B) (moderate) and Child-Pugh C (CP C) (severe) including a broad 
distribution of MELD scores (ranging from 6 to 24).  Approximately 50 patients (including at 
least 20% of patients with CP-C) will be enrolled in the study.  Patients will be screened for up to 
≤14 days prior to entering the study (Day 1).  Patients who meet all eligibility requirements will 
be randomized in a 1:1 ratio to one of two treatment groups:  Placebo or OCA.  Randomization 
will be stratified by CP class.  Baseline MELD scores will be monitored on an ongoing basis to 
ensure adequate distribution of MELD scores. 
Following completion of safety assessments and laboratory specimen collection, blinded 
investigational product will be dispensed with instruction to begin dosing the same day (Day 1) 
at OCA 5 mg or placebo once weekly.   
Double-Blind Primary Treatment Period:  During the primary treatment period (ie, Day 1 
through Week 48), clinic visits will occur approximately every 6 weeks for the assessment of 
safety, tolerability, PK, and PD (trough).  At each visit, trough PK assessments will be performed 
in all patients participating in the study.  Serial PK sampling will be performed at Week 12 and 
only after a patient uptitrates.  Following completion of the Week 48 visit, patients will remain 
on blinded investigational product and be seen at regular visits every 3 months until all patients 
complete the 48-week primary treatment period.  
Long -term Open Label Extension Phase: Once all patients have completed the double-blind 
48-week primary treatment period, patients will have the option to continue into an open-label 
LTSE and all patients will receive OCA.  Visits in the LTSE will occur every 3 months for up to 
5 years.  Patients on placebo during the primary treatment period will initiate study medication at 
OCA 5-mg once weekly and follow the dosing regimen based on their CP score.  Patients on 
OCA during the primary treatment period will continue the dose that they are on once unblinded.  
The open-label LTSE study design and study procedures will be described in a separate protocol 
and statistical analysis plan (SAP). 
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7.1.1. 
Study Design Diagram 
Figure 1: 
Study Design  
 
EOS = end of study; EOT = end of treatment; OCA = obeticholic acid 
*Initial dose titration of investigational product may occur at the Week 12 Visit, or any study visit thereafter for patients on all 
dosing regimens, based on tolerability and safety laboratory tests from the previous visit.  Subsequent dose titration(s) may occur 
no earlier than 6 weeks after the previous dose titration and will be based on tolerability and CP score.    
 
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures (Double-Blind Treatment Period) 
 
Double-Blind Treatment Period 
 
Weeks 
Screening 
Day 1 
3 
Safety 
Contacta  
6 
12 
18 
24 
30 
36 
48 
ET/ EOS 
Visit Window  
(+/-)b 
≤-1 to -14 
days 
±1 wk 
 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
 
Fast ≥8 h Prior to Visitc 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical/PBC Historyd 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Physical Exame 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
X 
MELD 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Assessments for Child-Pugh 
Scoref 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Questionnaires 
(Pruritus VAS, PBC-40, EQ- 
5D-5L, and CLDQ)g 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Randomization/Treatment 
Assigned 
 
X 
 
 
 
 
 
 
 
 
 
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Table 1: 
Schedule of Study Procedures (Double-Blind Treatment Period) (Continued) 
 
Double-Blind Treatment Period 
 
Weeks 
Screening 
Day 1 
3 
Safety 
Contacta  
6 
12 
18 
24 
30 
36 
48 
ET/ EOS 
Visit Window  
(+/-)b 
≤-1 to -14 
days 
±1 wk 
 
±1 wk 
±1 wk 
±1 wk 
±1 
wk 
±1 wk 
±1 wk 
±1 wk 
 
Dispense IPh 
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X 
Dose Titrationi 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
IP Accountability/Compliance 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
 
 
 
 
 
 
 
X 
X 
Urine-based β-hCG 
Pregnancy Testj 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Virology (HCV/HBsAG) 
X 
 
 
 
 
 
 
 
 
 
 
Serum 
Chemistry/Hematology/ 
Coagulation 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
IL-6, hs-CRP, TNF-α, IgM, 
IgG, IgA, CK 18 M30, others 
as determined during course 
of study 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
PK trough collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PK serial collection 
Will only occur when patient uptitrates.  Refer to Section 12 for PK sampling schedules and procedures. 
 
Fecal PK Analysis 
 
Bile Acid/C4/FGF-19 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
TE Fibroscan® 
 
X 
 
 
 
 
X 
 
 
X 
X 
ELF 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
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AE = adverse event; eCRF = electronic case report form; C4 = 7α-hydroxy-4-cholesten-3-one; CK-18-M30 = cytokeratin-18 neoepitope M30; CLDQ = Chronic Liver Disease 
Questionnaire; ELF = enhanced liver fibrosis; FGF-19 = fibroblast growth factor-19; hs-CRP = high-sensitivity C-reactive protein; IP = Investigational Product; MELD = Model 
of end stage liver disease; PK = pharmacokinetics; TE = transient elastography; wk(s) = week(s). 
a Patients should be contacted by telephone/email every 3 weeks (±1 week) between clinic visits starting at Week 3 and continuing to Week 48 to assess for AEs, concomitant 
medications, and verify that s/he is dosing as directed. 
b Visits should be based on Day 1. 
c The patient should be instructed to fast overnight (at least 8 hours) prior to each visit.  Fasting is required prior to all study visits (except Screening Visit 1) but water is 
permitted. 
d Medical history performed at Screening only.    
e The yearly physical exam will also include an assessment of smoking and alcohol consumption history and current habits for both.  Height will only be collected at Day 1 and 
Week 48. 
f Child-Pugh Score will be calculated based on ascites assessment, hepatic encephalopathy grade, and central laboratory evaluations per the Child-Pugh scoring system noted in the 
eCRF. 
g The EQ-5D-5L Quality of Life questionnaire is validated for use in multiple languages. If a validated translation is not available in the local language required for a specific 
study patient, the data from that questionnaire will not be collected.  The CLDQ measures change over time in patients with chronic liver disease.  
h Patients will be instructed to begin dosing on the Day 1 visit after completing all study assessments. (ie, on Day 1).  Patients will be instructed to take investigational product at 
approximately the same time of day.  Patients must be instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
i Initial dose titration of investigational product may occur at the Week 12 Visit, or any study visit thereafter for patients on all dosing regimens, based on CP score, tolerability 
and safety laboratory tests from the previous visit.  Subsequent dose titration(s) may occur no earlier than 6 weeks after the previous dose titration and will be based on tolerability 
and CP score. 
j Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry and at every visit.  If positive, a confirmatory blood test must be performed at 
the central laboratory.  If the confirmatory blood test is also positive, the patient may not continue in the study.  (Additional testing may be conducted where required, regionally) 
 
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7.1.3. 
Study Duration 
The study will include a 14-day screening period and a 48-week double-blind primary treatment 
period.  Following completion of the primary treatment period, patients will remain on blinded 
investigational product and be seen at regular intervals until all patients complete the primary 
treatment period (Figure 1).  Patients will have the option to continue into an open-label LTSE 
after all patients have completed the Week 48 procedures in which they will receive open-label 
treatment and be seen at regular visits every 3 months for up to 5 years.   
7.2. 
Number of Patients 
Approximately 50 patients will be enrolled in this study. 
7.3. 
Planned Dosing Regimen 
All patients will initiate investigational product once weekly with OCA 5-mg or matching 
placebo.   
All patients will initiate investigational product once weekly with OCA 5-mg or matching 
placebo.  Starting at Week 12, safety and tolerability of investigational product will be evaluated 
and, if tolerated, the patient can increase the dose to the next dose level as described below 
(Table 2): 
 At Week 12, if investigational product is tolerated and laboratory assessments from the 
Week 6 visit do not indicate a safety concern, the patient will change the dosing 
frequency to 5 mg twice weekly, at least 3 days apart.   
 Following an additional 6 weeks of treatment, if investigational product is tolerated, 
patients may be up-titrated to OCA 10 mg twice weekly at least 3 days apart, the 
maximum dose for patients with CP-C.  
 Following an additional 6 weeks of treatment, if tolerated, patients with CP-B may titrate 
to a maximum dose of OCA 5 mg once daily, the maximum dose for patients with CP-B.  
 If, during the course of the study, a patient transitions from CP- B to CP-C, or vice versa, 
the maximal dose for the new CP classification would apply. 
 
 
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Table 2: 
Planned OCA or Matching Placebo Dosing Regimen by Child-Pugh Score 
 
Child-Pugh B 
(Moderate Hepatic Impairment) 
Child-Pugh C 
(Severe Hepatic Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting Dose a (Day 1) 
5 mg once 
weekly 
matching placebo 
5 mg once 
weekly 
matching placebo 
Titration 1b (≥Week 12) 
5 mg twice 
weeklyc 
matching placebo 
5 mg twice 
weeklyc 
matching placebo 
Titration 2b (≥6 weeks 
after Titration 1) 
10 mg twice 
weeklyc 
matching placebo 
10 mg twice 
weeklyc 
matching placebo 
Titration 3b (≥6 weeks 
after Titration 2) 
5 mg once daily 
matching placebo 
NA 
matching placebo 
a Starting dose based on patient’s Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on patient 
tolerability and/or changes in Child-Pugh Score at any time during the study. 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
7.4. 
Dose Adjustment Criteria 
Dose titration may follow the scheduled dosing regimens described in Section 7.3 or occur due to 
tolerability concerns or as a result of changes in a patient’s CP Score. 
Dose titrations may involve increases or decreases in dosing frequency or dose and are 
dependent on tolerability (as assessed by a review of AEs and safety laboratory results).  In 
general, down-titration may be done in response to tolerability concerns and can occur at any 
time.  Up-titration will be done per protocol based on tolerability, as assessed by the Investigator, 
or following resolution of a tolerability concern that previously led to down-titration.  
Up-titrations may only occur to the maximum dose and frequency indicated for each dosing 
regimen as defined in Section 7.3. 
Scheduled Dose Titration - The first dose titration for any patient may occur no earlier than 
12 weeks following initiation of OCA or matching placebo.  Subsequent titrations in dose or 
dosing frequency for patients may occur no earlier than 6 weeks following an up-titration. 
Tolerability Dose Titration - Investigators may decrease the dosing frequency or dose as 
considered clinically appropriate (eg, tolerability; see Section 7.4.1) 
Dose Titration due to Change in Child-Pugh Score – Over the course of the study, a patient’s 
CP category may change.  When patients demonstrate a change in CP Score (as assessed per 
Table 12), dosing should be reassessed and modified if appropriate (Table 2).  Changes to the 
dosing regimen are not mandatory and should be based on clinical judgment as well as change in 
CP score.  Table 3 provides an overview of the possible changes in dosing regimen due to 
changes in CP Score.  Dosing should follow the titration schedule of the new dosing regimen 
such that the maximum dose within that dosing regimen is ultimately attained, based on 
tolerability and clinical judgment.    
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If a patient demonstrates an improvement to CP-A, they should follow the dosing regimen for 
patients with CP-B. 
Table 3: 
Changes in Dosing Regimen Due to Changes in Child Pugh Score 
Original 
Status 
New Statusa 
Child-Pugh B 
Moderate Hepatic Impairment 
Child-Pugh C 
Severe Hepatic Impairment 
Child-Pugh B 
No Change 
5 mg daily  10 mg twice weeklyb 
10 mg twice weeklyb  No change or 5 mg twice 
weekly 
5 mg twice weeklyb  No change or 5 mg once 
weekly 
Child-Pugh C 
10 mg twice weekly  5 mg daily 
5 mg twice weekly No change or 10 mg twice 
weeklyb 
5 mg once weekly 5 mg twice weekly  
No Change 
a Once a patient begins dosing with the new dosing regimen, titration should occur as described for that dosing 
regimen in Section 7.4.1.  
b Dosing per the twice weekly schedule must be at least 3 days apart. 
CP Scores will be calculated at all study visits. While PBC-specific versions of CP scores are 
available, this study will use the standard calculation (Pugh 1973, Lucey 1997).  All associated 
visit data (including central laboratory results) should be entered into the electronic case report 
form (eCRF) in a timely fashion to confirm that the patient’s CP Score has not changed.  If a 
change in CP Score is observed independent of a study visit, the patient should be contacted via 
phone to discuss the need for a dosing modification and should be asked to return to the 
investigative site as soon as possible if a new bottle of investigational product is required to be 
dispensed. 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements 
Tolerability of investigational product must be assessed prior to titrating a patient to a higher 
dose.  A review of AEs and available safety laboratory results (eg, chemistry, hematology, and 
coagulation) obtained within approximately 6 weeks of the up-titration visit must be performed 
as part of the investigational product tolerability assessment, prior to any planned up-titration in 
investigational product (eg, Week 6, laboratory results should be reviewed prior to titration at 
Week 12).  If for any reason, laboratory results are not available at the time of the planned 
up-titration visit, additional laboratory samples must be obtained and reviewed, prior to 
up-titrating the patient to a higher dose.  
To be eligible for a dose up-titration, patients should not be experiencing significant AEs that are 
suspected to be related to investigational product (eg, severe pruritus) or displaying other 
symptoms that may indicate intolerability of investigational product.  
7.4.2. 
Safety Criteria for Adjustment or Stopping Doses 
Investigational product may be temporarily decreased (eg, by decreasing dosing frequency) or 
temporarily or permanently stopped based on tolerability concerns.  The dose of investigational 
product should be resumed to the maintenance dose in a blinded manner once the issues relating 
to the lack of tolerability are resolved.   
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Subjects who discontinue investigational product are expected to continue in the study (and 
follow the regular visit schedule) until the end of the study, and the study will only terminate at 
the time. 
7.5. 
Criteria for Study Termination 
The Sponsor (Intercept Pharmaceuticals, Inc.) reserves the right to terminate the study at any 
time.  It is normal procedure to review the emerging clinical and safety data.  As a result of such 
a review or a recommendation by the Data Monitoring Committee (DMC), it may be necessary 
to stop the study before all patients have completed the study.  In addition, the Sponsor may 
terminate the study at an investigational site at any time (eg, Good Clinical Practice [GCP] 
noncompliance or poorly performing sites, as determined by the number of patients enrolled or 
the quality of the study data). 
The Investigator and/or Sponsor (or designee) must notify the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) of discontinuation of a site or the study and the 
reason for doing so. 
Investigators will be informed by the Sponsor as to when the final study visit is to be completed, 
and should then schedule all patients for the end of study (EOS) or end of treatment (EOT) Visit.  
8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Population 
This study will be conducted at approximately 20 international study sites with experience in 
treating patients with PBC with moderate to severe hepatic impairment defined as CP-B 
(moderate) and CP-C (severe).  Prospective patients will be identified primarily from the hospital 
and/or physician’s database of patients with PBC, or may be referred from other physicians.  
Patients may self-refer to an Investigator if they become aware of the study through local, 
national, or international PBC patient societies, forums, or networks. 
8.2. 
Patient Inclusion Criteria 
1. A definite or probable diagnosis of PBC (consistent with American Association for the 
Study of Liver Diseases [AASLD] and European Association for the Study of the Liver 
[EASL] Practice Guidelines [Lindor 2009, EASL 2009]), defined as having ≥2 of the 
following 3 diagnostic factors 
 History of elevated ALP levels for at least 6 months 
 Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer 
(<1:80), PBC-specific antibodies (anti-GP210 and/or anti-SP100) and/or 
antibodies against the major M2 components (PDC-E2, 2-oxo-glutaric acid 
dehydrogenase complex)  
 Liver biopsy consistent with PBC (collected at any time prior to Screening) 
2. Evidence of cirrhosis including at least one of the following: 
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 Biopsy indicating cirrhosis or a medical history with histological evidence of 
cirrhosis  
 Clinical evidence consistent with cirrhosis including: esophageal varices, ascites, 
encephalopathy, or portal hypertension 
  Liver stiffness as assessed by TE of >16.9kPa 
3. Satisfy the criteria of the modified CP classification for hepatic impairment during 
Screening (ie, within 14 days before the first dose of investigational product): 
 Moderate:  CP-B (Scores 7 to 9) or 
 Severe:  CP-C (Scores 10 to 12) 
4. MELD score of 6 to 24 at Screening 
5. Age ≥18 years 
6. Taking UDCA for at least 12 months (stable dose for ≥3 months) prior to Day 1, or 
unable to tolerate UDCA (no UDCA for ≥3 months) 
7. Contraception:  Female patients must be postmenopausal, surgically sterile, or if 
premenopausal (and not surgically sterile), be prepared to use ≥1 effective method of 
contraception during the study and for 30 days after the end of treatment visit.  Effective 
methods of contraception are considered to be those listed below: 
 Barrier method, ie, (a) condom (male or female) with spermicide or (b) 
diaphragm with spermicide; or 
 Intrauterine device; or 
 Vasectomy (partner); or 
 Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection); or 
 Abstinence, if in line with the preferred and usual lifestyle of the patient (where 
abstinence is defined as refraining from heterosexual intercourse)  
8. Must provide written informed consent and agree to comply with the study protocol. 
8.3. 
Patient Exclusion Criteria 
1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6) 
2. History of liver transplant or organ transplant  
3. History of alcohol or drug abuse within 12 months prior to Screening 
4. History or presence of other concomitant liver diseases including: 
a. Hepatitis C virus infection, RNA positive 
b. Active hepatitis B infection; however, patients who have seroconverted (hepatitis 
B surface antigen and hepatitis B e antigen negative) may be included in this 
study after consultation with the medical monitor 
c. Primary sclerosing cholangitis 
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d. Alcoholic liver disease 
e. Definite autoimmune liver disease or overlap hepatitis 
f. Gilbert's Syndrome 
5. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function 
during the Screening period 
6. Patients with history or presence of hepatorenal or hepatopulmonary syndrome 
7. Patients with significant active infection (ie spontaneous bacterial peritonitis) 
8. Patients with known or suspected hepatocellular carcinoma 
9. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
10. Participation in another investigational product, biologic, or medical device study within 
30 days prior to Screening.  Participation in a previous study of OCA is allowed with 
3 months washout prior to enrollment in this study 
11. Mental instability or incompetence, such that the validity of informed consent or ability 
to be compliant with the study is uncertain 
12. UDCA naïve (unless contraindicated). 
8.4. 
Patient Withdrawal Criteria 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product 
The following events are considered appropriate reasons for discontinuation of investigational 
product; 
 Patient begins treatment with commercially available OCA 
 The Investigator or Sponsor considers that it is advisable or in the best interest of the 
patient 
 The occurrence of clinical or laboratory AEs considered by the Investigator to be 
clinically important safety concerns and related to investigational product 
 Patient undergoes liver transplantation 
 There is a major violation of the clinical study protocol  
 The development of any exclusion criteria that might jeopardize safety (see 
Section 8.3 , Exclusion Criteria) 
 Pregnancy 
Patients who choose to discontinue investigational product prior to termination of the study are 
expected to also continue to follow the regular visit schedule, with the exception of PK sampling, 
through to study closure. 
Patients who undergo a liver transplant during the course of the study must discontinue 
investigational product and should complete early termination procedures, if possible.   
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The Investigator is encouraged to contact the Sponsor prior to discontinuing a patient from 
treatment.  The Investigator must notify the Sponsor study monitor by telephone or email as soon 
as possible if any patient prematurely withdraws from the study. 
8.4.1.1. 
Pregnancy 
Whenever the site is notified of a possible pregnancy, the patient should be asked to come in for 
an unscheduled visit to perform a serum pregnancy test.  If a female patient becomes pregnant, 
the patient must stop taking investigational product immediately and be withdrawn from the 
study.  The patient must be followed by the Investigator through pregnancy outcome.  The 
mother (and infant) will be followed as considered appropriate by the Investigator and the 
Medical Monitor.  For reporting purposes, pregnancy is not considered an AE (see 
Section 13.1.10). 
8.4.2. 
Other Reasons for Discontinuation of Investigational Product or Study 
Termination 
Subjects who discontinue investigational product are expected to continue in the study until the 
end of the study or at the discretion of the Sponsor.  If a patient experiences a suspected clinical 
outcomes event, he or she should continue the regular visit schedule and continue taking 
investigational product as long as the Investigator assesses it as safe.   
Early termination procedures should only be conducted if the patient withdraws consent (See 
Section 9.7.14).   
It is agreed that, for reasonable cause, either the Investigator or the Sponsor, may terminate this 
study. 
The following events are considered appropriate reasons for a subject to discontinue from the 
study: 
8.4.2.1. 
Withdrawal of Consent  
If the patient decides that it is in his/her best interest to discontinue from the study, he or she may 
withdraw consent.  It is fully understood that all patients volunteer for the study and that they 
may withdraw their consent to continue in the study at any time. 
A reasonable effort must be made to determine the reason(s) for patient discontinuation.  This 
information and date must be recorded in the appropriate eCRF. 
8.4.2.2. 
Lost to Follow-Up 
If a patient fails to return to the clinic for a study visit, and the Investigator ceases to have contact 
with the patient, he or she will be withdrawn from the study. 
A reasonable effort (ie two phone calls/messages, no response to registered letter) must be made 
to contact the patient and determine the reason(s) why a patient fails to return for a study visit or 
is lost to follow-up.  This information and date of contact must be recorded in the appropriate 
eCRF. 
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8.4.2.3. 
Elevated Liver Enzymes 
An increase in AST or ALT to >3× baseline (and >ULN) or total bilirubin >2× baseline (and 
>ULN) should be followed by repeat testing within 48 to 72 hours to confirm the abnormalities 
and to determine if they are increasing or decreasing.  Adverse event information should also be 
collected.  If symptoms persist or repeat testing shows AST or ALT >3× baseline (and >ULN) or 
total bilirubin >2× baseline (and >ULN), subjects should be followed as clinically indicated 
depending on other laboratory and clinical signs and symptoms.  The Investigator should obtain 
a history of concomitant medications (including nonprescription medications and herbal and 
dietary supplement preparations) and other possible causes of liver enzyme and bilirubin 
increases.  Any potentially hepatotoxic medications should be identified and discontinued if 
advisable. 
The Medical Monitor should be contacted, as appropriate. 
8.4.3. 
Patient Discontinuation Notification 
The Investigator must notify the Sponsor as soon as possible if any patient prematurely 
discontinues from the study.  The date when the patient is withdrawn and the primary reason(s) 
for discontinuation must be recorded in the eCRF; additional information may be requested by 
the Sponsor to complete a discontinuation narrative.  Patients will be considered “lost to 
follow-up” only after reasonable, documented attempts to reach the patient prove unsuccessful.  
In all cases, a reasonable effort must be made to determine the reason(s) that a patient fails to 
return for required study visits or discontinues from the study.  This information must be 
documented in the eCRF. 
If a patient is withdrawn from the study early (regardless of the cause), all of the EOS/EOT/ 
early termination (ET) evaluations are to be performed at the time of withdrawal, to the extent 
possible. 
9. 
TREATMENT OF PATIENTS 
9.1. 
Investigational Product Treatment Regimen 
The term investigational product refers to either OCA (provided as part of this clinical study) or 
placebo.   
Two treatment groups will be evaluated:  OCA and placebo.  Investigational product will be 
administered orally.  Each dose will be made up of 1 tablet (ie, one OCA 5-mg tablet or one 
OCA 10-mg tablet, or matching placebo).   
Investigational product will be taken orally with water for the duration of the study.  Patients will 
be instructed to begin dosing on Day 1 and are to take investigational product at approximately 
the same time on dosing days.  Patients must be instructed to swallow the tablet whole; they must 
not chew, divide, or crush the tablet. 
At each study visit where the dose of investigational product is administered at the site, all 
assessments, except for the post-dose collection of blood samples for the PK assessment, must be 
completed before administration of investigational product. 
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9.2. 
Concomitant Medications 
Patients must follow the medication restrictions outlined in the inclusion and exclusion criteria 
(Section 8) during the study. 
Concomitant medications (will be used at the discretion of the usual care provider (or 
Investigator if also the usual care provider).  Relevant information about all concomitant 
medications (including prescribed, over the-counter, or herbal preparations) taken prior to (ie, 
within 30 days of Screening) and during the study must be recorded in the source documents and 
eCRF, as well as any dose or dose regimen changes that occur during the study.  Concomitant 
medications should be stable prior to Day 1 (ie no change in dosing within 3 months of 
screening). 
PBC Specific Therapy 
Investigators will be encouraged to follow guidelines for care based upon local and institutional 
practice patterns and any relevant published practice guidelines.  Throughout the course of the 
study, Investigators are expected to monitor patients’ PBC regimens and, if responsible for usual 
care, may adjust the regimen in order to achieve locally-appropriate treatment goals.  These goals 
will be individualized, with the understanding that currently applicable PBC guidelines may vary 
among different geographic regions. 
Ideally, patients should generally remain on the baseline PBC therapies throughout the course of 
the study, unless the baseline PBC therapy is no longer considered clinically appropriate by the 
Investigator.  In addition, patients should be reminded to keep taking their blinded 
investigational product. 
9.2.1. 
Drug Interactions 
Patients taking bile acid sequestrants (BAS, including cholestyramine and its derivatives, 
colestipol, colesevelam, or other sequestrants) or aluminum hydroxide- or smectite-containing 
antacids should be instructed to stagger their dosing of investigational product and UDCA, 
ensuring at least 4 hours between doses of the BAS and/or these antacids and the investigational 
product (and UDCA; ie, BAS should be administered at minimum 4 hours before or 4 hours after 
investigational product administration). 
OCA taken concomitantly with warfarin may result in decreased international normalized ratio 
(INR) levels, therefore, INR should be monitored and the dosage of warfarin adjusted, as needed 
during treatment with OCA and after cessation of OCA, to maintain the target INR range.  
The effect of OCA on drug metabolizing enzymes has been evaluated in both in vitro and clinical 
studies.  The PK profile of caffeine, a sensitive CYP1A2 substrate probe, showed weak effect of 
OCA on CYP1A2. Based on these results, OCA may increase the exposure of narrow therapeutic 
index drugs that are substrates for CYP1A2, such as theophylline and tizanidine. 
Information related to additional drug-drug interaction studies is available in the current version 
of the IB.  The aforementioned sections of the IB should be referred to during the course of the 
study, and are accessible to investigators to help facilitate the assessment of potential drug-drug 
interactions (DDI) with OCA that may be observed in study patients. 
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9.2.2. 
Prohibited Medications 
Commercial OCA therapy (if available) is prohibited while on investigational product, and if 
prescribed during the course of the study, the Investigator should be cognizant of the possibility 
of double dosing.  Patients who continue with commercial OCA therapy must discontinue 
investigational product and are expected to continue through the end of the study (see 
Section 8.4.2).  Fibric acid derivatives (fibrates) and other medication intended to lower blood 
triglyceride levels are also prohibited while on investigational product. 
9.3. 
Treatment Compliance 
The Investigator should assess the patient’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Patients should be instructed to retain all bottles of investigational product, even if empty, and to 
return them to the Investigator at the indicated visits (Table 1).  The Investigator or designee 
should perform investigational product accountability (ie, count of returned tablets) and, if 
applicable, follow-up with the patient to retrieve any investigational product bottles that have not 
been returned.  
If the Investigator has concerns about a patient’s dosing compliance, he or she should discuss 
this with the patient, assess the reasons for noncompliance and the likelihood that the patient will 
remain noncompliant, and notify the Sponsor accordingly.   
9.4. 
Randomization and Blinding 
9.4.1. 
Methods of Assigning Patients to Treatment Groups 
This study will be conducted in a double-blind, placebo-controlled manner.  Enrolled patients 
who meet all eligibility requirements will be randomized in a 1:1 ratio to one of two treatment 
groups:  placebo or OCA based on a predefined randomization code (generated by Sponsor or 
designee) using an interactive web response system (IWRS), which the Sponsor intends will 
serve as a computer-based patient registration system at Screening and Day 1.   
Randomization will be stratified by CP class (CP-B or CP-C).  Baseline MELD scores will be 
monitored on an ongoing basis to ensure adequate distribution of MELD scores.  The IWRS will 
serve as the investigational product inventory and management system and may be integrated 
with the study database.  
The Investigator or designee will be required to register the patient in the IWRS and may be 
prompted to provide patient data necessary to properly randomize and allocate the patient to 
treatment.  A randomization number will be assigned and investigational product (OCA or 
placebo) dispensing information will be provided (eg, bottle numbers allocated) while 
maintaining the study blind.   
9.4.2. 
Blinding 
The patients, Investigator, and study site staff will be blinded to the patient’s treatment allocation 
during the patient’s participation in the double-blind phase of the study.     
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9.4.3. 
Emergency Unblinding Procedures 
Treatment assignment for individual patients will be made available to the Investigator for 
medical emergency use only (such as unblinding which is necessary in order to treat an SAE) 
through the IWRS system.  When possible, the Medical Monitor should be consulted in the event 
that a medical emergency necessitates unblinding (ie, in situations where knowledge of the 
blinded treatment assignment is necessary for further medical management of the patient).  If it is 
not reasonable to inform the Medical Monitor in advance of the unblinding, the Investigator must 
promptly document in the patient’s record the rationale for unblinding and should subsequently 
contact the Medical Monitor to explain any premature unblinding of treatment assignment.  
Procedures for unblinding a patient’s treatment will be provided separately to the Investigator.  
Similarly, if the Medical Monitor breaks the blind for an individual patient for the purpose of 
evaluating an emergent safety issue, the Medical Monitor will document within study 
documentation the rationale, circumstances, and the person or persons being informed about the 
unblinding. 
The DMC will have access to the IWRS and will be able to unblind individual patients.  Refer to 
Section 15.8  for further details regarding DMC access to blinded and unblinded data.  The DMC 
will document details about any unblinded patient data reviews in the closed session DMC 
minutes, which will be made available to the Sponsor only after the database is locked and the 
study is unblinded.  Cases of premature unblinding, as noted above, will also be reviewed by the 
DMC.  
Access to treatment assignments will also be made available to the designated Intercept staff 
responsible for expedited safety reporting of suspected unexpected serious adverse reactions 
(SUSARs) to the Regulatory Authorities. 
9.5. 
Assignment of Site and Patient Numbers 
9.5.1. 
Site Numbers 
Each study site selected to participate in this study will be assigned a site number by the Sponsor.  
The site number will be used to categorize patient data and to identify the site and/or Investigator 
within study documents.  This number will be recorded in the eCRF. 
9.5.2. 
Patient Numbers 
Patients will be identified by a unique six-digit number, independent of the randomization 
number.  The first three digits will represent the site number and the last three digits will 
represent the Screening number. 
9.6. 
Restrictions 
Participation in another investigational product, biologic, or medical device study within 30 days 
prior to Screening and during the course of the study is prohibited. 
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9.6.1. 
Fasting Requirement at Study Visits 
All patients must have been fasting for at least 8 hours prior to their Screening Visit and all 
subsequent study visits, as all analytes will be assayed in fasting blood or plasma samples.  
Water is permitted during the fasting period. 
9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visits should be based on Day 1 (not on the prior visit) unless stated otherwise.  For example, 
Week 6 should ideally occur 6 calendar weeks (± 7 days) following Day 1.   
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk and benefit of the 
study to the patient and will provide him/her with a copy of the informed consent form (ICF).  
The patient will be given sufficient time to consider the study before deciding whether or not to 
participate.  The patient will be informed that participation is voluntary and that her/his future 
medical treatment will not be compromised by participation in the study and that he or she can 
withdraw from the study at any time.  The patient must be willing and able to provide written 
informed consent (on hard copies or on electronic devices such as iPads) before entering the 
study.  The Investigator or a medically qualified designee is responsible for administering and 
documenting the written informed consent of the patient.  The patient will be given a copy of the 
patient information sheet (PIS) and his/her signed and dated consent form.  Patients will also be 
provided a separate ICF before providing blood samples for genetic analysis and must be willing 
and able to provide consent as described above. 
9.7.3. 
Assessing Cirrhosis 
To determine which dosing regimen patients should follow, cirrhosis should be assessed by the 
Investigator at Screening Visit 1.  Acceptable methods of confirming (via medical history) or 
assessing cirrhosis for purposes of the study are defined as a patient who has documented 
evidence or presence of one or more of the following cirrhosis indicators: 
 Biopsy results consistent with PBC Stage 4 (Ludwig 1978)   
 Transient Elastography Median Value ≥16.9 kPa (Corpechot 2012) 
 The presence of any of the following (unless exclusionary per Section 8.3) in the absence 
of acute liver failure: 
 Varices 
 Ascites 
 Radiological evidence of cirrhosis (nodular liver or enlargement of portal vein 
and splenomegaly) 
 Combined low platelet count (<140 000/mm3) with: 
 persistent decrease in serum albumin, or  
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 elevation in prothrombin time /INR (not due to antithrombotic agent use), or 
 elevated bilirubin (2× ULN) 
Patients will be dosed according to their CP Score calculated in the eCRF (see Section 14.1.1 and 
Table 12). 
Cirrhosis status should be reassessed as clinically indicated throughout the study.  Any change in 
cirrhosis status will necessitate re-evaluation of the dosing regimen. 
9.7.4. 
Screening Procedures (-1 day to 14 days prior to Day 1) 
The Screening Visit assessments must be performed within ≤14 days prior to Day 1 to determine 
whether the patient meets all the inclusion criteria and none of the exclusion criteria.  Patients 
who do not fulfill all eligibility criteria will not be enrolled in the study.  Patients may be 
rescreened after 2 months have elapsed from the date of their most recent screening visit 
procedure; however, all Screening procedures (including obtaining informed consent) should be 
repeated and a new three-digit Screening number assigned.   
Screening Visit procedures are as follows: 
 The patient is to review and sign the ICF.  Informed consent must be obtained from 
the patient before performing any study-related procedures, including Screening 
procedures. 
 Collect medical history (including smoking and alcohol consumption history and 
current habits of both). 
 PBC history  
 Verify inclusion and exclusion criteria for eligibility. 
 Perform a physical examination.  
 Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record any pretreatment-emergent AEs. 
 Record prior (if within 30 days of Screening) and current concomitant medications. 
 Perform a standard 12-lead electrocardiogram (ECG). 
 Perform assessments for calculation of CP Score (Section 14.1.1 ) 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Virology Screen (HCV and HBsAg) 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 Obtain urine sample for urinalysis (dipstick). 
 Perform a urine-based beta human chorionic gonadotropin (β-hCG) pregnancy test in 
females of childbearing potential.  
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 Provide kits and instructions for collection of stool specimens at home prior to the 
Day 1 visit 
 Instruct the patient to fast overnight (at least 8 hours) before the next visit (water is 
permitted) 
9.7.5. 
Day 1 Procedures (Randomization) 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits. 
 Review inclusion and exclusion criteria for eligibility. 
 Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
 Assess and record any pretreatment-emergent AEs. 
 Perform a physical examination.  
 Review and record prior concomitant medications. 
 Perform TE using the Fibroscan® TE device.  If TE has been done within 3 months 
of Day 1 and a report/adequate data are available, a pretreatment TE at Day 1 is not 
required.  If the TE cannot be performed on Day 1 (eg, device/technician 
unavailability, scheduling issues, TE data is needed to inform cirrhosis assessment, 
etc.), the procedure may be completed within the Day 1 visit window, (if data is 
needed for cirrhosis assessment) or as close as possible to the Day 1 visit, preferably, 
after patient eligibility has been confirmed. 
 Perform assessments for calculation of CP Score (Section 14.1.1) 
 Quality of Life and Patient questionnaires (Section 13.2.6). 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant heath care professional (HCP) or non-HCP related office 
visits that have occurred since the previous study visit. 
 Randomize the patient only if s/he meets all inclusion criteria and no exclusion 
criteria. 
 Record the visit in IWRS and dispense investigational product 
 Instruct the patient to begin dosing on the day after the Day 1 visit.  Instruct the 
patient to swallow the tablet whole; s/he must not chew, divide, or crush the 
tablet. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
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 Obtain blood samples for markers of inflammation 
 ELF (including HA, P3NP, and TIMP-1) 
 C4, and FGF-19, bile acids 
 Trough PK assessment 
 Obtain urine sample for urinalysis (dipstick). 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted 
9.7.6. 
Week 3 (Safety Contact) 
Patients should be contacted by telephone at Week 3 to assess for AEs and verify that s/he is 
dosing as directed. 
 Contact patient by phone/email. 
 Review and record prior concomitant medications. 
 Assess and record AEs. 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior to 
all study visits, but water is permitted. 
9.7.7. 
Week 6 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
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 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs (temperature, sitting heart rate, respiratory rate, and 
sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform a physical examination.  
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Quality of Life and Patient questionnaires (see Section 13.2.6). 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3). 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Record the visit in IWRS and dispense investigational product 
 Instruct the patient to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 C4, and FGF-19, bile acids 
 Trough PK assessment 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior to 
all study visits, but water is permitted. 
9.7.8. 
Week 12 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
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 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
 Assess and record AEs. 
 Perform a physical examination.  
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Quality of Life and Patient questionnaires (see Section 13.2.6). 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess for dose titration, if eligible 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Record the visit in IWRS and dispense investigational product 
 Instruct the patient to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Obtain blood samples for markers of inflammation 
 ELF (including HA, P3NP, and TIMP-1) 
 C4, and FGF-19, bile acids 
 Trough PK assessment 
 Serial PK assessment; the following procedures will be conducted in all patients: 
 30 minutes prior to dosing:  collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hr post dose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6 hours post dose 
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Note:  Patients should not consume any food for the duration of the 6-hour PK 
assessments except the meal replacement drink.  Patients should not drink any water until 
at least one hour post dose 
 Assess the patient’s supply of investigational product to ensure an adequate amount.   
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior to 
all study visits, but water is permitted. 
9.7.9. 
Week 18 and Week 30 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs (temperature, sitting heart rate, respiratory rate, and 
sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform a physical examination.  
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Quality of Life and Patient questionnaires (see Section 13.2.6). 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3). 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Record the visit in IWRS and dispense investigational product 
 Instruct the patient to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
 Obtain blood samples for 
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 Serum chemistry, hematology, and coagulation  
 C4, and FGF-19, bile acids 
 Trough PK assessment 
 Serial PK assessment will only be conducted in patients who are uptitrating to the 
next dose level.   
 30 minutes prior to dosing:  collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hr post dose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6 hours post dose 
Note:  Patients should not consume any food for the duration of the 6-hour PK 
assessments except the meal replacement drink.  Patients should not drink any water until 
at least one hour post dose 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior to 
all study visits, but water is permitted. 
9.7.10. 
Weeks 24 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
 Assess and record AEs. 
 Perform a physical examination.  
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
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 Quality of Life and Patient questionnaires (see Section 13.2.6). 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess for dose titration, if eligible. 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Obtain blood samples for markers of inflammation 
 ELF (including HA, P3NP, and TIMP-1) 
 C4, and FGF-19, bile acids 
 Trough PK assessment 
 Serial PK assessment; will only be conducted in patients who are uptitrating to 
the next dose level.   
 30 minutes prior to dosing:  collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hr post dose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6 hours post dose 
Note:  Patients should not consume any food for the duration of the 6-hour PK 
assessments except the meal replacement drink.  Patients should not drink any water until 
at least one hour post dose 
 Perform TE using the Fibroscan® TE device.   
 Assess the patient’s supply of investigational product to ensure an adequate amount.   
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior to 
all study visits, but water is permitted. 
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9.7.11. 
Week 36 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
 Assess and record AEs. 
 Perform a physical examination.  
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Quality of Life and Patient questionnaires (see Section 13.2.6). 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess for dose titration, if eligible 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Record the visit in IWRS and dispense investigational product 
 Instruct the patient to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Obtain blood samples for markers of inflammation 
 ELF (including HA, P3NP, and TIMP-1) 
 C4, and FGF-19, bile acids 
 Trough PK assessment 
 Serial PK assessment; will only be conducted in patients who are uptitrating to 
the next dose level.   
 30 minutes prior to dosing:  collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
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 Immediately following 1 hr post dose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6 hours post dose 
Note:  Patients should not consume any food for the duration of the 6-hour PK 
assessments except the meal replacement drink.  Patients should not drink any water until 
at least one hour post dose 
 Assess the patient’s supply of investigational product to ensure an adequate amount.   
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior to 
all study visits, but water is permitted. 
9.7.12. 
Week 48 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform a physical examination including smoking and alcohol consumption history 
and current habits for both.  
 Perform 12-Lead ECG 
 Perform TE using the Fibroscan® TE device.   
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Quality of Life and Patient questionnaires (see Section 13.2.6). 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Urinalysis (dipstick) 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
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 Serum chemistry, hematology, and coagulation  
 Obtain blood samples for markers of inflammation 
 ELF (including HA, P3NP, and TIMP-1) 
 C4, and FGF-19, bile acids 
 Trough PK assessment 
 Serial PK assessment; will only be conducted in patients who are uptitrating to 
the next dose level.   
 30 minutes prior to dosing:  collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hr post dose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6 hours post dose 
Note:  Patients should not consume any food for the duration of the 6-hour PK 
assessments except the meal replacement drink.  Patients should not drink any water until 
at least one hour post dose 
 Perform TE where available using the Fibroscan® TE device.   
 Schedule the follow-up visit and advise the patient: 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.13. 
Every 3 Months after Week 48  
Patients who have completed their 48-week double-blind treatment period will continue 
double-blind treatment until all randomized patients have completed their participation in the 
primary treatment period and the database is locked.  Assessments including a review of all AEs 
and safety laboratory results (eg, chemistry, hematology, and coagulation) will be done every 
3 months as described in Section 9.7.7.  Patients’ dose and dosing frequency may be titrated up 
or down within the appropriate dosing regimen based on the calculated CP Scores.  Up-titration 
should be done per Investigator discretion and be guided by the pre-titration tolerability 
assessments as described in Section 7.4 and should not exceed the indicated maximal dose and 
frequency indicated for their CP category.  Patients will then have the option to continue into an 
open-label LTSE.  
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9.7.14. 
End of Treatment/Early Termination Procedures for Patients that Withdraw 
from Investigational Product or Withdraw Consent 
Patients who discontinue investigational product are expected to continue in the study until the 
end of the study (EOS) or at the discretion of the Sponsor.     
EOT/ET procedures will be required whenever patients discontinue treatment with 
investigational product.  The EOT/ET visit and procedures listed below must be performed as 
close as possible to the patient’s last dose of investigational product.  When a patient 
discontinues investigational product but continues with regularly scheduled study visits, the EOS 
visit will be completed as the patient’s final study visit.  The actual investigational product 
discontinuation scenario (Table 4) will determine the sequence of the EOT/ET and EOS visits 
and procedures.  In some cases, the EOT/ET visit and procedures will precede the EOS visit; in 
others, the EOT/ET and EOS visits will be combined and performed as close as possible to the 
patient’s last dose of investigational product.   
When a patient ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (ET) (withdrawal of consent) or discontinuation, an 
EOT/EOS visit must be performed as near as possible to her/his last dose of investigational 
product and the procedures, listed below, performed.  The purpose of this visit is to conduct 
complete and/or final assessments on or as near as possible to the final day of dosing.  In some 
cases, the patient may discontinue on the day of a scheduled study visit.  In these cases, 
EOT/EOS visit procedures should be performed in place of the scheduled study visit procedures.  
The data will be recorded as EOT/ET and EOS procedures in the eCRF. 
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Table 4: 
Early Discontinuation Scenarios 
 
Investigational 
Product 
Consent 
Study Visit 
Status 
EOT Visita 
EOS 
Visita 
Early 
Termination 
Discontinued 
Withdrawn 
No additional 
visits except 
EOT/EOS 
Combined visit, completed as 
close as possible to last dose of 
investigational product 
Treatment 
Discontinuationb 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as close 
as possible to last 
dose of 
investigational 
product 
Complete 
at final 
study 
visit 
Discontinued 
Record review 
only 
Record review 
only 
Combined visit, completed as 
close as possible to last dose of 
investigational product 
Sponsor 
Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit, completed as 
close as possible to last dose of 
investigational product 
Pregnancy 
Discontinued 
Complete per the above scenarios - Early Termination or Treatment 
Discontinuation 
Treatment 
Interruption  
Interrupted 
Retained 
Regular Visit 
Schedule 
Complete as close 
as possible to last 
dose of 
investigational 
product 
Complete 
at final 
study 
visit 
Lost to Follow-
Up 
Discontinued 
LTF 
None 
Unable to complete due to LTF 
status 
EOS = end of study; EOT = end of treatment; LTF = lost to follow-up 
a Refer to Section 7.1.2   Schedule of Study Procedures for all procedures and evaluations required at the EOS and 
EOT Visits. 
b Includes initiation of commercially available OCA 
9.7.15. 
Unscheduled Safety Visit 
The Investigator may schedule an at-clinic Unscheduled/Safety Visit at any time if clinically 
warranted.  Unscheduled and/or repeat assessments, including additional laboratory tests or 
investigations, may be conducted.   
As appropriate, the Medical Monitor should be contacted. 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
The investigational product is a white, round, film coated tablet containing OCA 5 mg or 10 mg 
or matching placebo.  The tablets contain the following inactive ingredients:  microcrystalline 
cellulose, sodium starch glycolate, and magnesium stearate. 
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10.2. 
Investigational Product Packaging and Labeling 
The packaging and labeling of investigational product supplies will be performed according to 
Good Manufacturing Practice standards by a designated qualified vendor.  All investigational 
product will be provided as tablets for oral administration and provided in high density 
polyethylene bottles with heat induction seals and child resistant closures.  The bottle packaging 
will not reveal any information about the treatment dose contained in the bottle.  Multiple bottles 
may be dispensed to the patient at each visit to provide enough tablets for dosing until the next 
visit. 
The designated investigational product packaging/distribution vendor will also be responsible for 
the distribution of the investigational product to the Investigator. 
10.3. 
Investigational Product Storage 
Investigational product should be stored in the containers in which they are received from the 
Sponsor’s supplier, at 15C to 25C. 
10.4. 
Investigational Product Administration 
Refer to Section 9.1. 
10.5. 
Investigational Product Accountability and Disposal 
The Sponsor’s representative will send investigational product to the study site under appropriate 
storage conditions.  All shipments of investigational product should be unpacked and the 
contents reviewed immediately upon receipt.  If it is not possible to verify the contents 
immediately, they must be stored under the appropriate storage conditions until verification of 
the contents is possible (ideally, within 1 business day from receipt).  The pharmacist or designee 
should verify the investigational product against the shipment documentation.  The pharmacist or 
designee should contact the Sponsor immediately to report any concerns regarding the shipment.  
All investigational product will be provided for use only in this study and is not to be used for 
any other purpose.  The Investigator or designee will maintain a full record of investigational 
product accountability, including records of individual patient dispensing and final return or 
disposition (as directed by the Sponsor).  
The study monitor, also known as the Clinical Research Associate (CRA), will review 
accountability records against investigational product dispensed and that remaining in stock, 
during on site monitoring visits and when the study is completed, or if it is prematurely 
terminated.  The CRA will retrieve documentation detailing and confirming the return or 
destruction of the investigational product.  If the investigational product is to be returned to the 
Sponsor’s vendor for destruction, the CRA will also prepare the investigational product for 
shipment. 
11. 
OVERVIEW OF ASSESSMENTS 
The assessments supporting the objectives for the study are in Table 5: 
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Table 5: 
Table of Assessments 
Primary Objectives 
Assessments 
PK parameters 
OCA and its conjugates glyco-OCA, tauro-OCA, and OCA 
glucuronide 
Safety and tolerability  
SAEs and TEAEs, physical exam, ECG, vital signs, 
clinical laboratory assessments, discontinuations, pruritus 
and fatigue 
Secondary Objectives 
Assessments 
Changes in Risk Scores 
Changes in MELD and CP Score components  
Changes in liver biochemistry and hepatobiliary 
damage  
Total and direct bilirubin, ALP, ALT, AST, GGT, INR, 
creatinine, albumin, platelets  
PD parameters 
FGF-19, C4, and plasma, fecal bile acids 
Additional Objectives 
Assessments 
Markers of inflammation 
IL-6, hs-CRP, TNF-α, IgM, IgA, IgG, CK-18-M30, and 
others as determined during course of study.   
Noninvasive measurements of liver fibrosis, liver 
stiffness and cirrhosis 
Transient Elastography and ELF (including HA, P3NP, 
and TIMP-1) 
PK/PD relationship of OCA and liver biochemistry 
OCA and its conjugates, glyco-OCA tauro-OCA; and OCA 
glucuronide 
PK/PD relationship of OCA and bile acid 
homeostasis 
Bile acids 
Patient reported outcomes 
Pruritus VAS, PBC-40, EQ-5D-5L, CLDQ 
PK/PD relationship of OCA:  Markers of safety 
and tolerability 
Pruritus and fatigue 
Clinical outcomes 
Incidence and time to first occurrence of any of the 
following:  all-cause mortality, liver-related events 
resulting in death, hepatic failure leading to liver 
transplant, variceal bleed, hepatic encephalopathy, 
spontaneous bacterial peritonitis, ascites, hepatocellular 
carcinoma 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; C4 = 7α-hydroxy-
4-cholesten-3-one; CK-18-M30 = cytokeratin-18 neoepitope; CLDQ = Chronic Liver Disease Questionnaire; CP = 
Child-Pugh; ECG = electrocardiogram; ELF = enhanced liver fibrosis; FGF-19 = fibroblast growth factor-19; GGT 
= gamma-glutamyl transferase; HA = hyaluronic acid; HDL = high density lipoprotein; hs-CRP = high-sensitivity 
C-reactive protein; IgA = immunoglobulin; A IgG = immunoglobulin G; IgM = immunoglobulin M; INR = 
international normalized ratio; MACE = Major Adverse Cardiovascular Events; MELD = Model End Stage Liver 
Disease; OCA = obeticholic acid; P3NP = procollagen 3 N-terminal peptide; PD = pharmacodynamics; PK = 
pharmacokinetic; TEAE = treatment emergent adverse events; TIMP-1 = tissue inhibitor of metalloproteinase 1; 
SAE = serious adverse event; TNF-α = tumor necrosis factor-α, VAS = visual analog scale 
12. 
CLINICAL PHARMACOKINETIC ASSESSMENTS 
Pharmacokinetic analyses will be based on the PK population (Section 15.1).  Subjects with at 
least one PD assessment after dosing will be included in the combined PK/PD analyses.   
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12.1. 
Pharmacokinetic Blood Sampling 
Serial and trough PK assessments will be performed in all patients participating in the study.   
At each visit, patients will provide fasted blood samples for measurement of OCA and its 
conjugates glyco-OCA, tauro-OCA, and OCA glucuronide 30 minutes before administration of 
investigational product (predose) (Table 6).  Patients will then receive a dose of investigational 
product with approximately 240 mL of water.   
Serial PK blood samples will be obtained at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose.  
(see Table 7) on Week 12 and prior to uptitrating to the next dose level of OCA.  PK assessments 
will be based on patient’s current dosing regimen (ie, prior to uptitrating to the next dose level).   
Patients should not drink additional water for 1 hour after taking the dose of investigational 
product and will remain fasted until after the 1-hour sample is collected.  A meal will be 
provided following collection of the 1-hour PK sample; the meal will be a meal replacement 
drink with nutrition information that has been submitted to and approved by the Sponsor in 
advance.  No other food or drink (water is permitted) will be allowed until after the 6-hour 
sample collection. 
During the double-blind treatment period and double-blind LTSE: 
 Pharmacokinetic trough samples will be obtained from all patients at all visits prior to 
dose administration in accordance with Table 7. 
 Serial PK assessments will be performed in all patients at Week 12.  Thereafter, PK 
assessments will be conducted at every titration visit in those patients who were eligible 
and uptitrated their dose.  Sample collection for fecal analysis will occur concurrent with 
serial PK sampling visits only.   
Table 6: 
Acceptable Windows for Pharmacokinetic Sample Collection 
Nominal Sampling Time 
Acceptable Sampling Window 
Before administration of investigational product 
(predose or trough) 
Within 30 minutes before dosing 
0.5 to 1.5 hours after investigational product 
± 10 minutes 
2 to 2.5 hours after investigational product 
± 20 minutes 
3 to 6 hours after investigational product 
± 30 minutes 
 
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Table 7: 
Pharmacokinetic Sampling Schedule 
 
Double-Blind Treatment Period, Day 
 
Screening 
1 
6 
12 
18 
24 
30 
36 
48 
ET/EOT 
PK trough 
collectiona 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK serial 
collection 
and fecal 
analysis 
 
To occur at Week 12 and any up-titration visit 
 
EOT = end of treatment; AT = early termination; PK = pharmacokinetic  
a Pharmacokinetic trough samples will be obtained from all patients at all visits prior to dose administration. 
b Serial PK assessments will be performed in all patients at Week 12.  Thereafter, PK assessments will be conducted 
at every titration visit in those patients who were eligible and uptitrated their dose.  Sample collection for fecal 
analysis will occur concurrent serial PK sampling visits only. 
12.2. 
Processing and Handling of Pharmacokinetic Samples 
Whole blood will be collected at each scheduled sample time point.  Detailed procedures for the 
collection of blood samples including further processing into plasma will be provided in a 
separate laboratory manual.  The storage and shipment procedures for subsequent bioanalysis, 
will be provided to the investigational site in a separate document before the study is initiated. 
12.3. 
Bioanalysis 
Plasma concentrations of OCA and its conjugates glyco-OCA, tauro-OCA, and OCA 
glucuronide will be determined using a GLP validated liquid-chromatography mass 
spectrometry/ mass spectrometry method.  A detailed description of validation information and 
results from the bioanalytical assay will be provided in separate reports.  These samples may be 
used for evaluation of metabolites of OCA or other concomitant medication, for further 
evaluation of the bioanalytical method, and for analyses that provide information on the 
metabolic pathways used or impacted by OCA. These data would only be used for exploratory 
purposes and may not be included in the clinical study report. 
13. 
ASSESSMENT OF SAFETY 
Safety will be monitored and assessed by AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and clinical laboratory assessments.  
Safety will be assessed in terms of AEs.  All AEs, whether observed by the investigator, reported 
by the patient, noted from laboratory findings, or identified by other means, will be recorded 
from the time the patient signs his/her consent form (s)until the patient completes study 
participation (final Follow Up Visit). 
Recording AEs/SAEs in the electronic data capture (EDC) system is the method for reporting 
AEs/SAEs.  It is therefore imperative, that AEs/SAEs are recorded into the EDC. 
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13.1. 
Adverse Events and Serious Adverse Events 
13.1.1. 
Definitions of Adverse Events 
13.1.1.1. Adverse Event  
AEs are defined as any untoward medical occurrence associated with the use of the 
investigational product in humans, whether or not considered related to investigational product.  
An AE, also referred to as an adverse experience, can be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom, or disease temporally associated with any use of 
the investigational product, without any judgment about causality and irrespective of route of 
administration, formulation, or dose, including an overdose.   
AEs include, but are not limited to: (1) a worsening or change in nature, severity, or frequency of 
condition(s) present at the start of the study; (2) patient deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction.  For reporting purposes, pregnancy is not 
considered an AE.  
Patients should be questioned about AEs in a general way, without leading the patient or asking 
about the occurrence of any specific symptom.  The Investigator should attempt to establish a 
diagnosis of the event based on signs, symptoms, and/or other clinical information.  The 
diagnosis and not the individual signs/symptoms should be documented as the AE.  For example, 
if the underlying disease process is a stroke, it would not be appropriate to record the AE by 
describing the symptoms “sudden numbness, dizziness, and difficulty speaking.”  The AE 
medical term of “stroke or cerebrovascular accident” should be recorded as it more accurately 
describes the AE. 
13.1.1.2. Treatment-Emergent Adverse Event 
A treatment-emergent AE (TEAE) is any event not present before the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product.  
13.1.1.3. Serious Adverse Event  
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
 Death 
 Is immediately life threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
 Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
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Events not considered to be SAEs are hospitalizations for: 
 Routine monitoring of the studied indication and not associated with any deterioration 
in condition or AE; 
 Elective treatment for a pre-existing condition that did not worsen; 
 Respite care or observation when there is no AE associated with the hospitalization. 
13.1.2. 
Relationship to Investigational Product 
The Investigator will document her/his opinion of the relationship of the AE to treatment with 
the investigational product using the criteria outlined in Table 8.  An AE for which there is a 
“reasonable possibility” that the investigational product caused the AE is otherwise referred to as 
suspected adverse reaction (SAR).  “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the investigational product and the AE.   
If the relationship between the AE/SAE and the investigational product is determined to be 
“definite,” “probable,” or “possible” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 
Table 8: 
Relationship of Adverse Events to Investigational Product 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the investigational 
product or in which the investigational product level has been established in body fluids or tissue; that 
follows a known or expected response pattern to the suspected investigational product; and that is 
confirmed by improvement on stopping or reducing the dosage of the investigational product, and 
reappearance of the reaction on repeated exposure. 
Probable 
A reaction that follows a reasonable temporal sequence from administration of the investigational 
product; that follows a known or expected response pattern to the suspected investigational product; that 
is confirmed by stopping or reducing the dosage of the investigational product; and that could not be 
reasonably explained by the known characteristics of the patient’s clinical state. 
Possible 
A reaction that follows a reasonable temporal sequence from administration of the investigational 
product; that follows a known or expected response pattern to the suspected investigational product; but 
that could readily be produced by a number of other factors. 
Unlikely 
An event that does not follow a reasonable temporal sequence from administration of the investigational 
product; that does not follow a known or suspected response pattern to the suspected investigational 
product; and that could reasonably be explained by known characteristics of the patient’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
13.1.3. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, severe, 
life threatening, or death as defined in Table 9 must be entered on the AE eCRF.  It should be 
noted that the term “severe” used to grade intensity is not synonymous with the term “serious.”  
The assessment of severity is made regardless of investigational product relationship or of the 
seriousness of the AE.   
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Table 9: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Asymptomatic or mild symptoms, clinical or diagnostic observations only, or 
intervention not indicated. 
2 = Moderate 
Minimal, local or noninvasive intervention indicated; or limiting age-appropriate 
instrumental activities of daily living. 
3 = Severe 
Medically significant but not immediately life-threatening, hospitalization or 
prolongation of hospitalization indicated, disabling, or limiting self-care activities of 
daily living. 
13.1.3.1. Severity of Pruritus (as an Adverse Event) 
To ensure consistency in reporting, the following guidelines for assessing severity of pruritus 
should be used for AE reporting.  As pruritus is a patientive symptom, clinical judgment should 
be used to determine its severity and management Table 10.   
Table 10: 
Severity of Pruritus 
Pruritus 
Grade 
Clinical Description of Severity for Pruritus and Medical Intervention 
1 = Mild 
Generally localized; causing no limitation of usual activities or minimal sleep 
disturbance; the patient may experience slight discomfort.   
Medicinal intervention is not indicated. 
2 = Moderate 
Intense or widespread; causing some limitation of usual activities or sleep disturbance; 
the patient may experience annoying discomfort.   
Medicinal intervention may be indicated. 
3 = Severe 
Intense or widespread and interfering with activities of daily living (ADL), ie, causing 
inability to carry out usual activities, or severe sleep disturbance; the patient may 
experience intolerable discomfort.  
Medicinal intervention is typically indicated. 
13.1.4. 
Reporting of Adverse Events and Serious Adverse Events 
13.1.4.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the patient 
fully completes her/his study participation of the study. 
All AEs, whether believed by the Investigator to be related or unrelated to the investigational 
product, must be documented in the patient’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product.   
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13.1.4.2. Reporting of Serious Adverse Events 
In agreeing to the provisions of this protocol, the Investigator accepts all legal responsibilities for 
immediate reporting of SAEs to the Sponsor.  Immediate reporting implies within 24 hours of 
becoming aware of the occurrence of an SAE. 
All SAEs must be reported to the Sponsor (including suspected liver-related clinical outcome 
events that qualify as serious).  SAEs are reported by entering the SAE data into the study 
specific EDC system.  Entering the SAE data into the EDC system will automatically notify the 
Sponsor of the event.  In the event that the EDC system is inaccessible, an SAE may reported by: 
 E-mail to the SAE email address:  
 
 Fax using a paper SAE report form:  
 
 Telephone:  
 
If an SAE is reported by telephone or fax, an SAE Report form must also be completed in the 
EDC system as soon as the EDC system is accessible.  At a minimum, the following information 
should be provided at the time of the initial report:   
 Patient number  
 Event term  
 At least 1 criterion classifying the event as serious  
 Name and title of the reporting individual  
 Causal relationship to the investigational product  
The Investigator will assess whether the event is causally related to the investigational product.  
The Sponsor will also assess whether the event is causally related to the investigational product, 
in addition to assessing the overall safety profile of the investigational product.  The Sponsor will 
notify the appropriate regulatory agencies as well as all participating Investigators of Safety 
Reports/Expedited Safety Reports that occur during the study within the time frames required by 
each regulatory agency.  
Following the initial report, any additional information obtained by the Investigator about the 
SAE must be reported promptly to the Sponsor in the same manner as described above for the 
initial SAE report.  Any supporting source documentation should be faxed to 
 or 
emailed to 
 as soon as possible.   
The Investigator is responsible for submitting information on Safety Reports/Expedited Safety 
Reports received from the Sponsor to her/his local IRB/IEC, as directed by the local country 
requirements.  Documentation of the submissions to IRBs/IEC s must be retained in the 
appropriate study file(s).  As instructed by the Sponsor, Safety Reports/Expedited Safety Reports 
should be retained in the appropriate investigative site study files or with the IB.  
SAEs involving suspected liver-related clinical outcome events will be processed and reported 
by the Sponsor as described in Section 13.1.5. 
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13.1.5. 
Suspected Liver-Related Clinical Outcome Events  
Specified liver-related clinical outcome events may, by definition (see Section 13.1.1.3) qualify 
as SAEs.  The Sponsor must be notified of any SAEs within 24 hours of the site becoming aware 
of the event (see Section 13.1.4.2).  The Sponsor is responsible for regulatory reporting of SAEs, 
including expeditious reporting of SUSARs, which are defined as SAEs that are considered 
related (definitely, probably, or possibly related) to the investigational product and considered 
unexpected as defined in the IB. 
The Sponsor will consider the following list of clinical outcome events Medical Dictionary for 
Regulatory Activities (MedDRA preferred terms) to be disease related and exempt from 
expeditious regulatory reporting, but will continue to report them in a non-expeditious manner:  
death, end-stage liver disease (preferred term: chronic hepatic failure), liver transplant (preferred 
term: liver transplant), HCC (preferred term: hepatocellular carcinoma), variceal bleeding 
(preferred term: gastroesophageal variceal haemorrhage), ascites (preferred term: ascites), 
hepatic encephalopathy (preferred term: hepatic encephalopathy),  and spontaneous bacterial 
peritonitis (preferred term: peritonitis bacterial). 
13.1.5.1. Potential Clinical Outcome Events 
The events listed below will be initially assessed by the Investigator to determine if they are 
Potential Clinical Outcome Events.  These events will be evaluated by an Adjudication 
Committee (described in Section 15.9) to confirm if they meet the criteria to be considered 
Clinical Outcome Events.  
Potential Clinical Outcome Events: 
Hospitalization for clinical complications of cirrhosis. 
Given that the Potential Clinical Outcome Events could also meet the criteria of a SUSAR, 
which would necessitate unblinding for expedited reporting, the Sponsor will not expeditiously 
report suspected Potential Clinical Outcome events in order to retain the study blind and preserve 
the integrity of the clinical outcomes endpoint.  These events will be selected as a “potential 
study event” on the Adverse Event eCRF and will be submitted for adjudication to the 
Adjudication Committee as described in Section 15.9. 
13.1.6. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the EDC represent the official record of all AEs and SAEs reported 
in the study.  The Investigator should comply with requests by the Medical Monitor or other 
Sponsor personnel to record the SAE on the patient’s AE EDC.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the Sponsor, the Investigator should 
provide input into the SAE narrative and provide timely information to ensure prompt follow-up 
and closure of the SAE report. 
The Investigator and supporting personnel responsible for patient care should discuss with the 
Medical Monitor any need for supplemental investigations of SAEs.  The results of these 
additional assessments must be reported to the Medical Monitor. 
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13.1.7. 
Notification of Post-Study SAEs 
If an Investigator becomes aware of an SAE that may be attributable to the investigational 
product at any time after the end of the study, the Sponsor should be notified immediately (ie, 
within 24 hours) by following the instructions provided in Section 13.1.4.2. 
13.1.8. 
Notification of Post-Treatment SAEs for Subjects Who Continue in the Study 
Post-treatment SAEs that occur in subjects who remain in the study after investigational product 
has been discontinued must be reported to the Sponsor within 24 hours by following the 
instructions provided in Section 13.1.4.2. 
13.1.9. 
Follow-Up of AEs and SAEs 
All AEs must be followed during the course of the study until the AE resolves, is no longer of 
clinical concern, has stabilized or is otherwise explained, or the patient is lost to follow-up. 
AEs ongoing at the final visit that are deemed to be ‘possibly, probably, or definitely” related or 
of other clinical significance must be followed for as long as necessary to adequately evaluate 
the safety of the patient or until the event stabilizes, resolves, or is no longer of clinical concern.  
If resolved, a resolution date for the AE should be documented on the eCRF.  The Investigator 
must ensure that follow-up includes any supplemental investigations indicated to elucidate the 
nature and/or causality of the AE.  This may include additional laboratory tests or investigations, 
or consultation with other healthcare professionals, as considered clinically appropriate by the 
Investigator. 
All patients showing possible drug-induced liver injury should be followed until all 
abnormalities return to normal or to the baseline state.  Drug-induced liver injury may develop or 
progress even after the causative drug has been stopped.  Results should be recorded in the 
eCRF.  Note that longer follow-up can sometimes reveal an off-drug repetition of what had 
appeared to be drug-induced liver injury, indicating that liver injury was related to underlying 
liver disease. 
13.1.10. 
Pregnancy and Follow-Up  
Pregnancies are not considered AEs in and of themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical study, she must discontinue investigational 
product immediately and the Sponsor must be notified within 24 hours of the Investigator’s 
learning of the pregnancy by completing. 
In the situation that the EDC is not functioning, the Medical Monitor should be notified by 
telephone.  The investigator remains responsible for entering the pregnancy information into the 
EDC when the EDC becomes functional. 
Completing the pregnancy report in the EDC is not a substitute for reporting an AE/SAE when 
an AE/SAE has occurred.  In the situation when an AE/SAE has occurred, the AE/SAE reporting 
procedures described in Section 13.1.4 must also be followed. 
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13.2. 
Other Safety Parameters 
13.2.1. 
Medical History/Demographics 
A complete medical history will be obtained from the patient at screening.  Smoking and alcohol 
consumption history and current habits will be recorded.  Demographic characteristics (age, 
gender, race, and ethnicity) will be recorded. 
13.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the visits specified in the Schedule of Study Procedures (Table 1).  A basic physical 
examination should be performed, including all body systems pertinent to the patient.  Any 
clinically significant abnormality should be reported on the AE eCRF page for findings that 
appear after consent, and on the medical history eCRF for any finding present prior to consent.   
13.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits: oral temperature, sitting heart rate, respiratory rate 
and sitting blood pressure (BP).  When taking heart rate, respiratory rate and BP readings, 
patients should be seated quietly for a minimum of 3 minutes before the readings are taken.   
13.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected.  The Investigator or designee will review the 12-lead 
ECG and findings will be recorded in the eCRF as normal, abnormal but not clinically 
significant, or abnormal and clinically significant.  Any clinically significant abnormalities on 
ECGs recorded after Day 1 will also be documented as AEs and entered on the AE page of the 
eCRF.  
Investigative sites must retain a copy of all 12-lead ECGs evaluated by the Investigator or 
designee.  These ECGs must be clearly labeled with the Patient ID number, date and time. 
13.2.5. 
Laboratory Assessments 
Except for Screening, patients will be instructed to attend each study visit in a fasted state, 
preferably in the morning, and patients should remain fasted until their blood samples have been 
collected.  For visits that require fasting, the Investigator or designee will verify that the patient 
has fasted for at least 8 hours and record fasting status in the source and eCRF.  If the patient 
reports having eaten (water is permitted) within 8 hours, the Investigator or designee will 
document accordingly in the source and eCRF and remind the patient that fasting is required 
before all study visits. 
Blood samples for serum chemistry, coagulation, and hematology will be collected at every visit 
as detailed in the Schedule of Study Procedures (see Table 1).  The number and volume of 
samples to be collected at each visit will be detailed in the laboratory manual. 
Full instructions concerning the number and type of samples to be collected at each visit, the 
required sample volumes, sample collection methods, sample processing, labeling, and shipping 
will be provided in a separate procedural manual.  All necessary collection supplies will be 
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provided by the central laboratory and will be appropriately assembled for the specific 
evaluations required at each visit. 
All patients with laboratory tests containing clinically significant abnormal values are to be 
followed regularly until the values return to normal ranges; until a valid reason, other than 
investigational product related AE, is identified; or until further follow-up is deemed medically 
unnecessary.   
Laboratory samples will be stored for a maximum of up to 1 year after the end of the study 
(depending on stability) in the event that retesting is required, and destroyed after 1 year if not 
analyzed. 
The list of laboratory analytes to be tested is shown in Table 11. 
Table 11: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen, creatinine, direct bilirubin, 
total bilirubin, aspartate aminotransferase [AST, SGOT], 
alanine aminotransferase [ALT, SGPT], ALP, GGT, 
electrolytes [calcium, chloride, potassium, sodium], 
glucose, total protein, and blood lipids (total cholesterol, 
LDL, HDL and VLDL fractions and TG), magnesium, 
phosphorus, bicarbonate, unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free fatty acids 
Hematology 
Hemoglobin, hematocrit, white blood count with 
differential, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, platelets, red blood cell count 
(including MCV, MCH, MCHC) 
Coagulation 
PT, PTT, INR 
Urinalysis 
pH, specific gravity, total protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, albumin, 
creatine, leucocytes, nitrates, albumin/creatine ratio (if 
positive), dipstick 
Biomarkers of Hepatic Fibrosis and/or 
Inflammation  
IL-6, hs-CRP, TNF-α, IgM, IgA, IgG, CK-18-M30, and 
others as determined during course of study. 
Noninvasive measurements of liver fibrosis, liver 
stiffness and cirrhosis 
HA, P3NP, and TIMP-1 
Genetics 
DNA including single-nucleotide polymorphisms that may 
be involved in PBC; RNA 
Other 
OCA (parent and conjugates [glyco and tauro], 
OCA-glucuronide) and C4 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; C4 = 7α-hydroxy-4-cholesten-3-one; 
CK-18-M30 = cytokeratin-18 neoepitope M30; CP = Child-Pugh; ECG = electrocardiogram; ELF = enhanced liver fibrosis;  
FGF-19 = fibroblast growth factor-19; GGT = gamma-glutamyl transferase; HA = hyaluronic acid; HDL = high density lipoprotein;  
hs-CRP = high-sensitivity C-reactive protein; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M;  
IL-6 = Interleukin 6; INR = international normalized ratio; LGL = low-density lipoprotein; MCH = mean corpuscular hemoglobin;  
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; OCA = obeticholic acid;  
PBC = primary biliary cirrhosis; P3NP = procollagen 3 N-terminal peptide; PT = Prothrombin time; PTT = partial thromboplastin time; 
SGOT = Serum glutamic oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; TG = triglyceride;  
TIMP-1 = tissue inhibitor of metalloproteinase 1; TNF-α = tumor necrosis factor-α, VLDL = very-low density lipoprotein 
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Urine based β-hCG pregnancy tests will be performed in female patients of childbearing 
potential per protocol specified visits (see Table 1).  If a urine pregnancy test is positive, a serum 
pregnancy test must be performed to confirm the result.  If positive, the Sponsor must be notified 
and the patient will be followed as outlined in Section 13.1.10 until pregnancy outcome.  
International normalized ratio (INR) will be calculated based on prothrombin time value by the 
central laboratory.  MELD scores will be calculated based on creatinine, bilirubin, Na, and INR 
values, with modification by United Network for Organ Sharing.  Total OCA will be calculated 
based on OCA, tauro-OCA, glyco-OCA, and OCA glucuronide concentrations.  Laboratory 
analyte results may be used to calculate various cardiovascular risk and fibrosis measurement 
scores. 
13.2.6. 
Patient-Reported Outcomes and Healthcare Resource Use 
Data will be collected to determine the effects of OCA on health-related quality of life.  
Healthcare resource use as well as a general health status assessment (for the purposes of 
generating health utilities) will be used to support subsequent cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Assessments of patient-reported 
outcomes will take place during the visits indicated in Table 1.   
The following patient-reported outcomes will be used to evaluate the effects of OCA compared 
to placebo on improvements in health-related quality of life: 
 PBC-40:  The PBC-40 is a validated disease-specific 40-question quality of life 
questionnaire, which consists of 6 domains:  General Symptoms, Itch, Fatigue, 
Cognitive Function, Social, and Emotional (Jacoby 2005). 
 EQ-5D-5L:  The EQ-5D-5L consists of 2 sections – the descriptive system and the 
visual analogue scales (VASs).  The descriptive system is organized into 
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  Each dimension has 5 levels:  no problems, slight problems, 
moderate problems, severe problems, and extreme problems.  The VAS records the 
patient’s self-rated health on a 20-cm vertical, line with endpoints labelled “the best 
health you can imagine” and “the worst health you can imagine” (Herdman 2011, 
Oemar 2013). 
 Pruritus VAS:  A Visual Analogue Scale (VAS) will also be used to assess pruritus in 
individual patients. 
 Chronic Liver Disease Questionnaire (CLDQ):  The CLDQ is a disease-specific 
health related quality of life questionnaire for patients with chronic liver disease.  The 
questionnaire includes 29 items in the following domains: fatigue, activity, emotional 
function, abdominal symptoms, systemic symptoms, and worry).  Each question is 
answered on a scale from 1 (always) to 7 (never) with a higher score corresponding to 
a better quality of life.  The CLDQ produces a summary score and domain scores that 
correlate with the severity of liver disease (Younossi 1999). 
Patients will be asked to complete the questionnaires and initial and date each document.  The 
questionnaires should be filed in the patient’s study records.  These may require transcription to 
the eCRF by study site staff. 
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Healthcare resource use will be collected from eCRFs including number, reason for and duration 
of hospitalizations and emergency room visits, number of outpatient physician visits (patient 
reported), and use of concomitant medications.  The purpose is to evaluate the effects of OCA 
compared to placebo on patient-reported outcomes and healthcare resource. 
14. 
EFFICACY ASSESSMENTS 
14.1.1. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is calculated and reported within the EDC system 
based on data entered into the eCRF adding the scores from the 5 factors outlined in Table 12 
and can range from 5-15.  A total score of 5-6 is considered Grade A (mild, well-compensated 
disease); 7-9 is Grade B (moderate, significant functional compromise); and 10 and above is 
Grade C (severe, decompensated disease).  Calculation of the CP Score includes investigator 
assessments of ascites and hepatic encephalopathy, which may be assessed during the adverse 
event review at the scheduled visits, as well as total bilirubin, serum albumin, and prothrombin 
time, which will populate from the central laboratory.  Investigators will be responsible for 
determining the appropriate dosing regimen based on the CP score (Table 1 and Table 12).  Any 
change in CP Score will necessitate re-evaluation of the dosing regimen. 
Table 12: 
Child-Pugh Scoring System 
Factor 
Units 
Points 
1 
2 
3 
Serum bilirubin 
μmol/L 
<35 
35-50 
>50 
mg/dL 
<2.0 
2.0-3.0 
>3.0 
Serum albumin 
g/L 
>35 
28-35 
<28 
g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
Seconds prolonged 
0-3 
4-6 
>6 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites 
 
None 
Mild 
Moderate-
Severe 
Hepatic encephalopathya 
 
No 
Grade 1 or 2 
Grade 3 or 4 
a Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
 Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves 
 Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
 Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
 Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity  
 (Pugh 1973, Lucey 1997) 
14.1.2. 
Model of End Stage Liver Disease Score 
The MELD scoring system is used to assess the severity of chronic liver disease.  The MELD 
score is useful in assessing patients with significant decompensation and the MELD score is now 
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used by the United Network for Organ Sharing in the US and Eurotransplants to manage the 
organ allocation for liver transplantation.  The threshold for placement on an organ 
transplantation queue varies between regions across the globe but a score of 15 results in a place 
on the transplant waiting list in the US.   
An increasing MELD score is associated with increased severity of hepatic dysfunction and 
increased 3-month mortality risk.  The MELD score is derived from the patient’s serum total 
bilirubin, serum creatinine, and INR, as appropriate, to predict survival and is calculated 
according to the following formula: 
MELD = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] 
+ 6.43 
MELD score will be calculated and reported in whole numbers according to the frequency listed 
in Table 1. 
14.1.3. 
Changes in Liver Biochemistry and Hepatobiliary Damage 
ALP, ALT, AST, GGT, total and direct bilirubin, INR, creatinine, albumin, platelets will be 
measured according to the frequency listed in Table 1. 
14.2. 
Additional Assessments 
14.2.1. 
Markers of Inflammation, Apoptosis and Necrosis 
Blood samples for analytes including hs-CRP, IgM, TNF-α, and cytokeratin-18 neoepitope M30.  
Assessments will be performed according to the schedules presented Table 1. 
14.2.2. 
Noninvasive Measurements of Liver Stiffness and Fibrosis 
The ELF test assesses: HA, P3NP, and TIMP-1.  Samples will be assessed in patients according 
to the schedules presented in Table 1. 
The Fibroscan® TE device (Echosens, Paris, France) will be used at all study sites that have the 
equipment to collect hepatic stiffness measurements.  These study sites must have the staff 
trained in the use and data interpretation of the device.  This is a validated and non-invasive 
technique used to assess hepatic fibrosis which will be conducted according to according to the 
schedule presented in Table 1.   
14.2.3. 
Markers of FXR activation 
Blood samples will be collected in all patients to measure C4, FGF-19, and bile acids.  The 
results of these analyses will be used to assess the PK/PD response of OCA.  Blood samples will 
be assessed in patients according to the schedule presented in see Table 1.   
14.2.4. 
Potential Clinical Outcome Events 
Potential clinical outcome events will be evaluated by an Adjudication Committee (described in 
Section 15.8) to confirm if they meet the criteria to be considered Clinical Outcome Events.  
Given that the Potential Clinical Outcome Events could also meet the criteria of a SUSAR, 
which would necessitate unblinding for expedited reporting, the Sponsor will not expeditiously 
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report suspected Potential Clinical Outcome events in order to retain the study blind and preserve 
the integrity of the clinical outcomes endpoint.  These events will be selected as a “potential 
study event” on the Adverse Event eCRF and will be submitted for adjudication to the 
Adjudication Committee as described in Section 15.8  
15. 
STATISTICAL METHODS AND ANALYSES 
Individual subject data obtained from electronic case report forms (eCRFs), central laboratories, 
external sources, and any derived data will be presented in data listings by subject.  All data 
listings that contain an evaluation date will contain a relative study day.  Pre-treatment and on 
treatment study days are numbered relative to the day of the first dose of investigational product 
which is designated as Day 1.   
All output will be incorporated into Microsoft Word rich text format (.rtf) files, sorted and 
labeled according to the ICH recommendations, and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, Baseline, efficacy, and safety 
parameters.   
For categorical variables, summary tabulations of the number and percentage of subjects within 
each category (with a category for missing data) of the parameter will be presented.  Percentage 
calculations will be based on non-missing data, unless otherwise specified.  Percentages are 
rounded to 1 decimal place, unless otherwise specified.   
For continuous variables, the number of subjects, mean, standard deviation (SD), standard error 
of the mean (SEM), median, minimum, and maximum values will be presented.  The precision of 
summary statistics, unless otherwise, specified will be as follows:  mean and median to 1 more 
decimal place than the raw data, and SD and SEM to 2 decimal places more than the raw data.  
In general, the decimal places should not exceed 3 decimal places unless appropriate.  
Confidence intervals (CIs) will be provided and will be rounded to 1 decimal place, unless 
otherwise specified. 
Time-to-event data will be summarized using Kaplan-Meier (KM) methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of 
censored observations. 
There will be no formal hypothesis testing in this study.  However, summary statistics for each 
treatment group will be presented, as well as 95% CIs for the difference between the treatment 
groups. 
15.1. 
Analysis Populations 
The following patient populations will be evaluated and used for presentation and analysis of the 
data: 
 The Intent-to-Treat (ITT) Population will include all randomized patients who receive 
any amount of investigational product (OCA or placebo). The ITT Population will be the 
primary population used for summarizing efficacy assessments.  
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 The Safety Population will include all patients who received at least one dose of 
investigational product (placebo or OCA). The Safety Population will be the primary 
population used for safety analyses.  
 The PK population will include all patients receiving OCA who have adequate 
concentration-time profiles to characterize OCA and its conjugates and must not have any 
major protocol deviations that potentially affect exposure levels. 
15.2. 
Determination of Sample Size 
To reasonably characterize the PK of OCA in patients with hepatic impairment, a simulation-
based approach estimated a requirement of approximately 20 patients per OCA treatment group 
assuming a 15% discontinuation rate.  Ten patients on placebo will be included as a comparator.  
The assessment was based on 80% powering for the 90% confidence interval of the geometric 
mean ratio of Total OCA (sum of OCA, glyco OCA, and tauro OCA). 
15.3. 
Pharmacokinetic Analyses 
The PK Population will be used for analysis of PK parameters, which include plasma OCA 
(parent) and its conjugates (glyco-OCA and tauro-OCA), total OCA, OCA glucuronide, and 
potentially other conjugates or metabolites not yet identified. 
PK analysis will based on the PK population.  Values will be calculated using non-
compartmental methods.  The values will be summarized by active treatment group using 
descriptive statistics. 
15.4. 
Safety Analyses 
Safety analyses will be conducted using the Safety population.  Safety data, including AEs, 
vitals, ECG, and clinical laboratory results will be summarized by treatment group using the 
Safety Population. 
The incidence of TEAEs and SAEs will be tabulated by system organ class and preferred term 
for each treatment group, and similarly by severity and relationship to treatment.   
Laboratory parameters, physical examinations including vital signs, and ECGs will be 
summarized by treatment group using descriptive statistics at Baseline and at each scheduled 
post-Baseline visit.  The absolute change from baseline will also be summarized. 
CP scores will be summarized by treatment group at Baseline and at each post-Baseline visit. 
No inferential comparison of safety endpoints will be performed.  All safety comparisons will be 
descriptive. 
15.4.1. 
Adverse Events 
AEs will be coded using MedDRA.  Summary tables of TEAEs will be provided.   
Each AE summary will be displayed by treatment group.  Summaries that are displayed by SOC 
and PT will be ordered by descending order of incidence of system organ class and preferred 
term within each system organ class.  Summaries of the following types will be presented: 
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 Overall summary of TEAEs 
 Subject incidence of TEAEs and the total number of entries by MedDRA SOC and 
PT.  This summary will be repeated for all subgroups 
 Subject incidence of TEAEs by MedDRA SOC, PT, and highest severity.  At each 
level of subject summarization, a subject is classified according to the highest 
severity if the subject reported 1 or more events.  AEs with missing severity will be 
considered severe for this summary. 
 Subject incidence of TEAEs by MedDRA SOC, PT, and closest relationship to 
investigational product (Related/Not Related).  Related AEs are those with 
relationships reported as “Definite,” “Probable,” or “Possible,” and unrelated AEs are 
those with relationships reported as “Unlikely” or “Not Related.”  At each level of 
subject summarization, a subject is classified according to the closest relationship if 
the subject reported 1 or more events.  AEs with a missing relationship will be 
considered related for this summary. 
 Subject incidence of serious TEAEs and the total number of entries by MedDRA 
SOC and PT. 
 Subject incidence of TEAEs leading to investigational product withdrawal or study 
discontinuation by MedDRA SOC and PT.  This is a subset of the AEs where Action 
Taken with Study Treatment is checked as “Drug Withdrawn” or where “Subject 
Discontinued from Study” is checked. 
The following listings will be presented by treatment group and subject: 
 All adverse events. 
 Serious adverse events (This is a subset of the AEs where serious is marked as 
“Yes”). 
 Severe adverse events (This is a subset of AEs where severity is marked as “Severe”). 
 Related adverse events (This is a subset of the AEs where relationship marked as 
“Definite,” “Probable,” or “Possible”). 
 Adverse events leading to Study Drug Withdrawal or Study Discontinuation (This is a 
subset of the AEs where Action Taken with Study Treatment is checked as “Drug 
Withdrawn” or where “Subject Discontinued from Study” is checked). 
 Adverse events leading to death (This is a subset of the AEs where the corresponding 
AE number is specified on the Death eCRF). 
15.4.2. 
Clinical Laboratory Evaluations 
Laboratory parameters will be summarized in standard international (SI) system of units by 
treatment group using descriptive statistics at Baseline and at each on-study evaluation.  Re-test 
or unscheduled results will not be summarized but will be included in the data listings.  The 
change from Baseline will also be summarized.  Baseline is defined as the mean of all available 
evaluations prior to treatment.   
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In addition, shift tables (ie, low-normal-high at Baseline versus low-normal-high at post Baseline 
visit in a 3-by-3 contingency table) from Baseline to worst value, last value, and at each 
scheduled post-Baseline visit will be provided for hematology and serum chemistry by treatment 
group to assess changes in laboratory values from Baseline to each on-study evaluation.   
Vital Signs 
The results and change from Baseline to each on-study evaluation visit will be summarized by 
treatment group for weight, oral temperature, sitting heart rate, respiratory rate and sitting blood 
pressure. 
Electrocardiograms 
Electrocardiogram (ECG) results will be summarized at each on-study visit descriptively, 
including the number and percentage of subjects with normal, abnormal not clinically significant, 
and abnormal clinically significant results at Baseline and each on-study evaluation. 
15.4.3. 
Adverse Events of Special Interest 
Pruritus: Treatment-emergent pruritus, defined as any preferred term including “Prur,” will be 
summarized separately by the MedDRA SOC, treatment group, and PT as a subset of all TEAEs.  
This summary will be repeated for subjects with “new or worsened” pruritus events, as defined 
as follows: 
 Mild, moderate, or severe treatment-emergent pruritus events in subjects with no 
pruritus at Baseline, or 
 Worsening of the severity of the Baseline condition in subjects with pruritus at 
Baseline. 
Baseline pruritus is defined as the investigator’s rating of severity as collected on the PBC 
Disease History eCRF.  Subjects whose Baseline severity is severe will be counted as worsening 
if an AE of pruritus with severe is recorded. 
An analysis of treatment-emergent pruritus event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  Each individual patient year on study will be derived as the last 
known date during the study minus the first dose date plus 1 divided by 365.25 days/year.   
In order to explore the relationship between pruritus and the investigational product, the 
following time-to-event analyses will be performed: 
 Time to first onset of treatment-emergent pruritus  
 The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 
 Subjects who never reported an AE of pruritus will be censored at the date of last 
contact. 
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 Time to onset of the first moderate or severe treatment-emergent pruritus 
 The time to the start of the first moderate or severe pruritus will be calculated by 
date of onset of the first moderate or severe pruritus – date of first dose of 
investigational product +1. 
 Subjects who never reported a moderate or severe AE of pruritus will be censored 
at the date of completion or discontinuation. 
 Time to onset of the first severe treatment-emergent pruritus 
 The time to the start of the first severe pruritus will be calculated by date of onset 
of the first severe pruritus – date of first dose of investigational product +1. 
 Subjects who never reported a severe AE of pruritus will be censored at the date 
of completion or discontinuation. 
The analysis of time to first onset of treatment-emergent pruritus AE, time to onset of the first 
moderate or severe treatment-emergent pruritus and onset of the first severe treatment-emergent 
pruritus will include the number of subjects with pruritus (first onset, first moderate or severe, 
first severe), the number of subjects without pruritus (censored), and the minimum and 
maximum times in days.  KM estimates will be calculated by treatment group.  The quartiles, 
including the median time-to-event and their respective 2-sided 95% CIs, will be presented.  KM 
estimates will be plotted as a “survival curve” for each treatment group. 
Fatigue: Treatment-emergent fatigue is defined as any preferred term which includes “Fatigue.”  
New or worsened treatment-emergent fatigue is defined as follows: 
 Any mild, moderate, or severe treatment-emergent fatigue events in subjects with no 
fatigue at Baseline, or 
 Worsening of the severity of the Baseline condition in subjects with fatigue at 
Baseline. 
Baseline fatigue is defined as the Investigator’s rating of severity as collected on the PBC 
Disease History eCRF.  Subjects whose Baseline severity is severe will be counted as worsening 
if an AE of fatigue with severe is recorded. 
An analysis of treatment-emergent fatigue event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  Each individual patient year on study will be derived as the last 
known date during the study minus the first dose date plus 1 divided by 365.25 days/year.   
In order to explore the relationship between fatigue and the investigational product, the following 
time-to-event analyses will be performed: 
 Time to first onset of treatment-emergent fatigue  
 The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 
 Subjects who never reported an AE of fatigue will be censored at the date of last 
contact. 
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 Time to onset of the first moderate or severe treatment-emergent fatigue 
 The time to the start of the first moderate or severe fatigue will be calculated by 
date of onset of the first moderate or severe fatigue – date of first dose of 
investigational product +1. 
 Subjects who never reported a moderate or severe AE of fatigue will be censored 
at the date of last contact. 
 Time to onset of the first severe treatment-emergent fatigue 
 The time to the start of the first severe fatigue will be calculated by date of onset 
of the first severe fatigue – date of first dose of investigational product +1. 
 Subjects who never reported a severe AE of fatigue will be censored at the data of 
last contact. 
The analysis of time to first onset of treatment-emergent fatigue AE, time to onset of the first 
moderate or severe treatment-emergent fatigue and onset of the first severe treatment-emergent 
fatigue will include the number of subjects with pruritus (first onset, first moderate or severe, 
first severe), the number of subjects without fatigue (censored), and the minimum and maximum 
times in days.  KM estimates will be calculated by treatment group.  The quartiles, including the 
median time-to-event and their respective 2-sided 95% CIs, will be presented.  KM estimates 
will be plotted as a “survival curve” for each treatment group. 
15.5. 
Efficacy Analyses 
This study does not plan to test a formal hypothesis for any efficacy endpoint.   
The endpoints of efficacy assessments are change in bilirubin, INR, creatinine, albumin, 
platelets, ALT, AST, and GGT from baseline to Week 48 (end of the study), change from 
baseline to Week 48 in CP score and components of the CP score, and change from baseline to 
Week 48 in MELD and components of the MELD score.  Analyses of change from Baseline to 
Week 48 (end of study) will be modelled between treatment groups using ANCOVA model with 
change from Baseline as the dependent variable, treatment group and randomization stratification 
factor as fixed effects and the baseline value as a covariate.  The same analysis will be carried 
out using percentage change from Baseline as the dependent variable. 
Analyses of change from Baseline to Week 48 (end of study) will be modelled between 
treatment groups using ANCOVA model with change from Baseline as the dependent variable, 
treatment group and randomization stratification factor as fixed effects and the baseline value as 
a covariate.  The same analysis will be carried out using percentage change from Baseline as the 
dependent variable. 
Summary statistics of the laboratory values will be provided by treatment group.  The results, 
change from Baseline, and percentage change from Baseline values, as well as estimates of least-
square (LS) means, standard errors (StdErr), and 95% CIs, will be presented by treatment group.  
Estimates of the mean difference between treatment groups, the StdErr of the difference, and 
95% CI of the difference will also be presented.  No formal hypothesis testing will be performed. 
Risk Scores: Changes from baseline in the MELD score and in CP score will be summarized and 
analyzed using the Wilcoxon Rank Sum Test.  The median differences and 95% CI of the 
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median differences between treatment groups will be constructed using Hodges-Lehmann 
estimate.  If the median differences between treatments are not symmetrical around the median, 
the Sign Test may be used. 
Shifts in MELD scores from Baseline will be reported by visit using the following categories:  
<10, 10 to <12, 12 to <13, 13 to <14, 14 to <15, and ≥15.   
Child-Pugh class will be presented in shift tables showing the shift from baseline to each 
scheduled post-baseline visit by the count and percentage of subjects within each shift 
classification. 
Individual factors will be presented in a listing. 
15.6. 
Additional Efficacy Analyses 
Analyses of changes in liver stiffness and ELF, cytokeratin-and TIMP-1, and markers of 
inflammation will be summarized and analyzed using the same methodology specified for the 
key secondary analyses of change in bilirubin. 
The following clinical outcomes will be captured in the study: 
 All-cause mortality 
 Liver related death 
 Liver transplant 
 Variceal bleed 
 Hepatic encephalopathy 
 Bacterial peritonitis 
 Ascites 
 Hepatocellular carcinoma 
The incidence and time to first occurrence of any of the above listed clinical outcomes will be 
summarized by treatment group using the log rank test stratified by the randomization 
stratification factor.  Kaplan-Meier (KM) estimates of the distribution of the time-to-event will 
be tabulated and graphed by treatment group.  The tabulation will include the KM estimate of the 
medians and corresponding 95% CIs, if the medians can be estimated.  The number and percent 
of subjects censored and with events will be presented.  The hazard ratio and 95% CI will be 
estimated based on a Cox regression model stratified by randomization strata.  
In addition, the time to each of the above outcomes will be summarized by treatment group using 
the same methods as defined above. 
15.7. 
Handling of Missing Data 
Missing data will be assumed to be missing at random.  No data will be imputed. 
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15.8. 
Data Monitoring Committee 
An independent DMC that includes hepatologists, pharmaceutical physicians, 
epidemiology/cardiology expert(s), and statistician(s) not involved in the study as Investigators, 
adjudication committee members, or consultants.  The DMC will have oversight over the study 
conduct as defined by the DMC charter.  All members will have considerable experience with 
clinical study conduct and DMCs.  Any candidate found to have a conflict of interest or whose 
name is listed on the Food and Drug Administration (FDA) debarment list will not be offered 
membership.  Conflicts of interest will be assessed regularly, and if members are found to have a 
new conflict of interest they will be replaced. 
The DMC will meet approximately quarterly at scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review safety and efficacy data in order to ensure the safe and 
proper treatment of patients.  Based on review of these data, the DMC will advise the Sponsor on 
the validity and scientific merit of continuing the study. 
Written minutes of both the open and closed DMC sessions will be prepared.  The closed 
minutes will be made available to the appointed Sponsor representatives only after the database 
is locked.  
Data listings provided to the DMC do not contain individual patient treatment information; 
however, the DMC will have access to the database and may unblind individual patient data as 
appropriate.  Summary tables reviewed by the DMC during closed sessions will include an 
overall column containing information regarding all patients and separate treatment columns 
with ‘dummy’ labels, ie, the actual treatment groups are used, but are not identified.  Data 
reviewed during the meetings will include, at a minimum, disposition, demographics, exposure, 
clinical laboratory results, MedDRA-coded AEs, and AEs leading to early withdrawal of 
investigational product.  At each meeting, detailed narratives of interval SAEs (including events 
resulting in death) are reviewed by the DMC in addition to a cumulative list of all SAEs. 
The DMC may agree to adjust meeting frequency based upon actual and projected safety and 
efficacy data availability.  Adjustments to or stopping of the protocol defined doses may be 
considered based on DMC evaluation of OCA safety and tolerability. 
All Investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DMC relating to patient safety, which alter the 
conduct of this study.  The Investigators will inform the patients of such actions and the protocol, 
PIS, and ICF will be revised, as appropriate. 
15.9. 
Adjudication Committees 
All suspected liver-related clinical outcomes, major adverse cardiovascular events 
(MACE)/expanded MACE, and drug-related hepatic injury events that occur after administration 
of the first dose of investigational product will be reviewed by the following blinded adjudication 
committees, depending on event type, before inclusion in any analysis.  The 3 committees and 
event types they are responsible for adjudicating are as follows: 
 Cardiovascular Adjudication Committee (CAC):  Adjudicates all suspected MACE, 
including all deaths 
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 Hepatic Outcomes Committee:  Adjudicates all deaths and suspected liver-related 
outcomes 
 Hepatic Safety Committee:  Adjudicates all suspected drug-related hepatic injury 
events 
Each adjudication committee will have a charter that documents the reporting of events by the 
study site, definition of the suspected events to be adjudicated, supply of source documentation 
to the committee, entire data flow and process from committee membership, review of the events 
by the committee, reporting of the final assessment, and the working procedures of the 
committee.   
The adjudication committee members will include experts with relevant adjudication experience; 
they will not be involved in the study as Investigators, DMC members, or consultants.  Any 
candidate found to have a conflict or whose name is listed on the FDA debarment list is not 
offered membership.  Conflicts of interest are assessed regularly, and if members are found to 
have a new conflict of interest they will be replaced. 
The adjudication of suspected events will be based on available source documentation, including 
but not limited to individual clinical study data, hospital records, histology, discharge summaries, 
and/or death certificates.  The adjudication committees will not receive any individual patient 
treatment or site-specific information.  The assessment of events will be conducted in 
compliance with study-specific procedures, manuals, GCP, and all other applicable regulatory 
requirements, including the archiving of essential documents. 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
Study records at each site will be monitored at regular intervals by a representative of the 
Sponsor, the CRA.  The role of the CRA is to aid the Investigator in the maintenance and 
documentation of complete, accurate, legible, well organized and easily retrievable data.  In 
addition, the CRA will ensure the Investigator's understanding of all applicable regulations 
concerning the clinical evaluation of the investigational product and will ensure an understanding 
of the protocol, reporting responsibilities and the validity of the data.  This will include ensuring 
that full and appropriate essential documentation is available. 
In order to perform this role, the CRA must perform source data verification and as such must be 
given access to the patient’s primary source documentation (eg, paper or electronic medical 
records such as consent to participate in the study, visit dates, screening and randomization 
numbers, demographic information, medical history, disease history, physical examination, vital 
signs, laboratory assessments [copy of laboratory reports], AEs, concomitant medications, dates 
of dispensing investigational product, ECGs, etc) that support data entries in the eCRF.  The 
eCRF must be completed promptly after each visit to allow the progress and results of the study 
to be closely followed by the Medical Monitor. 
The Investigator may exercise judgment in allowing the CRA access to particular sections of the 
patient's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
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16.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IEC/IRB and/or 
regulatory agencies to conduct one or more site audits during or after the study and agrees to 
allow access to all study related documentation and information and be available for discussion 
about the study.   
17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the eCRF or ultimately 
transferred into the database to ensure accuracy and completeness.   
Training sessions, regular monitoring of the study at the study site by the Sponsor or designated 
personnel (eg, CRA), instruction manuals, data verification, cross checking and data audits will 
be performed to ensure quality of all study data.  Investigators’ meetings and/or onsite study 
initiations will be performed to prepare Investigators and other study site personnel for 
appropriate collection of study data. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit.  Please see Section 16.2 for more details regarding the audit 
process. 
18. 
ETHICS 
18.1. 
Ethics Review 
The final study protocol, including the final version of the PIS-IC and/or other patient 
information, must be approved or given a favorable opinion in writing by an IRB/IEC as 
appropriate.  The Investigator must submit written IRB/IEC approval to Intercept before he or 
she can enroll any patient into the study.  The Investigator is responsible for providing the IB and 
any other available safety information and information about payments and compensation 
available to study patients to the IRB/IEC for review. 
The Investigator is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements.  A favorable opinion on amendments will be obtained prior 
to implementation, unless the amendment is necessary to reduce immediate risk to study 
participants.  In addition, the IRB/IEC must approve all advertising used to recruit patients for 
the study.  The protocol must be reapproved by the IRB/ IEC upon receipt of amendments and 
annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product, 
according to local regulations and guidelines.  The Sponsor will provide this information to the 
Investigator. 
Progress reports and notifications of SARs will be provided to the IRB/IEC according to local 
regulations and guidelines.  Investigators or the Sponsor or its designee will provide reports to 
the IRB/IEC as requested, as a minimum annually, and after the study is complete. 
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18.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the Sponsor’s policies. 
18.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the patient is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Patients 
must also be notified that they are free to discontinue from the study at any time.  The patient 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The patient’s signed and dated consent form must be obtained before conducting any study 
procedures. 
18.4. 
Patient Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the patient will be 
regarded as confidential and confidentiality of all patients will be maintained.  Monitors (eg, 
CRA, Medical Monitor), auditors and inspectors will require access to a patient’s medical notes 
for the purpose of source document verification but the patient’s confidentiality will be 
maintained at all times.  An agreement for disclosure of any such information will be obtained in 
writing and is included in the statement of informed consent.  The study data shall not be 
disclosed to a third party (with the exception of auditors and/or regulatory authorities) without 
the written consent of the Sponsor.  All data shall be secured against unauthorized access. 
The Investigator will maintain a list of patient’s names and identifying information (eg, patient’s 
hospital number, unique patient number).  This list will not be collected by the Sponsor. 
The PIS will explain that study data will be stored in a computer database, maintaining 
confidentiality in accordance with national data protection legislation.  All data computer 
processed by the Sponsor or designee will be identified by unique patient number/randomization 
code/site number, only.   
When personal data on patients are stored or processed by computer, the data must be protected 
to prevent disclosure to unauthorized third parties.  The pertinent sections of the data protection 
laws in the country in which the protocol is being conducted will be complied with in full. 
The PIS-IC will explain that, for data verification purposes, authorized representatives of the 
Sponsor, regulatory authorities, or IEC/IRBs may require direct access to parts of the hospital or 
study site records relevant to the study, including patient’s medical history. 
19. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the patients for the duration of the study.  If the Investigator 
is not present in the study site during the assessment, he or she will leave instructions for the 
study site staff and a telephone number where he or she can be reached. 
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Named physician(s) will be responsible for the medical follow-up of patients, as applicable. 
19.1. 
Adverse Event Reporting 
The Investigator is responsible for recording AEs reported by the patient or discovered by any 
other means during the study.  In agreeing to the provisions of this protocol, the Investigator 
accepts all legal responsibilities for immediate reporting of SAEs to the Sponsor. 
19.2. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any significant way without 
proper notification to the Sponsor (or designee).  Only the Sponsor may amend the protocol.  
Any change in study conduct considered necessary by the Investigator will be made only after 
consultation with the Sponsor, who will then issue a formal protocol amendment to implement 
the change and obtain regulatory approval.  The only exception is when the Investigator 
considers a patient’s safety to be compromised if immediate action is not taken. 
19.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
 Approved PIS-IC (all versions) 
 IRB/IEC approvals (of protocol/amendments, patient questionnaires, etc)  
 Form FDA 1572  
 Current medical license of Investigators 
 Curriculum vitae of Investigators 
 Laboratory certification and reference ranges 
 Financial disclosure forms 
19.4. 
Ethics Review (IRB/IEC) 
Please see Section 18.1 for the Investigator’s responsibilities regarding ethics review. 
19.5. 
Archiving and Record Retention 
The Investigator should retain all correspondence relating to this study in the Investigator Site 
File (ISF).  Any study documents stored elsewhere should have their location referenced in the 
ISF. 
All documents relating to the study including the ISF itself, source documents and patient 
medical files (retained per country specific regulations), completed study patient log and 
confidential patient identification list will be retained by the Investigator until at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the Sponsor.  In the event that storage of records 
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becomes a problem at any time during this period, the Sponsor should be consulted for 
assistance.  At the end of the minimum period, the Investigator should obtain written 
authorization from the Sponsor before the destruction of any records.  The Investigator will 
notify the Sponsor if ownership of documents or responsibility for the study site is transferred.  
The Sponsor will inform Investigators should it become aware of any changes in storage 
requirements. 
20. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it Sponsors consistent 
with the Declaration of Helsinki.  Consistent with the recommendations of the editors of several 
leading medical journals, the International Committee of Medical Journal Editors (ICMJE), 
authorship of publications resulting from Intercept sponsored studies should fairly recognize the 
activities of those that have made a significant contribution to the study (http://www.icmje.org).  
Thus, it is anticipated that authorship will reflect the contribution made by the Sponsor 
personnel, the Investigators and others involved, such as statisticians.   
In recent years, issues about conflicts of interest and accuracy of the study data have been raised 
in the medical press.  Accordingly, the Sponsor has developed publication guidelines for clinical 
studies that are appropriate for this study.  Key issues include the following: 
 Clinical Trial Registries (eg, www.clinicaltrials.gov, www.clinicaltrialsregister.eu):  
A description of the study and relevant design elements (eg, basic design, objectives 
and endpoints, sample size, study population, and key inclusion/exclusion criteria) 
and results will be published online in a manner consistent with applicable regulatory 
guidelines. 
 Overview:  Investigators, reviewers and editors will have the right to audit the data to 
verify its accuracy. 
 Responsibility:  Each Investigator is responsible for the accuracy and completeness of 
all data from her/his site.  The Sponsor (or its representatives) is responsible for the 
accuracy of the data entered into the study databases and the analyses conducted. 
 Data Management:  The Sponsor will establish data management and SAP.  The 
Investigators will have the opportunity to provide input into the plans.  The 
Investigators will have the right to review the audit reports and data resolution 
decisions prior to the establishment of a clean file.  The Investigators will have the 
right to appoint appropriately qualified auditors, with GCP experience, to audit the 
Sponsor’s data prior to the establishment of a clean file.  The Investigators must 
provide adequate notice (at least 2 months) to the Sponsor of their intention to audit a 
study.  The audit should be conducted in a timely manner to allow the resolution of 
discrepancies before a clean file is established.  The Investigators will bear all the 
costs for the conduct of audits that they initiate, except those related to the resolution 
of data queries which the Sponsor will bear.  Such audits must be conducted in such a 
manner as to minimize the time to create the clean file. 
 Authorship:  Intercept, in collaboration with the Investigators, will establish the 
appropriate authorship and responsibility for drafting study documents in accordance 
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with the principles of the ICMJE.  All manuscripts will be reviewed and agreed upon 
before submission for publication by all authors.   
 Single Center Publication and Additional Publications:  This is a multicenter study 
and is designed to be published with complete data from all the study sites.  Single 
center publications are therefore not considered appropriate.  Any such publications 
should clearly state that the data are “extracted” from a multicenter study and that the 
study was not intended, or statistically powered, for data presentation by a single 
study site.   
 Intercept Review of External Manuscripts:  Consistent with this, Investigators must 
submit any drafts of any publications or presentations that may arise from this study 
to the Sponsor for review and approval and to ensure consistency with the policy in 
this protocol at least 30 days prior to submission for publication or presentation.  The 
Sponsor will have the right to request appropriate modification to correct facts and to 
represent its, or the Publication Committee’s, opinion if these differ with the proposed 
publication.  
 Confidentiality:  Investigators will conduct all interactions with the company and 
with third parties consistent with the executed confidentiality agreements.  While 
publication, by intention, presents the critical scientific data in a public forum, some 
information (such as future plans, results of preclinical studies or chemical formulae) 
may still need to remain confidential. 
 Medical Journal Review:  Upon request, all pertinent study data and information will 
be made available as supplemental information for journal editors and reviewers to 
evaluate and audit, eg, protocol and amendments, data tabulations, etc.  Arrangements 
will be made to maintain the confidentiality of such supplemental information. 
Arrangements will also be made to maintain the confidentiality of the identity of 
journal reviewers.  Records will be maintained of which documents and datasets were 
reviewed. 
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21. 
LIST OF REFERENCES 
Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Digestive and Liver Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin ME, Gish RG, et al. Changing Nomenclature for PBC: From ‘Cirrhosis’ to 
‘Cholangitis’. Gastroenterology. 2015b;149(6):1627-9. 
Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: From 'cirrhosis' to 
'cholangitis'. Hepatology. 2015c;62(5):1620-2. 
Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of 
liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 
2012;56(1):198-208. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51:237-267. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-36. 
Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the PBC-40, a 
disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 
2005;54(11):1622-9. 
Kim WR, Lindor KD, Locke GR, et al. Epidemiology and natural history of primary biliary 
cirrhosis in a US community. Gastroenterol. 2000;119:1631-1636. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis: AASLD Practice 
Guidelines. Hepatology. 2009;50(1):291-308. 
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver 
transplant waiting list: a report of a national conference organized by the American Society of 
Transplant Physicians and the American Association for the Study of Liver Diseases. Liver 
Transpl Surg. 1997;3(6):628-37. 
Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis 
(syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol. 1978;379(2):103-
12. 
Oemar M, Janssen B. EQ-5D-5L User Guide: Basic Information on how to use the EQ-5D-5L 
instrument. 2013 October;Version 2.0:1-28. 
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding 
oesophageal varices. Br J Surg. 1973;60(8):646-9. 
Younossi ZM, Guyatt G, Kiwi M, et al. Development of a disease specific questionnaire to 
measure health related quality of life in patients with chronic disease. Gut. 1999;45:295-300. 
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APPENDIX A. LIST OF STUDY 747-401 OUTCOME EVENTS 
Some of the specified clinical endpoints will also by definition (see Section 13.1) qualify as 
Serious Adverse Events (SAEs).  The sponsor must be notified of any SAEs within 24 hours of 
the site becoming aware of the event (see Section 13.1.4).  The Sponsor is responsible for 
regulatory reporting of SAEs including expeditious reporting of SAEs that are considered related 
to the investigational product and considered Unexpected by regulatory standards as defined in 
the Investigational Brochure. 
The Sponsor may consider the following lists of events to be exempt from expeditious regulatory 
reporting but will continue to report them in a non-expeditious manner: 
Potential Clinical Outcome Events: 
Liver-related events resulting in death 
Hepatic failure leading to liver transplant 
Variceal bleed 
Hepatic encephalopathy 
Spontaneous bacterial peritonitis 
Ascites 
Hepatocellular carcinoma 
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1. 
TITLE PAGE 
 
 
Clinical Study Protocol 747-401 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Pharmacokinetics and Safety of Obeticholic Acid in Patients with Primary 
Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
 
 
Version 2: 22 May 2017 
 
EudraCT Number: 2017-001762-13 
 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
USA 
 
TEL:  
 
 
CONFIDENTIAL 
The information contained herein is the property of Intercept Pharmaceuticals, Inc. and may not 
be reproduced, published, or disclosed to others without written authorization of Intercept 
Pharmaceuticals, Inc. 
 
 
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INVESTIGATOR’S AGREEMENT 
 
I have received and read the current version of the Investigator’s Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-401.  Having fully considered all the information available, 
I agree that it is ethically justifiable to give OCA to selected patients according to this protocol. 
I understand that all information concerning OCA supplied to me by the Sponsor, Intercept 
Pharmaceuticals, Inc., and/or its agents in connection with this study and not previously 
published is confidential information.  This includes the IB, clinical study protocol, case report 
forms (CRF), and any other preclinical and clinical data provided by the Sponsor. 
I understand that no data are to be made public or published without prior knowledge and written 
approval by the Sponsor. 
By my signature below, I hereby attest that I have read, understood and agreed to abide by all the 
conditions, instructions and restrictions contained in Protocol 747-401 and in accordance with 
Good Clinical Practice (CPMP/ICH/135/95), the Declaration of Helsinki, and all regulatory 
requirements for protection of human patients in clinical studies and privacy requirements for the 
protection of individual and company data. 
I acknowledge that the Sponsor of the study has the right to discontinue the study at any time. 
 
 
 
 
 
 
Investigator’s Name (Printed) 
 
 
 
 
 
 
Investigator’s Signature 
 
Date 
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STUDY PERSONNEL CONTACT INFORMATION 
Medical Monitor  
Primary Contact: 
 MD 
Medical Director, Pharmacovigilance, 
Intercept Pharmaceuticals, Inc. (Intercept) 
Telephone: 
 
Email: 
 
SAE Fax: 
 
SAE Email: 
 
 
 
 
 
 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product: 
Obeticholic Acid 
Name of Active Ingredient: 
Obeticholic acid (OCA); 6α-ethyl-chenodeoxycholic acid; (6-ECDCA) 
Title of Study:  
A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating the Pharmacokinetics and Safety 
of Obeticholic Acid in Patients with Primary Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
Investigators and/or Study Center(s):  
The study is planned to have approximately 35 investigational sites, globally. 
Study Period:  Patients will receive double-blind treatment for at 
least 48 weeks.  Patients who have completed their 48-week 
double blind treatment period will continue double-blind 
treatment until all randomized patients have completed their 
participation in the 48-week treatment period and the database for 
that period is locked (approximately 3 years).  Patients will then 
be given the option to go on open-label treatment. 
Phase of Development:   
Phase 4 
 
Objectives:   
Primary Objective: 
 
To evaluate the pharmacokinetics (PK) of OCA and its conjugates, glyco-OCA and tauro-OCA, and 
metabolite OCA glucuronide compared with placebo 
 
To evaluate the safety and tolerability of OCA treatment compared with placebo 
Secondary Objectives:  
 
To evaluate the effect of OCA treatment compared to placebo on:  
 
The model of end stage liver disease (MELD) score and its components 
 
Child-Pugh (CP) score and its components 
 
Liver biochemistry including total and direct bilirubin, alkaline phosphatase (ALP), and 
aminotransferases (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma 
glutamyl transaminase [GGT]), international normalized ratio (INR), creatinine, albumin, platelets 
 
Biomarkers of bile acid synthesis and homeostasis including fibroblast growth factor 19 (FGF-19), 
7α-hydroxy-4-cholesten-3-one (C4), and plasma bile acids 
Additional Objectives: 
 
To evaluate the effect of OCA treatment compared to placebo on: 
 
Markers of inflammation 
 
Noninvasive markers of liver fibrosis (Enhanced Liver Fibrosis [ELF]™ score) 
  
Noninvasive measurement of liver stiffness (transient elastography [TE]) 
 
To assess the PK/Pharmacodynamic (PD) relationship of OCA with: 
 
PK parameters compared to PD Parameters and Safety and Tolerability assessments 
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 
To assess patient reported outcomes (Pruritus Visual Analogue Scale [VAS], PBC-40, EQ 5D-5L, Chronic 
Liver Disease Questionnaire [CLDQ]) 
 
To assess clinical events consistent with end-stage liver disease 
 
Death (all-cause) 
 
Liver transplant 
 
Model of end stage liver disease (MELD) score ≥15 (for patients with MELD ≤12 at baseline)  
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
variceal bleed, hepatic encephalopathy (as defined by a West Haven score of ≥2), spontaneous 
bacterial peritonitis 
 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
 
Hepatocellular carcinoma (HCC) 
Methodology:  This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the PK and 
safety of OCA treatment in patients with primary biliary cholangitis (PBC) and moderate to severe hepatic 
impairment defined as Child-Pugh B (CP-B) (moderate) and Child-Pugh C (CP-C) (severe) including a broad 
distribution of MELD scores (ranging from 6 to 24).  Approximately 50 patients (including at least 20% of 
patients with CP-C) will be enrolled in the study.  Patients will be screened ≥14 days but not more than 28 days 
prior to entering the study (Day 1).  Patients who meet all eligibility requirements will be randomized in a 1:1 
ratio to one of two treatment groups:  Placebo or OCA.  Randomization will be stratified by CP class.  Baseline 
MELD scores will be monitored on an ongoing basis to ensure adequate distribution of MELD scores.   
Following completion of safety assessments and laboratory specimen collection, blinded investigational product 
will be dispensed with instruction to begin dosing the same day (Day 1) at OCA 5 mg or placebo once weekly.  
Double-Blind Treatment Period:  During the 48-week treatment period (ie, Day 1 through Week 48), an initial 
safety visit will occur at Week 3.  After the Week 6 Visit, subsequent clinic visits will occur approximately 
every 6 weeks for the assessment of safety, tolerability, PK, and PD.  At each visit (except screening and Week 
3), fasting PK assessments will be performed in all patients participating in the study.  Serial PK sampling will 
be performed at Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week double blind treatment period will continue double-blind treatment 
until all randomized patients have completed their 48-week treatment period and the database for that period is 
locked.  Patients will then be given the option to go on open-label treatment.   
Study Design Diagram 
OCA = obeticholic acid, PBC = primary biliary cholangitis 
Notes: Initial dose titration of investigational product may be considered as early as the Week 12 Visit, or any study visit 
thereafter for patients on all dosing regimens, based on tolerability and safety laboratory tests from the previous 
visit.  Subsequent dose titration(s) may occur no earlier than 6 weeks after the previous dose titration and will be 
based on tolerability and CP score.   
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Patients who complete Week 48 will continue double-blind treatment until all randomized patients have completed 
their participation in the 48-week treatment period and the database for that period is locked. 
Dosing Regimen:   
All patients will initiate investigational product once weekly with 5 mg OCA or matching placebo.  Titration 
may be considered as early as the Week 12 Visit.  Following visit procedures at Week 12, if the investigational 
product is tolerated and laboratory assessments do not indicate a safety concern, the patient may up-titrate to 
OCA 5 mg twice weekly and may start the higher dose regimen no earlier than 2 days after they took their last 
dose.  Dosing will then occur at least 3 days apart.  Every 6 weeks thereafter, based on safety and tolerability 
assessments, patients can be considered for further up titration as described below.  At each titration visit, the 
patient may start the higher dose regimen no earlier than 2 days after the prior dose. 
Patients with CP-B may titrate to a maximum dose of OCA 5 mg once daily. 
Patients with CP-C may titrate to a maximum dose of OCA 10 mg twice weekly at least 3 days apart.  
Planned OCA or Matching Placebo Dosing Regimen by Child-Pugh Score 
 
Child-Pugh B 
(Moderate Hepatic Impairment) 
Child-Pugh C 
(Severe Hepatic Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting Dose (Day 1) 
5 mg once 
weekly 
matching placebo 
5 mg once weekly 
matching placebo 
Titration 1a  
5 mg twice 
weeklyb 
matching placebo 
5 mg twice 
weeklyb 
matching placebo 
Titration 2a  
10 mg twice 
weeklyb 
matching placebo 
10 mg twice 
weeklyb 
matching placebo 
Titration 3a  
5 mg once daily 
matching placebo 
NA 
NA 
a Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on patient tolerability 
and/or changes in Child-Pugh Score at any time during the study. 
b Dosing per the twice weekly schedule must be at least 3 days apart. 
Over the course of the study, a patient’s CP category may change.  When a patient demonstrates a change in CP 
category, dosing should be reassessed and modified if appropriate.  Changes to the dosing regimen are not 
mandatory and should be based on clinical judgment and change in CP score.  The titration steps for CP-B and 
CP-C patients are identical with exception of the maximum allowed dose.  Therefore, if a patient changes CP 
class from B to C, or vice versa, the maximal dose for the new regimen will apply.  If a patient improves to CP-
A during the study, the maximal CP-B dose will still apply.  If a patient has not yet reached the maximal dose, 
the appropriate titration regimen should be followed.  
  
Maximum Dose for OCA or Matching Placebo for Changes in Child-Pugh Category 
Original Status 
New Statusa 
Child-Pugh A 
Child-Pugh B
Child-Pugh C
Child-Pugh B 
No change 
No change
10 mg twice weeklyb
Child-Pugh C 
5 mg once daily 
5 mg once daily
No change 
a Once a patient begins dosing with the new dosing regimen, titration should occur as described for the planned dosing 
regimen.  
b Dosing per the twice weekly schedule must be at least 3 days apart.
Number of Patients (planned):  Approximately 50 patients will be enrolled in this study. 
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Diagnosis and Main Criteria for Inclusion: 
Key Inclusion Criteria 
1. A definite or probable diagnosis of PBC (consistent with American Association for the Study of Liver 
Diseases [AASLD] and European Association for the Study of the Liver [EASL] Practice Guidelines, 
defined as having ≥2 of the following 3 diagnostic factors: 
 
History of elevated ALP levels for at least 6 months 
 
Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer (≤1:80), 
PBC-specific antibodies (anti-GP210 and/or anti-SP100) and/or antibodies against the major M2 
components (PDC-E2, 2-oxo-glutaric acid dehydrogenase complex)  
 
Liver biopsy consistent with PBC (collected at any time prior to Screening) 
2. Evidence of cirrhosis including at least one of the following: 
 
Biopsy results consistent with PBC Stage 4  
 
Liver stiffness as assessed by TE Median Value ≥16.9kPa 
 
Clinical evidence in the absence of acute liver failure consistent with cirrhosis including: 
gastroesophageal varices, ascites, radiological evidence of cirrhosis (nodular liver or enlargement 
of portal vein and splenomegaly) 
 
Combined low platelet count (<140 000/mm3) with 
 
persistent decrease in serum albumin, or  
 
elevation in prothrombin time/INR (not due to antithrombotic agent use), or 
 
elevated bilirubin (2× ULN) 
3. Satisfy the criteria of the modified CP classification for hepatic impairment during Screening (ie, within 
14 days before the first dose of investigational product): 
 
Moderate:  CP-B (Scores 7 to 9) or 
 
Severe:  CP-C (Scores 10 to12) 
4. MELD score of 6 to 24 at Screening 
5. Taking UDCA for at least 12 months (stable dose for ≥3 months) prior to Day 1, or unable to tolerate or 
unresponsive to UDCA (no UDCA for ≥3 months)  
Key Exclusion Criteria 
1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6) 
2. History of liver transplant or organ transplant 
3. History of alcohol or drug abuse within 12 months prior to Screening 
4. Hepatic encephalopathy (as defined by a West Haven score of ≥2) 
5. History or presence of other concomitant liver diseases including: 
 
Hepatitis C virus infection and RNA positive 
 
Active hepatitis B infection; however, patients who have seroconverted (hepatitis B surface 
antigen and hepatitis B antigen negative) may be included in this study after consultation with the 
medical monitor 
 
Primary sclerosing cholangitis 
 
Alcoholic liver disease 
 
Definite autoimmune liver disease or overlap hepatitis 
 
Gilbert's Syndrome 
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6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function prior to 
randomization 
Investigational Product, Dosage and Mode of Administration:  
OCA 5 mg or OCA 10 mg tablets, oral administration 
Placebo tablets, matched in size and appearance to OCA tablets, oral administration 
Duration of Treatment:   
Patients who have completed their 48-week double blind treatment period will continue double blind treatment 
until all randomized patients have completed their participation in the 48-week treatment period and the 
database for that period is locked (approximately 3 years).  Patients will then be given the option to go on open-
label treatment. 
Criteria for Evaluation: 
Primary Objectives 
Assessments 
PK parameters 
OCA and its conjugates, glyco-OCA and tauro-OCA, and 
metabolite OCA glucuronide 
Safety and tolerability  
SAEs and TEAEs, physical exam, ECG, vital signs, clinical 
laboratory assessments, discontinuations, pruritus, and fatigue 
Secondary Objectives 
Assessments 
Changes in risk scores 
Changes in MELD and in CP score and components of the 
CP score  
Changes in liver biochemistry and hepatobiliary 
damage  
Total and direct bilirubin, ALP, ALT, AST, GGT, INR, 
creatinine, albumin, platelets 
PD parameters 
FGF-19, C4, and plasma bile acids 
Additional Objectives 
Assessments 
Markers of inflammation 
IL-6, hs-CRP, TNF-α, IgM, IgA, IgG, CK-18-M30  
Noninvasive measurements of liver fibrosis, liver 
stiffness and cirrhosis 
TE and ELF (HA, P3NP, and TIMP-1) 
PK/PD relationship 
PK parameters compared to PD Parameters and Safety and 
Tolerability assessments (above) 
Patient-reported outcomes 
Pruritus VAS, PBC-40, EQ-5D-5L, CLDQ 
Clinical events 
Death (all-cause and liver-related), liver transplant, Model of 
end stage liver disease (MELD) score ≥15 (for patients with 
MELD ≤12 at baseline), Hospitalization for new onset or 
recurrence of: variceal bleed, hepatic encephalopathy, 
spontaneous bacterial peritonitis, Uncontrolled ascites, and 
HCC. 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
C4 = 7α-hydroxy-4-cholesten-3-one; CK-18-M30 = cytokeratin-18 neoepitope-M30; CLDQ = Chronic Liver Disease 
Questionnaire; CP = Child-Pugh; ECG = electrocardiogram; ELF = enhanced liver fibrosis; FGF-19 = fibroblast growth 
factor-19; GGT = gamma-glutamyl transferase; HA = hyaluronic acid; hs-CRP = high-sensitivity C-reactive protein;  
IgA = immunoglobulin; A IgG = immunoglobulin G; IgM = immunoglobulin M; IL-6 = interleukin 6; INR = international 
normalized ratio;  MELD = Model End Stage Liver Disease; OCA = obeticholic acid; P3NP = procollagen 3 N-terminal 
peptide; PBC = Primary Biliary Cholangitis; PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event; 
TE = Transient Elastography; TEAE = treatment emergent adverse events; TIMP-1 = tissue inhibitor of metalloproteinase 1; 
TNF-α = tumor necrosis factor; VAS = visual analog scale 
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Statistical Methods: 
Analysis Populations: 
The following patient populations will be evaluated and used for presentation and analysis of the data: 
 
The Intent-to-Treat (ITT) Population will include all randomized patients who receive any amount of 
investigational product (OCA or placebo).  The ITT Population will be the primary population used for 
summarizing efficacy assessments.  
 
The Safety Population will include all patients who received at least one dose of investigational product 
(placebo or OCA). The Safety Population will be the primary population used for safety analyses.  
 
The PK Population will include all patients receiving OCA who have adequate concentration-time 
profiles to characterize OCA and its conjugates and must not have any major protocol deviations that 
potentially affect exposure levels.   
Pharmacokinetic Analyses: 
The PK Population will be used for analysis of PK parameters, which include plasma OCA (parent) and its 
conjugates (glyco-OCA and tauro-OCA), total OCA, metabolite OCA glucuronide, and potentially other 
conjugates or metabolites not yet identified. 
Values will be calculated using non-compartmental methods.  The values will be summarized by active 
treatment group using descriptive statistics.  
Safety Analyses: 
Safety analyses will be conducted using the Safety population.  Safety data, including AEs, vital signs, 
electrocardiogram, and clinical laboratory results will be summarized by treatment group.  The incidence of 
treatment-emergent AEs (TEAEs) and serious AEs (SAEs) will be tabulated by system organ class and preferred 
term for each treatment group, and similarly by severity and relationship to treatment.  Laboratory parameters, 
physical examinations including vital signs, and electrocardiograms will be summarized by treatment group 
using descriptive statistics at Baseline and at each scheduled post-Baseline visit.  The absolute change from 
baseline will also be summarized.  No inferential comparison with formal statistical hypothesis testing will be 
performed for safety endpoints. 
Efficacy Analyses: 
This study does not plan to conduct a formal hypothesis testing for any efficacy endpoint.   
The endpoints of efficacy assessments are change in total and direct bilirubin, INR, creatinine, albumin, 
platelets, ALP, ALT, AST, and GGT from baseline to Week 48 (end of the study), change from baseline to 
Week 48 in CP score and components of the CP score, and change from baseline to Week 48 in MELD and 
components of the MELD score.  Analyses of change from Baseline to Week 48 (end of study) will be modelled 
between treatment groups using ANCOVA model with change from Baseline as the dependent variable, 
treatment group and randomization stratification factor as fixed effects and the baseline values as covariates.  
The same analysis will be carried out using percentage change from Baseline as the dependent variable. 
Additional Efficacy Analyses 
Analyses of changes in liver stiffness and ELF, cytokeratin-and TIMP-1, and markers of inflammation will be 
summarized and analyzed using the same methodology specified for the secondary analyses of change in 
bilirubin. 
The following endpoints consistent with end-stage liver disease will be captured in the study: 
 
Time to death (all cause) 
 
Time to liver-related death 
 
Time to liver transplant 
 
Model of end stage liver disease (MELD) score ≥15 (for patients with MELD ≤12 at baseline) 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
 
Time to variceal bleed 
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 
Time to hepatic encephalopathy (as defined by a West Haven score of ≥2) 
 
Time to spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 
Time to uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
The incidence and time to first occurrence of any of the above listed clinical events will be summarized by 
treatment group using the log rank test stratified by the randomization stratification factor.  Kaplan-Meier (KM) 
estimates of the distribution of the time-to-event will be tabulated and graphed by treatment group.  The 
tabulation will include the KM methodology using 25th, 50th (median), and 75th percentiles with associated 
2-sided 95% confidence intervals (CIs), as well as percentage of censored observations.  The number and 
percent of patients censored and with events will be presented.  The hazard ratio and 2-sided 95% CI will be 
estimated based on a Cox regression model stratified by randomization strata.  
In addition, the incidence and time to each of the above clinical events, and the incidence and time to occurrence 
of HCC will be summarized by treatment group using the same methods as defined above.   
Sample Size Justification: 
To reasonably characterize the PK of OCA in patients with hepatic impairment, a simulation based approach 
estimated a requirement of approximately 20 patients in the OCA treatment group assuming a 15% 
discontinuation rate.  Ten patients on placebo will be included as a comparator.  An additional 20 patients will 
be enrolled to support safety and efficacy evaluations.  Therefore, approximately 50 patients (including at least 
20% of patients with CP-C) will be randomized. 
 
 
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................18 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Overview of Disease State and OCA ..........................................................................21 
5.2. 
Nonclinical Experience with Obeticholic Acid ..........................................................21 
5.3. 
Clinical Development of Obeticholic Acid ................................................................21 
5.4. 
Rationale for Study Design and Dose for Investigational Product .............................22 
5.4.1. 
Rationale for Study Design .........................................................................................22 
5.4.2. 
Rationale for Obeticholic Acid Dose and Duration ....................................................23 
5.4.3. 
Rationale for Population Chosen ................................................................................24 
5.4.4. 
Rationale for Control Group .......................................................................................24 
5.5. 
Summary of Known Potential Risks with Investigational Product ............................24 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
6.1. 
Primary Objectives .....................................................................................................25 
6.2. 
Secondary Objectives .................................................................................................25 
6.3. 
Additional Objectives .................................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................26 
7.1. 
Overall Study Design ..................................................................................................26 
7.1.1. 
Study Design Diagram ................................................................................................27 
7.1.2. 
Schedule of Study Procedures ....................................................................................28 
7.1.3. 
Study Duration ............................................................................................................31 
7.2. 
Number of Patients .....................................................................................................31 
7.3. 
Planned Dosing Regimen ...........................................................................................31 
7.4. 
Dose Adjustment Criteria ...........................................................................................32 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements .................................................33 
7.5. 
Criteria for Study Termination ...................................................................................33 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................33 
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8.1. 
Patient Population .......................................................................................................33 
8.2. 
Patient Inclusion Criteria ............................................................................................33 
8.3. 
Patient Exclusion Criteria ...........................................................................................35 
8.4. 
Dose Adjustment, Interruption, and Withdrawal from Investigational 
Product or Study .........................................................................................................35 
8.4.1. 
Reasons for Additional Monitoring or Mandatory Interruption of 
Investigational Product ...............................................................................................36 
8.4.1.1. 
Reasons for Additional Monitoring Related to Liver Chemistries .............................36 
8.4.1.2. 
Reasons for Investigational Product Interruption Related to Elevated Liver 
Chemistries .................................................................................................................36 
8.4.1.3. 
Pregnancy ...................................................................................................................37 
8.4.2. 
Reasons for Mandatory Discontinuation of Investigational Product ..........................37 
8.4.3. 
Other Reasons for Discontinuation of Study or Investigational Product ...................37 
8.4.3.1. 
Withdrawal of Consent to Continue in the Study .......................................................38 
8.4.3.2. 
Lost to Follow-Up .......................................................................................................38 
8.4.4. 
Patient Discontinuation Notification ..........................................................................38 
9. 
TREATMENT OF PATIENTS ..................................................................................39 
9.1. 
Investigational Product Treatment Regimen ..............................................................39 
9.2. 
Concomitant Medications ...........................................................................................39 
9.2.1. 
Drug Interactions ........................................................................................................40 
9.2.2. 
Prohibited Medications ...............................................................................................40 
9.3. 
Treatment Compliance ................................................................................................40 
9.4. 
Randomization and Blinding ......................................................................................41 
9.4.1. 
Methods of Assigning Patients to Treatment Groups .................................................41 
9.4.2. 
Blinding ......................................................................................................................41 
9.4.3. 
Emergency Unblinding Procedures ............................................................................41 
9.5. 
Assignment of Site and Patient Numbers ...................................................................42 
9.5.1. 
Site Numbers ..............................................................................................................42 
9.5.2. 
Patient Numbers ..........................................................................................................42 
9.6. 
Restrictions .................................................................................................................42 
9.6.1. 
Fasting Requirement at Study Visits ..........................................................................42 
9.7. 
Visit Procedures ..........................................................................................................42 
9.7.1. 
Visit Windows ............................................................................................................42 
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9.7.2. 
Informed Consent Procedures .....................................................................................42 
9.7.3. 
Assessing Cirrhosis .....................................................................................................43 
9.7.4. 
Screening Procedures (14 days to 28 days prior to Day 1) .........................................43 
9.7.5. 
Day 1 Procedures (Randomization) ............................................................................44 
9.7.6. 
Week 3 Safety Visit Procedures .................................................................................46 
9.7.7. 
Week 6 Procedures .....................................................................................................46 
9.7.8. 
Week 9 through Week 48 (Safety Contact) ................................................................47 
9.7.9. 
Week 12, Week 24, Week 36 Procedures ...................................................................47 
9.7.10. 
Week 18 and Week 30 Procedures .............................................................................49 
9.7.11. 
Week 48 Procedures ...................................................................................................50 
9.7.12. 
Every 3 Months after Week 48 ...................................................................................52 
9.7.13. 
End of Study/Early Termination/End of Treatment Procedures for Patients 
that Withdraw from Investigational Product or Withdraw Consent ...........................53 
9.7.14. 
Unscheduled Safety Visit ...........................................................................................54 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............54 
10.1. 
Investigational Product ...............................................................................................54 
10.2. 
Investigational Product Packaging and Labeling .......................................................55 
10.3. 
Investigational Product Storage ..................................................................................55 
10.4. 
Investigational Product Administration ......................................................................55 
10.5. 
Investigational Product Accountability and Disposal .................................................55 
11. 
OVERVIEW OF ASSESSMENTS ............................................................................56 
12. 
CLINICAL PHARMACOKINETIC ASSESSMENTS .............................................56 
12.1. 
Pharmacokinetic Blood Sampling ..............................................................................57 
12.2. 
Processing and Handling of Pharmacokinetic Samples ..............................................58 
12.3. 
Bioanalysis ..................................................................................................................58 
13. 
ASSESSMENT OF SAFETY .....................................................................................59 
13.1. 
Adverse Events and Serious Adverse Events .............................................................59 
13.1.1. 
Definitions of Adverse Events ....................................................................................59 
13.1.1.1. 
Adverse Event .............................................................................................................59 
13.1.1.2. 
Serious Adverse Event ................................................................................................59 
13.1.1.3. 
Treatment-Emergent Adverse Event ..........................................................................60 
13.1.2. 
Relationship to Investigational Product ......................................................................60 
13.1.3. 
Recording Adverse Event Severity .............................................................................60 
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13.1.4. 
Reporting of Adverse Events and Serious Adverse Events ........................................61 
13.1.4.1. 
Reporting of Adverse Events ......................................................................................61 
13.1.4.2. 
Reporting of Serious Adverse Events .........................................................................61 
13.1.5. 
Additional Investigator Responsibilities for SAEs .....................................................62 
13.1.6. 
Notification of Post-Treatment SAEs for Patients Who Continue in the Study .........62 
13.1.7. 
Notification of Post-Study SAEs ................................................................................62 
13.1.8. 
Follow-Up of AEs and SAEs ......................................................................................63 
13.1.9. 
Pregnancy and Follow-Up ..........................................................................................63 
13.2. 
Other Safety Parameters .............................................................................................63 
13.2.1. 
Medical History/Demographics ..................................................................................63 
13.2.2. 
Physical Examination .................................................................................................64 
13.2.3. 
Vital Signs and Weight ...............................................................................................64 
13.2.4. 
Electrocardiogram .......................................................................................................64 
13.2.5. 
Laboratory Assessments .............................................................................................64 
13.2.6. 
Patient-Reported Outcomes and Healthcare Resource Use ........................................66 
14. 
EFFICACY ASSESSMENTS ....................................................................................67 
14.1. 
Biochemical Measures of Disease Severity ................................................................67 
14.1.1. 
Child-Pugh Score ........................................................................................................67 
14.1.2. 
Model of End Stage Liver Disease Score ...................................................................67 
14.1.3. 
Changes in Liver Biochemistry and Hepatobiliary Damage ......................................68 
14.2. 
Additional Assessments ..............................................................................................68 
14.2.1. 
Markers of Inflammation, Apoptosis and Necrosis ....................................................68 
14.2.2. 
Noninvasive Measurements of Liver Stiffness and Fibrosis ......................................68 
14.2.3. 
Markers of FXR activation .........................................................................................68 
14.2.4. 
Clinical Outcome Events ............................................................................................68 
15. 
STATISTICAL METHODS AND ANALYSES .......................................................68 
15.1. 
Analysis Populations ..................................................................................................69 
15.2. 
Determination of Sample Size ....................................................................................69 
15.3. 
Pharmacokinetic Analyses ..........................................................................................70 
15.4. 
Safety Analyses ..........................................................................................................70 
15.4.1. 
Adverse Events ...........................................................................................................70 
15.4.2. 
Clinical Laboratory Evaluations .................................................................................71 
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15.4.3. 
Adverse Events of Special Interest .............................................................................72 
15.5. 
Efficacy Analyses .......................................................................................................74 
15.6. 
Additional Efficacy Analyses .....................................................................................75 
15.7. 
Handling of Missing Data ...........................................................................................75 
15.8. 
Data Monitoring Committee .......................................................................................76 
15.9. 
Adjudication Committees ...........................................................................................76 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................77 
16.1. 
Study Monitoring ........................................................................................................77 
16.2. 
Audits and Inspections ................................................................................................78 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................78 
18. 
ETHICS ......................................................................................................................78 
18.1. 
Ethics Review .............................................................................................................78 
18.2. 
Ethical Conduct of the Study ......................................................................................79 
18.3. 
Written Informed Consent ..........................................................................................79 
18.4. 
Patient Confidentiality and Data Protection ...............................................................79 
19. 
INVESTIGATOR OBLIGATIONS ...........................................................................80 
19.1. 
Adverse Event Reporting ............................................................................................80 
19.2. 
Protocol Deviations ....................................................................................................80 
19.3. 
Regulatory Documentation .........................................................................................80 
19.4. 
Ethics Review (IRB/IEC) ...........................................................................................80 
19.5. 
Archiving and Record Retention ................................................................................80 
20. 
PUBLICATION POLICY ..........................................................................................81 
21. 
LIST OF REFERENCES ............................................................................................82 
APPENDIX A.  SUMMARY OF CHANGES:  PROTOCOL 747-401 VERSION 2 
(DATED 22 MAY 2017) ..................................................................................84 
 
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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................28 
Table 2: 
Planned OCA or Matching Placebo Dosing Regimen by Child-Pugh Score .............31 
Table 3: 
Maximum Daily dose based on change in Child-Pugh Category ...............................32 
Table 4: 
Early Discontinuation Scenarios .................................................................................54 
Table 5: 
Table of Assessments .................................................................................................56 
Table 6: 
Acceptable Windows for Pharmacokinetic Sample Collection ..................................58 
Table 7: 
Relationship of Adverse Events to Investigational Product .......................................60 
Table 8: 
Severity of Adverse Events ........................................................................................61 
Table 9: 
List of Laboratory Analytes to be Tested ...................................................................65 
Table 10:  Child-Pugh Scoring System ........................................................................................67 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................27 
Figure 2: 
Week 6 Sampling Schedule ........................................................................................57 
Figure 3: 
Pharmacokinetic Sampling Schedule .........................................................................57 
  
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this protocol. 
Abbreviation or Specialist Term 
Explanation 
6-ECDCA 
6α-ethyl chenodeoxycholic acid (also known as INT-747) 
AASLD 
American Association for the Study of Liver Diseases  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
antimitochondrial antibody 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
β-hCG 
beta human chorionic gonadotropin 
BAS 
bile acid sequestrants 
BP 
blood pressure 
C4 
7α-hydroxy-4-cholesten-3-one 
CAC 
Cardiovascular Adjudication Committee 
CI 
confidence interval 
CK-18-M30 
cytokeratin-18 neoepitope M30 
CLDQ 
Chronic Liver Disease Questionnaire 
CRA 
Clinical Research Associate 
CP 
Child Pugh 
eCRF 
electronic case report form 
HCC 
hepatocellular carcinoma 
Hs-CRP 
high sensitivity C-reactive protein 
CP 
Child-Pugh 
DDI 
Drug-drug interaction 
DMC 
Data Monitoring Committee 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
enhanced liver fibrosis 
EOS 
end of study 
EOT 
end of treatment 
ET 
Early termination 
FDA 
Food and Drug Administration 
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Abbreviation or Specialist Term 
Explanation 
FGF-19 
fibroblast growth factor-19 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
glyco-OCA 
glycine 6α-ethyl chenodeoxycholic acid 
HCC 
hepatocellular carcinoma 
HCP 
Health care professional 
HDLc 
high density lipoprotein 
IB 
Investigational Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
INR 
international normalized ratio  
IRB 
Institutional Review Board 
ISF 
Investigator site file 
ITT 
intent-to-treat  
IWRS 
interactive web response system 
KM 
Kaplan-Meier 
LDLc 
low density lipoprotein 
LTSE 
Long-term safety extension 
LS 
Least squares 
MACE 
Major adverse cardiovascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model of end stage liver disease  
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cholangitis (also known as primary biliary 
cirrhosis) 
PIS-IC 
patient information sheet/informed consent 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
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Abbreviation or Specialist Term 
Explanation 
SD 
standard deviation 
SEM 
standard error of the mean 
SI 
standard international system of units 
SOC 
System organ class 
SUSAR 
suspected unexpected serious adverse reaction 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
the Sponsor 
Intercept Pharmaceuticals, Inc. 
TNF-α 
tumor necrosis factor-alpha 
UDCA 
ursodeoxycholic acid 
UK 
United Kingdom  
ULN 
upper limit of normal 
US 
United States (of America) 
VAS 
Visual Analogue Scale 
VLDL 
very low density lipoprotein 
 
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5. 
INTRODUCTION 
5.1. 
Overview of Disease State and OCA 
Primary biliary cholangitis (PBC, also known as primary biliary cirrhosis [Beuers 2015a, 
Beuers 2015b, Beuers 2015c]) is a serious, life-threatening, cholestatic liver disease of unknown 
etiology that, without treatment, frequently progresses to hepatic fibrosis and eventual cirrhosis, 
hepatic decompensation, and necessitates liver transplantation or results in death.  PBC is a rare 
disease with reported prevalence in the US of 40.2/100 000 (Kim 2000).  PBC disproportionately 
affects women approximately 10:1 and is typically diagnosed in patients between 40 to 70 years 
of age.   
Historically, the only approved drug therapy for PBC has been the bile acid, ursodeoxycholic 
acid (UDCA), a physiological constituent of human bile (Lindor 2009).  While UDCA therapy 
had a marked effect on the treatment of PBC, up to 50% of patients showed a suboptimal 
response or no response to UDCA.  Such patients were at significantly increased risk of a poor 
clinical outcome due to PBC disease progression.   
Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist and modified bile acid derived 
from the primary human bile acid chenodeoxycholic acid (CDCA) (Pellicciari 2002), was 
developed for the treatment of PBC and to provide patients who have an inadequate response to 
or poor tolerance of UDCA a novel treatment option that was safe and effective.  In May 2016, 
the US Food and Drug Administration (FDA) granted accelerated approval for OCA (marketed 
as Ocaliva), for the treatment of patients with PBC in combination with UDCA in adults with an 
inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA.  In 
December 2016, the European Commission granted conditional approval for Ocaliva for the 
same indication.   
5.2. 
Nonclinical Experience with Obeticholic Acid 
Intercept Pharmaceuticals, Inc. (the Sponsor) has completed a standard battery of nonclinical 
safety pharmacology and toxicology studies.  No major nonclinical safety effects have been seen 
other than pharmacologic hepatic effects observed at high doses.  These pharmacologic hepatic 
effects are consistent with the detergent effects of a bile acid at exceedingly high hepatocellular 
exposure. 
5.3. 
Clinical Development of Obeticholic Acid 
As of 31 Jan 2017, approximately 2186 patients have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 525 patients had PBC, 686 patients had nonalcoholic steatohepatitis 
(NASH), 41 patients had diabetes mellitus/ nonalcoholic fatty liver disease (NAFLD), 
33 patients had alcoholic cirrhosis/portal hypertension, 52 patients had primary sclerosing 
cholangitis (PSC), and 5 patients had biliary atresia.  
Overall, the pharmacokinetic (PK) profile of OCA is consistent with that expected of a bile acid.  
Phase 1 studies demonstrated that OCA is rapidly absorbed and extensively conjugated with 
glycine and taurine to form glyco-OCA and tauro-OCA, respectively.  OCA and its conjugates 
are primarily eliminated via biliary excretion, and plasma concentration time profiles 
demonstrated multiple peaking with prolonged exposure, indicative of enterohepatic circulation.  
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Plasma concentrations of OCA and its conjugates spike shortly after meals, consistent with gall 
bladder emptying into the duodenum as expected of a bile acid. 
The OCA clinical development PBC program was based on a wide range of studies in PBC 
patients and healthy volunteers.  The clinical pharmacology studies supported the proposed 
dosing regimen:  10 mg fixed dose and a titration regimen starting at OCA 5 mg with titration to 
10 mg based on clinical and biochemical response.  The clinical program included a pivotal 
Phase 3 clinical study (747-301) and two Phase 2 clinical studies (747-201 and 747-202), which 
formed the primary basis of approval of OCA. 
Study 747-201 (59 patients) evaluated 2 doses of OCA (10 mg and 50 mg) given as monotherapy 
versus placebo.  Statistically significant and clinically relevant relative and absolute reductions 
from Baseline in alkaline phosphatase (ALP) were achieved with both doses of OCA versus 
placebo (p <0.0001).  Mean relative ALP reductions were 45% (OCA 10 mg) and 38% 
(OCA 50 mg) compared to an increase of 0.4% with placebo.  Further, significant improvements 
in gamma-glutamyl transferase (GGT) and in conjugated bilirubin were observed with both 
doses compared with placebo (p <0.05).  OCA also resulted in decreased circulating alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) levels. 
Study 747-202 (165 patients) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in patients on a stable therapeutic dose of UDCA.  Overall, the data from 747-202 were 
consistent with Study 747-201.  Statistically significant and clinically meaningful relative and 
absolute reductions in ALP were achieved with all 3 doses of OCA versus placebo (p <0.0001).  
Mean ALP reductions from baseline ranged from 21% to 25% compared to 3% with placebo.  
Improvements were also seen in GGT and ALT levels and in conjugated bilirubin levels. 
Study 747-301 (216 patients) was a Phase 3, double-blind, placebo-controlled, parallel-group 
study followed by a long-term safety extension (LTSE) using OCA in patients with PBC.  The 
primary endpoint for Study 747-301 was a composite endpoint based on the proportion of 
patients reaching specific criteria for ALP and bilirubin (ALP <1.67x upper limit of normal 
[ULN] with a ≥15% reduction and bilirubin ≤ULN).  Both OCA treatment groups met the 
primary endpoint of achieving a reduction in ALP to <1.67x ULN with a ≥15% reduction from 
baseline and a normal bilirubin level after 12 months of therapy.  The placebo group experienced 
a least squares (LS) mean decrease in ALP from baseline of 5%, compared to a significant LS 
mean decrease of 39% in the OCA 10 mg dose group and 33% in the OCA titration group (both 
OCA dose groups p <0.0001 versus placebo). 
The LTSE phases of both Phase 2 studies and the pivotal Phase 3 study support the long-term 
safety of OCA and demonstrate a durable therapeutic response.   
Study 747-302 is an ongoing randomized, double-blind, placebo-controlled clinical outcomes 
study, designed to confirm the clinical benefit of OCA treatment in patients with PBC.  This 
study is inclusive of patients with early to advanced stage PBC. 
5.4. 
Rationale for Study Design and Dose for Investigational Product 
5.4.1. 
Rationale for Study Design 
There are limited clinical data available to support the use of OCA in patients with PBC with 
moderate to severe hepatic impairment.  The current recommended dosing of such patients is 
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based on modeled systemic and hepatic concentrations.  Therefore, Study 747-401 is specifically 
designed to characterize the PK, safety, and efficacy of OCA in this patient population. 
PK and safety parameters will be evaluated as the primary objectives and efficacy parameters 
will be evaluated as secondary and additional objectives.  While the prognostic utility of ALP 
has been established by the Global PBC study group, increasing levels of bilirubin are more 
relevant to understanding the progression of end stage liver disease.  Consistently, bilirubin is a 
key marker of advancing disease as characterized by the Global PBC study group as well as its 
incorporation into model of end stage liver disease (MELD), Child-Pugh (CP), and Mayo risk 
scores.  As such, the potential of OCA to stabilize bilirubin levels will be evaluated. 
In order to generate data for the patient population in a timely fashion, Study 747-401 is 
designed with a relatively short-term, 1-year double-blind treatment period to gather primarily 
PK and safety data.  Therefore, the study will not formally test the long-term efficacy of OCA on 
clinical outcomes.   
Although Study 747-401 is not designed to formally evaluate clinical outcomes, these data will 
be collected and assessed as an additional objective.  Given the importance of evaluating clinical 
outcomes in patients with the most advanced form of the disease, these events will be 
prospectively adjudicated consistent with the procedures implemented in ongoing PBC studies.  
This will allow for a more robust meta-evaluation of clinical outcomes in patients with moderate 
to severe hepatic impairment following the completion of both studies.  
Study 747-302 is specifically designed to confirm clinical benefit across the spectrum of disease 
including patients with hepatic impairment.  Data collected from Study 747-401 will serve as a 
bridge to the 747-302 study. 
Taken together, data from this study will complement the data from Study 747-302 and offer the 
opportunity to better inform the benefit risk profile and appropriate treatment of 
hepatically-impaired patients.  
5.4.2. 
Rationale for Obeticholic Acid Dose and Duration 
Simulations using a physiologic PK model predicted changes in systemic and liver OCA 
concentrations associated with changes in the severity of hepatic impairment (CP Score).  Model 
simulations predicted that for mild (Child-Pugh A [CP-A]), moderate (Child-Pugh B [CP-B]), 
and severe (Child-Pugh C [CP-C]) hepatic impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to patients with normal hepatic function, whereas total 
OCA liver concentrations increase 1.1-, 1.5-, and 1.7-fold, respectively.  Because the liver is the 
primary site of action for the safety and efficacy of OCA, it is important to account for the 
differences in systemic and liver exposure when assessing effective doses.  It is also important to 
note that while hepatically impaired (CP-B and C) patients treated with OCA in Phase 1 and 2 
studies experienced plasma OCA exposures >10-fold higher than those in healthy patients, no 
apparent impact on the overall safety profile was observed, consistent with only a modest 
increase in liver exposure of OCA associated with hepatic impairment.  Together, the results 
from these analyses suggest that the doses of OCA administered to patients with moderate or 
severe hepatic impairment should be modestly lower than those for patients with normal hepatic 
function to achieve similar hepatic exposure.    
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Therefore, the current FDA-approved prescribing information for OCA includes a modified 
dosing regimen in patients with moderate and severe hepatic impairment that is designed to 
achieve liver exposures in these patients that would be similar to non-hepatically impaired 
patients through initiation at a lower dose (5 mg OCA once-weekly) followed by gradual 
up-titration (Section 7.3).   
The dosing regimen in this study follows the FDA-approved prescribing information, with the 
exception of the maximum allowed dose in patients with moderate impairment.  While the 
prescribing information allows for a maximum dose of 10 mg twice weekly for patients with 
moderate impairment, the protocol allows for a maximum dose of 5 mg once daily.  The choice 
of 5 mg once daily is supported by the estimated steady-state liver and plasma exposure of total 
OCA for patients with moderate hepatic impairment receiving a 5 mg once daily dose relative to 
healthy patients receiving a 10 mg dose.  A maximum allowed dose of 5 mg once daily in 
patients with moderate hepatic impairment is estimated to achieve liver exposure similar to non-
hepatically impaired patients receiving a 10 mg daily dose and maximize efficacy in this patient 
population. 
5.4.3. 
Rationale for Population Chosen 
Patients with PBC and moderate or severe hepatic impairment, based on CP score and varying 
levels of MELD, are the targeted population for this study as OCA has been studied primarily in 
early to moderate stages of liver impairment in patients with PBC.  There is a great need to 
extend therapies to PBC patients with more advanced liver impairment.  Given the unmet 
medical need and observed efficacy, safety and tolerability profile of OCA in early and moderate 
PBC, evaluating the effects of OCA in a late stage population is warranted. 
5.4.4. 
Rationale for Control Group  
The use of a randomized placebo control group added to established standard of care provides 
the best scientific evidence of efficacy and safety.  The use of a placebo control provides a 
concurrent comparator group, accounting for not only a placebo effect but continued standard of 
care.  The use of a placebo control is critical to assess the safety and tolerability of OCA but also 
as a comparator for the high rate of clinical events which are expected in this advanced 
population.  
5.5. 
Summary of Known Potential Risks with Investigational Product 
The primary AE shown to be related to OCA is pruritus.  Pruritus has also been observed in 
clinical studies with OCA in other indications, as well as in healthy patients, but with a much 
lower frequency than that observed in patients with PBC. 
Consistent with the dose-limiting hepatic toxicities observed in the non-clinical studies and the 
chemical characteristics of OCA as a bile acid and detergent, dose-related but reversible and 
asymptomatic increases in ALT and AST were observed in healthy volunteers treated with 
multiple doses of OCA starting at the 100 mg dose (Study 747-102).   
In patients with chronic liver disease such as PBC, hepatobiliary findings including increased 
transaminases and bilirubin and signs or symptoms of hepatic decompensation such as 
development of jaundice were observed.  These findings were seen more frequently with doses 
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of OCA 10 mg once daily to OCA 50 mg once daily (up to 5x the highest recommended dose).  
In addition, cholecystitis, including acute cholecystitis, was reported in association with 
treatment with OCA. 
Lipoprotein changes have also been observed with OCA dosing, including a decrease in high 
density lipoprotein (HDLc) and an increase in low density lipoprotein (LDLc).  Notably, in 
patients with PBC, the decrease in mean HDLc levels occurred early and stabilized within 
3 months after which time levels generally remained constant over the course of treatment.  The 
average levels of HDLc remained within normal limits.  Commensurate with decreases in HDLc, 
decreases in total cholesterol were observed in patients with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA treated patients with the exception of a 
modest transient and early rise after initiation of treatment. 
Based on previous PK and short-term studies in patients with hepatic impairment, increased 
systemic exposure was not associated with an apparent change in the safety profile of OCA as 
assessed by the incidence and severity of AEs or by changes in clinical laboratory tests.  
Hepatotoxicity has been associated with increased liver concentrations of OCA.  Hepatic 
impairment does not affect the ability of OCA to activate FXR in the intestine and the liver. 
Refer to the Investigator’s Brochure (IB) for additional information regarding the known 
potential risks with the investigational product. 
6. 
STUDY OBJECTIVES AND PURPOSE 
The study will be conducted in patients with PBC and moderate to severe hepatic impairment 
defined as CP-B and CP-C with MELD scores ranging from 6 to 24. 
6.1. 
Primary Objectives 
 To evaluate the PK of OCA and its conjugates, glyco-OCA and tauro-OCA, and OCA 
metabolite glucuronide compared with placebo 
 To evaluate the safety and tolerability of OCA treatment compared with placebo 
6.2. 
Secondary Objectives 
 To evaluate the effect of OCA treatment compared to placebo on:  
 The MELD score and its components 
 CP score and its components 
 Liver biochemistry including total and direct bilirubin, alkaline phosphatase 
(ALP), and aminotransferases (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], and gamma glutamyl transaminase [GGT]), international 
normalized ratio (INR), creatinine, albumin, platelets 
 Biomarkers of bile acid synthesis and homeostasis including fibroblast growth 
factor 19 (FGF-19), 7α-hydroxy-4-cholesten-3-one (C4), and plasma bile acids 
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6.3. 
Additional Objectives 
 To evaluate the effect of OCA treatment compared to placebo on: 
 Markers of inflammation 
 Noninvasive markers of liver fibrosis (Enhanced Liver Fibrosis [ELF]™score) 
 Noninvasive measurement of liver stiffness (transient elastography [TE]) 
 To assess the PK/Pharmacodynamic (PD) relationship of OCA with: 
 PK parameters compared to PD Parameters and Safety and Tolerability 
assessments 
 To assess patient reported outcomes (Pruritus Visual Analogue Scale [VAS], PBC-40, 
EQ 5D-5L, Chronic Liver Disease Questionnaire [CLDQ] 
 To assess clinical events consistent with end-stage liver disease 
 Death (all-cause) 
 Liver transplant 
 Model of end stage liver disease (MELD) score ≥15 (for patients with MELD ≥12 
at baseline) 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: variceal bleed, hepatic encephalopathy (as defined by a West 
Haven score of ≥2), spontaneous bacterial peritonitis 
 Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis 
at a frequency of at least twice in a month) 
 Hepatocellular carcinoma (HCC) 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the PK and 
safety of OCA treatment in patients with PBC and moderate to severe hepatic impairment 
defined as CP-B and CP-C including a broad distribution of MELD scores (ranging from 6 to 
24).  Approximately 50 patients (including at least 20% of patients with CP-C) will be enrolled 
in the study.  Patients will be screened ≥14 days but not more than 28 days prior to entering the 
study (Day 1).  Patients who meet all eligibility requirements will be randomized in a 1:1 ratio to 
one of two treatment groups:  Placebo or OCA.  Randomization will be stratified by CP class.  
Baseline MELD scores will be monitored on an ongoing basis to ensure adequate distribution of 
MELD scores. 
Following completion of safety assessments and laboratory specimen collection, blinded 
investigational product will be dispensed with instruction to begin dosing the same day (Day 1) 
at OCA 5 mg or placebo once weekly.   
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Double-Blind Treatment Period:  During the 48-week treatment period, an initial safety visit 
will occur at Week 3.  After the Week 6 Visit, subsequent clinic visits will occur approximately 
every 6 weeks for the assessment of safety, tolerability, PK, and PD.  At each visit (except 
screening and Week 3), fasting PK assessments will be performed in all patients participating in 
the study.  Serial PK sampling will be performed at Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week double blind treatment period will continue 
double-blind treatment until all randomized patients have completed their 48-week treatment 
period and the database for that period is locked.  Patients will then be given the option to go on 
open-label treatment. 
7.1.1. 
Study Design Diagram 
Figure 1: 
Study Design  
 
OCA = obeticholic acid, PBC = primary biliary cholangitis 
Note: Initial dose titration of investigational product may be considered as early as the Week 12 Visit, or any study visit 
thereafter for patients on all dosing regimens, based on tolerability and safety laboratory tests from the previous visit.  
Subsequent dose titration(s) may occur no earlier than 6 weeks after the previous dose titration and will be based on tolerability 
and CP score. 
Patients who complete Week 48 will continue double-blind treatment until all randomized patients have completed their 
participation in the 48-week treatment period and the database for that period is locked. 
 
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures  
Treatment Period (Weeks) 
Long-Term 
Safety Extension 
Screening 
Day 1a,b 
3c 
6d 
12 
18 
24 
30 
36 
48/ ET/ 
EOS/EOT 
Every 3 months 
Visit Window 
(+/-) 
-28 to -14 days 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±2 wks 
Fast ≥8 h Prior to Visite 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
Medical/PBC History 
X 
Inclusion/Exclusion Criteria 
X 
X 
Physical Examf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical and Surgical Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessments for Child-Pugh Scoreg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Questionnaires (Pruritus 
VAS, PBC-40, EQ- 5D-5L, and 
CLDQ)h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization/Treatment Assigned 
X 
Dispense IPi 
X 
X 
X 
X 
X 
X 
X 
X 
Dose Titration Assessmentj 
 
X 
X 
X 
X 
X 
X 
X 
IP Accountability/ 
Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 1: 
Schedule of Study Procedures (Continued) 
 
 
Treatment Period (Weeks) 
Long-Term 
Treatment 
Screening 
Day 1a,b 
3c 
6d 
12 
18 
24 
30 
36 
48/ ET/ 
EOS/EOT 
Every 3 months 
Visit Window  
(+/-) 
-28 to -14 days 
 
±1 wk 
 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±2 wks 
Urinalysis (dipstick) 
X 
X 
 
 
 
 
 
 
 
X 
Xo 
Urine-based β-hCG Pregnancy Testk 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Virology (HCV/HBsAG) 
X 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry/Hematology/ 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Markers of Inflammation: IL-6, 
hs-CRP, TNF-α, IgM, IgG, IgA, 
CK-18-M30  
 
X 
 
 
X 
 
X 
 
X 
X 
 
PK Fasting Collection 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
PK Serial Collectionl 
 
 
 
 
X 
X 
X 
X 
 
X 
 
PD Markers: Bile Acid/C4/FGF-19 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
TE/ELF (HA, P3NP, and TIMP-1)m 
 
X 
 
 
X 
 
X 
 
X 
X 
Xn 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
Xo 
Hepatic Ultrasoundp 
X 
 
 
 
 
 
X 
 
 
X 
Xn 
AE = adverse event; eCRF = electronic case report form; C4 = 7α hydroxy-4-cholesten-3-one; CK 18 M30 = cytokeratin-18 neoepitope M30; CLDQ = Chronic Liver Disease 
Questionnaire; ELF = enhanced liver fibrosis; ET = Early Termination; EOS = End of study; EOT = End of Treatment; ; FGF-19 = fibroblast growth factor-19; HA = hyaluronic 
acid; HCV = Hepatitis C virus; hs-CRP = high-sensitivity C-reactive protein;  IL-6 = Interleukin 6; IP = Investigational Product;  IgA = immunoglobulin A; IgG = immunoglobulin 
G; IgM = immunoglobulin M; P3NP = procollagen 3 N-terminal peptide;  PBC = primary biliary cirrhosis; PK = pharmacokinetics; TE = transient elastography; wk(s) = week(s), 
TNF-α = tumor necrosis factor-α; TIMP-1 = tissue inhibitor of metalloproteinase ; VAS = Visual Analogue Scale. 
a 
Visit schedule should be based on Day 1.  Day 1 visit must occur at least 2 weeks after screening visit. 
b 
Patients should be contacted by telephone/email every 3 weeks (±1 week) between clinic visits starting at Week 9 and continuing to Week 48 to assess for AEs, concomitant 
medications, medical/surgical procedures, and verify that s/he is dosing as directed. (see Section 9.7.8). 
c 
Preferably, the patient comes in to the clinic for this visit.  Alternatively, site will telephone the patient for assessments and a home health nurse will visit to draw safety labs. 
d 
Visit should occur 3, 4, or 5 days after taking the Week 6 dose. 
e 
The patient should be instructed to fast overnight (at least 8 hours) prior to each visit.  Fasting is required prior to all study visits, including screening, but water is permitted. 
f 
Height and assessment of smoking and alcohol consumption history and current habits will be assessed at Screening and Week 48.  Assessment of smoking and alcohol 
consumption history and current habits will be assessed quarterly after Week 48.    
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g 
Child-Pugh Score will be calculated based on ascites assessment, hepatic encephalopathy grade, and central laboratory evaluations per the Child-Pugh scoring system noted in 
the eCRF. 
h 
The EQ-5D-5L Quality of Life questionnaire is validated for use in multiple languages. If a validated translation is not available in the local language required for a specific 
study patient, the questionnaire will not be collected.  The CLDQ measures change over time in patients with chronic liver disease.  
i  
New investigational product bottles will be dispensed if the patient is up-titrated. Unless up-titrated, patients are expected to use up each investigational product bottle before 
a new bottle will be dispensed.  No new bottles will be dispensed if dose frequency is changed.  Patients will be instructed to begin dosing on Day 1, after completing all study 
assessments.  Patients will be instructed to take investigational product at approximately the same time of day.  Patients must be instructed to swallow the tablet whole; they 
must not chew, divide, or crush the tablet. 
j  
Dose titration of investigational product may occur starting after the Week 12 Visit, or any study visit thereafter for patients on all dosing regimens, based on CP score, 
tolerability, and safety laboratory tests from the previous visit.  Subsequent dose titration(s) may occur no earlier than 6 weeks after the previous dose titration and will be 
based on tolerability and CP score.   
k 
Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry and at every visit (except Week 3).  If positive, a confirmatory blood test 
must be performed at the central laboratory.  If the confirmatory blood test is also positive, the patient may not continue in the study.  (Additional testing may be conducted 
where required, regionally). 
l  
The patient will be given the option to return to the clinic the following morning for the 24-hour postdose sample or samples can be obtained by a home health care designee.. 
Patients who are discontinued from investigational product prior to completion of the study are encouraged to continue to follow the regular visit schedule, with the exception 
of PK sampling.   
m 
The noninvasive radiological liver fibrosis measurement devices (such as, FibroScan® device [Echosens; Paris, France]) will be used at all study sites to collect hepatic 
stiffness measurements.   
n 
Patients will complete a TE/ELF and ultrasound assessment, every 6 months (±2 weeks) after Week 48. 
o 
ECG and urine dipstick will be done yearly (±2 weeks) after Week 48 Visit.  
p 
Ultrasound will be conducted to enhance HCC surveillance.  For all on study (eg, post-Day 0) ultrasounds:  Unless HCC has already been confirmed by biopsy, a second 
 
confirmatory image (eg, MRI) should be obtained to confirm suspected HCC.   
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7.1.3. 
Study Duration 
Patients will receive double-blind treatment for at least 48 weeks.  Patients who have completed 
their 48-week double blind treatment period will continue double-blind treatment until all 
randomized patients have completed their 48-week treatment period and the database for that 
period is locked (approximately 3 years).  Patients will then be given the option to go on 
open-label treatment. 
7.2. 
Number of Patients 
Approximately 50 patients will be enrolled in this study. 
7.3. 
Planned Dosing Regimen 
All patients will initiate investigational product once weekly with OCA 5 mg or matching 
placebo (Table 2).  Titration may be considered as early as the Week 12 Visit.  Following visit 
procedures at Week 12, if the investigational product is tolerated and laboratory assessments do 
not indicate a safety concern, the patient may up-titrate to OCA 5 mg twice weekly and may start 
the higher dose regimen no earlier than 2 days after they took their last dose.  Dosing will then 
occur at least 3 days apart.  Every 6 weeks thereafter, based on safety and tolerability 
assessments, patients can be considered for further up titration as described below (Table 2).  At 
each titration visit, the patient may start the higher dose regimen no earlier than 2 days after the 
prior dose. 
Patients with CP-B may titrate to a maximum dose of OCA 5 mg once daily.  
Patients with CP-C may titrate to a maximum dose of OCA 10 mg twice weekly at least 3 days 
apart.  
If, during the course of the study, a patient transitions from CP- B to CP-C, or vice versa, the 
maximal dose for the new CP classification would apply (Table 3). 
Table 2: 
Planned OCA or Matching Placebo Dosing Regimen by Child-Pugh Score 
 
Child-Pugh B 
(Moderate Hepatic Impairment) 
Child-Pugh C 
(Severe Hepatic Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting Dose (Day 1) 
5 mg once 
weekly 
matching placebo 
5 mg once 
weekly 
matching placebo 
Titration 1a  
 
5 mg twice 
weeklyb 
matching placebo 
5 mg twice 
weeklyb 
matching placebo 
Titration 2a  
10 mg twice 
weeklyb 
matching placebo 
10 mg twice 
weeklyb 
matching placebo 
Titration 3a  
5 mg once daily 
matching placebo 
NA 
NA 
a Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on patient 
tolerability and/or changes in Child-Pugh Score at any time during the study. 
b Dosing per the twice weekly schedule must be at least 3 days apart. 
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7.4. 
Dose Adjustment Criteria 
Dose titration may follow the scheduled dosing regimens described in Section 7.3 or occur due to 
tolerability concerns or as a result of changes in a patient’s CP Score. 
Dose titrations may involve increases or decreases in dosing frequency and are dependent on 
tolerability (as assessed by a review of AEs and safety laboratory results).  In general, 
down-titration may be done in response to tolerability concerns and can occur at any time.  
Up-titration will be done per protocol based on tolerability, as assessed by the Investigator based 
on response, or following resolution of a tolerability concern that previously led to 
down-titration.  Up-titrations may only occur to the maximum dose and frequency indicated for 
each dosing regimen as defined in Section 7.3. 
Scheduled Dose Titration - After initiation of OCA or matching placebo, titration may be 
considered as early as the Week 12 Visit.  Subsequent titrations in dose or dosing frequency for 
patients may occur no earlier than 6 weeks following an up-titration. 
Tolerability Dose Titration - Investigators may decrease the dosing frequency or dose as 
considered clinically appropriate (eg, tolerability) 
Dose Titration due to Change in CP Score – Over the course of the study, a patient’s CP 
category may change.  When a patient demonstrates a change in CP category (as assessed per 
Table 10), dosing should be reassessed and modified if appropriate (Table 2).  Changes to the 
dosing regimen are not mandatory and should be based on clinical judgment and change in CP 
score.  The titration steps for CP-B and CP-C patients are identical with exception of the 
maximum allowed dose.  Therefore, if a patient changes CP class from B to C, or vice versa, the 
maximal dose for the new regimen will apply (Table 3).  If a patient improves to CP-A during 
the study, the maximal CP-B dose will still apply.  If a patient has not yet reached the maximal 
dose, the appropriate titration regimen (Table 2) should be followed.  
Table 3: 
Maximum Daily dose based on change in Child-Pugh Category 
Original Status 
New Statusa 
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Child-Pugh B 
No change 
No change 
10 mg twice weekly  
Child-Pugh C 
5 mg once daily 
5 mg once daily 
No change 
 
a  Once a patient begins dosing with the new dosing regimen, titration should occur as described for that dosing regimen in 
Section 7.3 .  
b Dosing per the twice weekly schedule must be at least 3 days apart. 
CP Scores will be calculated at all study visits (except Week 3).  While PBC-specific versions of 
CP scores are available, this study will use the standard calculation (Pugh 1973, Lucey 1997).  
All associated visit data (including central laboratory results) should be entered into the 
electronic case report form (eCRF) in a timely fashion to confirm that the patient’s CP Score has 
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not changed.  If a change in CP Score is observed independent of a study visit, the patient should 
be contacted via phone to discuss the need for a dosing modification and should be asked to 
return to the investigative site as soon as possible if a new bottle of investigational product is 
required to be dispensed. 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements 
Tolerability of investigational product must be assessed prior to titrating a patient to a higher 
dose.  To determine if a patient is eligible for a dose up-titration refer to Section 7.3. 
7.5. 
Criteria for Study Termination 
The Sponsor (Intercept Pharmaceuticals, Inc.) reserves the right to terminate the study at any 
time.  It is normal procedure to review the emerging clinical and safety data.  As a result of such 
a review or a recommendation by the Data Monitoring Committee (DMC), it may be necessary 
to stop the study before all patients have completed the study.  In addition, the Sponsor may 
terminate the study at an investigational site at any time (eg, Good Clinical Practice [GCP] 
noncompliance or poorly performing sites, as determined by the number of patients enrolled or 
the quality of the study data). 
The Investigator and/or Sponsor (or designee) must notify the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) of discontinuation of a site or the study and the 
reason for doing so. 
Investigators will be informed by the Sponsor as to when the final study visit is to be completed, 
and should then schedule all patients for the end of study (EOS) or end of treatment (EOT) Visit.  
8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Population 
This study will be conducted at approximately 35 international study sites with experience in 
treating patients with PBC with moderate to severe hepatic impairment defined as CP-B and 
CP-C.  Prospective patients will be identified primarily from the hospital and/or physician’s 
database of patients with PBC, or may be referred from other physicians.  Patients may self-refer 
to an Investigator if they become aware of the study through local, national, or international PBC 
patient societies, forums, or networks. 
8.2. 
Patient Inclusion Criteria 
1. A definite or probable diagnosis of PBC (consistent with American Association for the 
Study of Liver Diseases [AASLD] and European Association for the Study of the Liver 
[EASL] Practice Guidelines [Lindor 2009, EASL 2009]), defined as having ≥2 of the 
following 3 diagnostic factors: 
 History of elevated ALP levels for at least 6 months 
 Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer 
(≤1:80), PBC-specific antibodies (anti-GP210 and/or anti-SP100) and/or 
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antibodies against the major M2 components (PDC-E2, 2-oxo-glutaric acid 
dehydrogenase complex)  
 Liver biopsy consistent with PBC (collected at any time prior to Screening) 
2. Evidence of cirrhosis including at least one of the following: 
 Biopsy results consistent with PBC Stage 4  
 Liver stiffness as assessed by TE Median Value ≥16.9kPa 
 Clinical evidence in the absence of acute liver failure consistent with cirrhosis 
including: gastroesophageal varices, ascites, radiological evidence of cirrhosis 
(nodular liver or enlargement of portal vein and splenomegaly) 
 Combined low platelet count (<140 000/mm3) with 
 
persistent decrease in serum albumin, or  
 
elevation in prothrombin time /INR (not due to antithrombotic agent use), 
or 
 
elevated bilirubin (2× ULN) 
3. Satisfy the criteria of the modified CP classification for hepatic impairment during 
Screening (ie, within 14 days before the first dose of investigational product): 
 Moderate:  CP-B (Scores 7 to 9) or 
 Severe:  CP-C (Scores 10 to 12) 
4. MELD score of 6 to 24 at Screening 
5. Age ≥18 years 
6. Taking UDCA for at least 12 months (stable dose for ≥3 months) prior to Day 1, or 
unable to tolerate or unresponsive to UDCA (no UDCA for ≥3 months) 
7. Contraception:  Female patients must be postmenopausal, surgically sterile, or if 
premenopausal (and not surgically sterile), be prepared to use ≥1 effective method of 
contraception during the study and for 30 days after the end of treatment visit.  Effective 
methods of contraception are considered to be those listed below: 
 Barrier method, ie, (a) condom (male or female) with spermicide or 
(b) diaphragm with spermicide; or 
 Intrauterine device; or 
 Vasectomy (partner); or 
 Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection); or 
 Abstinence, if in line with the preferred and usual lifestyle of the patient (where 
abstinence is defined as refraining from heterosexual intercourse)  
8. Must provide written informed consent and agree to comply with the study protocol. 
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8.3. 
Patient Exclusion Criteria 
1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6) 
2. History of liver transplant or organ transplant  
3. History of alcohol or drug abuse within 12 months prior to Screening 
4. Hepatic encephalopathy (as defined by a West Haven score of ≥2 [AASLD, EASL 2014]) 
5. History or presence of other concomitant liver diseases including: 
a. Hepatitis C virus infection and RNA positive 
b. Active hepatitis B infection; however, patients who have seroconverted (hepatitis B 
surface antigen and hepatitis B e antigen negative) may be included in this study after 
consultation with the medical monitor 
c. Primary sclerosing cholangitis 
d. Alcoholic liver disease 
e. Definite autoimmune liver disease or overlap hepatitis 
f. Gilbert's Syndrome 
6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function 
prior to randomization 
7. Patients with history or presence of hepatorenal or hepatopulmonary syndrome 
8. Patients with significant active infection (ie spontaneous bacterial peritonitis) 
9. Patients with known or suspected hepatocellular carcinoma 
10. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
11. Participation in another investigational product, biologic, or medical device study within 
30 days prior to Screening.  Participation in a previous study of OCA is allowed with 
3 months washout prior to enrollment in this study 
12. Mental instability or incompetence, such that the validity of informed consent or ability 
to be compliant with the study is uncertain 
13. UDCA naïve (unless contraindicated) 
8.4. 
Dose Adjustment, Interruption, and Withdrawal from 
Investigational Product or Study 
Investigational product may be temporarily decreased (eg, by decreasing dosing frequency) or 
temporarily or permanently stopped based on tolerability concerns.  The dose of investigational 
product should be resumed to the maintenance dose in a blinded manner once the issues relating 
to the lack of tolerability are resolved.   
Patients who are discontinued from investigational product prior to completion of the study are 
encouraged to continue to follow the regular visit schedule, with the exception of PK sampling, 
but may withdraw consent at any time. 
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8.4.1. 
Reasons for Additional Monitoring or Mandatory Interruption of 
Investigational Product 
8.4.1.1. 
Reasons for Additional Monitoring Related to Liver Chemistries 
Patients who develop ALT or AST >2× baseline (and >ULN) or total bilirubin >1.5× baseline 
(and >ULN) should have repeat testing within 48 to 72 hours to confirm values.  Patients with 
persistent elevations (eg, additional lab testing per Investigator discretion) should be closely 
monitored.  Concomitant elevations in total bilirubin or INR with persistent increases in ALT or 
AST should also be closely monitored. 
8.4.1.2. 
Reasons for Investigational Product Interruption Related to Elevated Liver 
Chemistries 
Development of any of the following clinical laboratory values, without explanation, during the 
study mandates investigational product interruption: 
 AST and/or ALT >3× baseline (and >ULN) 
 Total bilirubin >2× baseline (and >ULN) 
Repeat testing within 48 to 72 hours to confirm the abnormalities and to determine if they are 
increasing or decreasing should be performed.  Detailed adverse event information should also 
be collected, and the patient should be investigated for possible causes of the liver chemistry 
changes, as appropriate.  The Investigator should obtain a history of concomitant medications 
(including nonprescription medications and herbal and dietary supplement preparations) and 
other possible causes of liver enzyme and bilirubin increases.  Any potentially hepatotoxic 
medications should be identified and discontinued if advisable.  
If symptoms persist or repeat testing shows AST or ALT >3× baseline (and >ULN) or total 
bilirubin >2× baseline (and >ULN), patients should be followed as clinically indicated depending 
on other laboratory and clinical signs and symptoms.   
For the purposes of this protocol, if the above referenced significant elevation in liver enzyme or 
bilirubin levels resolve following interruption of investigational product and no other cause for 
the elevation is identified, the elevations should be assumed to be related to investigational 
product and investigational product should be discontinued.  If the liver enzyme or bilirubin 
levels do not resolve following interruption of investigational product and no other cause for the 
elevation is identified, it may be assumed that the elevations were due to disease progression and 
the patient may be re-challenged following a discussion between the Investigator or designee and 
the Sponsor. 
Elevation of liver enzymes or bilirubin is based on comparison to baseline values defined as the 
mean of all available Screening and Day 1 values, which are the mean of all available 
evaluations prior to the first administration of investigational product.  At least 2 of these 
samples will be obtained a minimum of 2 weeks apart during the Screening period.  Elevations 
that occur gradually over the course of the study may be indicative of disease progression and 
should be assessed as clinically appropriate.  Liver enzyme and bilirubin elevations that occur 
over a shorter time, such as within a 6-month period, should be evaluated for drug-induced liver 
injury as provided in the guidelines below. 
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If at any time a patient develops signs or symptoms of hepatotoxicity such as new onset fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>7%) 
in combination with elevations in liver enzymes, investigational product should be interrupted 
and liver enzymes monitored until signs or symptoms resolve.  
Patients who develop evidence of severe drug-induced liver injury that is suspected to be 
causally related to the investigational product should be discontinued from investigational 
product and should not be rechallenged.  Severe drug-induced liver injury includes, but is not 
limited to, functional hepatic impairment, as indicated by rising bilirubin or INR that cannot be 
explained by progression of disease.  Natural progression of the underlying condition and other 
causal factors such as a common bile duct stone or development of other concurrent liver disease 
should be considered before the investigational product is permanently discontinued.  
If after all investigations and actions outlined above have been completed, the investigator 
determines that the elevations in liver biochemistries are considered not related to investigational 
product, the Sponsor must be contacted before investigational product can be reinitiated.  
Follow-up procedures for patients resuming treatment, including laboratory evaluations and 
physical examinations, must be performed after a maximum of 2 weeks of retreatment.  Results 
must be reported to the site as soon as possible so the Investigator can determine if it is 
appropriate for the patient to continue treatment.   
The Medical Monitor must be contacted in all cases of persistent liver biochemistry elevations. 
All hepatic injury events, regardless of relationship to investigational product, will be 
adjudicated by the Hepatic Safety Committee (see Section 15.9). 
8.4.1.3. 
Pregnancy 
If a female patient becomes pregnant, she must interrupt treatment with investigational product 
immediately, but should continue with the study visit schedule.  As described in Section 13.1.9 
pregnancy is not considered an AE for reporting purposes.  The patient may restart 
investigational product when she is no longer pregnant or breastfeeding (if applicable) at the 
discretion of the Investigator and after discussion with the Medical Monitor as described in 
Section 13.1.9).  New baseline procedures should include pregnancy testing. 
8.4.2. 
Reasons for Mandatory Discontinuation of Investigational Product 
Patients who undergo a liver transplant during the course of the study must discontinue 
investigational product and discontinue the study visit schedule.  However, these patients should 
be encouraged to consent to the semiannual telephone contact and/or continued record review 
only to allow for secondary outcome events data to be collected. 
8.4.3. 
Other Reasons for Discontinuation of Study or Investigational Product  
The following events are considered appropriate reasons for a patient to discontinue 
investigational product; however, these patients are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
 Patient begins treatment with commercially available OCA. 
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 The Investigator or Sponsor considers that it is advisable or in the best interest of the 
patient. 
 The occurrence of clinical or laboratory AEs considered by the Investigator to be 
clinically important safety concerns and related to study drug. 
 Withdrawal of consent  
 Consent may be fully withdrawn (in which case the patient discontinues both 
investigational product and study visits and procedures). 
 Consent may be modified to discontinue study visits but allow semi-annual 
telephone contact. 
 Consent may be modified to discontinue study visits or semi-annual telephone 
contact but allow continued access to medical records to assess for suspected 
major adverse cardiovascular events (MACE) and liver-related clinical events. 
  Early termination procedures should be conducted if the patient withdraws 
consent (see Section 9.7.13). 
The Investigator is encouraged to contact the Sponsor prior to discontinuing a patient from 
treatment.  The Investigator must notify the Sponsor study monitor by telephone or email as soon 
as possible if any patient prematurely withdraws from the study. 
8.4.3.1. 
Withdrawal of Consent to Continue in the Study  
If the patient decides that it is in his/her best interest to discontinue from the study, he or she may 
withdraw consent.  It is fully understood that all patients volunteer for the study and that they 
may withdraw their consent to continue in the study at any time. 
Early termination procedures should be conducted if the patient withdraws consent (See 
Section 9.7.13). 
A reasonable effort must be made to determine the reason(s) for patient discontinuation.  This 
information and date must be recorded in the appropriate eCRF. 
8.4.3.2. 
Lost to Follow-Up 
Patients will be considered “lost to follow-up” only after documented attempts to reach the 
patient prove unsuccessful.  A reasonable effort (ie, 2 phone calls/messages, no response to 
registered letter) must be made to contact the patient and determine the reason(s) why a patient 
fails to return for a study visit or is lost to follow-up.  This information and date of contact must 
be recorded in the appropriate eCRF. 
8.4.4. 
Patient Discontinuation Notification 
The Investigator must notify the Sponsor as soon as possible if any patient prematurely 
discontinues from the study.  The date when the patient is withdrawn and the primary reason(s) 
for discontinuation must be recorded in the eCRF; additional information may be requested by 
the Sponsor to complete a discontinuation narrative.  This information must be documented in 
the eCRF. 
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If a patient is withdrawn from the study early (regardless of the cause), all of the early 
termination (ET)/EOS evaluations are to be performed at the time of withdrawal, to the extent 
possible. 
9. 
TREATMENT OF PATIENTS 
9.1. 
Investigational Product Treatment Regimen 
The term investigational product refers to either OCA (provided as part of this clinical study) or 
placebo.   
Two treatment groups will be evaluated:  OCA and placebo.  Investigational product will be 
administered orally.  Each dose will be made up of 1 tablet (ie, one OCA 5 mg tablet or one 
OCA 10 mg tablet, or matching placebo).   
Investigational product will be taken orally with water for the duration of the study.  Patients will 
be instructed to begin dosing on Day 1 and are to take investigational product at approximately 
the same time on dosing days.  Patients must be instructed to swallow the tablet whole; they must 
not chew, divide, or crush the tablet. 
At each study visit where the dose of investigational product is administered at the site, all 
assessments, except for the post-dose collection of blood samples for the PK assessment, must be 
completed before administration of investigational product. 
9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.2) 
will be used at the discretion of the usual care provider (or Investigator if also the usual care 
provider).  Relevant information about all concomitant medications (including prescribed, over 
the-counter, or herbal preparations) taken within 30 days of Screening and during the study must 
be recorded in the source documents and eCRF, as well as any dose or dose regimen changes that 
occur during the study.  Concomitant medications should be stable prior to Day 1. 
PBC Specific Therapy 
Investigators will be encouraged to follow guidelines for care based upon local and institutional 
practice patterns and any relevant published practice guidelines.  Throughout the course of the 
study, Investigators are expected to monitor patients’ PBC regimens and, if responsible for usual 
care, may adjust the regimen to achieve locally-appropriate treatment goals.  These goals will be 
individualized, with the understanding that currently applicable PBC guidelines may vary across 
different geographic regions. 
Ideally, patients should generally remain on the baseline PBC therapies throughout the course of 
the study, unless the baseline PBC therapy is no longer considered clinically appropriate by the 
Investigator.  In addition, patients should be reminded to keep taking their blinded 
investigational product. 
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9.2.1. 
Drug Interactions 
Bile acid sequestrants (BAS, including cholestyramine and its derivatives, colestipol, 
colesevelam, or other sequestrants) or aluminum hydroxide- or smectite-containing antacids 
should not be taken within 4 hours of taking investigational product (and UDCA if applicable), 
ie, BAS should be administered at minimum 4 hours before or 4 hours after investigational 
product administration. 
OCA taken concomitantly with warfarin may result in decreased INR levels; therefore, INR 
should be monitored and the dosage of warfarin adjusted, as needed during treatment with OCA 
and after cessation of OCA, to maintain the target INR range.  
The effect of OCA on drug metabolizing enzymes has been evaluated in both in vitro and clinical 
studies.  The PK profile of caffeine, a sensitive CYP1A2 substrate probe, showed weak effect of 
OCA on CYP1A2.  Based on these results, OCA may increase the exposure of narrow 
therapeutic index drugs that are substrates for CYP1A2, such as theophylline and tizanidine. 
Information related to additional drug-drug interaction (DDI) studies is available in the current 
version of the IB.  The aforementioned sections of the IB should be referred to during the course 
of the study, and are accessible to Investigators to help facilitate the assessment of potential 
DDIs with OCA that may be observed in study patients. 
9.2.2. 
Prohibited Medications 
Commercial OCA therapy (if available) is prohibited while on investigational product, and if 
prescribed during the course of the study, the Investigator should be cognizant of the possibility 
of double dosing.  Patients who continue with commercial OCA therapy must discontinue 
investigational product and are expected to continue through the end of the study (see 
Section 8.4.3).   
9.3. 
Treatment Compliance 
The Investigator should assess the patient’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Patients should be instructed to retain all bottles of investigational product, even if empty, and to 
return them to the Investigator at the indicated visits (Table 1).  The Investigator or designee 
should perform investigational product accountability (ie, count of returned tablets) and, if 
applicable, follow-up with the patient to retrieve any investigational product bottles that have not 
been returned.  
If the Investigator has concerns about a patient’s dosing compliance, he or she should discuss 
this with the patient, assess the reasons for noncompliance and the likelihood that the patient will 
remain noncompliant, and notify the Sponsor accordingly.   
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9.4. 
Randomization and Blinding 
9.4.1. 
Methods of Assigning Patients to Treatment Groups 
This study will be conducted in a double-blind, placebo-controlled manner.  Enrolled patients 
who meet all eligibility requirements will be randomized in a 1:1 ratio to one of two treatment 
groups:  placebo or OCA based on a predefined randomization code (generated by Sponsor or 
designee) using an interactive web response system (IWRS), which the Sponsor intends will 
serve as a computer-based patient registration system at Screening and Day 1.   
Randomization will be stratified by CP class (CP-B or CP-C).  Baseline MELD scores will be 
monitored on an ongoing basis to ensure adequate distribution of MELD scores.  The IWRS will 
serve as the investigational product inventory and management system and may be integrated 
with the study database.  
The Investigator or designee will be required to register the patient in the IWRS and may be 
prompted to provide patient data necessary to properly randomize and allocate the patient to 
treatment.  A randomization number will be assigned and investigational product (OCA or 
placebo) dispensing information will be provided (eg, bottle numbers allocated) while 
maintaining the study blind.   
9.4.2. 
Blinding 
The Sponsor, patients, Investigator, and study site staff will be blinded to the patient’s treatment 
allocation during the patient’s participation in the double-blind phase of the study.     
9.4.3. 
Emergency Unblinding Procedures 
Treatment assignment for individual patients will be made available to the Investigator for 
medical emergency use only (such as unblinding which is necessary in order to treat an serious 
adverse event [SAE] through the IWRS system).  When possible, the Medical Monitor should be 
consulted in the event that a medical emergency necessitates unblinding (ie, in situations where 
knowledge of the blinded treatment assignment is necessary for further medical management of 
the patient).  If it is not reasonable to inform the Medical Monitor in advance of the unblinding, 
the Investigator must promptly document in the patient’s record the rationale for unblinding and 
should subsequently contact the Medical Monitor to explain any premature unblinding of 
treatment assignment.  Procedures for unblinding a patient’s treatment will be provided 
separately to the Investigator.  Similarly, if the Medical Monitor breaks the blind for an 
individual patient for the purpose of evaluating an emergent safety issue, the Medical Monitor 
will document within study documentation the rationale, circumstances, and the person or 
persons being informed about the unblinding. 
The DMC will have access to the IWRS and will be able to unblind individual patients.  Refer to 
Section 15.8 for further details regarding DMC access to blinded and unblinded data.  The DMC 
will document details about any unblinded patient data reviews in the closed session DMC 
minutes, which will be made available to the Sponsor only after the database is locked and the 
study is unblinded.  Cases of premature unblinding, as noted above, will also be reviewed by the 
DMC.  
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Access to treatment assignments will also be made available to the designated Intercept staff 
responsible for expedited safety reporting of suspected unexpected serious adverse reactions 
(SUSARs) to the Regulatory Authorities. 
9.5. 
Assignment of Site and Patient Numbers 
9.5.1. 
Site Numbers 
Each study site selected to participate in this study will be assigned a site number by the Sponsor.  
The site number will be used to categorize patient data and to identify the site and/or Investigator 
within study documents.  This number will be recorded in the eCRF. 
9.5.2. 
Patient Numbers 
Patients will be identified by a unique 6-digit number, independent of the randomization number.  
The first 3 digits will represent the site number and the last three digits will represent the 
Screening number. 
9.6. 
Restrictions 
Participation in another investigational product, biologic, or medical device study within 30 days 
prior to Screening and during the course of the study is prohibited.  Previous exposure to OCA 
(as a study participant or received commercial OCA therapy) is allowed provided patients 
haven’t taken OCA within 3 months prior to enrollment in this study. 
9.6.1. 
Fasting Requirement at Study Visits 
All patients must have been fasting for at least 8 hours prior to their Screening Visit and all 
subsequent study visits, as all analytes will be assayed in fasting blood or plasma samples.  
Water is permitted during the fasting period. 
9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visit windows are specified in the Schedule of Study Procedures (Table 1).  Visits should be 
based on Day 1 (not on the prior visit) unless stated otherwise.  For example, Week 6 should 
ideally occur 6 calendar weeks (± 7 days) following Day 1.   
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk, and benefit of the 
study to the patient and will provide him/her with a copy of the informed consent form (ICF).  
The patient will be given sufficient time to consider the study before deciding whether or not to 
participate.  The patient will be informed that participation is voluntary and that her/his future 
medical treatment will not be compromised by participation in the study and that he or she can 
withdraw from the study at any time.  The patient must be willing and able to provide written 
informed consent (on hard copies) before entering the study.  The Investigator or a medically 
qualified designee is responsible for administering and documenting the written informed 
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consent of the patient.  The patient will be given a copy of the patient information sheet (PIS) 
and his/her signed and dated consent form.  Patients will also be provided a separate ICF before 
providing blood samples for genetic analysis and must be willing and able to provide consent as 
described above. 
9.7.3. 
Assessing Cirrhosis 
Acceptable methods of confirming (via medical history) or assessing cirrhosis for purposes of 
the study are defined as a patient who has documented evidence or presence of one or more of 
the following cirrhosis indicators: 
 Biopsy results consistent with PBC Stage 4 (Ludwig 1978)   
 Transient Elastography Median Value ≥16.9 kPa (Corpechot 2012) 
 The presence of any of the following (unless exclusionary per Section 8.3) in the 
absence of acute liver failure: 
 Gastroesophageal varices 
 Ascites 
 Radiological evidence of cirrhosis (nodular liver or enlargement of portal vein 
and splenomegaly) 
 Combined low platelet count (<140 000/mm3) with: 
 persistent decrease in serum albumin, or  
 elevation in prothrombin time /INR (not due to antithrombotic agent use), or 
 elevated bilirubin (2× ULN) 
9.7.4. 
Screening Procedures (14 days to 28 days prior to Day 1) 
Informed consent must be obtained from the patient before performing any study-related 
procedures, including Screening procedures.  The Screening Visit assessments must be 
performed ≥14 days but less than 28 days prior to Day 1 to determine whether the patient meets 
all the inclusion criteria and none of the exclusion criteria.  Patients who do not fulfill all 
eligibility criteria will not be enrolled in the study.  Patients may be rescreened after 2 months 
have elapsed from the date of their most recent screening visit procedure; however, all Screening 
procedures (including obtaining informed consent) should be repeated and a new three-digit 
Screening number assigned.   
Screening Visit procedures are as follows: 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits. 
 Collect medical history. 
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 Collect PBC history.  
 Verify inclusion and exclusion criteria for eligibility. 
 Perform a physical examination, including height, smoking and alcohol consumption 
history, and current habits for both.  
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record any pretreatment-emergent AEs. 
 Record prior (if within 30 days of Screening) and current concomitant medications. 
 Perform a standard 12-lead electrocardiogram (ECG). 
 Perform assessments for calculation of CP Score (Section 14.1.1) 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Virology Screen (HCV and HBsAg) 
 Obtain urine sample for urinalysis (dipstick). 
 Perform a urine-based beta human chorionic gonadotropin (β-hCG) pregnancy test in 
females of childbearing potential.  
 Instruct the patient to fast overnight (at least 8 hours) before the next visit (water is 
permitted). 
 Record the visit in IWRS.  
 Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites).  If an ultrasound has 
been done within 12 months of Screening, and a report/adequate data are available, a 
pretreatment ultrasound at Screening is not required.  If the ultrasound cannot be 
performed at Screening (eg, device/technician unavailability, scheduling issues, etc), 
the procedure may be completed anytime within the screening visit window or on 
Day 0.  Results from the screening ultrasound should be reviewed to assess possible 
exclusion criteria prior to randomization. 
9.7.5. 
Day 1 Procedures (Randomization) 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits. 
 Review inclusion and exclusion criteria for eligibility. 
 Perform a physical examination.  
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 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant heath care professional (HCP) or non-HCP related office 
visits that have occurred since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record any pretreatment-emergent AEs. 
 Review and record prior concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (Section 13.2.6). 
 Randomize the patient only if s/he meets all inclusion criteria and no exclusion 
criteria. 
 Record the visit in IWRS and dispense investigational product 
 Instruct the patient to begin dosing on the day of the Day 1 Visit.   
 Obtain urine sample for urinalysis (dipstick). 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Markers of inflammation and fibrosis (IL-6, hs-CRP, TNF-α, IgM, IgG, IgA, 
CK-18-M30, ELF [HA, P3NP, and TIMP 1]) 
 Fasting PK assessment 
 Bile Acid/C4/FGF-19  
 Perform TE using the Fibroscan® TE device.  If the TE cannot be performed on 
Day 1 (eg, device/technician unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be completed within the Day 1 
Visit window, (if data is needed for cirrhosis assessment) or as close as possible to the 
Day 1 Visit, preferably, after patient eligibility has been confirmed.  Instruct the 
patient to take Day 1 dose on the day of this visit. 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
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9.7.6. 
Week 3 Safety Visit Procedures 
Preferably, the patient will come in to the clinic for this visit.  Alternatively, the site will 
telephone the patient for assessments and a home health nurse will visit to draw safety labs. 
 Verify that patient is dosing as directed. 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits. 
 Review and record prior concomitant medications. 
 Assess and record AEs. 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Schedule the next visit (Week 6), reiterate dosing instructions, and advise the patient: 
Week 6 Visit should occur 3, 4, or 5 days after taking the Week 6 dose, eg, if the 
Week 6 dose is taken on a Sunday, the patient should come in for the Week 6 Visit 
within the following Wednesday and Friday (Figure 2). 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.7. 
Week 6 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
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 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform a physical examination.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.6). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Bile Acids/C4/FGF-19 
 Fasting PK assessment 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.8. 
Week 9 through Week 48 (Safety Contact) 
Patients should be contacted by telephone/email at Week 9 and every 3 weeks afterward to 
Week 48. 
 Contact patient by phone/email. 
 Review and record prior concomitant medications. 
 Assess and record AEs. 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess investigational product compliance, perform investigational product 
accountability. 
9.7.9. 
Week 12, Week 24, Week 36 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
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 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Perform a physical examination.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.6). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible. (Refer to Section 7.3) 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed.   
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation 
 Markers of inflammation and fibrosis (IL-6, hs-CRP, TNF-α, IgM, IgG, IgA, 
CK-18-M30, ELF [HA, P3NP, and TIMP 1])  
 Bile Acid/C4/FGF-19  
 Fasting PK assessment 
 Perform TE using the Fibroscan® TE device.  If the TE cannot be performed on visit 
day (eg, device/technician unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be completed within the visit 
window (if data is needed for cirrhosis assessment) or as close as possible to the visit. 
 Perform an ultrasound for HCC surveillance at Week 24 ONLY (if equipment is 
unavailable, sites should make every attempt to use available community referral 
sites). 
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 Serial PK assessment at Week 12 and 24 ONLY (not done at Week 36 and 
Week 42); the following procedures will be conducted in all patients: 
 30 minutes prior to dosing:  collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hour postdose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at:  1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post dose 
Note:  Patients should only consume a meal following the 4-hour and 7-hour PK 
assessment times (see Figure 3).  Patients should not drink any water until at least one 
hour postdose. 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.10. 
Week 18 and Week 30 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF. 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Perform a physical examination.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.6). 
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 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3). 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed.   
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Bile Acid/C4/FGF-19  
 Fasting PK assessment 
 Serial PK assessment; the following procedures will be conducted in all patients: 
 30 minutes prior to dosing: collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hour postdose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours postdose 
Note:  Patients should only consume meal following the 4-hour and 7-hour PK 
assessment times (see Figure 3).  Patients should not drink any water until at least one 
hour post dose 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.11. 
Week 48 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
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 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Perform a physical examination, including smoking and alcohol consumption history, 
and current habits for both.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform ECG. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.6). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3). 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed. 
 Perform urinalysis (dipstick) 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Markers of inflammation and fibrosis (IL-6, hs-CRP, TNF-α, IgM, IgG, IgA, 
CK-18-M30, ELF [HA, P3NP, and TIMP 1]) 
 Fasting PK assessment 
 Bile Acids/C4/FGF-19 
 Serial PK assessment; the following procedures will be conducted in all patients: 
 30 minutes prior to dosing: collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.   
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
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 Immediately following 1 hour post dose blood draw, administer meal replacement 
(to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post dose 
Note:  Patients should only consume meal following the 4-hour and 7-hour PK 
assessment times (see Figure 3).  Patients should not drink any water until at least one 
hour post dose 
 Perform TE using the Fibroscan® TE device.  If the TE cannot be performed on visit 
day (eg, device/technician unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be completed within the visit 
window (if data are needed for cirrhosis assessment) or as close as possible to the 
visit. 
 Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.12. 
Every 3 Months after Week 48  
Quarterly 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Perform a physical examination, including smoking and alcohol consumption history, 
and current habits for both.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
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 Administer Quality of Life and Patient questionnaires (see Section 13.2.6). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3 ). 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed. 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
Patients will complete a TE/ELF (HA, P3NP and TIMP 1) and ultrasound (for HCC 
surveillance) assessment, every 6 months (±2 weeks) after Week 48.  
ECG and urine will be done yearly (±2 weeks) after Week 48.    
9.7.13. 
End of Study/Early Termination/End of Treatment Procedures for Patients that 
Withdraw from Investigational Product or Withdraw Consent 
Patients who discontinue investigational product before Week 48 are expected to continue in the 
study until the end of the study (EOS [when subject terminates the study]) or at the discretion of 
the Sponsor.     
EOT (when subject discontinues investigational product)/ET procedures will be required 
whenever patients discontinue treatment with investigational product (Table 1, Section 9.7.11).  
The EOT/ET Visit (Table 1) and procedures listed below (Table 4) must be performed as close 
as possible to the patient’s last dose of investigational product.  When a patient discontinues or 
interrupts investigational product and continues with regularly scheduled study visits, the EOS 
Visit will be completed as the patient’s final study visit.  The actual investigational product 
discontinuation scenario (Table 4) will determine the sequence of the EOT/ET and EOS Visits 
and procedures.  In some cases, the EOT/ET Visit and procedures will precede the EOS Visit; in 
others, the EOT/ET and EOS Visits will be combined and performed as close as possible to the 
patient’s last dose of investigational product.  EOT and EOS Visits are encouraged but at no time 
will a missed EOT or EOS visit be considered a protocol deviation. 
When a patient ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (ET) (withdrawal of consent) or discontinuation, an 
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EOT/EOS Visit must be performed as near as possible to her/his last dose of investigational 
product and the procedures, listed below, performed.  The purpose of this visit is to conduct 
complete and/or final assessments on or as near as possible to the final day of dosing.  In some 
cases, the patient may discontinue on the day of a scheduled study visit.  In these cases, 
EOT/EOS Visit procedures should be performed in place of the scheduled study visit procedures.  
The data will be recorded as EOT/ET and EOS procedures in the eCRF. 
Table 4: 
Early Discontinuation Scenarios 
 
Investigational 
Product 
Consent 
Study Visit 
Status 
EOT Visita 
EOS 
Visita 
Early 
Termination 
Discontinued 
Withdrawn 
No additional 
visits except 
EOT/EOS 
Combined visit, completed as 
close as possible to last dose of 
investigational product. 
Treatment 
Discontinuationb 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as close as 
possible to last dose 
of investigational 
product. 
Complete 
at final 
study 
visit. 
Discontinued 
Record review 
only 
Record review 
only 
Combined visit, completed as 
close as possible to last dose of 
investigational product. 
Sponsor 
Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit, completed as 
close as possible to last dose of 
investigational product. 
Pregnancy 
Discontinued 
Complete per the above scenarios - Early Termination or Treatment 
Discontinuation 
Lost to Follow-
Up 
Discontinued 
LTF 
None 
Unable to complete due to LTF 
status 
EOS = end of study; EOT = end of treatment; LTF = lost to follow-up 
a Refer to Section 7.1.2, Schedule of Study Procedures for all procedures and evaluations required at the EOS and 
EOT Visits.  
b Includes initiation of commercially available OCA. 
9.7.14. 
Unscheduled Safety Visit 
The Investigator may schedule an at-clinic Unscheduled/Safety Visit at any time if clinically 
warranted.  Unscheduled and/or repeat assessments, including additional laboratory tests or 
investigations, may be conducted.   
As appropriate, the Medical Monitor should be contacted. 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
The investigational product is a white, round, film coated tablet containing OCA 5 mg or 10 mg 
or matching placebo.  The tablets contain the following inactive ingredients:  microcrystalline 
cellulose, sodium starch glycolate, and magnesium stearate. 
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10.2. 
Investigational Product Packaging and Labeling 
The packaging and labeling of investigational product supplies will be performed according to 
Good Manufacturing Practice standards by a designated qualified vendor.  All investigational 
product will be provided as tablets for oral administration and provided in high density 
polyethylene bottles with heat induction seals and child resistant closures.  The bottle packaging 
will not reveal any information about the treatment dose contained in the bottle.  Multiple bottles 
may be dispensed to the patient at each visit to provide enough tablets for dosing until the next 
visit. 
The designated investigational product packaging/distribution vendor will also be responsible for 
the distribution of the investigational product to the Investigator. 
10.3. 
Investigational Product Storage 
All OCA tablet strengths provided to clinical study sites in support of clinical studies are to be 
shipped and stored at 15˚C to 25˚C.  Temperature excursions within the range of 2˚C and 30˚C 
for no more than a 6-month period are acceptable, and the OCA tablet continues to be suitable 
for use in clinical studies.   Additionally, temperature excursions within the range -20˚C to 40˚C 
for no more than 7 days are acceptable, and the OCA tablet continues to be suitable for use in 
clinical studies.  
10.4. 
Investigational Product Administration 
Refer to Section 9.1. 
10.5. 
Investigational Product Accountability and Disposal 
The Sponsor’s representative will send investigational product to the study site under appropriate 
storage conditions.  All shipments of investigational product should be unpacked and the 
contents reviewed immediately upon receipt.  If it is not possible to verify the contents 
immediately, they must be stored under the appropriate storage conditions until verification of 
the contents is possible (ideally, within 1 business day from receipt).  The pharmacist or designee 
should verify the investigational product against the shipment documentation.  The pharmacist or 
designee should contact the Sponsor immediately to report any concerns regarding the shipment.  
All investigational product will be provided for use only in this study and is not to be used for 
any other purpose.  The Investigator or designee will maintain a full record of investigational 
product accountability, including records of individual patient dispensing and final return or 
disposition (as directed by the Sponsor).  
The study monitor, also known as the Clinical Research Associate (CRA), will review 
accountability records against investigational product dispensed and that remaining in stock, 
during on site monitoring visits and when the study is completed, or if it is prematurely 
terminated.  The CRA will retrieve documentation detailing and confirming the return or 
destruction of the investigational product.  If the investigational product is to be returned to the 
Sponsor’s vendor for destruction, the CRA will also prepare the investigational product for 
shipment. 
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11. 
OVERVIEW OF ASSESSMENTS 
The assessments supporting the objectives for the study are in Table 5: 
Table 5: 
Table of Assessments 
Primary Objectives 
Assessments 
PK parameters 
OCA and its conjugates glyco-OCA and tauro-OCA, and 
metabolite OCA glucuronide 
Safety and tolerability  
SAEs and TEAEs, physical exam, ECG, vital signs, 
clinical laboratory assessments, discontinuations, pruritus, 
and fatigue 
Secondary Objectives 
Assessments 
Changes in risk scores 
Changes in MELD and CP Score components  
Changes in liver biochemistry and hepatobiliary 
damage  
Total and direct bilirubin, ALP, ALT, AST, GGT, INR, 
creatinine, albumin, platelets 
PD parameters 
FGF-19, C4, and plasma bile acids 
Additional Objectives 
Assessments 
Markers of inflammation 
IL-6, hs-CRP, TNF-α, IgM, IgA, IgG, CK-18-M30,  
Noninvasive measurements of liver fibrosis, liver 
stiffness and cirrhosis 
Transient Elastography/ELF (HA, P3NP, and TIMP-1) 
PK/PD relationship 
PK parameters compared to PD Parameters and Safety and 
Tolerability assessments (above) 
Patient-reported outcomes 
Pruritus VAS, PBC-40, EQ-5D-5L, CLDQ 
Clinical events 
Death (all-cause and liver-related), liver transplant, Model 
of end stage liver disease (MELD) score ≥15 (for patients 
with MELD ≤12 at baseline), Hospitalization for new onset 
or recurrence of: variceal bleed, hepatic encephalopathy, 
spontaneous bacterial peritonitis, Uncontrolled ascites, and 
HCC. 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
C4 = 7α-hydroxy-4-cholesten-3-one; CK-18-M30 = cytokeratin-18 neoepitope-M30; CLDQ = Chronic Liver 
Disease Questionnaire; CP = Child-Pugh; ECG = electrocardiogram; ELF = enhanced liver fibrosis;  
FGF-19 = fibroblast growth factor-19; GGT = gamma-glutamyl transferase; HA = hyaluronic acid; hs-CRP = high-
sensitivity C-reactive protein; IgA = immunoglobulin; A IgG = immunoglobulin G; IgM = immunoglobulin M;  
IL-6 = interleukin 6; INR = international normalized ratio; MELD = Model End Stage Liver Disease;  
OCA = obeticholic acid; P3NP = procollagen 3 N-terminal peptide; PBC = Primary Biliary Cholangitis;  
PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event; TE = Transient Elastography;  
TEAE = treatment emergent adverse events; TIMP-1 = tissue inhibitor of metalloproteinase 1; TNF-α = tumor 
necrosis factor; VAS = visual analog scale 
12. 
CLINICAL PHARMACOKINETIC ASSESSMENTS 
Pharmacokinetic analyses will be based on the PK population (Section 15.1).  Patients in the PK 
Population with at least one PD assessment after dosing will be included in the combined PK/PD 
analyses.   
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12.1. 
Pharmacokinetic Blood Sampling 
Serial and fasting PK assessments will be performed in all patients participating in the study.   
At Day 1, and Weeks 6, 12, 18, 24, 30, 36, and 48, patients will provide fasted blood samples for 
measurement of OCA and its conjugates, glyco-OCA and tauro-OCA, and metabolite OCA 
glucuronide 30 minutes before administration of investigational product (predose for ≥12 weeks) 
(Table 6).  Patients will then receive a dose of investigational product with approximately 
240 mL of water.   
Week 6 Visit should occur 3, 4, or 5 days after the Week 6 dose (eg, if the Week 6 dose of 
investigational product is taken on a Sunday, the patient should come in for the Week 6 Visit 
between Wednesday and Friday [Figure 2]).   
Figure 2: 
Week 6 Sampling Schedule 
 
IP = investigational product; PK = pharmacokinetic 
At Weeks 12, 18, 24, 30, and 48, serial PK blood samples will be obtained at 0.5, 0.75, 1, 1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours postdose (Figure 3) for all patients.  The patient will be given 
the option to return to the clinic the following morning for the 24-hour postdose sample or 
samples can be obtained by a home health care designee.  The home health care agency must be 
advised one week in advance of the appointment.   
Figure 3: 
Pharmacokinetic Sampling Schedule 
 
h = hour; IP = investigational product; PK = pharmacokinetic  
Patients should not drink additional water for 1 hour after taking the dose of investigational 
product and will remain fasted until after the 1-hour sample is collected.  A meal will be 
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provided following collection of the 1-, 4-, and 7-hour PK sample; the meal will be a meal 
replacement drink with nutrition information that has been submitted to and approved by the 
Sponsor in advance.  No other food or drink (water is permitted) will be allowed until after the 
7-hour sample collection. 
During the treatment period: 
 Pharmacokinetic fasting samples will be obtained from all patients at Weeks 6, 12, 
18, 24, 30, 36, and 48 prior to dose administration in accordance with Figure 3 . 
 Serial PK assessments will be performed in all patients at Weeks 12, 18, 24, 30, and 
48.   
Table 6: 
Acceptable Windows for Pharmacokinetic Sample Collection 
Nominal Sampling Time 
Acceptable Sampling Window 
Before administration of investigational product 
(predose or fasting) 
Within 30 minutes before dosing 
0.5 to 1.5 hours after investigational product 
± 10 minutes 
2 to 2.5 hours after investigational product 
± 20 minutes 
3 to 24 hours after investigational product 
± 30 minutes 
12.2. 
Processing and Handling of Pharmacokinetic Samples 
Whole blood will be collected at each scheduled sample timepoint.  Detailed procedures for the 
collection of blood samples including further processing into plasma will be provided in a 
separate laboratory manual.  The storage and shipment procedures for subsequent bioanalysis, 
will be provided to the investigational site and home health care company in a separate document 
before the study is initiated. 
12.3. 
Bioanalysis 
Plasma concentrations of OCA and its conjugates, glyco-OCA and tauro-OCA, and metabolite 
OCA glucuronide will be determined using a validated liquid-chromatography mass 
spectrometry/mass spectrometry (LC/MS/MS) method.  A detailed description of validation 
information and results from the bioanalytical assay will be provided in separate reports.  These 
samples may be used for evaluation of metabolites of OCA or other concomitant medication, for 
further evaluation of the bioanalytical method, and for analyses that provide information on the 
metabolic pathways used or impacted by OCA. 
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13. 
ASSESSMENT OF SAFETY 
13.1. 
Adverse Events and Serious Adverse Events 
13.1.1. 
Definitions of Adverse Events 
13.1.1.1. Adverse Event  
AEs are defined as any untoward medical occurrence associated with the use of the 
investigational product in humans, whether or not considered related to investigational product.  
An AE, also referred to as an adverse experience, can be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom, or disease temporally associated with any use of 
the investigational product, without any judgment about causality and irrespective of route of 
administration, formulation, or dose, including an overdose.   
AEs include, but are not limited to: (1) a worsening or change in nature, severity, or frequency of 
condition(s) present at the start of the study; (2) patient deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction.  For reporting purposes, pregnancy is not 
considered an AE.  
Patients should be questioned about AEs in a general way, without leading the patient or asking 
about the occurrence of any specific symptom.  The Investigator should attempt to establish a 
diagnosis of the event based on signs, symptoms, and/or other clinical information.  The 
diagnosis and not the individual signs/symptoms should be documented as the AE.  For example, 
if the underlying disease process is a stroke, it would not be appropriate to record the AE by 
describing the symptoms “sudden numbness, dizziness, and difficulty speaking.”  The AE 
medical term of “stroke or cerebrovascular accident” should be recorded as it more accurately 
describes the AE. 
13.1.1.2. Serious Adverse Event  
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
 Death 
 Is immediately life threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
 Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Events not considered to be SAEs are hospitalizations for: 
 Routine monitoring of the studied indication and not associated with any deterioration 
in condition or AE; 
 Elective treatment for a pre-existing condition that did not worsen; 
 Respite care or observation when there is no AE associated with the hospitalization. 
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13.1.1.3. Treatment-Emergent Adverse Event 
A treatment-emergent AE (TEAE) is any event not present before the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
13.1.2. 
Relationship to Investigational Product 
The Investigator will document her/his opinion of the relationship of the AE to treatment with 
the investigational product using the criteria outlined in Table 7.  An AE for which there is a 
“reasonable possibility” that the investigational product caused the AE is otherwise referred to as 
suspected adverse reaction (SAR).  “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the investigational product and the AE.   
If the relationship between the AE/SAE and the investigational product is determined to be 
“definite,” “probable,” or “possible” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 
Table 7: 
Relationship of Adverse Events to Investigational Product 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the investigational 
product or in which the investigational product level has been established in body fluids or tissue; that 
follows a known or expected response pattern to the suspected investigational product; and that is 
confirmed by improvement on stopping or reducing the dosage of the investigational product, and 
reappearance of the reaction on repeated exposure. 
Probable 
A reaction that follows a reasonable temporal sequence from administration of the investigational 
product; that follows a known or expected response pattern to the suspected investigational product; that 
is confirmed by stopping or reducing the dosage of the investigational product; and that could not be 
reasonably explained by the known characteristics of the patient’s clinical state. 
Possible 
A reaction that follows a reasonable temporal sequence from administration of the investigational 
product; that follows a known or expected response pattern to the suspected investigational product; but 
that could readily be produced by a number of other factors. 
Unlikely 
An event that does not follow a reasonable temporal sequence from administration of the investigational 
product; that does not follow a known or suspected response pattern to the suspected investigational 
product; and that could reasonably be explained by known characteristics of the patient’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
13.1.3. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 8, must be entered on the AE eCRF.  It should be noted that the term 
“severe” used to grade intensity is not synonymous with the term “serious.”  The assessment of 
severity is made regardless of investigational product relationship or of the seriousness of the 
AE. 
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Table 8: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Causing no limitation of usual activities; the patient may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the patient may experience annoying 
discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the patient may experience intolerable 
discomfort or pain. 
13.1.4. 
Reporting of Adverse Events and Serious Adverse Events 
13.1.4.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the patient 
fully completes her/his study participation of the study. 
All AEs, whether believed by the Investigator to be related or unrelated to the investigational 
product, must be documented in the patient’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product.  Redacted medical record source documentation will be requested for all 
SAEs and emergency room visits. 
13.1.4.2. Reporting of Serious Adverse Events 
In agreeing to the provisions of this protocol, the Investigator accepts all legal responsibilities for 
immediate reporting of SAEs to the Sponsor.  Immediate reporting implies within 24 hours of 
becoming aware of the occurrence of an SAE. 
All SAEs must be reported to the Sponsor (including suspected liver-related clinical outcome 
events that qualify as serious).  SAEs are reported by entering the SAE data into the study 
specific EDC system.  Entering the SAE data into the EDC system will automatically notify the 
Sponsor of the event.  In the event that the EDC system is inaccessible, an SAE may reported by: 
 E-mail to the SAE email address:  
 
 Fax using a paper SAE report form:  
 
If an SAE is reported by fax, an SAE Report form must also be completed in the EDC system as 
soon as the EDC system is accessible.  At a minimum, the following information should be 
provided at the time of the initial report:   
 Patient number  
 Event term  
 At least 1 criterion classifying the event as serious  
 Name and title of the reporting individual  
 Causal relationship to the investigational product  
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The Investigator will assess whether the event is causally related to the investigational product.  
The Sponsor will also assess whether the event is causally related to the investigational product, 
in addition to assessing the overall safety profile of the investigational product.  The Sponsor will 
notify the appropriate regulatory agencies as well as all participating Investigators of Safety 
Reports/Expedited Safety Reports that occur during the study within the time frames required by 
each regulatory agency.  
Following the initial report, any additional information obtained by the Investigator about the 
SAE must be reported promptly to the Sponsor in the same manner as described above for the 
initial SAE report.  Any supporting source documentation should be faxed to 
 or 
emailed to 
 as soon as possible.   
The Investigator is responsible for submitting information on Safety Reports/Expedited Safety 
Reports received from the Sponsor to her/his local IRB/IEC, as directed by the local country 
requirements.  Documentation of the submissions to IRBs/IEC s must be retained in the 
appropriate study file(s).  As instructed by the Sponsor, Safety Reports/Expedited Safety Reports 
should be retained in the appropriate investigative site study files or with the IB.  
13.1.5. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the EDC represent the official record of all AEs and SAEs reported 
in the study.  The Investigator should comply with requests by the Medical Monitor or other 
Sponsor personnel to record the SAE on the patient’s AE EDC.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the Sponsor, the Investigator should 
provide input into the SAE narrative and provide timely information to ensure prompt follow-up 
and closure of the SAE report. 
The Investigator and supporting personnel responsible for patient care should discuss with the 
Medical Monitor any need for supplemental investigations of SAEs.  The results of these 
additional assessments must be reported to the Medical Monitor. 
13.1.6. 
Notification of Post-Treatment SAEs for Patients Who Continue in the Study 
Post-treatment SAEs that occur in patients who remain in the study after investigational product 
has been discontinued must be reported to the Sponsor within 24 hours by following the 
instructions provided in Section 13.1.4.2 . 
SAEs that occur in patients who discontinue investigational product, initiate treatment with 
commercially available Ocaliva, and remain in the study must be reported to the Sponsor within 
24 hours by following the instructions provided in Section 13.1.4.2. 
13.1.7. 
Notification of Post-Study SAEs  
All SAEs that occur within 30 days following discontinuation from the study, whether or not 
they are related to the investigational product, must be reported to the Sponsor within 24 hours 
by following the instructions provided in Section 13.1.4.2. 
If an Investigator becomes aware of an SAE that may be attributable to the investigational 
product at any time after the end of the study, the Sponsor should be notified immediately 
(ie, within 24 hours) by following the instructions provided in Section 13.1.4.2. 
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13.1.8. 
Follow-Up of AEs and SAEs 
All AEs must be followed during the course of the study until the AE resolves, is no longer of 
clinical concern, has stabilized or is otherwise explained, or the patient is lost to follow-up. 
AEs ongoing at the final visit that are deemed to be “possibly, probably, or definitely” related or 
of other clinical significance must be followed for as long as necessary to adequately evaluate 
the safety of the patient or until the event stabilizes, resolves, or is no longer of clinical concern.  
If resolved, a resolution date for the AE should be documented on the eCRF.  The Investigator 
must ensure that follow-up includes any supplemental investigations indicated to elucidate the 
nature and/or causality of the AE.  This may include additional laboratory tests or investigations, 
or consultation with other healthcare professionals, as considered clinically appropriate by the 
Investigator. 
All patients showing possible drug-induced liver injury should be followed until all 
abnormalities return to normal or to the baseline state.  Drug-induced liver injury may develop or 
progress even after the causative drug has been stopped.  Results should be recorded in the 
eCRF.  Note that longer follow-up can sometimes reveal an off-drug repetition of what had 
appeared to be drug-induced liver injury, indicating that liver injury was related to underlying 
liver disease. 
13.1.9. 
Pregnancy and Follow-Up  
Pregnancies are not considered AEs in and of themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical study, she must interrupt treatment with 
investigational product immediately (see Section 8.4.1.3) and the Sponsor must be notified 
within 24 hours of the Investigator’s awareness of the pregnancy by completing the Pregnancy 
CRF in the EDC system and downloading and completing the Pregnancy Report Form.  The 
Pregnancy Report Form must be emailed to 
 or faxed to 
  The patient and neonate must be followed for outcome information and/or as 
considered appropriate by the Investigator and Sponsor. 
The patient may restart investigational product when she is no longer pregnant or breastfeeding 
(if applicable) at the discretion of the Investigator and after discussion with the Medical Monitor.  
The patient must have a negative pregnancy test before restarting investigational product.  If a 
patient’s pregnancy is terminated early (planned or unplanned), she must have termination of the 
pregnancy confirmed by a serum β-hCG test before restarting investigational product.  
Completing the Pregnancy Report Form is not a substitute for reporting an AE/SAE when and 
AE/SAE has occurred.  In the situation when an AE/SAE has occurred, the AE/SAE reporting 
procedures described in Section 13.1.4 must also be followed. 
13.2. 
Other Safety Parameters 
13.2.1. 
Medical History/Demographics 
A complete medical history will be obtained from the patient at screening.  Demographic 
characteristics (age, gender, race, and ethnicity) will be recorded. 
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13.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the visits specified in the Schedule of Study Procedures (Table 1).  A basic physical 
examination should be performed, including all body systems pertinent to the patient.  Smoking 
and alcohol consumption history and current habits will be recorded.  Any clinically significant 
abnormality should be reported on the AE eCRF page for findings that appear after consent, and 
on the medical history eCRF for any finding present prior to consent.   
13.2.3. 
Vital Signs and Weight 
Vital signs (oral temperature, sitting heart rate, respiratory rate and sitting blood pressure [BP]) 
and weight will be assessed at indicated visits (Table 1).  When taking heart rate, respiratory rate 
and BP readings, patients should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
13.2.4. 
Electrocardiogram  
Standard ECGs will be collected.  The Investigator or designee will review the ECG and findings 
will be recorded in the eCRF as normal, abnormal but not clinically significant, or abnormal and 
clinically significant.  Any clinically significant abnormalities on ECGs recorded after Day 1 will 
also be documented as AEs and entered on the AE page of the eCRF.  
Investigative sites must retain a copy of all ECGs evaluated by the Investigator or designee.  
These ECGs must be clearly labeled with the Patient ID number, date, and time.  Full 
instructions will be provided for forwarding the ECGs for central reading. 
13.2.5. 
Laboratory Assessments 
Except for Screening, patients will be instructed to attend each study visit in a fasted state, 
preferably in the morning, and patients should remain fasted until their blood samples have been 
collected.  At all visits (except screening), the Investigator or designee will verify that the patient 
has fasted for at least 8 hours and record fasting status in the source and eCRF.  If the patient 
reports having eaten (water is permitted) within 8 hours, the Investigator or designee will 
document accordingly in the source and eCRF and remind the patient that fasting is required 
before all study visits. 
Blood samples for serum chemistry, coagulation, and hematology; and urine samples will be 
collected at visits as detailed in the Schedule of Study Procedures (see Table 1).  The number and 
volume of samples to be collected at each visit will be detailed in the laboratory manual. 
Full instructions concerning the number and type of samples to be collected at each visit, the 
required sample volumes, sample collection methods, sample processing, labeling, and shipping 
will be provided in a separate procedural manual.  All necessary collection supplies will be 
provided by the central laboratory and will be appropriately assembled for the specific 
evaluations required at each visit. 
All patients with laboratory tests containing clinically significant abnormal values are to be 
followed regularly until the values return to normal ranges; until a valid reason, other than 
investigational product related AE, is identified; or until further follow-up is deemed medically 
unnecessary.   
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Laboratory samples will be stored for a maximum of up to 1 year after the end of the study 
(depending on stability) in the event that retesting is required, and destroyed after 1 year if not 
analyzed. 
The list of laboratory analytes to be tested is shown in Table 9. 
Table 9: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen, creatinine, direct bilirubin, 
total bilirubin, aspartate aminotransferase [AST, SGOT], 
alanine aminotransferase [ALT, SGPT], ALP, GGT, 
electrolytes [calcium, chloride, potassium, sodium], 
glucose, total protein, and blood lipids (total cholesterol, 
LDL, HDL and VLDL fractions and TG), CPK, 
magnesium, phosphorus, bicarbonate, unconjugated 
(indirect) bilirubin, conjugated (direct) bilirubin, free fatty 
acids, TFT (TSH, free T3 and free T4) 
Hematology 
Hemoglobin, hematocrit, white blood count with 
differential, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, platelets, red blood cell count 
(including MCV, MCH, MCHC) 
Coagulation 
PT, PTT, INR 
Urinalysis (dipstick) 
pH, specific gravity, total protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, albumin, 
creatine, leucocytes, nitrates, albumin/creatine ratio (if 
positive), pregnancy 
Markers of Inflammation  
IL-6, hs-CRP, TNF-α, IgM, IgA, IgG, CK-18-M30 
Noninvasive measurements of liver fibrosis, liver 
stiffness and cirrhosis 
ELF (HA, P3NP, and TIMP-1) 
TE 
PK assessments 
OCA (parent and conjugates [glyco and tauro], metabolite 
OCA-glucuronide)  
PD markers 
C4, FGF-19 and plasma bile acids 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; C4 = 7α-hydroxy-4-cholesten-3-one; 
CK-18-M30 = cytokeratin-18 neoepitope M30; CP = Child-Pugh; CPK = creatine phosphokinase; ECG = electrocardiogram; ELF = enhanced 
liver fibrosis; FGF-19 = fibroblast growth factor-19; GGT = gamma-glutamyl transferase; HA = hyaluronic acid; HDL = high density lipoprotein; 
hs-CRP = high-sensitivity C-reactive protein; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M;  
IL-6 = Interleukin 6; INR = international normalized ratio; LGL = low-density lipoprotein; MCH = mean corpuscular hemoglobin;  
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; OCA = obeticholic acid;  
PBC = primary biliary cirrhosis; P3NP = procollagen 3 N-terminal peptide; PT = Prothrombin time; PTT = partial thromboplastin time; SGOT = 
Serum glutamic oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; TE = Transient Elastography; TG = triglyceride; TFT = 
thyroid function test; TIMP-1 = tissue inhibitor of metalloproteinase 1; TNF-α = tumor necrosis factor-α, VLDL = very-low density lipoprotein 
Laboratory reference ranges for the study will be based on the laboratory vendor range. 
Urine based β-hCG pregnancy tests will be performed in female patients of childbearing 
potential per protocol specified visits (see Table 1).  If a urine pregnancy test is positive, a serum 
pregnancy test must be performed to confirm the result.  If positive, the Sponsor must be notified 
and the patient will be followed as outlined in Section 13.1.9 until pregnancy outcome.  
INR will be calculated based on prothrombin time value by the central laboratory.  MELD scores 
will be calculated based on creatinine, bilirubin, Na, and INR values, with modification by 
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United Network for Organ Sharing.  Total OCA will be calculated based on OCA, tauro-OCA, 
glyco-OCA, and metabolite OCA glucuronide concentrations.  Laboratory analyte results may be 
used to calculate various cardiovascular risk and fibrosis measurement scores. 
13.2.6. 
Patient-Reported Outcomes and Healthcare Resource Use 
Data will be collected to determine the effects of OCA on health-related quality of life.  
Healthcare resource use as well as a general health status assessment (for the purposes of 
generating health utilities) will be used to support subsequent cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Assessments of patient-reported 
outcomes will take place during the visits indicated in Table 1.   
The following patient-reported outcomes will be used to evaluate the effects of OCA compared 
to placebo on improvements in health-related quality of life: 
 PBC-40:  The PBC-40 is a validated disease-specific 40-question quality of life 
questionnaire, which consists of 6 domains:  General Symptoms, Itch, Fatigue, 
Cognitive Function, Social, and Emotional (Jacoby 2005). 
 EQ-5D-5L:  The EQ-5D-5L consists of 2 sections – the descriptive system and the 
visual analogue scales (VASs).  The descriptive system is organized into 
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  Each dimension has 5 levels:  no problems, slight problems, 
moderate problems, severe problems, and extreme problems.  The VAS records the 
patient’s self-rated health on a 20-cm vertical, line with endpoints labelled “the best 
health you can imagine” and “the worst health you can imagine” (Herdman 2011, 
Oemar 2013). 
 Pruritus VAS:  A VAS will also be used to assess pruritus in individual patients. 
 CLDQ:  The CLDQ is a disease-specific health related quality of life questionnaire 
for patients with chronic liver disease.  The questionnaire includes 29 items in the 
following domains: fatigue, activity, emotional function, abdominal symptoms, 
systemic symptoms, and worry).  Each question is answered on a scale from 
1 (always) to 7 (never) with a higher score corresponding to a better quality of life.  
The CLDQ produces a summary score and domain scores that correlate with the 
severity of liver disease (Younossi 1999). 
Patients will be asked to complete the questionnaires and initial and date each document.  The 
questionnaires should be filed in the patient’s study records.  These may require transcription to 
the eCRF by study site staff. 
Healthcare resource use will be collected from eCRFs including number, reason for and duration 
of hospitalizations and emergency room visits, number of outpatient physician visits (patient 
reported), and use of concomitant medications.  The purpose is to evaluate the effects of OCA 
compared to placebo on patient-reported outcomes and healthcare resource. 
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14. 
EFFICACY ASSESSMENTS 
14.1. 
Biochemical Measures of Disease Severity 
14.1.1. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is calculated and reported within the EDC system 
based on data entered into the eCRF by adding the scores from the 5 factors outlined in Table 10 
and can range from 5-15.  A total score of 5-6 is considered Grade A (mild, well-compensated 
disease); 7-9 is Grade B (moderate, significant functional compromise); and 10 and above is 
Grade C (severe, decompensated disease).  Calculation of the CP Score includes Investigator 
assessments of ascites and hepatic encephalopathy, which may be assessed during the adverse 
event review at the scheduled visits, as well as total bilirubin, serum albumin, and prothrombin 
time, which will populate from the central laboratory.  Investigators will be responsible for 
determining the appropriate dosing regimen based on the CP score (Table 1 and Table 10).  Any 
change in CP Score will necessitate re-evaluation of the dosing regimen. 
Table 10: 
Child-Pugh Scoring System 
Factor 
Units 
Points 
1 
2 
3 
Serum bilirubin 
mg/dL 
<2.0 
2.0-3.0 
>3.0 
Serum albumin 
g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
Seconds prolonged 
0-3 
4-6 
>6 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites 
 
None 
Mild 
Moderate-
Severe 
Hepatic encephalopathya 
 
0 
Grade 1 or 2 
Grade 3 or 4 
a Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
 Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves 
 Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
 Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
 Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity  
 (Pugh 1973, Lucey 1997) 
14.1.2. 
Model of End Stage Liver Disease Score 
The MELD scoring system is used to assess the severity of chronic liver disease.  The MELD 
score is useful in assessing patients with significant decompensation, and the MELD score is 
now used by the United Network for Organ Sharing in the US and Eurotransplants to manage the 
organ allocation for liver transplantation.  The threshold for placement on an organ 
transplantation queue varies between regions across the globe.   
An increasing MELD score is associated with increased severity of hepatic dysfunction and 
increased 3-month mortality risk.  The MELD score is derived from the patient’s serum total 
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bilirubin, serum creatinine, and INR, as appropriate, to predict survival and is calculated 
according to the following formula (Kamath 2007): 
MELD = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] 
+ 6.43  
MELD score will be calculated and reported in whole numbers according to the frequency listed 
in Table 1. 
14.1.3. 
Changes in Liver Biochemistry and Hepatobiliary Damage 
ALP, ALT, AST, GGT, total and direct bilirubin, INR, creatinine, albumin, platelets will be 
measured according to the frequency listed in Table 1. 
14.2. 
Additional Assessments 
14.2.1. 
Markers of Inflammation, Apoptosis and Necrosis 
Blood samples for analytes including IL-6, hs-CRP, IgA, IgG, IgM, TNF-α, cytokeratin-18 
neoepitope M30.  Assessments will be performed according to the schedules presented in 
Table 1. 
14.2.2. 
Noninvasive Measurements of Liver Stiffness and Fibrosis 
The ELF test assesses: HA, P3NP, and TIMP-1.  Samples will be assessed in patients according 
to the schedules presented in Table 1. 
The Fibroscan® TE device (Echosens, Paris, France) will be used at all study sites that have the 
equipment to collect hepatic stiffness measurements.  These study sites must have the staff 
trained in the use and data interpretation of the device.  This is a validated and non-invasive 
technique used to assess hepatic fibrosis which will be conducted according to the schedule 
presented in Table 1.   
14.2.3. 
Markers of FXR activation 
Blood samples will be collected in all patients to measure C4, FGF-19, and bile acids.  The 
results of these analyses will be used to assess the PK/PD response of OCA.  Blood samples will 
be assessed in patients according to the schedule presented in see Table 1.   
14.2.4. 
Clinical Outcome Events 
Clinical outcome events will be evaluated by an Adjudication Committee (described in 
Section 15.9) to confirm if they meet the criteria to be considered Clinical Outcome Events.  
15. 
STATISTICAL METHODS AND ANALYSES 
Individual patient data obtained from electronic case report forms (eCRFs), central laboratories, 
external sources, and any derived data will be presented in data listings by patient.  All data 
listings that contain an evaluation date will contain a relative study day.  Pre-treatment and on 
treatment study days are numbered relative to the day of the first dose of investigational product 
which is designated as Day 1.   
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All output will be incorporated into Microsoft Word rich text format (.rtf) files, sorted and 
labeled according to the ICH recommendations, and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, Baseline, efficacy, and safety 
parameters.   
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) of the parameter will be presented.  Percentage 
calculations will be based on non-missing data, unless otherwise specified.  Percentages are 
rounded to 1 decimal place, unless otherwise specified.   
For continuous variables, the number of patients, mean, standard deviation (SD), standard error 
of the mean (SEM), median, minimum, and maximum values will be presented.  The precision of 
summary statistics, unless otherwise, specified will be as follows:  mean and median to 1 more 
decimal place than the raw data, and SD and SEM to 2 decimal places more than the raw data.  
In general, the decimal places should not exceed 3 decimal places unless appropriate.  
Confidence intervals (CIs) will be provided and will be rounded to 1 decimal place, unless 
otherwise specified. 
Time-to-event data will be summarized using Kaplan-Meier (KM) methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of 
censored observations. 
There will be no formal hypothesis testing in this study.  However, summary statistics for each 
treatment group will be presented, as well as 95% CIs for the difference between the treatment 
groups. 
15.1. 
Analysis Populations 
The following patient populations will be evaluated and used for presentation and analysis of the 
data: 
 The Intent-to-Treat (ITT) Population will include all randomized patients who receive 
any amount of investigational product (OCA or placebo).  The ITT Population will be 
the primary population used for summarizing efficacy assessments.  
 The Safety Population will include all patients who received at least one dose of 
investigational product (placebo or OCA). The Safety Population will be the primary 
population used for safety analyses.  
 The PK population will include all patients receiving OCA who have adequate 
concentration-time profiles to characterize OCA and its conjugates and must not have 
any major protocol deviations that potentially affect exposure levels. 
15.2. 
Determination of Sample Size 
To reasonably characterize the PK of OCA in patients with hepatic impairment, a 
simulation-based approach estimated a requirement of approximately 20 patients in the OCA 
treatment group assuming a 15% discontinuation rate.  Ten patients on placebo will be included 
as a comparator.  An additional 20 patients will be enrolled to support safety and efficacy 
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evaluations.  Therefore, approximately 50 patients (including at least 20% of patients with CP-C) 
will be randomized.  
15.3. 
Pharmacokinetic Analyses 
The PK Population will be used for analysis of PK parameters, which include plasma OCA 
(parent) and its conjugates (glyco-OCA and tauro-OCA), total OCA, metabolite OCA 
glucuronide, and potentially other conjugates or metabolites not yet identified. 
PK analysis will based on the PK population.  Values will be calculated using 
non-compartmental methods.  The values will be summarized by active treatment group using 
descriptive statistics. 
15.4. 
Safety Analyses 
Safety analyses will be conducted using the Safety population.  Safety data, including AEs, vital 
signs, ECG, and clinical laboratory results will be summarized by treatment group using the 
Safety Population. 
The incidence of TEAEs and SAEs will be tabulated by system organ class (SOC) and preferred 
term for each treatment group, and similarly by severity and relationship to treatment.   
Laboratory parameters, physical examinations including vital signs, and ECGs will be 
summarized by treatment group using descriptive statistics at Baseline and at each scheduled 
post-Baseline visit.  The absolute change from baseline will also be summarized. 
CP scores will be summarized by treatment group at Baseline and at each post-Baseline visit. 
No inferential comparison with formal statistical hypothesis testing will be performed for safety 
endpoints.  
15.4.1. 
Adverse Events 
AEs will be coded using MedDRA.  Summary tables of TEAEs will be provided.   
Each AE summary will be displayed by treatment group.  Summaries that are displayed by SOC 
and PT will be ordered by descending order of incidence of system organ class and preferred 
term within each system organ class.  Summaries of the following types will be presented: 
 Overall summary of TEAEs. 
 Patient incidence of TEAEs and the total number of entries by MedDRA SOC and 
PT.  This summary will be repeated for all subgroups. 
 Patient incidence of TEAEs by MedDRA SOC, PT, and highest severity.  At each 
level of patient summarization, a patient is classified according to the highest severity 
if the patient reported 1 or more events.  AEs with missing severity will be considered 
severe for this summary. 
 Patient incidence of TEAEs by MedDRA SOC, PT, and closest relationship to 
investigational product (Related/Not Related).  Related AEs are those with 
relationships reported as “Definite,” “Probable,” or “Possible,” and unrelated AEs are 
those with relationships reported as “Unlikely” or “Not Related.”  At each level of 
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patient summarization, a patient is classified according to the closest relationship if 
the patient reported 1 or more events.  AEs with a missing relationship will be 
considered related for this summary. 
 Patient incidence of serious TEAEs and the total number of entries by MedDRA SOC 
and PT. 
 Patient incidence of TEAEs leading to investigational product withdrawal or study 
discontinuation by MedDRA SOC and PT.  This is a subset of the AEs where Action 
Taken with Study Treatment is checked as “Drug Withdrawn” or where “Patient 
Discontinued from Study” is checked. 
The following listings will be presented by treatment group and patient: 
 All adverse events. 
 Serious adverse events (This is a subset of the AEs where serious is marked as 
“Yes”). 
 Severe adverse events (This is a subset of AEs where severity is marked as “Severe”). 
 Related adverse events (This is a subset of the AEs where relationship marked as 
“Definite,” “Probable,” or “Possible”). 
 Adverse events leading to Study Drug Withdrawal or Study Discontinuation (This is a 
subset of the AEs where Action Taken with Study Treatment is checked as “Drug 
Withdrawn” or where “Patient Discontinued from Study” is checked). 
 Adverse events leading to death (This is a subset of the AEs where the corresponding 
AE number is specified on the Death eCRF). 
15.4.2. 
Clinical Laboratory Evaluations 
Laboratory parameters will be summarized in standard international (SI) system of units by 
treatment group using descriptive statistics at Baseline and at each on-study evaluation.  Re-test 
or unscheduled results will not be summarized but will be included in the data listings.  The 
change from Baseline will also be summarized.  Baseline is defined as the mean of all available 
evaluations prior to treatment.   
In addition, shift tables (ie, low-normal-high at Baseline versus low-normal-high at post Baseline 
visit in a 3-by-3 contingency table) from Baseline to worst value, last value, and at each 
scheduled post-Baseline visit will be provided for hematology and serum chemistry by treatment 
group to assess changes in laboratory values from Baseline to each on-study evaluation.   
Vital Signs and Weight 
The results and change from Baseline to each on-study evaluation visit will be summarized by 
treatment group for weight, oral temperature, sitting heart rate, respiratory rate and sitting blood 
pressure. 
Electrocardiograms 
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Electrocardiogram (ECG) results will be summarized at each on-study visit descriptively, 
including the number and percentage of patients with normal, abnormal not clinically significant, 
and abnormal clinically significant results at Baseline and each on-study evaluation. 
15.4.3. 
Adverse Events of Special Interest 
Pruritus: Treatment-emergent pruritus, defined as any preferred term including “Prur,” will be 
summarized separately by the MedDRA SOC, treatment group, and PT as a subset of all TEAEs.  
This summary will be repeated for patients with “new or worsened” pruritus events, as defined as 
follows: 
 Mild, moderate, or severe treatment-emergent pruritus events in patients with no 
pruritus at Baseline, or 
 Worsening of the severity of the Baseline condition in patients with pruritus at 
Baseline. 
Baseline pruritus is defined as the investigator’s rating of severity as collected on the PBC 
Disease History eCRF.  Patients whose Baseline severity is severe will be counted as worsening 
if an AE of pruritus with severe is recorded. 
An analysis of treatment-emergent pruritus event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  Each individual patient year on study will be derived as the last 
known date during the study minus the first dose date plus 1 divided by 365.25 days/year.   
In order to explore the relationship between pruritus and the investigational product, the 
following time-to-event analyses will be performed: 
 Time to first onset of treatment-emergent pruritus  
 The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 
 Patients who never reported an AE of pruritus will be censored at the date of last 
contact. 
 Time to onset of the first moderate or severe treatment-emergent pruritus 
 The time to the start of the first moderate or severe pruritus will be calculated by 
date of onset of the first moderate or severe pruritus – date of first dose of 
investigational product +1. 
 Patients who never reported a moderate or severe AE of pruritus will be censored 
at the date of completion or discontinuation. 
 Time to onset of the first severe treatment-emergent pruritus 
 The time to the start of the first severe pruritus will be calculated by date of onset 
of the first severe pruritus – date of first dose of investigational product +1. 
 Patients who never reported a severe AE of pruritus will be censored at the date of 
completion or discontinuation. 
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The analysis of time to first onset of treatment-emergent pruritus AE, time to onset of the first 
moderate or severe treatment-emergent pruritus, and onset of the first severe treatment-emergent 
pruritus will include the number of patients with pruritus (first onset, first moderate or severe, 
first severe), the number of patients without pruritus (censored), and the minimum and maximum 
times in days.  KM estimates will be calculated by treatment group.  The tabulation will include 
the KM estimate methodology using 25th, 50th (median), and 75th percentiles of the medians and 
corresponding with associated 2-sided 95% confidence intervals (CIs), if the medians can be 
estimated as well as percentage of censored observations. 
Fatigue: Treatment-emergent fatigue is defined as any preferred term which includes “Fatigue.”  
New or worsened treatment-emergent fatigue is defined as follows: 
 Any mild, moderate, or severe treatment-emergent fatigue events in patients with no 
fatigue at Baseline, or 
 Worsening of the severity of the Baseline condition in patients with fatigue at 
Baseline. 
Baseline fatigue is defined as the Investigator’s rating of severity as collected on the PBC 
Disease History eCRF.  Patients whose Baseline severity is severe will be counted as worsening 
if an AE of fatigue with severe is recorded. 
An analysis of treatment-emergent fatigue event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  Each individual patient year on study will be derived as the last 
known date during the study minus the first dose date plus 1 divided by 365.25 days/year.   
In order to explore the relationship between fatigue and the investigational product, the following 
time-to-event analyses will be performed: 
 Time to first onset of treatment-emergent fatigue  
 The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 
 Patients who never reported an AE of fatigue will be censored at the date of last 
contact. 
 Time to onset of the first moderate or severe treatment-emergent fatigue 
 The time to the start of the first moderate or severe fatigue will be calculated by 
date of onset of the first moderate or severe fatigue – date of first dose of 
investigational product +1. 
 Patients who never reported a moderate or severe AE of fatigue will be censored 
at the date of last contact. 
 Time to onset of the first severe treatment-emergent fatigue 
 The time to the start of the first severe fatigue will be calculated by date of onset 
of the first severe fatigue – date of first dose of investigational product +1. 
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 Patients who never reported a severe AE of fatigue will be censored at the data of 
last contact. 
The analysis of time to first onset of treatment-emergent fatigue AE, time to onset of the first 
moderate or severe treatment-emergent fatigue, and onset of the first severe treatment-emergent 
fatigue will include the number of patients with pruritus (first onset, first moderate or severe, 
first severe), the number of patients without fatigue (censored), and the minimum and maximum 
times in days.  KM estimates will be calculated by treatment group.  The quartiles, including the 
median time-to-event and their respective 2-sided 95% CIs, will be presented.  KM estimates 
will be plotted as a “survival curve” for each treatment group. 
15.5. 
Efficacy Analyses 
This study does not plan to test a formal hypothesis for any efficacy endpoint.   
The endpoints of efficacy assessments are change in total and direct bilirubin, INR, creatinine, 
albumin, platelets, ALP, ALT, AST, and GGT from baseline to Week 48 (end of the study), 
change from baseline to Week 48 in CP score and components of the CP score, and change from 
baseline to Week 48 in MELD and components of the MELD score.  Analyses of change from 
Baseline to Week 48 (end of study) will be modelled between treatment groups using ANCOVA 
model with change from Baseline as the dependent variable, treatment group and randomization 
stratification factor as fixed effects and the baseline value as a covariate.  The same analysis will 
be carried out using percentage change from Baseline as the dependent variable. 
Analyses of change from Baseline to Week 48 (end of study) will be modelled between 
treatment groups using ANCOVA model with change from Baseline as the dependent variable, 
treatment group and randomization stratification factor as fixed effects and the baseline value as 
a covariate.  The same analysis will be carried out using percentage change from Baseline as the 
dependent variable. 
Summary statistics of the laboratory values will be provided by treatment group.  The results, 
change from Baseline, and percentage change from Baseline values, as well as estimates of least-
square (LS) means, standard errors (StdErr), and 2-sided 95% CIs, will be presented by treatment 
group.  Estimates of the mean difference between treatment groups, the StdErr of the difference, 
and 2-sided 95% CI of the difference will also be presented.   
Risk Scores: Changes from baseline in the MELD score and in CP score will be summarized and 
analyzed using the Wilcoxon Rank Sum Test.  The median differences and 95% CI of the 
median differences between treatment groups will be constructed using Hodges-Lehmann 
estimate.  If the median differences between treatments are not symmetrical around the median, 
the Sign Test may be used. 
Shifts in MELD scores from Baseline will be reported by visit using the following categories:  
<10, 10 to <12, 12 to <13, 13 to <14, 14 to <15, and ≥15.   
CP class will be presented in shift tables showing the shift from baseline to each scheduled post-
baseline visit by the count and percentage of patients within each shift classification. 
Individual factors will be presented in a listing. 
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15.6. 
Additional Efficacy Analyses 
Analyses of changes in liver stiffness and ELF, cytokeratin-and TIMP-1, and markers of 
inflammation will be summarized and analyzed using the same methodology specified for the 
key secondary analyses of change in bilirubin. 
The following clinical endpoints will be captured in the study: 
 Time to death (all-cause) 
 Time to liver-related death 
 Time to liver transplant 
 Model of end stage liver disease (MELD) score ≥15 (for patients with MELD ≤12 at 
baseline) 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
 Time to variceal bleed 
 Time to hepatic encephalopathy (as defined by a West Haven score of ≥2) 
 Time to spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 Time to uncontrolled ascites (diuretic resistant ascites requiring therapeutic 
paracentesis at a frequency of at least twice in a month). 
 
The incidence and time to first occurrence of any above listed clinical events will be summarized 
by treatment group using the log rank test stratified by the randomization stratification factor.  
KM estimates of the distribution of the time-to-event will be tabulated and graphed by treatment 
group.  The tabulation will include the KM methodology using 25th, 50th (median), and 75th 
percentiles with associated 2-sided 95% confidence intervals (CIs), as well as percentage of 
censored observations.  The number and percent of patients censored and with events will be 
presented.  The hazard ratio and 2-sided 95% CI will be estimated based on a Cox regression 
model stratified by randomization strata.  
In addition, the incidence and time to each of the above clinical events, and the incidence and 
time to occurrence of hepatocellular carcinoma (HCC) will be summarized by treatment group 
using the same methods as defined above. 
15.7. 
Handling of Missing Data 
Missing data will be assumed to be missing at random.  No data will be imputed. 
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15.8. 
Data Monitoring Committee 
An independent DMC includes hepatologists, pharmaceutical physicians, 
epidemiology/cardiology expert(s), and statistician(s) not involved in the study as Investigators, 
adjudication committee members, or consultants.  The DMC will have oversight of the study 
conduct as defined by the DMC charter.  All members will have considerable experience with 
clinical study conduct and DMCs.  Any candidate found to have a conflict of interest or whose 
name is listed on the Food and Drug Administration (FDA) debarment list will not be offered 
membership.  Conflicts of interest will be assessed regularly, and if members are found to have a 
new conflict of interest they will be replaced. 
The DMC will meet approximately quarterly at scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review safety and efficacy data in order to ensure the safe and 
proper treatment of patients.  Based on review of these data, the DMC will advise the Sponsor on 
the validity and scientific merit of continuing the study. 
Written minutes of both the open and closed DMC sessions will be prepared.  The closed 
minutes will be made available to the appointed Sponsor representatives only after the database 
is locked.  
Data listings provided to the DMC do not contain individual patient treatment information; 
however, the DMC will have access to the database and may unblind individual patient data as 
appropriate.  Summary tables reviewed by the DMC during closed sessions will include an 
overall column containing information regarding all patients and separate treatment columns 
with ‘dummy’ labels, ie, the actual treatment groups are used, but are not identified.  Data 
reviewed during the meetings will include, at a minimum, disposition, demographics, exposure, 
clinical laboratory results, MedDRA-coded AEs, and AEs leading to early withdrawal of 
investigational product.  At each meeting, detailed narratives of interval SAEs (including events 
resulting in death) are reviewed by the DMC in addition to a cumulative list of all SAEs. 
The DMC may agree to adjust meeting frequency based upon actual and projected safety and 
efficacy data availability.  Adjustments to or stopping of the protocol defined doses may be 
considered based on DMC evaluation of OCA safety and tolerability. 
All Investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DMC relating to patient safety, which alter the 
conduct of this study.  The Investigators will inform the patients of such actions and the protocol, 
PIS, and ICF will be revised, as appropriate. 
15.9. 
Adjudication Committees 
All suspected liver-related clinical events, major adverse cardiovascular events 
(MACE)/expanded MACE, and drug-related hepatic injury events that occur after administration 
of the first dose of investigational product will be reviewed by the following blinded adjudication 
committees, depending on event type, before inclusion in any analysis.  The 3 committees and 
event types they are responsible for adjudicating are as follows: 
 Cardiovascular Adjudication Committee (CAC):  Adjudicates all suspected MACE, 
including all deaths 
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 Hepatic Outcomes Committee:  Adjudicates all deaths and suspected liver-related 
outcomes 
 Hepatic Safety Committee:  Adjudicates all suspected drug-related hepatic injury 
events 
Each adjudication committee will have a charter that documents the reporting of events by the 
study site, definition of the suspected events to be adjudicated, supply of source documentation 
to the committee, entire data flow and process from committee membership, review of the events 
by the committee, reporting of the final assessment, and the working procedures of the 
committee.   
The adjudication committee members will include experts with relevant adjudication experience; 
they will not be involved in the study as Investigators, DMC members, or consultants.  Any 
candidate found to have a conflict or whose name is listed on the FDA debarment list is not 
offered membership.  Conflicts of interest are assessed regularly, and if members are found to 
have a new conflict of interest they will be replaced. 
The adjudication of suspected events will be based on available source documentation, including 
but not limited to individual clinical study data, hospital records, histology, discharge summaries, 
and/or death certificates.  The adjudication committees will not receive any individual patient 
treatment or site-specific information.  The assessment of events will be conducted in 
compliance with study-specific procedures, manuals, GCP, and all other applicable regulatory 
requirements, including the archiving of essential documents. 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
Study records at each site will be monitored at regular intervals by a representative of the 
Sponsor, the CRA.  The role of the CRA is to aid the Investigator in the maintenance and 
documentation of complete, accurate, legible, well organized and easily retrievable data.  In 
addition, the CRA will ensure the Investigator's understanding of all applicable regulations 
concerning the clinical evaluation of the investigational product and will ensure an understanding 
of the protocol, reporting responsibilities and the validity of the data.  This will include ensuring 
that full and appropriate essential documentation is available. 
In order to perform this role, the CRA must perform source data verification and as such must be 
given access to the patient’s primary source documentation (eg, paper or electronic medical 
records such as consent to participate in the study, visit dates, screening and randomization 
numbers, demographic information, medical history, disease history, physical examination, vital 
signs, laboratory assessments [copy of laboratory reports], AEs, concomitant medications, dates 
of dispensing investigational product, ECGs, etc) that support data entries in the eCRF.  The 
eCRF must be completed promptly after each visit to allow the progress and results of the study 
to be closely followed by the Medical Monitor. 
The Investigator may exercise judgment in allowing the CRA access to particular sections of the 
patient's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
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16.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IEC/IRB, and/or 
regulatory agencies to conduct one or more site audits during or after the study and agrees to 
allow access to all study-related documentation and information and be available for discussion 
about the study.   
17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the eCRF or ultimately 
transferred into the database to ensure accuracy and completeness.   
Training sessions, regular monitoring of the study at the study site by the Sponsor or designated 
personnel (eg, CRA), instruction manuals, data verification, cross checking, and data audits will 
be performed to ensure quality of all study data.  Investigators’ meetings and/or onsite study 
initiations will be performed to prepare Investigators and other study site personnel for 
appropriate collection of study data. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit.   
18. 
ETHICS 
18.1. 
Ethics Review 
The final study protocol, including the final version of the PIS-IC and/or other patient 
information, must be approved or given a favorable opinion in writing by an IRB/IEC as 
appropriate.  The Investigator must submit written IRB/IEC approval to Intercept before he or 
she can enroll any patient into the study.  The Investigator is responsible for providing the IB and 
any other available safety information and information about payments and compensation 
available to study patients to the IRB/IEC for review. 
The Investigator is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements.  A favorable opinion on amendments will be obtained prior 
to implementation, unless the amendment is necessary to reduce immediate risk to study 
participants.  In addition, the IRB/IEC must approve all advertising used to recruit patients for 
the study.  The protocol must be reapproved by the IRB/ IEC upon receipt of amendments and 
annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product, 
according to local regulations and guidelines.  The Sponsor will provide this information to the 
Investigator. 
Progress reports and notifications of SARs will be provided to the IRB/IEC according to local 
regulations and guidelines.  Investigators or the Sponsor or its designee will provide reports to 
the IRB/IEC as requested, as a minimum annually, and after the study is complete. 
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18.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki, “(64th World Medical Association [WMA] General Assembly, 
Fortaleza, Brazil, October 2013),”and are consistent with ICH/GCP, applicable regulatory 
requirements and the Sponsor’s policies. 
18.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the patient is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Patients 
must also be notified that they are free to discontinue from the study at any time.  The patient 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The patient’s signed and dated consent form must be obtained before conducting any study 
procedures. 
The Investigator(s) must maintain the original, signed ICF. A copy of the ICF must be given to 
the patient. 
18.4. 
Patient Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the patient will be 
regarded as confidential and confidentiality of all patients will be maintained.  Monitors 
(eg, CRA, Medical Monitor), auditors and inspectors will require access to a patient’s medical 
notes for the purpose of source document verification but the patient’s confidentiality will be 
maintained at all times.  An agreement for disclosure of any such information will be obtained in 
writing and is included in the statement of informed consent.  The study data shall not be 
disclosed to a third party (with the exception of auditors and/or regulatory authorities) without 
the written consent of the Sponsor.  All data shall be secured against unauthorized access. 
The Investigator will maintain a list of patient’s names and identifying information (eg, patient’s 
hospital number, unique patient number).  This list will not be collected by the Sponsor. 
The PIS-IC will explain that study data will be stored in a computer database, maintaining 
confidentiality in accordance with national data protection legislation.  All data computer 
processed by the Sponsor or designee will be identified by unique patient number/randomization 
code/site number, only.   
When personal data on patients are stored or processed by computer, the data must be protected 
to prevent disclosure to unauthorized third parties.  The pertinent sections of the data protection 
laws in the country in which the protocol is being conducted will be complied with in full. 
The PIS-IC will explain that, for data verification purposes, authorized representatives of the 
Sponsor, regulatory authorities, or IEC/IRBs may require direct access to parts of the hospital or 
study site records relevant to the study, including patient’s medical history. 
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19. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the patients for the duration of the study.  If the Investigator 
is not present in the study site during the assessment, he or she will leave instructions for the 
study site staff and a telephone number where he or she can be reached. 
Named physician(s) will be responsible for the medical follow-up of patients, as applicable. 
19.1. 
Adverse Event Reporting 
The Investigator is responsible for recording AEs reported by the patient or discovered by any 
other means during the study.  In agreeing to the provisions of this protocol, the Investigator 
accepts all legal responsibilities for immediate reporting of SAEs to the Sponsor. 
19.2. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any significant way without 
proper notification to the Sponsor (or designee).  Only the Sponsor may amend the protocol.  
Any change in study conduct considered necessary by the Investigator will be made only after 
consultation with the Sponsor, who will then issue a formal protocol amendment to implement 
the change and obtain regulatory approval.  The only exception is when the Investigator 
considers a patient’s safety to be compromised if immediate action is not taken. 
19.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
 Approved PIS-IC (all versions) 
 IRB/IEC approvals (of protocol/amendments, patient questionnaires, etc)  
 Form FDA 1572  
 Current medical license of Investigators 
 Curriculum vitae of Investigators 
 Laboratory certification and reference ranges 
 Financial disclosure forms 
19.4. 
Ethics Review (IRB/IEC) 
Please see Section 18.1 for the Investigator’s responsibilities regarding ethics review. 
19.5. 
Archiving and Record Retention 
The Investigator should retain all essential documents and correspondence relating to this study 
in the Investigator Site File (ISF).  Any study documents stored elsewhere should have their 
location referenced in the ISF table of contents or in a note to file. 
All documents relating to the study including the ISF itself, source documents and patient 
medical files (retained per country specific regulations), completed study patient log and 
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confidential patient identification list will be retained by the Investigator until at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the Sponsor.  In the event that storage of records 
becomes a problem at any time during this period, the Sponsor should be consulted for 
assistance.  At the end of the minimum period, the Investigator should obtain written 
authorization from the Sponsor before the destruction of any records.  The Investigator will 
notify the Sponsor if ownership of documents or responsibility for the study site is transferred.  
The Sponsor will inform Investigators should it become aware of any changes in storage 
requirements. 
20. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it Sponsors consistent 
with the Declaration of Helsinki.  Consistent with the recommendations of the editors of several 
leading medical journals, the International Committee of Medical Journal Editors (ICMJE), 
authorship of publications resulting from Intercept sponsored studies should fairly recognize the 
activities of those that have made a significant contribution to the study (http://www.icmje.org).  
Thus, it is anticipated that authorship will reflect the contribution made by the Sponsor 
personnel, the Investigators and others involved, such as statisticians.   
In recent years, issues about conflicts of interest and accuracy of the study data have been raised 
in the medical press.  Accordingly, the Sponsor has developed publication guidelines for clinical 
studies that are appropriate for this study.  Key issues include the following: 
 Clinical Trial Registries (eg, www.clinicaltrials.gov, www.clinicaltrialsregister.eu):  
A description of the study and relevant design elements (eg, basic design, objectives 
and endpoints, sample size, study population, and key inclusion/exclusion criteria) 
and results will be published online in a manner consistent with applicable regulatory 
guidelines. 
 Overview:  Investigators, reviewers and editors will have the right to audit the data to 
verify its accuracy. 
 Responsibility:  Each Investigator is responsible for the accuracy and completeness of 
all data from her/his site.  The Sponsor (or its representatives) is responsible for the 
accuracy of the data entered into the study databases and the analyses conducted. 
 Data Management:  The Sponsor will establish data management and SAP.  The 
Investigators will have the opportunity to provide input into the plans.  The 
Investigators will have the right to review the audit reports and data resolution 
decisions prior to the establishment of a clean file.  The Investigators will have the 
right to appoint appropriately qualified auditors, with GCP experience, to audit the 
Sponsor’s data prior to the establishment of a clean file.  The Investigators must 
provide adequate notice (at least 2 months) to the Sponsor of their intention to audit a 
study.  The audit should be conducted in a timely manner to allow the resolution of 
discrepancies before a clean file is established.  The Investigators will bear all the 
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costs for the conduct of audits that they initiate, except those related to the resolution 
of data queries which the Sponsor will bear.  Such audits must be conducted in such a 
manner as to minimize the time to create the clean file. 
 Authorship:  Intercept, in collaboration with the Investigators, will establish the 
appropriate authorship and responsibility for drafting study documents in accordance 
with the principles of the ICMJE.  All manuscripts will be reviewed and agreed upon 
before submission for publication by all authors.   
 Single Center Publication and Additional Publications:  This is a multicenter study 
and is designed to be published with complete data from all the study sites.  Single 
center publications are therefore not considered appropriate.  Any such publications 
should clearly state that the data are “extracted” from a multicenter study and that the 
study was not intended, or statistically powered, for data presentation by a single 
study site.   
 Intercept Review of External Manuscripts:  Consistent with this, Investigators must 
submit any drafts of any publications or presentations that may arise from this study 
to the Sponsor for review and approval and to ensure consistency with the policy in 
this protocol at least 30 days prior to submission for publication or presentation.  The 
Sponsor will have the right to request appropriate modification to correct facts and to 
represent its, or the Publication Committee’s, opinion if these differ with the proposed 
publication.  
 Confidentiality:  Investigators will conduct all interactions with the company and 
with third parties consistent with the executed confidentiality agreements.  While 
publication, by intention, presents the critical scientific data in a public forum, some 
information (such as future plans, results of preclinical studies or chemical formulae) 
may still need to remain confidential. 
 Medical Journal Review:  Upon request, all pertinent study data and information will 
be made available as supplemental information for journal editors and reviewers to 
evaluate and audit, eg, protocol and amendments, data tabulations, etc.  Arrangements 
will be made to maintain the confidentiality of such supplemental information. 
Arrangements will also be made to maintain the confidentiality of the identity of 
journal reviewers.  Records will be maintained of which documents and datasets were 
reviewed. 
21. 
LIST OF REFERENCES 
Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Digestive and Liver Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin ME, Gish RG, et al. Changing Nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Gastroenterology. 2015b;149(6):1627-9. 
Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: From 'cirrhosis' to 
'cholangitis'. Hepatology. 2015c;62(5):1620-2. 
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Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of 
liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 
2012;56(1):198-208. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51(2):237-67. 
Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European 
Association for the Study of the Liver and the American Association for the Study of Liver 
Diseases. J Hepatol. 2014 Sep;61(3):642-59. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-36. 
Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the PBC-40, a 
disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 
2005;54(11):1622-9. 
Kamath PS, Kim WR. The model for end-stage liver disease (MELD). Hepatology. 2007 
Mar;45(3):797-805. 
Kim WR, Lindor KD, Locke GR, et al. Epidemiology and natural history of primary biliary 
cirrhosis in a US community. Gastroenterol. 2000;119:1631-36. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis: AASLD Practice 
Guidelines. Hepatology. 2009;50(1):291-308. 
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver 
transplant waiting list: a report of a national conference organized by the American Society of 
Transplant Physicians and the American Association for the Study of Liver Diseases. Liver 
Transpl Surg. 1997;3(6):628-37. 
Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis 
(syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol. 
1978;379(2):103-12. 
Oemar M, Janssen B. EQ-5D-5L User Guide: Basic Information on how to use the EQ-5D-5L 
instrument. 2013 October;Version 2.0:1-28. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-72. 
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding 
oesophageal varices. Br J Surg. 1973;60(8):646-9. 
Younossi ZM, Guyatt G, Kiwi M, et al. Development of a disease specific questionnaire to 
measure health related quality of life in patients with chronic disease. Gut. 1999;45(2):295-300. 
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APPENDIX A. SUMMARY OF CHANGES:  PROTOCOL 747-401 VERSION 2 (DATED 22 MAY 2017) 
Please note that Protocol 747 401 Version 1 was generated to specifically address US FDA post-marketing requirements but 
was not submitted to other Regulatory/Competent Authorities or Ethics Committees due to ongoing negotiations. The changes 
in Version 2 were incorporated based on FDA review of Version 1 of the protocol.  In general: 
 Background information was included to estimate the exposure difference between healthy subjects and patients with 
moderate hepatic impairment to support the rationale for dose selection (Section 5.4.2) 
 Additional PK sampling times were added to adequately characterize the PK of OCA and its active metabolites at 
steady-state in patients with moderate and severe impairment when dosing weekly to biweekly (Section 12) 
 The period between screening and Day 1 was extended to at least 14 days to establish a baseline for serum biomarkers with 
at least two samples two weeks apart (Schedule of Study Procedures, Section 9.7.4) 
 The Week 3 contact Visit by email/telephone was changed to a Safety Visit to assess evidence of early hepatotoxicity 
(Schedule of Study Procedures, Section 9.7.6) 
 Guidelines were added to assess patients for evidence of hepatotoxicity at each visit (Section 8.4.1.2). 
The table below includes substantial revisions made to Protocol 747-401 under Version 2.  Revised text in Version 2 is indicated in 
bold font, and the text deleted from Version 1 is crossed out in the table below.  (Minor/editorial changes and non-substantial changes 
are not listed individually in the summary table below). 
Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
Title Page 
(For FDA Review Only) 
EudraCT Number: 2017-001762-13 
Added  
EudraCT 
Number 
STUDY 
PERSONNEL 
CONTACT 
INFORMATION 
Emergency Contact Information 
Medical Monitor - 24-hour Emergency Reporting 
Contact: 
 MD, Medical Director, 
Drug Safety,  
Intercept Pharmaceuticals, Inc. 
Mobile: 
  
Medical Monitor  
Primary 
Contact: 
 MD, Medical Director, Ph
Intercept Pharmaceuticals, Inc. (Intercept)
Telephone: 
  
Email: 
 
Updated 
contact list. 
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Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
Telephon
e: 
  
Email: 
 
Or if Not Available: 
Contact: 
 MD, PhD,  
Intercept Pharmaceuticals, Inc. 
Telephon
e: 
 
SAE Contact Information 
SAE Fax: 
 
SAE email address 
 
Telephone 
 
 
Clinical Operations and Project Management 
Contact: 
 VP, Clinical 
Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 
 
 
 
 
 
SAE Fax: 
 
SAE Email: 
 
 
 
Synopsis, 
Investigators 
The study is planned to have approximately 20 
investigational sites, globally 
The study is planned to have approximately 35 
investigational sites, globally 
Updated site 
numbers. 
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Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
and/or Study 
Center(s) 
Synopsis, Study 
Period, 7.1.3, 
Study Duration 
Studied Period: The study will include a 14-day screening 
period and a 48-week double-blind primary treatment 
period.  Following completion of the Week 48 visit, 
patients will remain on blinded investigational product and 
be seen at regular intervals until all patients complete the 
primary treatment period at which point all patients will 
transition to an open-label long-term safety extension 
(LTSE). 
Study Period:  Patients will receive double-blind treatment 
for at least 48 weeks.  Patients who have completed their 
48-week double blind treatment period will continue 
double blind treatment until all randomized patients have 
completed their participation in the 48-week treatment 
period and the database for that period is locked 
(approximately 3 years).  Patients will then be given the 
option to go on open-label treatment. 
Updated 
description of 
study period. 
Synopsis, 
Objectives 6.1 
Primary 
Objectives; 6.2 
Secondary 
Objectives, 6.3, 
Additional 
Objectives,  
:  In patients with Moderate to Severe PBC: 
• 
To evaluate the pharmacokinetics (PK) of OCA and its 
conjugates, glyco-OCA, tauro-OCA, and OCA glucuronide  
 
Liver biochemistry including total bilirubin 
 
… aspartate aminotransferase [AST], and 
gamma glutamyl transaminase [GGT 
 
 
 
Biomarkers of bile acid synthesis and 
homeostasis including fibroblast growth factor 
19 (FGF 19), 7α hydroxy-4-cholesten-3-one 
(C4), and plasma and fecal bile acids 
 
To assess the PK/Pharmacodynamic (PD) relationship 
of OCA on: 
 ̀
ALP, total bilirubin, and aminotransferases 
 ̀
Bile acid homeostasis 
 ̀
Safety and tolerability (eg pruritus) 
 
 
• To evaluate the pharmacokinetics (PK) of OCA and its 
conjugates, glyco-OCA, tauro-OCA, and metabolite OCA 
glucuronide compared with placebo 
 
Liver biochemistry including total and direct 
bilirubin 
 
… aspartate aminotransferase [AST], and gamma 
glutamyl transaminase [GGT],), international 
normalized ratio (INR), creatinine, albumin, 
platelets   
 
Biomarkers of bile acid synthesis and 
homeostasis including fibroblast growth factor 
19 (FGF 19), 7α hydroxy-4-cholesten-3-one 
(C4), and plasma bile acids 
 
To assess the PK/Pharmacodynamic (PD) relationship of 
OCA with: 
 ̀
PK parameters compared to PD Parameters and 
Safety and Tolerability assessments (above)   
 
Clarified 
study 
objectives. 
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Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
• 
To assess clinical outcomes consistent with end-stage 
liver disease 
• 
To assess patient reported outcomes (Pruritus Visual 
Analogue Scale [VAS], PBC-40, EQ 5D-5L, Chronic 
Liver Disease Questionnaire [CLDQ]) 
• 
To assess clinical events consistent with end-stage liver 
disease 
Synopsis, 
Methodology 
and Section 7.1. 
Overall Study 
Design 
Patients will be screened for up to ≤14 days… 
Patients will be screened ≥14 days but not more than 
28 days… 
Extended to 
14 days to 
satisfy PMR 
for 2 baseline 
measurement
s. 
Synopsis,  
Double-Blind 
Treatment 
Period, 7.1, 
Overall Study 
Design 
Double-Blind Primary Treatment Period 
… (ie, Day 1 through Week 48), clinic visits will occur 
approximately every 6 weeks for the assessment of safety, 
tolerability, PK, and PD (trough).  At each visit, trough PK 
assessments will be performed in all patients participating 
in the study.  Serial PK sampling will be performed at 
Week 12 and only after a patient uptitrates.  Following 
completion of the Week 48 visit, patients will remain on 
blinded investigational product and be seen at regular visits 
every 3 months until all patients complete the 48 week 
primary treatment period. 
…  Double-Blind Treatment Period:  …(ie, Day 1 through 
Week 48), an initial safety visit will occur at Week 3.  
After the Week 6, subsequent clinic visits will occur 
approximately every 6 weeks for the assessment of safety, 
tolerability, PK, and PD.  At each visit (except screening 
and Week 3), fasting PK assessments will be performed in 
all patients participating in the study.  Serial PK sampling 
will be performed at Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week double-blind 
treatment period will continue double blind treatment 
until all randomized patients have completed their 48-
week treatment period and the database for that period is 
locked.  Patients will then be given the option to go on 
open-label treatment.   
Updated 
description of 
study period. 
Synopsis, Long -
term Open Label 
Extension Phase 
Long -term Open Label Extension Phase 
Once all patients have completed the double-blind 48 week 
primary treatment period, patients will have the option to 
continue into an open-label long term safety extension and 
all patients will receive OCA.  Visits in the LTSE will 
occur every 3 months for up to 5 years.  Patients on placebo 
during the primary treatment period will initiate study 
medication at 5-mg OCA once weekly and follow the 
dosing regimen based on their CP score.  Patients on OCA 
Section deleted. 
Updated 
description of 
study. 
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Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
during the primary treatment period will continue the dose 
that they are on once unblinded. 
Synopsis and 
Section 7.1.1, 
Study Design 
Diagram 
 
EOS = end of study; EOT = end of treatment, OCA = obeticholic acid 
*Initial dose titration of investigational product may occur at the Week 12 
Visit, or any study visit … 
 
Note: Initial dose titration of investigational product may be considered as 
early as the Week 12 visit, or any study visit thereafter for patients on all 
dosing regimens, based on …. 
Patients who complete Week 48 will continue double-blind treatment 
until all randomized patients have completed their participation in the 
48-week treatment period and the database for that period is locked. 
Updated 
study 
diagram. 
Synopsis, 
Dosing Regimen, 
Section,  7.3 
(Table 2) 
All patients will initiate investigational product once 
weekly with 5 -mg OCA or matching placebo.  Starting at 
Week 12, safety and tolerability of investigational product 
will be evaluated and, if tolerated, the patient can increase 
the dose to the next dose level as described below: 
• At Week 12, if investigational product is tolerated and 
laboratory assessments from the Week 6 visit do not 
indicate a safety concern, the patient will change the 
dosing frequency to 5 mg twice weekly, at least 3 days 
apart.   
 Following an additional 6 weeks of treatment, if 
investigational product is tolerated, patients may be up-
titrated to OCA 10 mg twice weekly at least 3 days 
apart, the maximum dose for patients with CP-C.  
 Following an additional 6 weeks of treatment, if 
tolerated, Patients with CP-B may titrate to a maximum 
dose of OCA 5 mg once daily, the maximum dose for 
patients with CP-B.  
All patients will initiate investigational product once weekly 
with 5 mg OCA or matching placebo.  Titration may be 
considered as early as the Week 12 Visit.  Following visit 
procedures at Week 12, if the investigational product is 
tolerated and laboratory assessments do not indicate a safety 
concern, the patient may up-titrate to OCA 5 mg twice 
weekly and may start the higher dose regimen no earlier 
than 2 days after they took their last dose.  Dosing will 
then occur at least 3 days apart.  Every 6 weeks thereafter, 
based on safety and tolerability assessments, patients can 
be considered for further up titration as described below.  
At each titration visit, the patient may start the higher 
dose regimen no earlier than 2 days after the prior dose. 
Patients with CP-B may titrate to a maximum dose of OCA 
5 mg once daily. 
 
Patients with CP-C may titrate to a maximum dose of 
OCA 10 mg twice weekly at least 3 days apart.  
 
Updated table 
for clarity. 
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Key Change 
• 
If, during the course of the study, a patient transitions 
from CP- B to CP-C, or vice versa, the maximal dose 
for the new CP classification would apply. 
 
Planned OCA or Matching Placebo Dosing Regimen by 
Child-Pugh Score 
 
Child-Pugh B 
(Moderate Hepatic 
Impairment) 
Child-Pugh C 
(Severe Hepatic 
Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting Dose 
a (Day 1) 
5 mg 
once 
weekly 
matching 
placebo 
5 mg 
once 
weekly 
matching 
placebo 
Titration 1b 
(≥Week 12) 
5 mg 
twice 
weeklyc 
matching 
placebo 
5 mg 
twice 
weeklyc 
matching 
placebo 
Titration 2b 
(≥6 weeks 
after Titration 
1) 
10 mg 
twice 
weeklyc 
matching 
placebo 
10 mg 
twice 
weeklyc 
matching 
placebo 
Titration 3b 
(≥6 weeks 
after Titration 
2) 
5 mg 
once 
daily 
matching 
placebo 
NA 
matching 
placebo 
 
 
aStarting dose based on patient’s Child-Pugh Score at Screening. 
bPlanned titration regimen is shown; however, the titration of dose and/or 
frequency is dependent on patient tolerability and/or changes in Child-
Pugh Score at any time during the study. 
cDosing per the twice weekly schedule must be at least 3 days apart. 
 
Child-Pugh B 
(Moderate Hepatic 
Impairment) 
Child-Pugh C 
(Severe Hepatic 
Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting Dose 
(Day 1) 
5 mg 
once 
weekly 
matching 
placebo 
5 mg once 
weekly 
matching 
placebo 
Titration 1a  
5 mg 
twice 
weeklyb 
matching 
placebo 
5 mg 
twice 
weeklyc 
matching 
placebo 
Titration 2a  
10 mg 
twice 
weeklyb 
matching 
placebo 
10 mg 
twice 
weeklyc 
matching 
placebo 
Titration 3a  
5 mg 
once 
daily 
matching 
placebo 
NA 
NA 
 
aPlanned titration regimen is shown; however, the titration of dose 
and/or frequency is dependent on patient tolerability and/or changes in 
Child-Pugh Score at any time during the study 
bDosing per the twice weekly schedule must be at least 3 days apart. 
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Key Change 
(insertion) 
If, during the course of the study, a patient transitions 
from CP- B to CP-C, or vice versa, the maximal dose for 
the new CP classification would apply.   If a patient 
demonstrates an improvement to CP-A, they should 
follow the dosing regimen for patients with CP-A. 
 
Over the course of the study, a patient’s CP category may 
change.  When a patient demonstrates a change in CP 
category, dosing should be reassessed and modified if 
appropriate.  Changes to the dosing regimen are not 
mandatory and should be based on clinical judgment and 
change in CP score.  The titration steps for CP-B and CP-C 
patients are identical with exception of the maximum allowed 
dose.  Therefore, if a patient changes CP class from B to C, or 
vice versa, the maximal dose for the new regimen will apply.  
If a patient improves to CP-A during the study, the maximal 
CP-B dose will still apply.  If a patient has not yet reached the 
maximal dose, the appropriate titration regimen should be 
followed.  
 
 
 
a Once a patient begins dosing with the new dosing regimen, 
titration should occur as described for the planned dosing 
regimen.  
b 
Dosing per the twice weekly schedule must be at least 3 
days apart. 
Added to 
provide 
more 
information 
on dosing. 
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Key Change 
Synopsis and 
Section 8.2, Key 
Inclusion 
Criteria 
2. Evidence of cirrhosis including at least one of the 
following: 
 ̀
Biopsy indicating cirrhosis or a medical history with 
histological evidence of cirrhosis  
 ̀
Clinical evidence consistent with cirrhosis including: 
esophageal varices, ascites, encephalopathy, or portal 
hypertension 
 ̀
 Liver stiffness as assessed by TE of >16.9kPa 
 
 
 
 
 
 
 
 
 
 
6. Age ≥18 years 
7. Taking UDCA for at least 12 months (stable dose for 
≥3 months) prior to Day 1, or unable to tolerate UDCA 
(no UDCA for ≥3 months)  
8. Contraception:  Female patients must be 
postmenopausal, surgically sterile, or if premenopausal 
(and not surgically sterile), be prepared to use ≥1 
effective method of contraception during the study and 
for 30 days after the end of treatment visit.  Effective 
methods of contraception are considered to be those 
listed below: 
 
Barrier method, ie, (a) condom (male or female) 
with spermicide or (b) diaphragm, with 
spermicide; or  
 
Intrauterine device; or  
2. Evidence of cirrhosis including at least one of the 
following: 
 Biopsy results consistent with PBC Stage 4  
 Liver stiffness as assessed by TE Median Value 
≥16.9 kPa 
 Clinical evidence in the absence of acute liver failure 
consistent with cirrhosis including: gastroesophageal 
varices, ascites, radiological evidence of cirrhosis 
(nodular liver or enlargement of portal vein and 
splenomegaly) 
 Combined low platelet count (<140 000/mm3) with 
 persistent decrease in serum albumin, or  
 elevation in prothrombin time/INR (not due to 
antithrombotic agent use), or 
 elevated bilirubin (2× ULN) 
 
6. Taking UDCA for at least 12 months (stable dose for 
≥3 months) prior to Day 1, or unable to tolerate or 
unresponsive to UDCA (no UDCA for ≥3 months)  
 
 
Provided 
more details 
regarding 
inclusion 
requirements.  
Only listed 
inclusions 
directly 
related to 
PBC in 
synopsis.   
Other criteria 
were deleted 
from 
synopsis but 
remain in the 
main body.  
Only criteria 
with changes 
are presented 
in this SOC. 
The full 
inclusion/ 
exclusion list 
is in the body 
of the 
protocol. 
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Key Change 
 
Vasectomy (partner), or  
 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection, or 
 
Abstinence, if in line with the preferred and usual 
lifestyle of the patient (where abstinence is defined 
as refraining from heterosexual intercourse) 
9. Must provide written informed consent and agree to 
comply with the study protocol. 
Synopsis and 
Section 8.3, Key 
Exclusion 
Criteria 
4. History or presence …: 
 
Hepatitis C virus infection RNA positive 
5. 
In the opinion of the Investigator, fluctuating or 
rapidly deteriorating hepatic function during the 
Screening period 
6. Patients with history or presence of hepatorenal or 
hepatopulmonary syndrome 
7. Patients with significant active infection (ie 
spontaneous bacterial peritonitis) 
8. Patients with known or suspected hepatocellular 
carcinoma 
9. History of known or suspected clinically significant 
hypersensitivity to OCA or any of its components 
10. Participation in another investigational product, 
biologic, or medical device study within 30 days prior 
to Screening.  Participation in a previous study of OCA 
is allowed with 3 months washout prior to enrollment 
in this study 
4. Hepatic encephalopathy (as defined by a West Haven 
score of ≥2) 
5. 
History or presence …: 
 
Hepatitis C virus infection and RNA positive 
6. In the opinion of the Investigator, fluctuating or rapidly 
deteriorating hepatic function prior to randomization 
Added 
additional 
key exclusion 
criteria #4.  
Other criteria 
were deleted 
from 
synopsis but 
remain in the 
main body.  
Only criteria 
with changes 
are presented 
in this SOC. 
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Key Change 
11. Mental instability or incompetence, such that the 
validity of informed consent or ability to be compliant 
with the study is uncertain 
12. UDCA naïve (unless contraindicated). 
Synopsis, 
Duration of 
Treatment 
The study will include a 14-day screening period and a 48 
week double -blind primary treatment period.   Following 
completion of the Week 48 visit, patients will remain on 
blinded investigational product and be seen at regular visits 
every 3 months until all patients complete the double-blind 
48 week primary treatment period.  Hence, depending on 
the rate of patient enrollment, patients will be exposed to 
investigational product for a minimum of 1 year up to 
approximately 2 years during the blinded period.  
Following completion of the blinded period, Patients will 
have the option to continue into an extension during which 
they will receive open label treatment and be seen at regular 
visits every 3 months for up to 5 years.  
Patients who have completed their 48-week double blind 
treatment period will continue double blind treatment 
until all randomized patients have completed their 
participation in the 48-week treatment period and the 
database for that period is locked (approximately 
3 years).  Patients will then be given the option to go on 
open-label treatment.    
Updated 
description of 
study. 
Synopsis, 
Criteria for 
Evaluation and 
11, Overview of 
Assessments, 
Table 5, 
Additional 
Objectives 
PD Parameters;   
plasma, fecal 
bile acids 
PK 
Plasma 
concentrations 
of OCA and its 
conjugates, 
glyco-OCA, 
tauro-OCA; and 
metabolite OCA 
glucuronide 
Clarified 
study 
parameter for 
evaluation. 
Changes in MELD and in CP score  
 
Changes in MELD and in CP score and 
components of the CP score 
 
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Key Change 
PD parameters 
fecal bile acids 
PK/PD parameters 
bile acids 
Markers of inflammation 
IL-6, hs-CRP, 
TNF-α, IgM, 
IgA, IgG, CK 
18 M30, and 
others as 
determined 
during course 
of study.   
 
IL-6, hs-CRP, 
TNF-α, IgM, IgA, 
IgG, CK 18 M30, 
PK/PD relationship of OCA and liver 
biochemistry 
OCA and its 
conjugates, 
glyco-OCA 
tauro-OCA; 
and OCA 
glucuronide 
PK/PD relationship 
PK parameters 
compared to PD 
Parameters and 
Safety and 
Tolerability 
assessments 
(above) 
PK/PD relationship of OCA and bile acid 
homeostasis 
Bile acids 
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Key Change 
Clinical Outcomes 
Incidence and 
time to first 
occurrence of 
any of the 
following:  all-
cause 
mortality, 
liver-related 
events 
resulting in 
death, hepatic 
failure leading 
to liver 
transplant, 
variceal bleed, 
hepatic 
encephalopath
y, spontaneous 
bacterial 
peritonitis, 
ascites, 
hepatocellular 
carcinoma 
Clinical Events 
Death (all-cause 
and liver-related), 
liver transplant, 
Model of end stage 
liver disease 
(MELD) score ≥15 
(for patients with 
MELD ≤12 at 
baseline), 
Hospitalization for 
new onset or 
recurrence of: 
variceal bleed, 
hepatic 
encephalopathy, 
spontaneous 
bacterial peritonitis, 
Uncontrolled 
ascites, and HCC. 
Synopsis, 
Statistical 
Methods, Safety 
Analyses 
The absolute change from baseline will also be 
summarized.  No inferential comparison of safety endpoints 
will be performed. 
The absolute change from baseline will also be summarized.  
No inferential comparison with formal statistical hypothesis 
testing will be performed for safety endpoints. 
Clarified 
statistical 
methods. 
Synopsis, 
Statistical 
Methods, 
Additional 
Efficacy 
Analyses 
The following clinical outcomes will be captured in the 
study: 
 
All-cause mortality 
 
Liver related death 
 
Liver transplant 
The following endpoints consistent with end-stage liver 
disease will be captured in the study: 
 
Time to death (all cause) 
 
Time to liver-related death 
 
Time to liver transplant 
Clarified 
statistical 
methods. 
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Key Change 
 
Variceal bleed 
 
Hepatic encephalopathy 
 
Bacterial peritonitis 
 
Ascites 
 
Hepatocellular carcinoma 
 
 
 
 
 
 
 
 
 
 
The incidence and time to first occurrence of any of the 
above listed clinical outcomes will be summarized ….The 
tabulation will include the KM estimate of the medians and 
corresponding 95% confidence intervals (CIs), if the 
medians can be estimated.  … The hazard ratio and 95% CI 
will be estimated based on a Cox regression model 
stratified by randomization strata. 
In addition, the incidence and time to each of the above 
outcomes  will be summarized by treatment group using the 
same methods as defined above.   
 
Model of end stage liver disease (MELD) 
score ≥15 (for patients with MELD ≤12 at 
baseline) 
 
Hospitalization (as defined by a stay of 
24 hours or greater) for new onset or 
recurrence of: 
 
Time to variceal bleed 
 
Time to hepatic encephalopathy (as 
defined by a West Haven score of ≥2) 
 
Time to spontaneous bacterial peritonitis 
(confirmed by diagnostic paracentesis) 
 
Time to uncontrolled ascites (diuretic 
resistant ascites requiring therapeutic 
paracentesis at a frequency of at least twice 
in a month) 
The incidence and time to first occurrence of the above listed 
clinical outcomes will be summarized ….The tabulation will 
include the KM methodology using 25th, 50th (median), and 
75th percentiles with associated 2-sided 95% confidence 
intervals (CIs), as well as percentage of censored 
observations.  ….  The hazard ratio and 2-sided 95% CI will 
be estimated based on a Cox regression model stratified by 
randomization strata. 
In addition, the incidence and time to each of the above 
clinical events, and the incidence and time to occurrence 
of hepatocellular carcinoma (HCC) will be summarized by 
treatment group using the same methods as defined above. 
 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
Synopsis and 
Section 15.2, 
Sample Size, 
To reasonably characterize the PK of OCA in patients with 
hepatic impairment, a simulation-based approach estimated 
a requirement of approximately 20 patients per OCA 
treatment group assuming a 15% discontinuation rate.  Ten 
patients on placebo will be included as a comparator.  The 
assessment was based on 80% powering for the 90% 
confidence interval of the geometric mean ratio of Total 
OCA (sum of OCA, glyco OCA, and tauro OCA). 
To reasonably characterize the PK of OCA in patients with 
hepatic impairment, a simulation based approach estimated a 
requirement of approximately 20 patients in the OCA 
treatment group assuming a 15% discontinuation rate.  Ten 
patients on placebo will be included as a comparator.  An 
additional 20 patients will be enrolled to support safety 
and efficacy evaluations.  Therefore, approximately 
50 patients (including at least 20% of patients with CP-C) 
will be randomized. 
 
5.2,  Nonclinical 
Experience with 
Obeticholic Acid 
Insertion 
Intercept Pharmaceuticals, Inc. (the Sponsor) has 
completed a standard battery of nonclinical safety 
pharmacology and toxicology studies.  No major 
nonclinical safety effects have been seen other than 
pharmacologic hepatic effects observed at high doses.  
These pharmacologic hepatic effects are consistent with 
the detergent effects of a bile acid at exceedingly high 
hepatocellular exposure. 
Added 
section to 
briefly 
address 
nonclinical 
studies. 
5.3, Clinical 
Development of 
Obeticholic Acid 
As of 31 Jan 2016, approximately 1726 patients have 
received at least 1 dose of OCA.  Of these, 844 were 
healthy volunteers, 458 patients had PBC, 330 patients had 
nonalcoholic steatohepatitis, 41 patients had diabetes 
mellitus/ nonalcoholic fatty liver disease, 33 patients had 
alcoholic cirrhosis/portal hypertension, and 20 patients had 
primary sclerosing cholangitis (PSC). 
As of 31 Jan 2017, approximately 2186 patients have 
received at least 1 dose of OCA.  Of these, 844 were healthy 
volunteers, 525 patients had PBC, 686 patients had 
nonalcoholic steatohepatitis (NASH), 41 patients had 
diabetes mellitus/ nonalcoholic fatty liver disease (NAFLD), 
33 patients had alcoholic cirrhosis/portal hypertension, 
52 patients had primary sclerosing cholangitis (PSC), and 
5 patients had biliary atresia. 
Updated 
numbers of 
patients who 
have received 
OCA. 
5.4, 
 
Rationale 
for Study Design 
and Dose for 
Investigational 
Product 
 
5.4  Rationale for Study Design and Dose for 
Investigational Product 
Inserted new 
header for 
clarity  
5.4.1, Rationale 
for Study Design 
Patients with moderate or severe hepatic impairment (Child 
Pugh B or C) will constitute approximately 20% of the 
patients included in the ongoing clinical outcomes Study 
747 302 which was specifically designed to confirm clinical 
benefit across the spectrum of disease including patients 
The 747-401 study is specifically designed to confirm 
clinical benefit across the spectrum of disease including 
patients with hepatic impairment.  Data collected from Study 
747 401 will serve as a bridge to the 747-302 study. 
Clarified the 
intent of the 
401 study. 
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Key Change 
with hepatic impairment.  Data collected from Study 747 
401 will serve as a bridge between the two studies. 
5.4.2, Rationale 
for Obeticholic 
Acid Dose and 
Duration 
Results from the hepatic impairment study (747-103) 
indicate that plasma exposure increases, in comparison to 
subjects with normal liver function, with increasing severity 
of impairment as classified by Child Pugh A (CP A), CP B 
or Child Pugh C (CP C) scores by 1.4-, 8.0-, and 13 fold, 
respectively.  No apparent impact on the overall safety 
profiles were observed in this study.  Liver exposure, 
however, modestly increased by 1.1-, 1.5, and 1.7-fold, 
respectively, as shown in simulations using a physiologic 
PK model developed to characterize OCA and its 
conjugates.  Together, the results from these analyses 
suggest that the doses of OCA administered to patients with 
moderate or severe hepatic impairment should be modestly 
lower than those for patients with normal hepatic function 
to achieve similar hepatic exposure. 
 
 
 
(insertion) 
 
 
 
 
 
 
 
 
 
 
 
Simulations using a physiologic PK model predicted changes in 
systemic and liver OCA concentrations associated with changes 
in the severity of hepatic impairment (CP Score).  Model 
simulations predicted that for mild (Child-Pugh A [CP-A]), 
moderate (Child-Pugh B [CP-B]), and severe (Child-Pugh C 
[CP-C]) hepatic impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to patients with normal 
hepatic function, whereas total OCA liver concentrations 
increase 1.1-, 1.5-, and 1.7-fold, respectively.  Because the liver is 
the primary site of action for the safety and efficacy of OCA, it is 
important to account for the differences in systemic and liver 
exposure when assessing effective doses.  It is also important to 
note that while hepatically impaired (CP-B and C) patients 
treated with OCA in Phase 1 and 2 studies experienced plasma 
OCA exposures >10-fold higher than those in healthy patients, 
no apparent impact on the overall safety profile was observed, 
consistent with only a modest increase in liver exposure of OCA 
associated with hepatic impairment.  Together, the results from 
these analyses suggest that the doses of OCA administered to 
patients with moderate or severe hepatic impairment should be 
modestly lower than those for patients with normal hepatic 
function to achieve similar hepatic exposure.    
Therefore, the current FDA-approved prescribing information 
for OCA includes a modified dosing regimen in patients with 
moderate and severe hepatic impairment that is designed to 
achieve liver exposures in these patients that would be similar to 
non-hepatically impaired patients through initiation at a lower 
Added 
rationale for 
OCA dosing 
in hepatically 
impaired 
patients. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
 
Therefore, a modified dosing regimen is recommended for 
OCA in patients with moderate and severe hepatic 
impairment that is designed to initiate doses to achieve 
plasma exposures levels of OCA similar to those without 
hepatic impairment or CP-A.  After which, subjects may 
then titrate their doses upwards to achieve liver exposures 
that would be similar in both patient populations.  This 
modified dosing regimen was selected based on the 
established safety and tolerability of OCA in subjects with 
PBC, along with PK/PD modeling and simulations.  
Patients will initiate dosing at OCA 5 mg once weekly.  
Starting at Week 12, if the prior dose regimen was 
tolerated, the patients will increase the dosing frequency to 
5 mg twice weekly (at least 3 days apart).  After 6 weeks, a 
second titration may occur to OCA 10 mg twice weekly as 
long as tolerated.  Patients classified as CP B may further 
titrate their dose upwards to OCA 5 mg once daily after 
6 weeks on the OCA 10 mg twice weekly regimen. 
dose (5 mg OCA once-weekly) followed by gradual up-titration 
(Section 7.3).   
The dosing regimen in this study follows the FDA-approved 
prescribing information, with the exception of the maximum 
allowed dose in patients with moderate impairment.  While the 
prescribing information allows for a maximum dose of 10 mg 
twice weekly for patients with moderate impairment, the 
protocol allows for a maximum dose of 5 mg once daily.  The 
choice of 5 mg once daily is supported by the estimated steady-
state liver and plasma exposure of total OCA for patients with 
moderate hepatic impairment receiving a 5 mg once daily dose 
relative to healthy patients receiving a 10 mg dose.  A maximum 
allowed dose of 5 mg once daily in patients with moderate 
hepatic impairment is estimated to achieve liver exposure 
similar to non-hepatically impaired patients receiving a 10 mg 
daily dose and maximize efficacy in this patient population. 
 
7.1.2, Schedule 
of Study 
Procedures 
Schedule of Study Procedures (Double-Blind Treatment 
Period) 
Schedule of Study Procedures 
Updated 
procedures to 
match 
updated study 
design. 
7.1.2, Schedule 
of Study 
Procedures, Visit 
Windows 
≤-1 to -14 days 
-28 to -14 days 
Updated 
procedures to 
match 
updated study 
design. 
7.1.2, Schedule 
of Study 
Procedures, Visit 
Weeks Row 
Week 3: Safety Contact 
Week 48 
Under Long-Term Treatment 
Week 3 
Week 48/ET/EOS/EOT 
Every 3 months 
Week 3 
telephone/em
ail contact 
visit now a 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
laboratory 
safety visit. 
7.1.2, Schedule 
of Study 
Procedures 
(Insertion) 
 
Dose Titration 
IL-6, hs-CRP, TNF-α, IgM, IgG, IgA, CK-18-M30, others 
as determined during course of study 
Fecal PK Analysis 
TE Fibroscan® 
ELF 
MELD 
PK trough Collection 
Column: Long-Term Treatment 
Procedures: Medical and Surgical Procedures 
Dose Titration Assessment 
Markers of Inflammation: IL-6, hs CRP, TNF-α, IgM, IgG, 
IgA, CK-18-M30 
 
 
 
TE/ELF (HA, P3NP, and TIMP 1) 
PK Fasting Collection 
Updated 
procedures to 
match 
updated study 
design 
7.1.2, Table 1, 
Schedule of 
Study 
Procedures 
Footnotes 
a 
Patients should be contacted by telephone/email every 
3 weeks (±1 week) between clinic visits starting at Week 3 
and continuing to Week 48 to assess for AEs, concomitant 
medications, and verify that s/he is dosing as directed. 
b 
Visits should be based on Day 1. 
c 
The patient should be instructed to fast overnight (at 
least 8 hours) prior to each visit.  Fasting is required prior to 
all study visits (except Screening Visit 1) but water is 
permitted. 
d 
Medical history performed at Screening only.    
e 
The yearly physical exam will also include an 
assessment of smoking and alcohol consumption history 
and current habits for both.  Height will only be collected at 
Day 1 and Week 48.    
f 
Child-Pugh Score will be calculated based on ascites 
assessment, hepatic encephalopathy grade, and central 
laboratory evaluations per the Child-Pugh scoring system 
noted in the eCRF. 
g 
The EQ-5D-5L Quality of Life questionnaire is 
validated for use in multiple languages. If a validated 
aVisit schedule should be based on Day 1.  Day 1 visit 
must occur at least 2 weeks after screening visit. 
bPatients should be contacted by telephone/email every 
3 weeks (±1 week) between clinic visits starting at Week 9 
and continuing to Week 48 to assess for AEs, concomitant 
medications, medical/surgical procedures, and verify that 
s/he is dosing as directed. 
c Preferably, the patient comes in to the clinic for this 
visit.  Alternatively, site will telephone the patient for 
assessments and home health nurse will visit to draw 
safety labs. 
d Visit should occur 3, 4, or 5 days after taking the Week 6 
dose. 
e 
The patient should be instructed to fast overnight (at least 
8 hours) prior to each visit.  Fasting is required prior to all 
study visits, including screening, but water is permitted. 
f Height and assessment of smoking and alcohol 
consumption history and current habits will be assessed at 
Screening and Week 48.   Assessment of smoking and 
Updated 
procedures to 
match 
updated study 
design 
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translation is not available in the local language required for 
a specific study patient, the data from that questionnaire 
will not be collected.  The CLDQ measures change over 
time in patients with chronic liver disease.  
h 
Patients will be instructed to begin dosing on the Day 1 
visit after completing all study assessments. (ie, on Day 1).  
Patients will be instructed to take investigational product at 
approximately the same time of day.  Patients must be 
instructed to swallow the tablet whole; they must not chew, 
divide, or crush the tablet. 
i 
Initial dose titration of investigational product may 
occur at the Week 12 Visit, or any study visit thereafter for 
patients on all dosing regimens, based on CP score, 
tolerability and safety laboratory tests from the previous 
visit.  Subsequent dose titration(s) may occur no earlier than 
6 weeks after the previous dose titration and will be based 
on tolerability and CP score. 
j 
Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry and at every 
visit.  If positive, a confirmatory blood test must be 
performed at the central laboratory.  If the confirmatory 
blood test is also positive, the patient may not continue in 
the study.  (Additional testing may be conducted where 
required, regionally) 
alcohol consumption history and current habits will be 
assessed quarterly after Week 48. 
g 
Child-Pugh Score will be calculated based on ascites 
assessment, hepatic encephalopathy grade, and central 
laboratory evaluations per the Child-Pugh scoring system 
noted in the eCRF. 
h 
The EQ-5D-5L Quality of Life questionnaire is validated 
for use in multiple languages. If a validated translation is not 
available in the local language required for a specific study 
patient, the questionnaire will not be collected.  The CLDQ 
measures change over time in patients with chronic liver 
disease.  
i 
New investigational product bottles will be dispensed 
if the patient is titrated. Unless up-titrated, patients are 
expected to use up each investigational product bottle 
before a new bottle will be dispensed.  No new bottles will 
be dispensed if dose frequency is changed.  Patients will be 
instructed to begin dosing on Day 1, after completing all 
study assessments.  Patients will be instructed to take 
investigational product at approximately the same time of 
day.  Patients must be instructed to swallow the tablet whole; 
they must not chew, divide, or crush the tablet. 
j 
Dose titration of investigational product may occur 
starting after the Week 12 Visit, or any study visit thereafter 
for patients on all dosing regimens, based on CP score, 
tolerability and safety laboratory tests from the previous visit.  
Subsequent dose titration(s) may occur no earlier than 
6 weeks after the previous dose titration and will be based on 
tolerability and CP score.   
k Urine β-hCG pregnancy tests must be performed in females 
of childbearing potential prior to entry and at every visit 
(except Week 3).  If positive, a confirmatory blood test must 
be performed at the central laboratory.  If the confirmatory 
blood test is also positive, the patient may not continue in the 
study.  (Additional testing may be conducted where required, 
regionally). 
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l The patient will be given the option to return to the 
clinic the following morning for the 24-hour postdose 
sample or samples can be obtained by a home health care 
designee.  Patients who are discontinued from 
investigational product prior to completion of the study 
are encouraged to continue to follow the regular visit 
schedule, with the exception of PK sampling.   
m The noninvasive radiological liver fibrosis 
measurement devices (such as, FibroScan® device 
[Echosens; Paris, France]) will be used at all study sites to 
collect hepatic stiffness measurements. 
n Patients will complete a TE/ELF and ultrasound 
assessment, every 6 months (±2 weeks) after Week 48. 
O ECG and urine dipstick will be done yearly 
(±2 weeks) after Week 48 Visit. 
p 
Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds:  Unless HCC has already been confirmed by 
biopsy, a second confirmatory image (eg, MRI) should be 
obtained to confirm suspected HCC. 
7.1.3, Study 
Duration 
The study will include a 14-day screening period and a 
48 week double-blind primary treatment period.  Following 
completion of the primary treatment period, patients will 
remain on blinded investigational product and be seen at 
regular intervals until all patients complete the primary 
treatment period (Figure 1).  Patients will have the option to 
continue into an open-label LTSE after all patients have 
completed the Week 48 procedures in which they will 
receive open-label treatment and be seen at regular visits 
every 3 months for up to 5 years. 
Patients will receive double-blind treatment for at least 
48 weeks.  Patients who have completed their 48-week 
double blind treatment period will continue double blind 
treatment until all randomized patients have completed 
their 48-week treatment period and the database for that 
period is locked (approximately 3 years).  Patients will 
then be given the option to go on open-label treatment. 
Updated 
description of 
study period. 
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7.3, Planned 
Dosing Regimen 
All patients will initiate investigational product once 
weekly with 5-mg OCA or matching placebo.  Starting at 
Week 12, safety and tolerability of investigational product 
will be evaluated and, if tolerated, the patient can increase 
the dose to the next dose level as described below 
(Table 2): 
• 
At Week 12, if investigational product is tolerated and 
laboratory assessments from the Week 6 visit do not 
indicate a safety concern, the patient will change the dosing 
frequency to 5 mg twice weekly, at least 3 days apart.  
 
Following an additional 6 weeks of treatment, if 
investigational product is tolerated, patients may be up 
titrated to OCA 10 mg twice weekly at least 3 days apart, 
the maximum dose for patients with CP-C 
 
 
Following an additional 6 weeks of treatment, if 
tolerated, patients with CP-B may titrate to a maximum 
dose of OCA 5 mg once daily, the maximum dose for 
patients with CP-B. 
 
All patients will initiate investigational product once weekly 
with 5-mg OCA or matching placebo.   Titration may be 
considered as early as the Week 12 visit.  Following visit 
procedures at Week 12, if the investigational product is 
tolerated and laboratory assessments do not indicate a safety 
concern, the patient will up-titrate to OCA 5 mg twice 
weekly and may start the higher dose regimen no earlier 
than 2 days after they took their last dose.  Dosing will 
then occur at least 3 days apart.  Every 6 weeks thereafter, 
based on safety and tolerability assessments, patients can 
be considered for further up titration as described below 
(Table 3).  At each titration visit, the patient may start the 
higher dose regimen no earlier than 2 days after the prior 
dose. 
 
Patients with CP-C may titrate to a maximum dose of OCA 
10 mg twice weekly at least 3 days apart.  
Patients with CP-B may titrate to a maximum dose of OCA 
5 mg once daily. 
Clarified 
dosing 
regimen. 
7.4, Dose 
Adjustment 
Criteria, 
Scheduled Dose 
Titration 
The first dose titration for any patient may occur no earlier 
than 12 weeks following initiation of OCA or matching 
placebo. 
After initiation of OCA or matching placebo, titration may 
be considered as early as the Week 12 visit.   
Clarified 
dosing 
regimen. 
7.4.1, Pre-
Titration 
Tolerability 
Assessment 
Requirements 
Tolerability of investigational product must be assessed 
prior to titrating a patient to a higher dose.  A review of 
AEs and available safety laboratory results (eg, chemistry, 
hematology, and coagulation) obtained within 
approximately 6 weeks of the up-titration visit must be 
performed as part of the investigational product tolerability 
assessment, prior to any planned up-titration in 
investigational product (eg, Week 6, laboratory results 
should be reviewed prior to titration at Week 12).  If for any 
reason, laboratory results are not available at the time of the 
Tolerability of investigational product must be assessed prior 
to titrating a patient to a higher dose.  To determine if a 
patient is eligible for a dose up-titration refer to 
Section 7.3 
Clarified 
dosing 
regimen. 
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Key Change 
planned up titration visit, additional laboratory samples 
must be obtained and reviewed, prior to up titrating the 
patient to a higher dose. 7.3 
To be eligible for a dose up-titration, patients should not be 
experiencing significant AEs that are suspected to be 
related to investigational product (eg, severe pruritus) or 
displaying other symptoms that may indicate intolerability 
of investigational product. 
7.4.2., Safety 
Criteria for 
Adjustment or 
Stopping Doses 
 
Investigational product may be temporarily decreased (eg, 
by decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability concerns.  The 
dose of investigational product should be resumed to the 
maintenance dose in a blinded manner once the issues 
relating to the lack of tolerability are resolved.   
Subjects who discontinue investigational product are 
expected to continue in the study (and follow the regular 
visit schedule) until the end of the study, and the study will 
only terminate at the time. 
 
This 
information 
has been 
incorporated 
into Section 
8.4, which 
was renamed  
8.4. Dose 
Adjustment, 
Interruption, 
and 
Withdrawal 
from 
Investigation
al Product or 
Study and 
additional 
text was 
added.  
8.4,  Dose 
Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
8.4  Patient Withdrawal Criteria 
 
(Insertion) 
Dose Adjustment, Interruption, and Withdrawal from 
Investigational Product or Study 
Investigational product may be temporarily decreased 
(eg, by decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability concerns.  The 
dose of investigational product should be resumed to the 
maintenance dose in a blinded manner once the issues 
relating to the lack of tolerability are resolved.   
Section 
revised to 
integrate 
withdrawal 
criteria in one 
section of 
protocol.  
Text was 
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Patients who are discontinued from investigational 
product prior to completion of the study are encouraged 
to continue to follow the regular visit schedule, with the 
exception of PK sampling, but may withdraw consent at 
any time. 
previously in 
Section 7.4.2. 
8.4.1. 
Reasons 
for Additional 
Monitoring or 
Mandatory 
Interruption of 
Investigational 
Produc 
8.4.1. 
Reasons for Mandatory Discontinuation of 
Investigational Product 
Moved to 8.4.2 
 
 
8.4.1. 
Reasons for Additional Monitoring or Mandatory 
Interruption of Investigational Product 
Heading text 
updated.  
8.4.1.1, Reasons 
for Additional 
Monitoring 
Related to Liver 
Chemistries 
8.4.1.1. Pregnancy 
8.4.1.1. Reasons for Additional Monitoring Related to 
Liver Chemistries 
Patients who develop ALT or AST >2x baseline (and 
>ULN) or total bilirubin >1.5x baseline (and >ULN) 
should have repeat testing within 48 to 72 hours to 
confirm values.  Patients with persistent elevations (eg, 
additional lab testing per Investigator discretion) should 
be closely monitored.  Concomitant elevations in total 
bilirubin or INR with persistent increases in ALT or AST 
should also be closely monitored. 
Pregnancy 
moved to 
Section 
8.4.1.3.  New 
Section with 
text added. 
8.4.1.2. Reasons 
for 
Investigational 
Product 
Interruption 
Related to 
Elevated Liver 
Chemistries 
(Insertion) 
8.4.1.2. Reasons for Investigational Product Interruption 
Related to Elevated Liver Chemistries 
Development of any of the following clinical laboratory 
values, without explanation, during the study mandates 
investigational product interruption: 
• 
AST and/or ALT >3× baseline (and >ULN) 
• 
Total bilirubin >2× baseline (and >ULN) 
Repeat testing within 48 to 72 hours to confirm the 
abnormalities and to determine if they are increasing or 
decreasing should be performed.  Detailed adverse event 
information should also be collected, and the patient 
should be investigated for possible causes of the liver 
chemistry changes, as appropriate.  The Investigator 
New Section 
added to meet 
PMR 
requirements. 
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should obtain a history of concomitant medications 
(including nonprescription medications and herbal and 
dietary supplement preparations) and other possible 
causes of liver enzyme and bilirubin increases.  Any 
potentially hepatotoxic medications should be identified 
and discontinued if advisable.  
If symptoms persist or repeat testing shows AST or ALT 
>3× baseline (and >ULN) or total bilirubin >2× baseline 
(and >ULN), patients should be followed as clinically 
indicated depending on other laboratory and clinical signs 
and symptoms.   
For the purposes of this protocol, if the above referenced 
significant elevation in liver enzyme or bilirubin levels 
resolve following interruption of investigational product 
and no other cause for the elevation is identified, the 
elevations should be assumed to be related to 
investigational product and investigational product 
should be discontinued.  If the liver enzyme or bilirubin 
levels do not resolve following interruption of 
investigational product and no other cause for the 
elevation is identified, it may be assumed that the 
elevations were due to disease progression and the patient 
may be re-challenged following a discussion between the 
Investigator or designee and the Sponsor. 
Elevation of liver enzymes or bilirubin is based on 
comparison to baseline values defined as the mean of all 
available Screening and Day 0 values, which are the mean 
of all available evaluations prior to the first 
administration of investigational product.  At least 2 of 
these samples will be obtained a minimum of 2 weeks 
apart during the Screening period.  Elevations that occur 
gradually over the course of the study may be indicative 
of disease progression and should be assessed as clinically 
appropriate.  Liver enzyme and bilirubin elevations that 
occur over a shorter time, such as within a 6-month 
period, should be evaluated for drug-induced liver injury 
as provided in the guidelines below. 
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If at any time a patient develops signs or symptoms of 
hepatotoxicity such as new onset fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>7%) in combination with 
elevations in liver enzymes, investigational product should 
be interrupted and liver enzymes monitored until signs or 
symptoms resolve.  
Patients who develop evidence of severe drug-induced 
liver injury that is suspected to be causally related to the 
investigational product should be discontinued from 
investigational product and should not be rechallenged.  
Severe drug-induced liver injury includes, but is not 
limited to, functional hepatic impairment, as indicated by 
rising bilirubin or INR that cannot be explained by 
progression of disease.  Natural progression of the 
underlying condition and other causal factors such as a 
common bile duct stone or development of other 
concurrent liver disease should be considered before the 
investigational product is permanently discontinued.  
If after all investigations and actions outlined above have 
been completed, the investigator determines that the 
elevations in liver biochemistries are considered not 
related to investigational product, the Sponsor must be 
contacted before investigational product can be 
reinitiated.  Follow-up procedures for patients resuming 
treatment, including laboratory evaluations and physical 
examinations, must be performed after a maximum of 2 
weeks of retreatment.  Results must be reported to the site 
as soon as possible so the Investigator can determine if it 
appropriate for the patient is to continue treatment.   
The Medical Monitor must be contacted in all cases of 
persistent liver biochemistry elevations. 
All hepatic injury events, regardless of relationship to 
investigational product, will be adjudicated by the 
Hepatic Safety Committee (see Section 15.9) 
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Key Change 
8.4.1.3, 
Pregnancy 
(Insertion) 
Whenever the site is notified of a possible pregnancy, the 
patient should be asked to come in for an unscheduled visit 
to perform a serum pregnancy test.  If a female patient 
becomes pregnant, the patient must stop taking 
investigational product immediately and be withdrawn from 
the study… 
8.4.1.3. Pregnancy 
If a female patient becomes pregnant, she must interrupt 
treatment with investigational product immediately, but 
should continue with the study visit schedule.  As 
described in Section 13.1.10 pregnancy is not considered 
an AE for reporting purposes.  The patient may restart 
investigational product when she is no longer pregnant or 
breastfeeding (if applicable) at the discretion of the 
Investigator and after discussion with the Medical 
Monitor as described in Section 13.1.10).  New baseline 
procedures should include pregnancy testing. 
Was Section 
8.4.1.1 
8.4.2,  Reasons 
for Mandatory 
Discontinuation 
of 
Investigational 
Product 
8.4.2. 
Other Reasons for Discontinuation of 
Investigational Product or Study Termination 
8.4.2. 
Reasons for Mandatory Discontinuation of 
Investigational Product 
Patients who undergo a liver transplant during the course 
of the study must discontinue investigational product and 
discontinue the study visit schedule.  However, these 
patients should be encouraged to consent to the 
semiannual telephone contact and/or continued record 
review only to allow for secondary outcome events data to 
be collected. 
Now Section 
8.4.3 and text 
added. 
 
8.4.2.3. Elevated Liver Enzymes 
Section deleted. 
Information 
in 8.4.1.2 
now covers 
this. 
8.4.3,  Other 
Reasons for 
Discontinuation 
of 
Investigational 
Product or Study 
Termination   
 
Subjects who discontinue investigational product are 
expected to continue in the study until the end of the study 
or at the discretion of the Sponsor.  If a patient experiences 
a suspected clinical outcomes event, he or she should 
continue the regular visit schedule and continue taking 
investigational product as long as the Investigator assesses 
it as safe.   
Early termination procedures should only be conducted if 
the patient withdraws consent (See Section 9.7.14).   
8.4.3. 
Other Reasons for Discontinuation of 
Investigational Product or Study Termination 
The following events are considered appropriate reasons for a 
patient to discontinue investigational product; however, 
these patients are expected to continue in the study until 
study termination (or at the discretion of the Sponsor): 
• 
Patient begins treatment with commercially available 
OCA. 
• 
The Investigator or Sponsor considers that it is 
advisable or in the best interest of the patient. 
Was Section 
8.4.2 and 
additional 
text added. 
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Pr ot oc ol 7 4 7- 4 0 1 
Versi o n 2: 2 2 Ma y 2 0 1 7
 
Pa ge 1 0 9
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n 
Ori gi n al Te xt ( Versi o n 1, 2 0 D ec 2 0 1 6) 
Re vise d Te xt ( Versi o n 2,  2 2 M a y 2 0 1 7) 
Ke y C h a n ge 
It is a gree d t hat, f or reas o na ble ca use, eit her t he 
I n vesti gat or or t he S p o ns or, ma y ter mi nate t his st u d y. 
T he f oll o wi n g e ve nts are c o nsi d ere d a p pr o priate reas o ns f or 
a s u bject t o disc o nti n ue fr o m t he st u d y: 
•  
T he occ urre nce of cli nical or l a b or at or y A Es 
c o nsi dere d b y t he I n vesti g at or t o be cli nic all y i m p ort a nt 
s afet y c o ncer ns a n d relate d t o st u d y dr u g. 
•  
Wit h dr a w al of c o nse nt  
 
C o nse nt m a y be f ull y wit h dr a w n (i n w hic h c ase 
t he p atie nt disc o nti n ues b ot h i n vesti g ati o n al 
pr o d uct a n d st u d y visits a n d pr oce d ures). 
 
C o nse nt m a y be m o difie d t o disc o nti n ue st u d y 
visits b ut all o w se mi- a n n u al tele p h o ne c o nt act. 
 
C o nse nt m a y be m o difie d  t o disc o nti n ue st u d y 
visits or se mi- a n n u al tele p h o ne c o nt act b ut all o w 
c o nti n ue d access t o me dic al rec or ds t o assess f or 
s us pecte d m aj or a d verse c ar di o v asc ul ar e ve nts 
( M A C E) a n d li ver-rel ate d cli nic al o utc o mes. 
 
E arl y ter mi n ati o n pr o ce d ures s h o ul d be 
c o n d ucte d if t he p atie nt wit h dr a ws c o nse nt ( See 
Secti o n 9. 7. 1 2)  
8. 4. 3. 1.
  
Wit h dra wal 
of C o nse nt t o 
C o nti n ue i n t he 
St u d y 
8. 4. 3. 1.  Wit h dra wal of C o nse nt  
…  t heir c o nse nt t o c o nti n ue i n t he st u d y at a n y ti me 
(I nserti o n) 
A reas o na ble eff ort m ust be ma de t o … 
8. 4. 3. 1.  Wit h dr a w al of C o nse nt t o C o nti n ue i n t he St u d y 
 
E arl y ter mi n ati o n pr oce d ures s h o ul d be c o n d u cte d if t he 
p atie nt wit h dr a ws c o nse nt ( See Secti o n 9. 7. 1 2). 
A d de d m ore 
i nf or mati o n 
re gar di n g 
wit h dra wal 
fr o m st u d y. 
8. 4. 3. 2.  L ost t o 
F oll o w- U p 
8. 4. 2. 2.  L ost t o F oll o w- U p 
If a patie nt fails t o ret ur n t o t he cli nic f or a st u d y visit, an d 
t he I n vesti gat or ceases t o ha ve c o ntact wit h t he patie nt, he 
or s he will be wit h dra w n fr o m t he st u d y. 
8. 4. 3. 2.  L ost t o F oll o w- U p 
P atie nts will be  c o nsi dere d “l ost t o f oll o w u p ” o nl y after 
d oc u me nte d atte m pts t o re ac h t he p atie nt pr o ve 
u ns uccessf ul.   
U p date d te xt. 
8. 4. 4,  Patie nt 
Disc o nti n uati o n 
N otificati o n 
8. 4. 3.  
Patie nt Disc o nti n uati o n N otificati o n 
T he I n vesti gat or m ust n otif y t he S p o ns or as s o o n as 
p ossi ble if a n y patie nt pre mat urel y disc o nti n ues fr o m t he 
st u d y.  T he date w he n t he patie nt is wit h dra w n a n d t he 
8. 4. 4 .  
Patie nt Disc o nti n uati o n N otificati o n 
T he I n vesti gat or m ust n otif y t he S p o ns or as s o o n as p ossi ble 
if a n y patie nt pre mat urel y disc o nti n ues fr o m t he st u d y.  T he 
date w he n t he patie nt is wit h dra w n a n d t he pri mar y reas o n(s) 
Clarifie d te xt. 
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primary reason(s) for discontinuation must be recorded in 
the eCRF; additional information may be requested by the 
Sponsor to complete a discontinuation narrative.  Patients 
will be considered “lost to follow up” only after reasonable, 
documented attempts to reach the patient prove 
unsuccessful.  In all cases, a reasonable effort must be made 
to determine the reason(s) that a patient fails to return for 
required study visits or discontinues from the study.  This 
information must be documented in the eCRF. 
for discontinuation must be recorded in the eCRF; additional 
information may be requested by the Sponsor to complete a 
discontinuation narrative.  This information must be 
documented in the eCRF. 
9.2, Concomitant 
Medications 
Patients must follow the medication restrictions outlined in 
the inclusion and exclusion criteria (Section ) during the 
study. 
Concomitant medications will be used at the discretion of 
the usual care provider (or Investigator if also the usual care 
provider).  … taken prior to (ie, within 30 days of 
Screening) and …  Concomitant medications should be 
stable prior to Day 1 (ie no change in dosing within 
3 months of screening). 
Concomitant medications (other than prohibited 
concomitant medications listed in Section 9.2.2) will be 
used at the discretion of the usual care provider (or 
Investigator if also the usual care provider).  … taken within 
30 days of Screening and during the study must be recorded 
in the source documents and …  Concomitant medications 
should be stable prior to Day 1. 
Clarified use 
of 
concomitant 
meds. 
9.2.1, Drug 
Interactions 
Patients taking bile acid sequestrants (BAS, including 
cholestyramine and its derivatives, colestipol, colesevelam, 
or other sequestrants) or aluminum hydroxide- or smectite-
containing antacids should be instructed to stagger their 
dosing of investigational product and UDCA, ensuring at 
least 4 hours between doses of the BAS and/or these 
antacids and the investigational product (and UDCA; ie, 
BAS should be administered at minimum 4 hours before or 
4 hours after investigational product administration). 
Bile acid sequestrants (BAS, including cholestyramine and its 
derivatives, colestipol, colesevelam, or other sequestrants) or 
aluminum hydroxide- or smectite-containing antacids should 
not be taken within 4 hours of taking investigational 
product (and UDCA if applicable), ie, BAS should be 
administered at minimum 4 hours before or 4 hours after 
investigational product administration).   
Clarified use 
of 
concomitant 
meds. 
9.2.2, Prohibited 
Medications 
Patients who continue with commercial OCA therapy must 
discontinue investigational product and are expected to 
continue through the end of the study (see Section 8.4.2).  
Fibric acid derivatives (fibrates) and other medication 
intended to lower blood triglyceride levels are also 
prohibited while on investigational product.) 
Patients who continue with commercial OCA therapy must 
discontinue investigational product and are expected to 
continue through the end of the study (see Section 8.4.3).   
Some patient 
may be 
expected to 
be on 
fibrates. 
9.4.2, Blinding 
The patients, Investigator, and study site staff will be 
blinded to… 
The Sponsor, patients, Investigator, and study site staff will 
be blinded to… 
 
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Key Change 
9.6, Restrictions 
Participation in another investigational product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the study is prohibited.   
Participation in another investigational product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the study is prohibited.  Previous 
exposure to OCA (as a study participant or received 
commercial OCA therapy) is allowed within 3 months 
prior to enrollment in this study 
Updated to 
include 
patients who 
may be on 
prescribed 
OCA and 
who received 
investigationa
l OCA as 
study 
participants. 
9.7.1, Visit 
Procedures 
(Insertion) 
Visit windows are specified in the Schedule of Study 
Procedures (Table 1). 
Added text 
pointing to 
visit windows 
for study 
procedures. 
9.7.2, Informed 
Consent 
Procedures 
…The patient must be willing and able to provide written 
informed consent (on hard copies or on electronic devices 
such as iPads) before entering the study.   
The patient must be willing and able to provide written 
informed consent (on hard copies) before entering the study.   
Updated 
language. 
9.7.3, Assessing 
Cirrhosis 
To determine which dosing regimen patients should follow, 
cirrhosis should be assessed by the Investigator at 
Screening Visit 1.  Acceptable methods of confirming (via 
medical history) or assessing cirrhosis for purposes of the 
study are defined as a patient who has documented 
evidence or presence of one or more of the following 
cirrhosis indicators: 
 
varices 
 
Patients will be dosed according to their CP Score 
calculated in the eCRF (see Section 14.1.1 and Table 12). 
Cirrhosis status should be reassessed as clinically indicated 
throughout the study.  Any change in cirrhosis status will 
necessitate re-evaluation of the dosing regimen. 
Acceptable methods of confirming (via medical history) or 
assessing cirrhosis for purposes of the study are defined as a 
patient who has documented evidence or presence of one or 
more of the following cirrhosis indicators: 
 
 
Gastroesophageal varices 
Clarified 
assessment 
instructions. 
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Key Change 
9.7.4, Screening 
Procedures 
Screening Procedures (-1 day to 14 days prior to Day 1) 
Screening Procedures (14 days to 28 days prior to Day 1) 
Updated 
procedures to 
match 
updated 
protocol 
design. 
The Screening Visit assessments must be performed within 
≤14 days prior to Day 1 to… 
The Screening Visit assessments must be performed ≥14 days 
prior to Day 1 to… 
The patient is to review and sign the ICF 
 
• 
Verify that the patient has fasted for at least 8 hours. 
 
Record fasting status in the source and eCRF 
 
If the patient reports having eaten within 
8 hours, document accordingly in the source and 
eCRF and remind the patient that fasting is 
required prior to all study visits 
• 
Obtain blood samples for serum chemistry, 
hematology, and coagulation tests. 
 
• 
Perform a physical examination. 
Perform a physical examination, including smoking and 
alcohol consumption history, and current habits for both. 
(Insertion) 
• 
Record the visit in IWRS 
 
Perform TE using the Fibroscan® TE device.  If TE has 
been done within 3 months of Day 1 and a 
report/adequate data are available, a pretreatment TE at 
Day 1 is not required.  If the TE cannot be performed on 
Day 1 (eg, device/technician unavailability, scheduling 
issues, TE data is needed to inform cirrhosis assessment, 
etc.), the procedure may be completed within the Day 1 
Visit window, (if data is needed for cirrhosis 
assessment) or as close as possible to the Day 1 Visit, 
preferably, after patient eligibility has been confirmed.  
Instruct the patient to take Day 1 dose on the day of this 
visit. 
 
 
Perform TE using the Fibroscan® TE device.  If the TE 
cannot be performed on Day 1 (eg, device/technician 
unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be 
completed within the Day 1 Visit window, (if data is 
needed for cirrhosis assessment) or as close as possible to 
the Day 1 Visit, preferably, after patient eligibility has 
been confirmed.  Instruct the patient to take Day 1 dose on 
the day of this visit. 
 
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Key Change 
• 
Provide kits and instructions for collection of stool 
specimens at home prior to the Day 1 visit 
 
Perform an ultrasound for HCC surveillance (if equipment 
is unavailable, sites should make every attempt to use 
available community referral sites).  If an ultrasound has 
been done within 12 months of Screening, and a 
report/adequate data are available, a pretreatment 
ultrasound at Screening is not required.  If the ultrasound 
cannot be performed at Screening (eg, device/technician 
unavailability, scheduling issues, etc), the procedure may 
be completed anytime within the screening visit window 
or on Day 0.  Results from the screening ultrasound should 
be reviewed to assess possible exclusion criteria prior to 
randomization. 
 
Clarified 
sampling 
procedures. 
9.7.5, Day 1 
Procedures 
 ̀
Obtain blood samples for markers of inflammation 
 ̀
ELF (including HA, P3NP, and TIMP-1) 
 ̀
Trough PK assessment 
Markers of inflammation and fibrosis (IL-6, hs-CRP, TNF-α, 
IgM, IgG, IgA, CK -8-M30, HA, P3NP, and TIMP 1) 
Fasting PK assessment 
Clarified 
sampling 
procedures 
…, after patient eligibility has been confirmed 
… after patient eligibility has been confirmed.  Instruct the 
patient to take Day 1 dose on the day of this visit. 
Clarified 
procedures 
• 
Record the visit in IWRS and dispense investigational 
product 
 ̀
Instruct the patient to begin dosing on the day.  
 
 
 
(Second to last bullet)  …the procedure may be completed 
within the Day 1 visit window, (if data is needed for 
cirrhosis assessment) or as close as possible to the Day 1 
visit, preferably, after patient eligibility has been confirmed. 
 
Record the visit in IWRS and dispense investigational 
product 
 Instruct the patient to begin dosing on the day of the 
Day 1 visit. 
 
…the procedure may be completed within the Day 1 visit 
window, (if data is needed for cirrhosis assessment) or as close 
as possible to the Day 1 visit, preferably, after patient 
eligibility has been confirmed.  Instruct the patient to take 
Day 1 dose on the day of this visit. 
Updated 
procedures to 
match 
updated 
protocol 
design. 
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Key Change 
9.7.6, Week 3 
Safety Visit 
Procedures 
Week 3 (Safety Contact) 
Week 3 Safety Visit Procedures 
Updated 
procedures to 
match 
updated 
protocol 
design per 
PMR 
requirements. 
Patients should be contacted by telephone at Week 3 to 
assess for AEs and verify that s/he is dosing as directed. 
• 
Contact patient by phone/email. 
Preferably, the patient will come in to the clinic for this 
visit.  Alternatively, the site will telephone the patient for 
assessments and a home health nurse will visit to draw 
safety labs.  
Verify that patient is dosing as directed. 
• 
Verify that the patient has fasted for at least 8 hours. 
 ̀
Record fasting status in the source and eCRF 
• If the patient reports having eaten within 8 hours, 
document accordingly in the source and eCRF and 
remind the patient that fasting is required prior to all 
study visits. 
• Review and record prior concomitant medications. 
• Assess and record AEs. 
• Review and record any non-study related medical or 
surgical treatment procedures and any medically 
relevant HCP or non-HCP related office visits that 
have occurred since the previous study visit. 
• Assess investigational product compliance, perform 
investigational product accountability 
 
• Obtain blood samples for 
 ̀
Serum chemistry, hematology, and coagulation  
 
Schedule the next visit, reiterate dosing instructions, and 
advise the patient: 
 
Week 6 visit should occur 3, 4, or 5 days after taking the 
Week 6 dose, eg if the Week 6 dose is taken on a Sunday, 
the patient should come in for the Week 6 visit within the 
following Wednesday and Friday (Figure 2). 
 
•  
 ̀
NOT to take investigational product on the morning 
of the next visit, and  
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Key Change 
 ̀
To bring the investigational product bottle(s); s/he 
will dose at the clinic (if this is in compliance with 
the established dosing frequency), and 
 ̀
To fast overnight (at least 8 hours) prior to the next 
visit.  Fasting is required prior to all study visits, but 
water is permitted. 
9.7.8, Week 9 
through Week 48 
(Safety Contact) 
(Insertion) 
Patients should be contacted by telephone/email at Week 
9 and every 3 weeks afterward to Week 48. 
• 
Contact patient by phone/email. 
• 
Review and record prior concomitant medications. 
• 
Assess and record AEs. 
• 
Review and record any non-study related medical or 
surgical treatment procedures and any medically 
relevant HCP or non-HCP related office visits that 
have occurred since the previous study visit. 
• 
Assess investigational product compliance, perform 
investigational product accountability. 
Section 
added to 
provide 
guidance for 
telephone/em
ail safety 
contact. 
9.7.9,  Week 12, 
Week 24, Week 
36 Procedures 
Week 12 Procedures 
 
 
 
 
 
 
 
 
 
Obtain blood samples for markers of inflammation 
 ̀
ELF (including HA, P3NP, and TIMP-1) 
 ̀
C4, and FGF-19, bile acids 
 ̀
Trough PK assessment 
 
Week 12, Week 24, Week 36 Procedures 
• 
Assess investigational product compliance, perform 
investigational product accountability 
• 
Dispense investigational product only if there is dose 
increase or as needed. No new investigational product 
bottles will be dispensed if there is only change in 
dosing frequency of the same dose level. Patients are 
expected to use up each investigational product bottle 
before a new bottle will be dispensed. 
• 
Assess for dose titration, if eligible. (Refer to 
Section 7.3) 
 Obtain blood samples for 
 ̀
Serum chemistry, hematology, and coagulation  
 ̀
Markers of Inflammation (IL-6, hs-CRP, TNF-α, 
IgM, IgG, IgA, CK-18-M30) 
 ̀
Bile Acid/C4/FGF-19 
Updated 
procedures to 
match 
updated 
protocol 
design. 
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Key Change 
 ̀
Fasting PK assessment 
• 
Perform a urine-based β-hCG pregnancy test in 
females of childbearing potential. 
 
Perform TE using the Fibroscan® TE device.  If the 
TE cannot be performed on visit day (eg, 
device/technician unavailability, scheduling issues, 
TE data is needed to inform cirrhosis assessment, 
etc.), the procedure may be completed within the 
visit window (if data is needed for cirrhosis 
assessment) or as close as possible to the visit. 
• 
Serial PK assessment; the following procedures will be 
conducted in all patients 
• 
Serial PK assessment at Week 12 and 24 ONLY (not 
done at Week 36 and Week 42); the following procedures 
will be conducted in all patients 
Updated 
procedures to 
match 
updated 
protocol 
design. 
9.7.9,  Week 12, 
Week 24, Week 
36 Procedures 
Note:  Patients should not consume any food for the 
duration of the 6-hour PK assessments except the meal 
replacement drink.   
Note:  Patients should only consume meal following the 
4-hour and 7- hour PK assessment times (see Figure 3).   
Added more 
sampling 
times. 
Insertion 
 
Perform an ultrasound for HCC surveillance at Week 24 
ONLY (if equipment is unavailable, sites should make 
every attempt to use available community referral sites). 
 
 
• 
Assess the patient’s supply of investigational product 
to ensure an adequate amount. 
deleted 
Deleted for 
clarity. 
9.7.10  Week 18 
and Week 30 
Procedures 
 
 
 
 
 
Added the following procedure: 
• 
Dispense investigational product only if there is dose 
increase or as needed. No new IP bottles will be dispensed 
if there is only change in dosing frequency of the same 
dose level. Patients are expected to use up each IP bottle 
before a new bottle will be dispensed.   
Section 
merged into 
9.7.8, 
additional PK 
assessments 
added per 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
 ̀
Obtain blood samples for markers of inflammation 
 ̀
ELF (including HA, P3NP, and TIMP-1) 
 ̀
C4, and FGF-19, bile acids 
 ̀
Trough PK assessment 
 
 
 
 
 
 
 
 
 
Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6 hours 
post dose 
 Obtain blood samples for 
 
Serum chemistry, hematology, and coagulation  
 
Markers of inflammation and fibrosis (IL 6, 
hs-CRP, TNF α, IgM, IgG, IgA, CK 18 M30, 
ELF [HA, P3NP, and TIMP 1]) 
 
Fasting PK assessment 
 
Bile Acid/C4/FGF-19 
• 
Serial PK assessment at Week 12 and 24 ONLY (not 
done at Week 36); the following procedures will be 
conducted in all patients: ̀
 
 
 
Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6 7, 8, 9, 
and 24 hours post dose 
PMR 
requirements. 
Note:  Patients should not consume any food for the 
duration of the 6-hour PK assessments except the meal 
replacement drink.   
Note:  Patients should only consume a meal following the 
4-hour and 7- hour PK assessment times (see Figure 3).   
Added more 
sampling 
times. 
9.7.10, Week 24 
Procedures 
9.7.10, Week 24 Procedures 
deleted 
Incorporated 
into Section 
9.7.8 
9.7.11, Week 48 
Procedures 
9.7.12 
9.7.10, Week 48 Procedures 
Updated 
language. 
• 
Perform a physical examination,  
• 
Perform a physical examination, including smoking and 
alcohol consumption history, and current habits for both 
Clarify study 
procedures. 
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Key Change 
(Insertion) 
• 
Assess investigational product compliance, perform 
investigational product accountability. 
• 
Dispense investigational product only if there is dose 
increase or as needed.  No new investigational 
product bottles will be dispensed if there is only 
change in dosing frequency of the same dose level.  
Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed. 
• 
Assess for dose titration, if eligible (refer to 
Section 7.3) 
 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites). 
 
Clarify study 
procedures. 
Obtain blood samples for markers of inflammation 
 ̀
ELF (including HA, P3NP, and TIMP-1) 
 ̀
C4, and FGF-19, bile acids 
 ̀
Trough PK assessment 
 
• 
Perform urinalysis (dipstick) 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and coagulation  
 
Markers of inflammation and fibrosis (IL 6, hs-
CRP, TNF α, IgM, IgG, IgA, CK 18 M30, ELF 
[HA, P3NP, and TIMP 1]) 
 
Fasting PK assessment 
 
Bile Acid/C4/FGF-19 
Clarify study 
procedures. 
• 
Serial PK assessment; will only be conducted in 
patients who are uptitrating to the next dose level. 
• 
Serial PK assessment; the following procedures will be 
conducted in all patients. 
Updated 
language. 
 
 
Immediately following 1 hr post dose blood draw, 
administer meal replacement (to be consumed within 
5 – 10 minutes)  
Added more 
sampling 
times. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
 ̀
Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 
and 24 hours post dose.  
Note:  Patients should not consume any food for the 
duration of the 6-hour PK assessments except the meal 
replacement drink.   
Note:  Patients should only consume meal following the 
4-hour and 7- hour PK assessment times (see Figure 3).   
Added more 
sampling 
times. 
Perform TE using the Fibroscan® TE device.   
Perform TE using the Fibroscan® TE device.  If the TE 
cannot be performed on visit day (eg, device/technician 
unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be 
completed within the visit window (if data is needed for 
cirrhosis assessment) or as close as possible to the visit. 
Clarified 
procedural 
instructions. 
• 
Assess the patient’s supply of investigational product 
to ensure an adequate amount.   
 
Clarified 
procedural 
instructions 
• 
Schedule the follow-up visit and advise the patient: 
• 
Schedule the next visit, reiterate dosing instructions, 
and advise the patient: 
 ̀
NOT to take investigational product on the morning 
of the next visit, and  
 ̀
To bring the investigational product bottle(s); s/he 
will dose at the clinic (if this is in compliance with the 
established dosing frequency), and 
 ̀
To fast overnight (at least 8 hours) prior to the next 
visit.  Fasting is required prior to all study visits, but 
water is permitted. 
Clarify study 
procedures. 
9.7.12, Every 3 
Months after 
Week 48 
9.7.13 
Patients who have completed their 48-week double-blind 
treatment period will continue double blind treatment until 
all randomized patients have completed their participation 
in the primary treatment period and the database is 
locked…. and should not exceed the indicated maximal 
dose and frequency indicated for their CP category.  
9.7.11. Every 3 Months after Week 48 
Quarterly 
 
Verify that the patient has fasted for at least 8 hours. 
 
Record fasting status in the source and eCRF 
 
If the patient reports having eaten within 
8 hours, document accordingly in the source and 
Clarified 
dispensing 
instructions. 
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Key Change 
Patients will then have the option to continue into an open-
label LTSE. 
 
 
eCRF and remind the patient that fasting is 
required prior to all study visits, but water is 
permitted. 
 
Perform a physical examination, including smoking 
and alcohol consumption history, and current habits 
for both.  
 
Review and record any non-study related medical or 
surgical treatment procedures and any medically 
relevant HCP or non-HCP related office visits that 
have occurred since the previous study visit. 
 
Assess and record vital signs (oral temperature, 
sitting heart rate, respiratory rate, and sitting blood 
pressure). 
 
Assess and record AEs. 
 
Review and record concomitant medications. 
 
Perform assessments for calculation of CP Score 
(Section 14.1.1). 
 
Administer Quality of Life and Patient 
questionnaires (see Section 13.2.6). 
 
Assess investigational product compliance, perform 
investigational product accountability. 
 
Dispense investigational product only if there is dose 
increase or as needed.  No new investigational 
product bottles will be dispensed if there is only 
change in dosing frequency of the same dose level.  
Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed. 
 
Assess for dose titration, if eligible (refer to 
Section 7.3 ). 
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Key Change 
 
Perform urinalysis (dipstick) 
 
Perform a urine-based β-hCG pregnancy test in 
females of childbearing potential. 
 
Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 
Schedule the next visit, reiterate dosing instructions, 
and advise the patient: 
 
NOT to take investigational product on the 
morning of the next visit, and  
 
To bring the investigational product bottle(s); s/he 
will dose at the clinic (if this is in compliance with 
the established dosing frequency), and 
 
To fast overnight (at least 8 hours) prior to the next 
visit.  Fasting is required prior to all study visits, 
but water is permitted. 
Patients will complete a TE/ELF (HA, P3NP and TIMP 1) 
and ultrasound (for HCC surveillance) assessment, every 
6 months (±2 weeks) after Week 48. 
ECG will be done yearly (±2 weeks) after Week 48. 
9.7.13,  End of 
Study/Early 
Termination 
Procedures for 
Patients that 
Withdraw from 
Investigational 
Product or 
9.1.14;   End of Treatment/Early Termination Procedures 
for Patients that Withdraw from Investigational Product or 
Withdraw Consent … 
Patients who discontinue investigational product before are 
expected to continue … 
 
EOT/ET procedures will be required whenever patients 
discontinue treatment with investigational product 
 
9.7.12. . End of Study/Early Termination/End of Treatment 
Procedures for Patients that Withdraw from Investigational 
Product or Withdraw Consent … 
Patients who discontinue investigational product before 
Week 48 are expected to continue ... 
 
EOT (when subject discontinues investigational product)/ET 
procedures will be required whenever patients discontinue 
treatment with investigational product (Table 1, 
Section 9.7.10) 
Clarified 
procedures. 
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Key Change 
Withdraw 
Consent 
 
When a patient discontinues investigational product but 
continues with regularly scheduled study visits, the EOS 
Visit will be completed as the patient’s final study visit. 
 
 
(Insertion) 
 
 
When a patient discontinues or interrupts investigational 
product and continues with regularly scheduled study visits, 
the EOS Visit will be completed as the patient’s final study 
visit. 
 
 
EOT and EOS visits are encouraged but at no time will a 
missed EOT or EOS visit be considered a protocol 
deviation. 
9.7.13,  Table 5, 
row 5 
Treatment Interruption  
Interrupted Retained Regular 
Visit Schedule 
Complete as close as possible to last dose 
of investigational product Complete at final study visit 
Deleted  
Removed to 
reduce 
confusion 
10.3, 
Investigational 
Product Storage 
Investigational product should be stored in the containers in 
which they are received from the Sponsor’s supplier, at 
15ºC to 25ºC. 
All OCA tablet strengths provided to clinical trial sites in 
support of clinical studies are to be shipped and stored at 
15˚C to 25˚C.  Temperature excursions within the range 
of 2˚C and 30˚C for no more than a 6-month period are 
acceptable, and the OCA tablet continues to be suitable 
for use in clinical studies.   Additionally, temperature 
excursions within the range -20˚C to 40˚C for no more 
than 7 days are acceptable, and the OCA tablet continues 
to be suitable for use in clinical studies. 
Updated 
storage 
conditions 
per the 
Investigator’s 
Brochure. 
12, 12.1, 
Pharmacokinetic 
Blood Sampling 
 
Subjects with at least one PD assessment after dosing will 
be included in the combined PK/PD analyses 
 
Serial and trough PK assessments will be performed in all 
patients participating in the study. 
 
 
At each visit, patients will provide… 
 
 
Patients in the PK Population with at least one PD 
assessment after dosing will be included in the combined 
PK/PD analyses 
Serial and fasting PK assessments will be performed in all 
patients participating in the study. 
 
At Day 1, and Weeks 6, 12, 18, 24, 30, 36, and 48, patients 
will provide… 
Specific dates 
are required 
to obtain 
optimum PK 
results 
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Key Change 
(Insertion) 
 
Week 6 visit should occur 3, 4, or 5 days after the Week 6 
dose, (eg if the Week 6 dose of drug is taken on a Sunday, 
the patient should come in for the Week 6 visit between 
Wednesday and Friday [Figure 2]). 
(Insertion) 
 
…serial PK blood samples will be obtained at 0.5, 0.75, 1, 
1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose… 
 
Figure 2: 
Week 6 Sampling Schedule 
  
IP = investigational product; PK = pharmacokinetic 
At Weeks 12, 18, 24, 30, and 48, Serial PK blood samples 
will be obtained at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9 
and 24 hours postdose (Figure 3) for all patients.  The 
patient will be given the option to return to the clinic the 
following morning for the 24-hour postdose sample or 
samples can be obtained by a home health care designee.  
The home health care agency must be advised one week in 
advance of the appointment.   
Added 
diagram and 
language to 
clarify PK 
sampling 
procedures. 
(Insertion) 
Figure 3: 
Pharmacokinetic Sampling Schedule 
 
OCA = obeticholic acid; PK = pharmacokinetic 
Added 
diagram and 
language to 
clarify PK 
sampling 
procedures. 
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Key Change 
12.1, 
Pharmacokinetic 
Blood Sampling 
 
Table 7: Pharmacokinetic Sampling Schedule 
 
Replaced 
with other 
Figures 2 and 
3. 
During the double-blind treatment period and double-blind 
LTSE: 
• 
Pharmacokinetic trough samples will be obtained from 
all patients at all visits prior to dose administration in 
accordance with Table 7. 
• 
Serial PK assessments will be performed in all patients 
at Week 12.  Thereafter, PK assessments will be conducted 
at every titration visit in those patients who were eligible 
and uptitrated their dose.  Sample collection for fecal 
analysis will occur concurrent with serial PK sampling 
visits only.   
During the treatment period: 
• 
Pharmacokinetic fasting samples will be obtained from 
all patients at Weeks 6, 12, 18, 24, 30, 36, and 48 prior to 
dose administration in accordance with Figure 3. 
• 
Serial PK assessments will be performed in all patients 
at Weeks 12, 18, 24, 30, and 48.   
Clarify PK 
sampling and 
collection 
procedures. 
12.2,  Processing 
and Handling of 
Pharmacokinetic 
Samples 
The storage and shipment procedures for subsequent 
bioanalysis will be provided to the investigational site and 
in a separate document before the study is initiated. 
The storage and shipment procedures for subsequent 
bioanalysis will be provided to the investigational site and 
home health care company in a separate document before 
the study is initiated. 
Added option 
of using 
home health 
care service. 
13, Assessment 
of Safety 
Safety will be monitored and assessed by AEs/SAEs, 
medical history, physical examination, vital signs 
measurements, ECG results, and clinical laboratory 
assessments.  
Safety will be assessed in terms of AEs.  All AEs, whether 
observed by the investigator, reported by the patient, noted 
from laboratory findings, or identified by other means, will 
be recorded from the time the patient signs his/her consent 
deleted 
Safety 
information 
updated to 
match 
Protocol 747-
302. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
form (s)until the patient completes study participation (final 
Follow Up Visit). 
Recording AEs/SAEs in the electronic data capture (EDC) 
system is the method for reporting AEs/SAEs.  It is 
therefore imperative, that AEs/SAEs are recorded into the 
EDC. 
13.1.1.3.
 
Treatment-
Emergent 
Adverse Event 
 
13.1.1.2 
A treatment-emergent AE (TEAE) is any event not present 
before the initiation of the investigational product or any 
event already present that worsens in either intensity or 
frequency following exposure to the investigational 
product. 
Moved to Section 13.1.3. Recording Adverse Event 
Severity 
 
Safety 
information 
updated to 
match 
Protocol 747-
302.   
 
Safety 
information 
updated to 
match 
Protocol 747-
302. 
13.1.3.1. Severity 
of Pruritus (as an 
Adverse Event) 
To ensure consistency in reporting, the following guidelines 
for assessing severity of pruritus should be used for AE 
reporting.  As pruritus is a patientive symptom, clinical 
judgment should be used to determine its severity and 
management Table 10 
Table 10 deleted. 
 
Safety 
information 
updated to 
match 
Protocol 747-
302. 
13.1.4.1.
 
Reporting of 
Adverse Events 
(Insertion) 
….  Redacted medical record source documentation will 
be requested for all SAEs and emergency room visits. 
Safety 
information 
updated to 
match 
Protocol 747-
302. 
13.1.4.2.
 
Reporting of 
• 
Telephone:  
 
If an SAE is reported by telephone or fax, … 
If an SAE is reported by fax, … 
Number no 
longer in use. 
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Key Change 
Serious Adverse 
Events 
 
 
 
 
13.1.5.1.
 
Potential 
Clinical 
Outcome Events 
 
The events listed below will be initially assessed by the 
Investigator to determine if they are Potential Clinical 
Outcome Events.  These events will be evaluated by an 
Adjudication Committee (described in Section 15.9) to 
confirm if they meet the criteria to be considered Clinical 
Outcome Events.  
Potential Clinical Outcome Events: 
Hospitalization for clinical complications of cirrhosis. 
Given that the Potential Clinical Outcome Events could also 
meet the criteria of a SUSAR, which would necessitate 
unblinding for expedited reporting, the Sponsor will not 
expeditiously report suspected Potential Clinical Outcome 
events in order to retain the study blind and preserve the 
integrity of the clinical outcomes endpoint.  These events 
will be selected as a “potential study event” on the Adverse 
Event eCRF and will be submitted for adjudication to the 
Adjudication Committee as described in Section 15.9. 
 
Safety 
information 
updated to 
match 
Protocol 747-
302. 
13.1.7.
 
Notification 
of Post-
Treatment SAEs 
for Patients Who 
Continue in the 
Study 
13.1.7. Notification of Post-Study SAEs  
If an Investigator becomes aware of an SAE that may be 
attributable to the investigational product at any time after 
the end of the study, the Sponsor should be notified 
immediately (ie, within 24 hours) by following the 
instructions provided in Section 13.1.4.2 
13.1.7. Notification of Post-Treatment SAEs for Patients 
Who Continue in the Study 
Post-treatment SAEs that occur in patients who remain in 
the study after investigational product has been 
discontinued must be reported to the Sponsor within 
24 hours by following the instructions provided in 
Section 13.1.4.2. 
SAEs that occur in patients who discontinue 
investigational product, initiate treatment with 
commercially available Ocaliva, and remain in the study 
must be reported to the Sponsor within 24 hours by 
following the instructions provided in Section 13.1.4.2. 
Safety 
information 
updated to 
match 
Protocol 747-
302.  Deleted 
text is already 
in Section 
13.1.8. 
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Key Change 
13.1.8.
 
Notification 
of Post--Study 
SAEs  
 
(Insertion) 
13.1.8. Notification of Post-Study SAEs  
All SAEs that occur within 30 days following 
discontinuation from the study, whether or not they are 
related to the investigational product, must be reported to 
the Sponsor within 24 hours by following the instructions 
provided in Section 13.1.4.2. 
 
Safety 
information 
updated to 
match 
Protocol 747-
302. 
13.1.8.
 
Notification 
of Post-
Treatment SAEs 
for Subjects Who 
Continue in the 
Study 
13.1.8. Notification of Post-Treatment SAEs for Subjects 
Who Continue in the Study 
Post-treatment SAEs that occur in subjects who remain in 
the study after investigational product has been 
discontinued must be reported to the Sponsor within 24 
hours by following the instructions provided in 
Section 13.1.4.2 
Moved to 13.1.7 
Safety 
information 
updated to 
match 
Protocol 747-
302 9 (moved 
to 13.1.7). 
13.1.10, 
Pregnancy and 
Follow-up 
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant 
while she is enrolled in the clinical study, she must 
discontinue investigational product immediately and the 
Sponsor must be notified within 24 hours of the 
Investigator’s learning of the pregnancy by completing. 
In the situation that the EDC is not functioning, the Medical 
Monitor should be notified by telephone.  The investigator 
remains responsible for entering the pregnancy information 
into the EDC when the EDC becomes functional. 
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant 
while she is enrolled in the clinical study, she must interrupt 
treatment with investigational product immediately (see 
Section) and the Sponsor must be notified within 24 hours of 
the Investigator’s awareness of the pregnancy by completing 
the Pregnancy CRF in the EDC system and downloading 
and completing the Pregnancy Report Form.  The 
Pregnancy Report Form must be emailed to 
 or faxed to 
   
The patient and neonate must be followed for outcome 
information and/or as considered appropriate by the 
Investigator and Sponsor. 
The patient may restart investigational product when she 
is no longer pregnant or breastfeeding (if applicable) at 
the discretion of the Investigator and after discussion with 
the Medical Monitor.  The patient must have a negative 
pregnancy test before restarting investigational product.  
If a patient’s pregnancy is terminated early (planned or 
unplanned), she must have termination of the pregnancy 
Safety 
information 
updated to 
match 
Protocol 747-
302. 
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Key Change 
confirmed by a serum β-hCG test before restarting 
investigational product. 
13.2.2, Physical 
Examination 
13.2.1 
(Insertion) 
13.2.2 
A basic physical examination… Smoking and alcohol 
consumption history and current habits will be 
recorded…. 
Clarified 
assessments 
13.2.5, 
Laboratory 
Assessments 
For visits that require fasting, the Investigator or designee 
will verify that the patient has fasted for at least 8 hours …   
At all visits (except screening), the Investigator or designee 
will verify that the patient has fasted for at least 8 hours… 
Clarified visit 
procedures 
Blood samples for serum chemistry, coagulation, and 
hematology will be collected at every visit… 
Blood samples for serum chemistry, coagulation, and 
hematology and urine samples will be collected at visits… 
Clarified 
what samples 
will be 
collected. 
13.2.5, 
Laboratory 
Assessments, 
Table 9 
 
Added the following labs: 
 
Serum Chemistry 
 
CPK, TFT (TSH, free T3 and free T4) 
 
Urinalysis (dipstick) 
 
Pregnancy 
 
Noninvasive measurement… 
 
ELF (HA, P3NP, and TIMP-1), TE 
Updated lab 
tests to be 
performed. 
Biomarkers of Hepatic Fibrosis and/or Inflammation;  IL-6, 
hs-CRP, TNF-α, IgM, IgA, IgG, CK 18 M30, and others as 
determined during course of study 
Markers of Inflammation; IL-6, hs-CRP, TNF-α, IgM, IgA, 
IgG, CK-18-M30 
Clarified 
assessments 
Genetics;  DNA including single-nucleotide 
polymorphisms that may be involved in PBC; RNA 
deleted 
No longer 
doing this 
analysis. 
13.2.5, 
Laboratory 
Assessments 
(Insertion) 
PD markers: C4, FGF-19 and plasma bile acids 
Added new 
row  
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Key Change 
13.2.5, 
Laboratory 
Assessments 
(Insertion) 
Laboratory reference ranges for the study will be based 
on the laboratory vendor range. 
Added to 
satisfy PMR 
request. 
14.1.1, Child-
Pugh Score, 
Table 10 
Factor 
Unit
s 
Points 
Deletion 
 
 
 
 
Encephalopathy now 0 
Simplified 
CP scoring 
procedure. 
1 
2 
3 
Serum bilirubin 
μmo
l/L 
<3
5 
35-50 
>50 
Serum albumin 
g/L 
>3
5 
28-35 
<28 
Hepatic encephalopathy 
 
No 
 
 
14.2.1,  Markers 
of Inflammation, 
Apoptosis and 
Necrosis 
Blood samples for analytes including hs-CRP, IgM, TNF-α, 
and cytokeratin-18, neoepitope M30. 
Blood samples for analytes including IL-6, hs-CRP, IgA, 
IgG, IgM, TNF-α, and cytokeratin-18, neoepitope M30. 
Added 
additional 
markers. 
15.4, Safety 
Analyses 
No inferential comparison of safety endpoints will be 
performed.  All safety comparisons will be descriptive. 
No inferential comparison with formal statistical hypothesis 
testing will be performed for safety endpoints. 
Clarified 
statistical 
analyses. 
15.4.3, Adverse 
Events of Special 
Interest 
…  The quartiles, including the median time-to-event and 
their respective 2-sided 95% CIs, will be presented.  KM 
estimates will be plotted as a “survival curve” for each 
treatment group. 
…  The tabulation will include the KM estimate 
methodology using 25th, 50th (median), and 75th percentiles 
of the medians and corresponding with associated 2-sided 
95% confidence intervals (CIs), if the medians can be 
estimated as well as percentage of censored observations. 
Clarified 
statistical 
analyses. 
15.5, Efficacy 
Analyses, 4th 
paragraph 
…  The results, change from Baseline, and percentage 
change from Baseline values, as well as estimates of least-
square (LS) means, standard errors (StdErr), and 95% CIs, 
will be presented by treatment group.  Estimates of the 
mean difference between treatment groups, the StdErr of 
the difference, and 95% CI of the difference will also be 
presented.  No formal hypothesis testing will be performed. 
The results, change from Baseline, and percentage change 
from Baseline values, as well as estimates of least-square 
(LS) means, standard errors (StdErr), and 2-sided 95% CIs, 
will be presented by treatment group.  Estimates of the mean 
difference between treatment groups, the StdErr of the 
difference, and 2-sided 95% CI of the difference will also be 
presented 
Clarified 
statistical 
analyses. 
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Key Change 
15.6, Additional 
Efficacy 
Analyses 
The following clinical outcomes will be captured in the 
study: 
• 
All cause mortality 
• 
Liver related death 
• 
Liver transplant 
• 
Variceal bleed 
• 
Hepatic encephalopathy 
• 
Bacterial peritonitis 
• 
Ascites 
• 
Hepatocellular carcinoma 
The following clinical endpoints will be captured in the 
study : 
• 
Time to death (all-cause ) 
• Time to liver-related death 
• Time to hepatic failure leading to liver transplant 
•  Model of end stage liver disease (MELD) score ≥15 
(for patients with MELD ≤12 at baseline) 
• Hospitalization (as defined by a stay of 24 hours or 
greater) for new onset or recurrence of: 
 
Time to variceal bleed 
 
Time to hepatic encephalopathy (as defined by 
a West Haven score of ≥2) 
 
Time to spontaneous bacterial peritonitis 
(confirmed by diagnostic paracentesis) 
• Time to uncontrolled ascites (diuretic resistant ascites 
requiring therapeutic paracentesis at a frequency of at 
least twice in a month). 
 
The incidence and time to first occurrence of any above listed 
clinical events will be summarized by treatment group using 
the log rank test stratified by the randomization stratification 
factor.  KM estimates of the distribution of the time-to-event 
will be tabulated and graphed by treatment group.  The 
tabulation will include the KM methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% 
confidence intervals (CIs), as well as percentage of censored 
observations.  The number and percent of patients censored 
and with events will be presented.  The hazard ratio and 2-
Clarified 
statistical 
endpoints. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
sided 95% CI will be estimated based on a Cox regression 
model stratified by randomization strata.  
In addition, the incidence and time to each of the above 
clinical events, and the incidence and time to occurrence 
of hepatocellular carcinoma (HCC) will be summarized 
by treatment group using the same methods as defined 
above. 
 
18.3, Written 
Informed 
Consent 
(Insertion) 
The Investigator(s) must maintain the original, signed 
ICF. A copy of the ICF must be given to the patient. 
Updated 
language. 
21, List of 
References 
(Insertion) 
Hepatic encephalopathy in chronic liver disease: 2014 
practice guideline by the European Association for the 
Study of the Liver and the American Association for the 
Study of Liver Diseases. J Hepatol 2014 Sep;61(3):642-59. 
Kamath PS, Kim WR. The model for end-stage liver 
disease (MELD). Hepatology 2007 Mar;45(3):797-805. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl-
chenodeoxycholic acid (6-ECDCA), a potent and selective 
FXR agonist endowed with anticholestatic activity. J Med 
Chem. 2002 Aug 15;45(17):3569-72. 
Added new 
references  
Appendix A, List 
of Study 747-401 
Outcome Events 
Some of the specified clinical endpoints will also by 
definition (see Section 13.1) qualify as Serious Adverse 
Events (SAEs).  The sponsor must be notified of any SAEs 
within 24 hours of the site becoming aware of the event 
(see Section 13.1.4).  The Sponsor is responsible for 
regulatory reporting of SAEs including expeditious 
reporting of SAEs that are considered related to the 
investigational product and considered Unexpected by 
regulatory standards as defined in the Investigational 
Brochure. 
 
This is 
covered in 
the main text. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
The Sponsor may consider the following lists of events to 
be exempt from expeditious regulatory reporting but will 
continue to report them in a non-expeditious manner: 
Potential Clinical Outcome Events: 
Liver-related events resulting in death 
Hepatic failure leading to liver transplant 
Variceal bleed 
Hepatic encephalopathy 
Spontaneous bacterial peritonitis 
Ascites 
Hepatocellular carcinoma 
 
Page 219 of 603


1. 
TITLE PAGE 
 
 
Clinical Study Protocol 747-401 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Pharmacokinetics and Safety of Obeticholic Acid in Patients with Primary 
Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
 
 
Version 3:  04 Jan 2018 
 
EudraCT Number: 2017-001762-13 
 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
USA 
 
TEL:  +1 858 652 6800 
 
 
CONFIDENTIAL 
The information contained herein is the property of Intercept Pharmaceuticals, Inc. and may not 
be reproduced, published, or disclosed to others without written authorization of Intercept 
Pharmaceuticals, Inc. 
 
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INVESTIGATOR’S AGREEMENT 
 
I have received and read the current version of the Investigator’s Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-401.  Having fully considered all the information available, 
I agree that it is ethically justifiable to give OCA to selected patients according to this protocol. 
I understand that all information concerning OCA supplied to me by the Sponsor, Intercept 
Pharmaceuticals, Inc., and/or its agents in connection with this study and not previously 
published is confidential information.  This includes the IB, clinical study protocol, case report 
forms (CRF), and any other preclinical and clinical data provided by the Sponsor. 
I understand that no data are to be made public or published without prior knowledge and written 
approval by the Sponsor. 
By my signature below, I hereby attest that I have read, understood and agreed to abide by all the 
conditions, instructions and restrictions contained in Protocol 747-401 and in accordance with 
Good Clinical Practice (CPMP/ICH/135/95), the Declaration of Helsinki, and all regulatory 
requirements for protection of human patients in clinical studies and privacy requirements for the 
protection of individual and company data. 
I acknowledge that the Sponsor of the study has the right to discontinue the study at any time. 
 
 
 
 
 
 
Investigator’s Name (Printed) 
 
 
 
 
 
 
Investigator’s Signature 
 
Date 
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STUDY PERSONNEL CONTACT INFORMATION 
Medical Monitor  
Primary Contact: 
 MD 
Senior Medical Director, Clinical Division  
INC Research/inVentiv Health 
  
 
Secondary Contact: 
 DO, MSPH 
Senior Medical Director 
Intercept Pharmaceuticals, Inc. (Intercept) 
 
 
24-Hour Telephone: 
 
 
SAE Fax: 
 
SAE Email: 
 
 
 
 
 
 
 
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Protocol 747-401 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product: 
Obeticholic Acid 
Name of Active Ingredient: 
Obeticholic acid (OCA); 6α-ethyl-chenodeoxycholic acid; (6-ECDCA) 
Title of Study:  
A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating the Pharmacokinetics and Safety 
of Obeticholic Acid in Patients with Primary Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
Investigators and/or Study Center(s):  
The study is planned to have approximately 35 investigational sites, globally. 
Study Period:  Patients will receive double-blind treatment for at 
least 48 weeks.  Patients who have completed their 48-week 
double blind treatment period will continue double-blind 
treatment until all randomized patients have completed their 
participation in the 48-week treatment period and the database for 
that period is locked (approximately 3 years).  An open-label 
extension study in which all patients receive OCA will be 
considered following review of blinded safety and PK data. 
Phase of Development:   
Phase 4:  US, Canada, and the EU 
Phase 3b:  All other regions 
 
Objectives:   
Primary Objective: 
 
To evaluate the pharmacokinetics (PK) of OCA and its conjugates, glyco-OCA and tauro-OCA, and 
metabolite OCA glucuronide compared with placebo 
 
To evaluate the safety and tolerability of OCA treatment compared with placebo 
Secondary Objectives:  
 
To evaluate the effect of OCA treatment compared to placebo on:  
 
The model of end stage liver disease (MELD) score and its components 
 
Child-Pugh (CP) score and its components 
 
Liver biochemistry including total and direct bilirubin, alkaline phosphatase (ALP), and 
aminotransferases (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma 
glutamyl transaminase [GGT]), international normalized ratio (INR), creatinine, albumin, platelets 
 
Biomarkers of bile acid synthesis and homeostasis including fibroblast growth factor 19 (FGF-19), 
7α-hydroxy-4-cholesten-3-one (C4), and plasma bile acids 
Additional Objectives: 
 
To evaluate the effect of OCA treatment compared to placebo on: 
 
Noninvasive markers of liver fibrosis (Enhanced Liver Fibrosis [ELF]™ score) 
  
Noninvasive measurement of liver stiffness (transient elastography [TE]) 
 
To assess the PK/Pharmacodynamic (PD) relationship of OCA with: 
 
PK parameters compared to PD parameters and safety and tolerability assessments 
 
To assess patient reported outcomes (Pruritus Visual Analogue Scale [VAS], PBC-40, EQ 5D-5L, Chronic 
Liver Disease Questionnaire [CLDQ]) 
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 
To assess clinical events consistent with end-stage liver disease 
 
Death (all-cause) 
 
Liver transplant 
 
MELD score ≥15 (for patients with MELD ≤12 at baseline)  
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
variceal bleed, hepatic encephalopathy (as defined by a West Haven score of ≥2), spontaneous 
bacterial peritonitis 
 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
 
Hepatocellular carcinoma (HCC) 
Methodology:  This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the PK and 
safety of OCA treatment in patients with primary biliary cholangitis (PBC) and moderate to severe hepatic 
impairment defined as Child-Pugh B (CP-B) (moderate) and Child-Pugh C (CP-C) (severe) including a broad 
distribution of MELD scores (ranging from 6 to 24).  Approximately 50 patients (including at least 20% of 
patients with CP-C) will be enrolled in the study.  Patients will be screened ≥14 days but not more than 28 days 
prior to entering the study (Day 1).  Patients who meet all eligibility requirements will be randomized in a 
1:1 ratio to one of two treatment groups:  Placebo or OCA.  Randomization will be stratified by CP class.  
Baseline MELD scores will be monitored on an ongoing basis to ensure adequate distribution of MELD scores.   
Following completion of safety assessments and laboratory specimen collection, blinded investigational product 
will be dispensed with instruction to begin dosing the same day (Day 1) at OCA 5 mg or placebo once weekly.  
Double-Blind Treatment Period:  During the 48-week treatment period (ie, Day 1 through Week 48), an initial 
safety visit will occur at Week 3.  After the Week 6 Visit, subsequent clinic visits will occur approximately 
every 6 weeks for the assessment of safety, tolerability, PK, and PD.  Titration may be considered as early as the 
Week 12 Visit.  Fasting PK assessments will be performed in all patients participating in the study on Day 1, 
Week 6, and Week 36.  Serial PK sampling (which also includes a fasted PK assessment) will be performed at 
Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week double blind treatment period will continue double-blind treatment 
until all randomized patients have completed their 48-week treatment period and the database for that period is 
locked.  An open-label extension study in which all patients receive OCA will be considered following review 
of blinded safety and PK data.   
Study Design Diagram 
OCA = obeticholic acid, PBC = primary biliary cholangitis 
Notes: Initial dose titration of investigational product may be considered as early as the Week 12 Visit, or any study visit 
thereafter for patients on all dosing regimens, based on tolerability and safety laboratory tests from the previous 
visit.  Subsequent dose titration(s) may occur no earlier than 6 weeks after the previous dose titration and will be 
based on tolerability.   
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Patients who complete Week 48 will continue double-blind treatment until all randomized patients have completed 
their participation in the 48-week treatment period and the database for that period is locked. 
Dosing Regimen:   
All patients will initiate investigational product once weekly with 5 mg OCA or matching placebo.  Titration 
may be considered as early as the Week 12 Visit.  Following visit procedures at Week 12, if the investigational 
product is tolerated and laboratory assessments do not indicate a safety concern, the patient may up-titrate to 
OCA 5 mg twice weekly and may start the higher dose regimen no earlier than 2 days after they took their last 
dose.  Dosing will then occur at least 3 days apart.  Every 6 weeks thereafter, based on tolerability assessments, 
patients can be considered for further up titration as described below.  At each titration visit, the patient may 
start the higher dose regimen no earlier than 2 days after the prior dose. 
 
Patients may titrate to a maximum dose of OCA 10 mg twice weekly at least 3 days apart.  
Planned OCA or Matching Placebo Dosing Regimen 
 
Child-Pugh B and Child-Pugh C 
(Moderate and Severe Hepatic Impairment) 
 
Treatment Group 
 
OCA 
Placebo 
Starting Dose (Day 1) 
5 mg once weekly 
matching placebo once weekly 
Titration 1a  
5 mg twice weeklyb 
matching placebo twice weeklyb  
Titration 2a  
10 mg twice weeklyb 
matching placebo twice weeklyb 
a Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on patient tolerability. 
b Dosing per the twice weekly schedule must be at least 3 days apart. 
 
Number of Patients (planned):  Approximately 50 patients will be enrolled in this study. 
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Diagnosis and Main Criteria for Inclusion: 
Key Inclusion Criteria 
1. A definite or probable diagnosis of PBC (consistent with American Association for the Study of Liver 
Diseases [AASLD] and European Association for the Study of the Liver [EASL] Practice Guidelines, 
defined as having ≥2 of the following 3 diagnostic factors: 
 
History of elevated ALP levels for at least 6 months 
 
Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer (≤1:80), 
PBC-specific antibodies (anti-GP210 and/or anti-SP100) and/or antibodies against the major M2 
components (PDC-E2, 2-oxo-glutaric acid dehydrogenase complex)  
 
Liver biopsy consistent with PBC (collected at any time prior to Screening) 
2. Evidence of cirrhosis including at least one of the following: 
 
Biopsy results consistent with PBC Stage 4  
 
Liver stiffness as assessed by TE Value ≥16.9kPa 
 
Clinical evidence in the absence of acute liver failure consistent with cirrhosis including: 
gastroesophageal varices, ascites, radiological evidence of cirrhosis (nodular liver or enlargement 
of portal vein and splenomegaly) 
 
Combined low platelet count (<140 000/mm3) with 
 
persistent decrease in serum albumin, or  
 
elevation in prothrombin time/INR (not due to antithrombotic agent use), or 
 
elevated bilirubin (2× ULN) 
3. Satisfy the criteria of the modified CP classification for hepatic impairment during Screening: 
 
Moderate:  CP-B (Scores 7 to 9) or 
 
Severe:  CP-C (Scores 10 to12) 
4. MELD score of 6 to 24 at Screening 
5. Taking UDCA for at least 12 months (stable dose for ≥3 months) prior to Day 1, or unable to tolerate or 
unresponsive to UDCA (no UDCA for ≥3 months)  
Key Exclusion Criteria 
1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6) 
2. History of liver transplant or organ transplant 
3. History of alcohol or drug abuse within 12 months prior to Screening 
4. Current hepatic encephalopathy (as defined by a West Haven score of ≥2) 
5. History or presence of other concomitant liver diseases including: 
 
Hepatitis C virus infection and RNA positive 
 
Active hepatitis B infection; however, patients who have seroconverted (hepatitis B surface 
antigen and hepatitis B e antigen negative) may be included in this study after consultation with 
the Medical Monitor 
 
Primary sclerosing cholangitis 
 
Alcoholic liver disease 
 
Definite autoimmune liver disease or overlap hepatitis 
 
Gilbert’s Syndrome 
Page 227 of 603


Protocol 747-401 
Version 3: 04 Jan 2018
Page 9
 
Confidential and Proprietary 
6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function prior to 
randomization 
Investigational Product, Dosage and Mode of Administration:  
OCA 5 mg or OCA 10 mg tablets, oral administration 
Placebo tablets, matched in size and appearance to OCA tablets, oral administration 
Duration of Treatment:   
Patients who have completed their 48-week double blind treatment period will continue double blind treatment 
until all randomized patients have completed their participation in the 48-week treatment period and the 
database for that period is locked (approximately 3 years).  An open-label extension study in which all patients 
receive OCA will be considered following review of blinded safety and PK data. 
Criteria for Evaluation: 
Primary Objectives 
Assessments 
PK parameters 
OCA and its conjugates, glyco-OCA and tauro-OCA, and 
metabolite OCA glucuronide 
Safety and tolerability  
SAEs and TEAEs, physical exam, ECG, vital signs, clinical 
laboratory assessments, discontinuations, pruritus, and fatigue 
Secondary Objectives 
Assessments 
Changes in risk scores 
Changes in MELD and in CP scores and components of the 
CP score and MELD score 
Changes in liver biochemistry and hepatobiliary 
damage  
Total and direct bilirubin, ALP, ALT, AST, GGT, INR, 
creatinine, albumin, platelets 
PD parameters 
FGF-19, C4, and plasma bile acids 
Additional Objectives 
Assessments 
Noninvasive measurements of liver fibrosis, liver 
stiffness and cirrhosis 
TE and ELF (HA, P3NP, and TIMP-1) 
PK/PD relationship 
PK parameters compared to PD parameters and safety and 
tolerability assessments (above) 
Patient-reported outcomes 
Pruritus VAS, PBC-40, EQ-5D-5L, CLDQ 
Clinical events 
Death (all-cause and liver-related), liver transplant, MELD 
score ≥15 (for patients with MELD ≤12 at baseline), 
hospitalization for new onset or recurrence of: variceal bleed, 
hepatic encephalopathy, spontaneous bacterial peritonitis, 
uncontrolled ascites, and HCC. 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
C4 = 7α-hydroxy-4-cholesten-3-one; CLDQ = Chronic Liver Disease Questionnaire; CP = Child-Pugh; ECG = 
electrocardiogram; ELF = enhanced liver fibrosis; FGF-19 = fibroblast growth factor-19; GGT = gamma-glutamyl 
transferase; HA = hyaluronic acid; INR = international normalized ratio;  MELD = Model End Stage Liver Disease; OCA = 
obeticholic acid; P3NP = procollagen 3 N-terminal peptide; PBC = Primary Biliary Cholangitis; PD = pharmacodynamic; 
PK = pharmacokinetic; SAE = serious adverse event; TE = Transient Elastography; TEAE = treatment emergent adverse 
events; TIMP-1 = tissue inhibitor of metalloproteinase 1; VAS = visual analog scale 
Page 228 of 603


Protocol 747-401 
Version 3: 04 Jan 2018
Page 10
 
Confidential and Proprietary 
Statistical Methods: 
Analysis Populations: 
The following patient populations will be evaluated and used for presentation and analysis of the data: 
 
The Intent-to-Treat (ITT) Population will include all randomized patients who receive any amount of 
investigational product (OCA or placebo).  The ITT Population will be the primary population used for 
summarizing efficacy assessments.  
 
The Safety Population will include all patients who received at least one dose of investigational product 
(placebo or OCA). The Safety Population will be the primary population used for safety analyses.  
 
The PK Population will include all patients receiving OCA who have adequate concentration-time 
profiles to characterize OCA and its conjugates and must not have any major protocol deviations that 
potentially affect exposure levels.   
Pharmacokinetic Analyses: 
The PK Population will be used for analysis of PK parameters, which include plasma OCA (parent) and its 
conjugates (glyco-OCA and tauro-OCA), total OCA, metabolite OCA glucuronide, and potentially other 
conjugates or metabolites not yet identified. 
Values will be calculated using non-compartmental methods.  The values will be summarized by active 
treatment group using descriptive statistics.  
Safety Analyses: 
Safety analyses will be conducted using the Safety population.  Safety data, including AEs, AEs of special 
interest including pruritus and hepatic safety, vital signs, electrocardiogram, and clinical laboratory results will 
be summarized by treatment group.  The incidence of treatment-emergent AEs (TEAEs) and serious AEs 
(SAEs) will be tabulated by system organ class and preferred term for each treatment group, and similarly by 
severity and relationship to treatment.  Laboratory parameters, physical examinations including vital signs, and 
electrocardiograms will be summarized by treatment group using descriptive statistics at Baseline and at each 
scheduled post-Baseline visit.  The absolute change from baseline will also be summarized.  No inferential 
comparison with formal statistical hypothesis testing will be performed for safety endpoints. 
Efficacy Analyses: 
This study does not plan to conduct a formal hypothesis testing for any efficacy endpoint.   
The endpoints of efficacy assessments are change in total and direct bilirubin, INR, creatinine, albumin, 
platelets, ALP, ALT, AST, and GGT from baseline to Week 48 (end of the study), change from baseline to 
Week 48 in CP score and components of the CP score, and change from baseline to Week 48 in MELD and 
components of the MELD score.  Analyses of change from Baseline to Week 48 (end of study) will be modelled 
between treatment groups using ANCOVA model with change from Baseline as the dependent variable, 
treatment group and randomization stratification factor as fixed effects and the baseline values as covariates.  
The same analysis will be carried out using percentage change from Baseline as the dependent variable. 
Additional Efficacy Analyses 
Analyses of changes in liver stiffness (TE) and liver fibrosis (ELF [HA, P3NP, and TIMP-1]) will be 
summarized and analyzed using the same methodology specified for the secondary analyses of change in 
bilirubin. 
The following endpoints consistent with end-stage liver disease will be captured in the study: 
 
Time to death (all cause) 
 
Time to liver-related death 
 
Time to liver transplant 
 
MELD score ≥15 (for patients with MELD ≤12 at baseline) 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
 
Time to variceal bleed 
Page 229 of 603


Protocol 747-401 
Version 3: 04 Jan 2018
Page 11
 
Confidential and Proprietary 
 
Time to hepatic encephalopathy (as defined by a West Haven score of ≥2) 
 
Time to spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 
Time to uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
The incidence and time to first occurrence of any of the above listed clinical events will be summarized by 
treatment group using the log rank test stratified by the randomization stratification factor.  Kaplan-Meier (KM) 
estimates of the distribution of the time-to-event will be tabulated and graphed by treatment group.  The 
tabulation will include the KM methodology using 25th, 50th (median), and 75th percentiles with associated 
2-sided 95% confidence intervals (CIs), as well as percentage of censored observations.  The number and 
percent of patients censored and with events will be presented.  The hazard ratio and 2-sided 95% CI will be 
estimated based on a Cox regression model stratified by randomization strata.  
In addition, the incidence and time to each of the above clinical events, and the incidence and time to occurrence 
of HCC will be summarized by treatment group using the same methods as defined above.   
Sample Size Justification: 
To reasonably characterize the PK of OCA in patients with hepatic impairment, a simulation based approach 
estimated a requirement of approximately 20 patients in the OCA treatment group assuming a 15% 
discontinuation rate.  A total of 30 patients is adequate with 10 patients on placebo to be included as a 
comparator and 20 patients on OCA.  An additional 20 patients will be enrolled to support safety and efficacy 
evaluations.  Therefore, approximately 50 patients (including at least 20% of patients with CP-C) will be 
randomized in a 1:1 ratio to 1 of 2 treatment groups:  Placebo and OCA. 
 
 
 
Page 230 of 603


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Page 236 of 603


Protocol 747-401 
Version 3: 04 Jan 2018
Page 18
 
Confidential and Proprietary 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this protocol. 
Abbreviation or Specialist Term 
Explanation 
6-ECDCA 
6α-ethyl chenodeoxycholic acid (also known as INT-747) 
AASLD 
American Association for the Study of Liver Diseases  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
antimitochondrial antibody 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
β-hCG 
beta human chorionic gonadotropin 
BAS 
bile acid sequestrants 
BP 
blood pressure 
C4 
7α-hydroxy-4-cholesten-3-one 
CAC 
Cardiovascular Adjudication Committee 
CI 
confidence interval 
CLDQ 
Chronic Liver Disease Questionnaire 
CRA 
Clinical Research Associate 
CP 
Child-Pugh 
eCRF 
electronic case report form 
DDI 
drug-drug interaction 
DMC 
Data Monitoring Committee 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
enhanced liver fibrosis 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
Page 237 of 603


Protocol 747-401 
Version 3: 04 Jan 2018
Page 19
 
Confidential and Proprietary 
Abbreviation or Specialist Term 
Explanation 
glyco-OCA 
glycine 6α-ethyl chenodeoxycholic acid 
HCC 
hepatocellular carcinoma 
HCP 
health care professional 
HDL 
high-density lipoprotein 
IB 
Investigational Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio  
IRB 
Institutional Review Board 
ISF 
Investigator site file 
ITT 
intent-to-treat  
IWRS 
interactive web response system 
KM 
Kaplan-Meier 
LDL 
low-density lipoprotein 
LTSE 
long-term safety extension 
LS 
least squares 
MACE 
major adverse cardiovascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model of end stage liver disease  
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cholangitis (also known as primary biliary 
cirrhosis) 
PIS 
patient information sheet 
PK 
pharmacokinetic 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
SD 
standard deviation 
SEM 
standard error of the mean 
SI 
standard international system of units 
SOC 
system organ class 
Page 238 of 603


Protocol 747-401 
Version 3: 04 Jan 2018
Page 20
 
Confidential and Proprietary 
Abbreviation or Specialist Term 
Explanation 
StdErr 
standard error 
SUSAR 
suspected unexpected serious adverse reaction 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
the Sponsor 
Intercept Pharmaceuticals, Inc. 
TIPS 
transjugular intrahepatic portosystemic shunt 
UDCA 
ursodeoxycholic acid 
UK 
United Kingdom  
ULN 
upper limit of normal 
US 
United States (of America) 
VAS 
visual analogue scale 
VLDL 
very low-density lipoprotein 
 
Page 239 of 603


Protocol 747-401 
Version 3: 04 Jan 2018
Page 21
 
Confidential and Proprietary 
5. 
INTRODUCTION 
5.1. 
Overview of Disease State and OCA 
Primary biliary cholangitis (PBC, also known as primary biliary cirrhosis [Beuers 2015a, 
Beuers 2015b, Beuers 2015c]) is a serious, life-threatening, cholestatic liver disease of unknown 
etiology that, without treatment, frequently progresses to hepatic fibrosis and eventual cirrhosis, 
hepatic decompensation, and necessitates liver transplantation or results in death.  PBC is a rare 
disease with reported prevalence in the US of 40.2/100 000 (Kim 2000).  PBC disproportionately 
affects women approximately 10:1 and is typically diagnosed in patients between 40 to 70 years 
of age.   
Historically, the only approved drug therapy for PBC has been the bile acid, ursodeoxycholic 
acid (UDCA), a physiological constituent of human bile (Lindor 2009).  While UDCA therapy 
had a marked effect on the treatment of PBC, up to 50% of patients showed a suboptimal 
response or no response to UDCA.  Such patients were at significantly increased risk of a poor 
clinical outcome due to PBC disease progression.   
Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist and modified bile acid derived 
from the primary human bile acid chenodeoxycholic acid (CDCA) (Pellicciari 2002), was 
developed for the treatment of PBC and to provide patients who have an inadequate response to 
or poor tolerance of UDCA a novel treatment option that was safe and effective.   
In May 2016, the US Food and Drug Administration (FDA) granted accelerated approval for 
OCA (marketed as Ocaliva), for the treatment of patients with PBC in combination with UDCA 
in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate 
UDCA.  In December 2016, the European Commission granted conditional approval for Ocaliva 
for the same indication, and in May 2017 Ocaliva received approval from Health Canada.  
Study 747-401 is considered a Phase 4 study in regions where OCA has received regulatory 
approval for PBC (ie, in the US, Canada, and the EU).  In all other regions, this study is 
considered Phase 3b. 
5.2. 
Nonclinical Experience with Obeticholic Acid 
Intercept Pharmaceuticals, Inc. (the Sponsor) has completed a standard battery of nonclinical 
safety pharmacology and toxicology studies.  No major nonclinical safety effects have been seen 
other than pharmacologic hepatic effects observed at high doses.  These pharmacologic hepatic 
effects are consistent with the detergent effects of a bile acid at exceedingly high hepatocellular 
exposure. 
5.3. 
Clinical Development of Obeticholic Acid 
As of 13 Oct 2017, approximately 2690 subjects have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 552 patients had PBC, 1141 patients had nonalcoholic 
steatohepatitis (NASH), 41 patients had diabetes mellitus/ nonalcoholic fatty liver disease 
(NAFLD), 33 patients had alcoholic cirrhosis/portal hypertension, 73 patients had primary 
sclerosing cholangitis (PSC), and 6 patients had biliary atresia.  
Overall, the pharmacokinetic (PK) profile of OCA is consistent with that expected of a bile acid.  
Phase 1 studies demonstrated that OCA is rapidly absorbed and extensively conjugated with 
Page 240 of 603


Protocol 747-401 
Version 3: 04 Jan 2018
Page 22
 
Confidential and Proprietary 
glycine and taurine to form glyco-OCA and tauro-OCA, respectively.  OCA and its conjugates 
are primarily eliminated via biliary excretion, and plasma concentration time profiles 
demonstrated multiple peaking with prolonged exposure, indicative of enterohepatic circulation.  
Plasma concentrations of OCA and its conjugates spike shortly after meals, consistent with gall 
bladder emptying into the duodenum as expected of a bile acid. 
The OCA clinical development PBC program was based on a wide range of studies in PBC 
patients and healthy volunteers.  The clinical pharmacology studies supported the proposed 
dosing regimen:  10 mg fixed dose and a titration regimen starting at OCA 5 mg with titration to 
10 mg based on clinical and biochemical response.  The clinical program included a pivotal 
Phase 3 clinical study (747-301) and two Phase 2 clinical studies (747-201 and 747-202), which 
formed the primary basis of approval of OCA. 
Study 747-201 (59 patients) evaluated 2 doses of OCA (10 mg and 50 mg) given as monotherapy 
versus placebo.  Statistically significant and clinically relevant relative and absolute reductions 
from Baseline in alkaline phosphatase (ALP) were achieved with both doses of OCA versus 
placebo (p <0.0001).  Mean relative ALP reductions were 45% (OCA 10 mg) and 38% 
(OCA 50 mg) compared to an increase of 0.4% with placebo.  Further, significant improvements 
in gamma-glutamyl transferase (GGT) and in conjugated bilirubin were observed with both 
doses compared with placebo (p <0.05).  OCA also resulted in decreased circulating alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) levels. 
Study 747-202 (165 patients) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in patients on a stable therapeutic dose of UDCA.  Overall, the data from 747-202 were 
consistent with Study 747-201.  Statistically significant and clinically meaningful relative and 
absolute reductions in ALP were achieved with all 3 doses of OCA versus placebo (p <0.0001).  
Mean ALP reductions from baseline ranged from 21% to 25% compared to 3% with placebo.  
Improvements were also seen in GGT and ALT levels and in conjugated bilirubin levels. 
Study 747-301 (216 patients) was a Phase 3, double-blind, placebo-controlled, parallel-group 
study followed by a long-term safety extension (LTSE) using OCA in patients with PBC.  The 
primary endpoint for Study 747-301 was a composite endpoint based on the proportion of 
patients reaching specific criteria for ALP and bilirubin (ALP <1.67x upper limit of normal 
[ULN] with a ≥15% reduction and bilirubin ≤ULN).  Both OCA treatment groups met the 
primary endpoint of achieving a reduction in ALP to <1.67x ULN with a ≥15% reduction from 
baseline and a normal bilirubin level after 12 months of therapy.  The placebo group experienced 
a least squares (LS) mean decrease in ALP from baseline of 5%, compared to a significant LS 
mean decrease of 39% in the OCA 10 mg dose group and 33% in the OCA titration group (both 
OCA dose groups p <0.0001 versus placebo). 
The LTSE phases of both Phase 2 studies and the pivotal Phase 3 study support the long-term 
safety of OCA and demonstrate a durable therapeutic response.   
Study 747-302 is an ongoing randomized, double-blind, placebo-controlled clinical outcomes 
study, designed to confirm the clinical benefit of OCA treatment in patients with PBC.  This 
study is inclusive of patients with early to advanced stage PBC. 
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5.4. 
Rationale for Study Design and Dose for Investigational Product 
5.4.1. 
Rationale for Study Design 
There are limited clinical data available to support the use of OCA in patients with PBC with 
moderate to severe hepatic impairment.  The current recommended dosing of such patients is 
based on modeled systemic and hepatic concentrations.  Therefore, Study 747-401 is specifically 
designed to characterize the PK, safety, and efficacy of OCA in this patient population. 
PK and safety parameters will be evaluated as the primary objectives and efficacy parameters 
will be evaluated as secondary and additional objectives.  While the prognostic utility of ALP 
has been established by the Global PBC study group, increasing levels of bilirubin are more 
relevant to understanding the progression of end stage liver disease.  Consistently, bilirubin is a 
key marker of advancing disease as characterized by the Global PBC study group as well as its 
incorporation into model of end stage liver disease (MELD), Child-Pugh (CP), and Mayo risk 
scores.  As such, the potential of OCA to stabilize bilirubin levels will be evaluated. 
In order to generate data for the patient population in a timely fashion, Study 747-401 is 
designed with a relatively short-term, 1-year double-blind treatment period to gather primarily 
PK and safety data.  Therefore, the study will not formally test the long-term efficacy of OCA on 
clinical outcomes.   
Although Study 747-401 is not designed to formally evaluate clinical outcomes, these data will 
be collected and assessed as an additional objective.  Given the importance of evaluating clinical 
outcomes in patients with the most advanced form of the disease, these events will be 
prospectively adjudicated consistent with the procedures implemented in ongoing PBC studies.  
This will allow for a more robust meta-evaluation of clinical outcomes in patients with moderate 
to severe hepatic impairment following the completion of both studies.  
Study 747-302 is specifically designed to confirm clinical benefit across the spectrum of disease 
including patients with hepatic impairment.  Data collected from Study 747-401 will serve as a 
bridge to the 747-302 study. 
Taken together, data from this study will complement the data from Study 747-302 and offer the 
opportunity to better inform the benefit risk profile and appropriate treatment of 
hepatically-impaired patients.  
5.4.2. 
Rationale for Obeticholic Acid Dose and Duration 
Simulations using a physiologic PK model predicted changes in systemic and liver OCA 
concentrations associated with changes in the severity of hepatic impairment (CP Score).  Model 
simulations predicted that for mild (Child-Pugh A [CP-A]), moderate (Child-Pugh B [CP-B]), 
and severe (Child-Pugh C [CP-C]) hepatic impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to patients with normal hepatic function, whereas total 
OCA liver concentrations increase 1.1-, 1.5-, and 1.7-fold, respectively.  Because the liver is the 
primary site of action for the safety and efficacy of OCA, it is important to account for the 
differences in systemic and liver exposure when assessing effective doses.  It is also important to 
note that while hepatically impaired (CP-B and C) patients treated with OCA in Phase 1 and 
2 studies experienced plasma OCA exposures >10-fold higher than those in healthy patients, no 
apparent impact on the overall safety profile was observed, consistent with only a modest 
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increase in liver exposure of OCA associated with hepatic impairment.  Together, the results 
from these analyses suggest that the doses of OCA administered to patients with moderate or 
severe hepatic impairment should be modestly lower than those for patients with normal hepatic 
function to achieve similar hepatic exposure.    
Therefore, the current FDA-approved prescribing information for OCA includes a modified 
dosing regimen in patients with moderate and severe hepatic impairment that is designed to 
achieve liver exposures in these patients that would be similar to non-hepatically impaired 
patients through initiation at a lower dose (5 mg OCA once-weekly) followed by gradual 
up-titration (Section 7.3).   
5.4.3. 
Rationale for Population Chosen 
Patients with PBC and moderate or severe hepatic impairment, based on CP score and varying 
levels of MELD, are the targeted population for this study as OCA has been studied primarily in 
early to moderate stages of liver impairment in patients with PBC.  There is a great need to 
extend therapies to PBC patients with more advanced liver impairment.  Given the unmet 
medical need and observed efficacy, safety and tolerability profile of OCA in early and moderate 
PBC, evaluating the effects of OCA in a late stage population is warranted. 
5.4.4. 
Rationale for Control Group  
The use of a randomized placebo control group added to established standard of care provides 
the best scientific evidence of efficacy and safety.  The use of a placebo control provides a 
concurrent comparator group, accounting for not only a placebo effect but continued standard of 
care.  The use of a placebo control is critical to assess the safety and tolerability of OCA but also 
as a comparator for the high rate of clinical events which are expected in this advanced 
population.  
5.5. 
Importance of Monitoring of Disease Progression 
Given PBC is a chronic, progressive liver disease, it is important that patients with PBC are 
closely monitored to ensure early identification of decompensation and/or liver injury.  More 
extensive safety monitoring and appropriate dosing adjustments, interruptions, and 
discontinuations will be implemented to improve patient oversight and safety.  Investigators, 
together with the Sponsor’s Medical Monitor, will consistently and frequently assess individual 
patients to determine on an ongoing basis the totality of a patient’s clinical profile, which 
includes careful evaluation of signs and symptoms of potential hepatic injury and/or 
decompensation coupled with rules-based laboratory monitoring. 
Patients will be monitored for potential hepatic injury and/or decompensation.  Criteria for 
implementing dosing adjustments, interruptions, or discontinuations, and close monitoring 
procedures postdose-adjustment are described in Section 8.4 and Section 7.6.  The more 
extensive monitoring is important given the elevated risk of decompensation and potential for 
higher hepatic exposure to OCA in this population. 
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5.6. 
Summary of Known Potential Risks with Investigational Product 
The rate of progression and risk of decompensation is variable and may be rapid in certain 
patients, necessitating closer surveillance of patients at risk.   
Clinical Data 
In two Phase 2 studies and a Phase 3 study evaluating OCA in the treatment of subjects with 
PBC, hepatic adverse events were observed in subjects receiving doses of OCA ranging from the 
maximum approved dose of 10 mg once daily to 50 mg (5 times the highest recommended dose).   
Recent safety findings in NASH clinical trials include 2 cases of hepatic decompensation 
reported as SUSARs, 1 of which resulted in death.  Both cases involved numerous confounding 
factors that make evaluation of association with treatment difficult.  Details for both events are 
provided in the Investigator’s Brochure Addendum 1 to Version Number: 16 (31 March 2017), 
Effective Date: 02 October 2017. 
The primary AE shown to be related to OCA is pruritus.  Pruritus has also been observed in 
clinical studies with OCA in other indications, as well as in healthy subjects, with the highest 
frequency observed in subjects with PBC.  The incidence and severity of pruritus have been 
shown to be dose dependent, but there is no evidence of association with stage or progression of 
underlying disease. 
Changes in lipid profiles have also been observed with OCA dosing, including an increase in 
low-density lipoprotein (LDL) cholesterol and a decrease in high-density lipoprotein (HDL) 
cholesterol.  The clinical significance of these lipid findings remains unclear and is being studied 
further. 
Independent data monitoring committees (DMCs) have performed detailed reviews of several 
studies including the Phase 3, clinical outcomes study in PBC (747-302) and the Phase 3, pivotal 
study in NASH with fibrosis (747-303).  The DMC reviewed data (unmasked for PBC and 
unblinded by treatment group for NASH with a total of approximately 1000 subjects) in closed 
sessions, which excluded participation of the Sponsor.  Based on these reviews, the DMC 
recommended that both studies continue without modification. 
Post-Marketing Cases in PBC 
As of September 2017, greater than 3000 patients have received Ocaliva in the post-marketing 
setting.  In patients with moderate to severe hepatic impairment (Child-Pugh B and C), liver 
decompensation, liver failure, and death have been reported when Ocaliva was dosed up to 
7 times the recommended once weekly starting dose for such patients.  Based on the initial 
medical assessment of these cases, which included patients having undergone liver transplant, 
there was insufficient evidence suggesting a causal relationship between higher than 
recommended dosing and the reported adverse events. However, Intercept Pharmaceuticals, Inc. 
(the Sponsor) continues to assess the potential association between adverse events, including 
deaths, and the higher than recommended dosing of Ocaliva observed in PBC patients with 
moderate to severe hepatic impairment (Child-Pugh B and C) through ongoing post-marketing 
pharmacovigilance activities. 
Signs and symptoms reported in patients experiencing liver-related adverse events who received 
Ocaliva include:  increases in bilirubin and other liver enzymes, new or worsening pruritus, new 
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or worsening fatigue, vague neuropsychiatric symptoms (such as dysphoria), abdominal pain, 
nausea, vomiting, diarrhea, dehydration, jaundice, and liver decompensation. 
Refer to the IB for additional information regarding the known potential risks with the 
investigational product. 
6. 
STUDY OBJECTIVES AND PURPOSE 
The study will be conducted in patients with PBC and moderate to severe hepatic impairment 
defined as CP-B and CP-C with MELD scores ranging from 6 to 24. 
6.1. 
Primary Objectives 
 To evaluate the PK of OCA and its conjugates, glyco-OCA and tauro-OCA, and OCA 
metabolite glucuronide compared with placebo 
 To evaluate the safety and tolerability of OCA treatment compared with placebo 
6.2. 
Secondary Objectives 
 To evaluate the effect of OCA treatment compared to placebo on:  
 The MELD score and its components 
 CP score and its components 
 Liver biochemistry including total and direct bilirubin, alkaline phosphatase 
(ALP), and aminotransferases (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], and gamma glutamyl transaminase [GGT]), international 
normalized ratio (INR), creatinine, albumin, platelets 
 Biomarkers of bile acid synthesis and homeostasis including fibroblast growth 
factor 19 (FGF-19), 7α-hydroxy-4-cholesten-3-one (C4), and plasma bile acids 
6.3. 
Additional Objectives 
 To evaluate the effect of OCA treatment compared to placebo on: 
 Noninvasive markers of liver fibrosis (Enhanced Liver Fibrosis [ELF]™score) 
 Noninvasive measurement of liver stiffness (transient elastography [TE]) 
 To assess the PK/Pharmacodynamic (PD) relationship of OCA with: 
 PK parameters compared to PD parameters and safety and tolerability 
assessments 
 To assess patient reported outcomes (Pruritus Visual Analogue Scale [VAS], PBC-40, 
EQ 5D-5L, Chronic Liver Disease Questionnaire [CLDQ] 
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 To assess clinical events consistent with end-stage liver disease 
 Death (all cause) 
 Liver transplant 
 MELD score ≥15 (for patients with MELD ≤12 at baseline) 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: variceal bleed, hepatic encephalopathy (as defined by a West 
Haven score of ≥2), spontaneous bacterial peritonitis 
 Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis 
at a frequency of at least twice in a month) 
 Hepatocellular carcinoma (HCC) 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the PK and 
safety of OCA treatment in patients with PBC and moderate to severe hepatic impairment 
defined as CP-B and CP-C including a broad distribution of MELD scores (ranging from 6 to 
24).  Approximately 50 patients (including at least 20% of patients with CP-C) will be enrolled 
in the study.  Patients will be screened ≥14 days but not more than 28 days prior to entering the 
study (Day 1).  Patients who meet all eligibility requirements will be randomized in a 1:1 ratio to 
1 of 2 treatment groups:  Placebo or OCA.  Randomization will be stratified by CP class.  
Baseline MELD scores will be monitored on an ongoing basis to ensure adequate distribution of 
MELD scores. 
Following completion of safety assessments and laboratory specimen collection, blinded 
investigational product will be dispensed with instruction to begin dosing the same day (Day 1) 
at OCA 5 mg or placebo once weekly.   
Double-Blind Treatment Period:  During the 48-week treatment period, an initial safety visit 
will occur at Week 3.  After the Week 6 Visit, subsequent clinic visits will occur approximately 
every 6 weeks for the assessment of safety, tolerability, PK, and PD. Titration may be considered 
as early as the Week 12 Visit (see Section 7.3).  Fasting PK assessments will be performed in all 
patients participating in the study on Day 1, Week 6, and Week 36.  Serial PK sampling (which 
also includes a fasted PK assessment) will be performed at Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week, double-blind treatment period will continue 
double-blind treatment until all randomized patients have completed their 48-week treatment 
period and the database for that period is locked.  An open-label extension study in which all 
patients receive OCA will be considered following review of blinded safety and PK data. 
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7.1.1. 
Study Design Diagram 
Figure 1: 
Study Design  
 
OCA = obeticholic acid, PBC = primary biliary cholangitis 
Notes:  Initial dose titration of investigational product may be considered as early as the Week 12 Visit, or any study 
visit thereafter for patients on all dosing regimens, based on tolerability and safety laboratory tests from the 
previous visit.  Subsequent dose titration(s) may occur no earlier than 6 weeks after the previous dose titration 
and will be based on tolerability. 
Patients who complete Week 48 will continue double-blind treatment until all randomized patients have 
completed their participation in the 48-week treatment period and the database for that period is locked. 
 
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures  
 
 
Double-Blind Treatment Period (Weeks)b 
Double-Blind 
Extension 
Screening 
Day 1a 
3c 
6d 
12 
18 
24 
30 
36 
42c 
48/ ET/ 
EOS/EOT 
Every 3 
months 
Visit Window  
(+/-) 
-28 to -14 
days 
 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±2 wks 
Fast ≥8 h Prior to Visite 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/PBC History 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examf 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Vital Signs and Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Medical and Surgical Procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessments for Child-Pugh 
Scoreg 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Patient Questionnaires (Pruritus 
VAS, PBC-40, EQ- 5D-5L, and 
CLDQ)h 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Randomization/Treatment 
Assigned 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense IPi 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dose Titration Assessmentj 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
IP Accountability/ 
Compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 1: 
Schedule of Study Procedures (Continued) 
 
 
Double-Blind Treatment Period (Weeks)b 
Double-Blind 
Extension 
Screening 
Day 1a 
3c 
6d 
12 
18 
24 
30 
36 
42c  
48/ ET/ 
EOS/EOT 
Every 3 
months 
Visit Window  
(+/-) 
-28 to -14 
days 
 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±2 wks 
Urinalysis  
X 
X 
 
 
 
 
 
 
 
 
X 
Xp 
Urine-based β-hCG Pregnancy 
Testk 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Virology (HCV/HBsAg) 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry/Hematology/ 
Coagulationl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase and Lipase 
Sample to be collected if the patient experiences acute pancreatitis or cholecystitis. 
PK Fasting Collection 
 
X 
 
X 
 
 
 
 
X 
 
 
 
PK Serial Collectionm 
 
 
 
 
X 
X 
X 
X 
 
 
X 
 
PD Markers: Bile 
Acid/C4/FGF-19 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
TE/ELF (HA, P3NP, and 
TIMP-1)n 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Xo 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
X 
Xp 
Hepatic Ultrasoundq 
Xr 
Xs 
 
 
 
 
X 
 
 
 
X 
Xo 
Gallbladder assessment 
(ultrasound) 
Xr 
Xs 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; eCRF = electronic case report form; C4 = 7α hydroxy-4-cholesten-3-one; CLDQ = Chronic Liver Disease Questionnaire; ELF = enhanced liver fibrosis; ET = 
Early Termination; EOS = End of study; EOT = End of Treatment; ; FGF-19 = fibroblast growth factor-19; HA = hyaluronic acid; HCV = Hepatitis C virus; IP = Investigational 
Product; P3NP = procollagen 3 N-terminal peptide;  PBC = primary biliary cirrhosis; PK = pharmacokinetics; TE = transient elastography; wk(s) = week(s), TIMP-1 = tissue 
inhibitor of metalloproteinase ; VAS = Visual Analogue Scale. 
a Visit schedule should be based on Day 1.  Day 1 visit must occur at least 2 weeks after screening visit. 
b Patients should be contacted by telephone/email every 3 weeks (±1 week) between clinic visits starting at Week 9 and continuing to Week 48 to assess for AEs, concomitant 
medications, medical/surgical procedures, and verify that s/he is dosing as directed. (see Section 9.7.8). 
c Preferably, the patient comes in to the clinic for this visit.  Alternatively, site will telephone the patient for assessments and a home health nurse will visit to draw safety labs. 
d Visit should occur 3, 4, or 5 days after taking the Week 6 dose. 
Page 249 of 603


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7.1.3. 
Study Duration 
Patients will receive double-blind treatment for at least 48 weeks.  Patients who have completed 
their 48-week, double-blind treatment period will continue double-blind treatment until all 
randomized patients have completed their 48-week treatment period and the database for that 
period is locked (approximately 3 years).    An open-label extension study in which all patients 
receive OCA will be considered following review of blinded safety and PK data. 
7.2. 
Number of Patients 
Approximately 50 patients will be enrolled in this study. 
7.3. 
Planned Dosing Regimen 
All patients will initiate investigational product once weekly with OCA 5 mg or matching 
placebo (Table 2).  Titration may be considered as early as the Week 12 Visit.  Following visit 
procedures at Week 12, if the investigational product is tolerated and laboratory assessments do 
not indicate a safety concern, the patient may up-titrate to OCA 5 mg twice weekly and may start 
the higher dose regimen no earlier than 2 days after they took their last dose.  Dosing will then 
occur at least 3 days apart.  Every 6 weeks thereafter, based on tolerability assessments, patients 
can be considered for further up titration as described below (Table 2).  At each titration visit, the 
patient may start the higher dose regimen no earlier than 2 days after the prior dose. 
Patients may titrate to a maximum dose of OCA 10 mg twice weekly at least 3 days apart.  
Table 2: 
Planned OCA or Matching Placebo Dosing Regimen 
 
Child-Pugh B and Child-Pugh C 
(Moderate and Severe Hepatic Impairment) 
Treatment Group 
OCA 
Placebo 
Starting Dose (Day 1) 
5 mg once weekly 
matching placebo once weekly 
Titration 1a  
 
5 mg twice weeklyb 
matching placebo twice weeklyb 
Titration 2a  
10 mg twice weeklyb 
matching placebo twice weeklyb 
a Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on patient 
tolerability. 
b Dosing per the twice weekly schedule must be at least 3 days apart. 
7.4. 
Monitoring and Management of Potential Hepatic Injury and/or 
Disease Progression 
Given the chronic nature of PBC, it is important to monitor for potential hepatic injury, disease 
progression and/or hepatic decompensation.  Child-Pugh and MELD scores will be reviewed at 
each visit where labs are drawn (Table 1).  In addition, adverse events, signs and symptoms of 
potential hepatic injury or decompensation, and laboratory values will also be reviewed at 
regular intervals as described in Section 7.1.2.  Based on biochemical and clinical assessments, 
the investigational product may be interrupted or discontinued per criteria discussed in 
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 Each protocol-specified visit (Table 1)  
 Unscheduled visits as needed in the event of signs or symptoms of suspected hepatic 
injury or decompensation or if laboratory alerts have been triggered 
It is important that the laboratory assessments be completed as required and that the central 
laboratory be used for assessments whenever possible.  In the event that a patient cannot return 
to the clinic for a scheduled or unscheduled visit, or there is an event that triggers a need for an 
immediate assessment, the use of a local lab is permissible at the discretion of the Investigator. In 
these cases, the Investigator will obtain the laboratory results and the laboratory normal ranges. 
The process for assessing criteria is presented in Figure 2, and the specific threshold(s) for each 
laboratory analyte to trigger mandatory repeat testing and, potentially, a complete patient 
evaluation (depending on the repeat result) are summarized in Table 3. 
Figure 2: 
DILI Management Algorithm 
  
DILI = drug-induced liver injury; IP = Investigational Product 
NOTE 
Other laboratory criteria include:  ALT, AST, total bilirubin, INR, and electrolytes (sodium). 
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Table 3: 
Liver Laboratory Criteria for Monitoring of Suspected Hepatic Injury or 
Potential Hepatic Decompensation and Criteria for Interruption or 
Discontinuation of Investigational Product 
A. Laboratory Criteria for Monitoring Suspected Hepatic Injury 
Laboratory Parameter 
Action Taken 
Rechallenging Criteria 
Total Bilirubin 
 
If a patient interrupts IP, they may be 
rechallenged after a minimum of 30 days if 
fully resolved OR stable and approved by 
the Medical Monitor and Investigator. 
Baseline ≤ULN and ≥3x baseline 
Interrupt IP 
Baseline >ULN and ≥2x Baseline 
Interrupt IP 
ALT or AST 
 
>3x baseline (and >ULN) 
Interrupt IP 
≥2x baseline 
Repeat Test in 2 to 3 days, 
interrupt IP if still elevated 
Electrolytesa 
 
Sodium <130 mEq/L 
Repeat Test in 2 to 3 days, 
interrupt IP if still below limit 
B. 
 Laboratory Criteria for Monitoring Potential Hepatic Decompensation (Absence of Clinical Symptoms) 
Total Bilirubin 
Closely monitor until 
normalization or stabilization. 
 
If values continue to increase 
relative to the baseline value, 
interrupt IP. 
The patient may be rechallenged after a 
minimum of 30 days if fully resolved OR 
stable and approved by the Medical 
Monitor and Investigator. 
 
If laboratory values do not normalize, IP 
should not be restarted. 
Baseline ≤ULN and 1.5 mg/dL increase 
from baseline 
Baseline >ULN and 1.0 mg/dL increase 
from baseline 
INRb 
 
 
>0.3 increase from baseline 
Closely monitor until 
normalization or stabilization. 
 
If values continue to increase 
relative to the baseline value, 
interrupt IP. 
The patient may be rechallenged after a 
minimum of 30 days if fully resolved OR 
stable and approved by the Medical 
Monitor and Investigator. 
 
If laboratory values do not normalize, IP 
should not be restarted. 
≥2.0 unless due to vitamin K deficiency 
Discontinue IP permanently  
Continue to return for scheduled study 
visits for safety follow up. Monitor closely 
for clinical outcomes per protocol. 
C. Laboratory Criteria for Monitoring Potential Hepatic Decompensation in the Presence of Clinical Symptoms  
Total bilirubin thresholds defined in 
Part B OR an INR increase from baseline 
of ≥1.5 are observed in the presence of 
clinical symptoms of cholestatic hepatitis 
or hepatic encephalopathyc  
Discontinue IP permanently 
Continue to return for scheduled study 
visits for safety follow up. Monitor closely 
for clinical outcomes per protocol. 
IP = investigational product 
a Sodium will be measured as an assessment of liver failure (hyponatremia). 
b Does not apply in patients on anti-coagulants. 
c  Symptoms of cholestatic hepatitis includes dark urine and jaundice.  Symptoms of hepatic encephalopathy may include lack of 
awareness, shortened attention span, lethargy, gross disorientation, or coma (unresponsive to verbal or noxious stimuli). 
It should be noted that it is difficult to recognize every potential marker of hepatic or renal 
deterioration.  There is no substitute for good medical judgment.  Investigators will be reminded 
to be cautious and mindful in their evaluation of patients’ symptoms, signs, and laboratory 
results.  However, for example, a single abnormal laboratory analyte result may be artefactual; 
accordingly, Investigators will be allowed to implement an alternate follow-up procedure if 
considered appropriate based on their medical judgement, but only after documented agreement 
with the Sponsor’s Medical Monitor. 
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7.4.3. 
Clinical Criteria for Monitoring for Potential Hepatic Decompensation 
Patients will be monitored for potential hepatic decompensation events throughout the study.  
Clinical criteria for monitoring these events and the interruption/discontinuation of 
investigational product is summarized in Table 4. 
Investigational product should be discontinued permanently if the patient received a liver 
transplant or experiences multi-organ failure as defined in Table 4, Part A.  Patients should 
continue to return for scheduled study visits for safety follow-up.  
Patients who experience other potential hepatic decompensation events defined in Table 4, 
Part B should be closely monitored until normalization or stabilization.  Patients may be 
rechallenged after a minimum of 30 days if fully resolved OR stable and approved by the 
Medical Monitor and Investigator.   
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Table 4: 
Clinical Criteria for Monitoring Potential Hepatic Decompensation Events 
and Interruption / Discontinuation of Investigational Product 
A. Hepatic Decompensation Events Requiring Mandatory Discontinuation of Investigational Product 
Decompensation Event 
Action Taken / 
Rechallenging Criteria 
Liver Transplant 
Multi-organ failure requiring hospitalization 
Discontinue IP permanently and follow patients 
until normalization/stabilization. 
 
Continue to return for scheduled study visits for 
safety follow up. 
B. Hepatic Decompensation Events Requiring Interruption of Investigational Product 
 Liver failure defined as worsening synthetic 
function that is persistently worse relative to 
baseline and/or progressive over time (see Table 3, 
Part B)a 
 Variceal bleeding or recurrent variceal bleedingb 
documented by endoscopy or accompanied by 
anemia or melena with a hemoglobin drop of ≥2 
g/dL 
 Ascitesc including: 
o Worsening – requires increase in drug therapy or 
surgical intervention (paracentesis or shunt 
procedure) 
o Refractory ascites – unresponsive to medication; 
patient not candidate for transjugular intrahepatic 
portosystemic shunt (TIPS) or shunt; requires 
large volume paracentesis 
o Hyponatremia (≤125 mEq/L) secondary to ascites 
 Spontaneous Bacterial Peritonitis 
 Hepatic Encephalopathy, Grade ≥2 
 Any liver-related event requiring hospitalization and 
treatment (except multi-organ failure) 
 Hepatorenal syndrome Type 1 or Type 2 and acute 
kidney injury, hepatopulmonary syndrome, or 
portopulmonary syndrome 
Closely monitor until normalization or stabilization. 
 
The patient may be rechallenged after a minimum 
of 30 days if fully resolved OR stable and approved 
by the Medical Monitor and Investigator 
 
IP should be re-initiated at a lower dose (or lower 
dose frequency) and titrated per Investigator 
discretion. 
a Patients experiencing INR ≥2.0 unless due to vitamin K deficiency should be discontinued from IP permanently without 
rechallenge and should to return for scheduled study visits for safety follow up. 
b Endoscopic confirmation of gastric or duodenal varices without evidence of bleeding should be closely monitored; 
investigational product may be interrupted at Investigator discretion 
c New onset ascites requiring treatment should be closely monitored; investigational product may be interrupted at Investigator 
discretion 
7.5. 
Dose Titration Criteria 
Dose titration may follow the scheduled dosing regimens described in Section 7.3 or occur due to 
tolerability concerns. 
Dose titrations may involve increases or decreases in dosing frequency and are dependent on 
tolerability (as assessed by a review of AEs and safety laboratory results).  In general, 
down-titration may be done in response to tolerability concerns and can occur at any time.  
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Up-titration will be done per protocol based on tolerability, as assessed by the Investigator based 
on response, or following resolution of a tolerability concern that previously led to 
down-titration.  Up-titrations may only occur to the maximum dose and frequency indicated as 
defined in Section 7.3. 
Scheduled Dose Titration - After initiation of OCA or matching placebo, titration may be 
considered as early as the Week 12 Visit.  Subsequent titrations in dose for patients may occur no 
earlier than 6 weeks following an up-titration. 
Tolerability Dose Titration - Investigators may decrease the dosing frequency or dose as 
considered clinically appropriate (eg, tolerability). 
7.5.1. 
Pre-Titration Tolerability Assessment Requirements 
Tolerability of investigational product must be assessed prior to titrating a patient to a higher 
dose.  To determine if a patient is eligible for a dose titration refer to Section 7.3. 
7.6. 
Close Observation 
If investigational product is interrupted or discontinued as described in Section 8.4, patients 
should be closely monitored (contacted by the site a minimum of every 2 weeks and scheduled 
visits every 6 weeks; if returning to the site for a scheduled visit is not feasible, use of a local lab 
may be permissible at the Investigator's discretion).  At a minimum, the following assessments 
should be conducted at each study visit:   
 Physical exam and thorough review of patient reported signs and symptoms,  
 Liver biochemistry (including ALP, ALT, AST, GGT, total and conjugated bilirubin, 
creatinine, and albumin), prothrombin time (PT)/INR, serum electrolytes, and 
assessment of Child Pugh (only if the patient is at the study site) and MELD scores.  
In addition, a trough pharmacokinetic sample for assessment of OCA serum drug levels and its 
major metabolites should be obtained in any patient who develops an AE that is indicative of or 
consistent with hepatic injury or decompensation.  
The following additional monitoring procedures should be performed for events of potential 
hepatic injury (per FDA Guidance for Industry on Drug Induced Liver Injury) or suspected 
hepatic decompensation based on criteria described in Section 7.4.1, Section 7.4.2, and 
Section 7.4.3.  These cases need to be discussed with the Sponsor's Medical Monitor: 
 Repeating liver biochemistry and function tests as described in Section 7.4.2.  
Frequency of retesting can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the patient is asymptomatic, as clinically 
indicated.  
 Obtaining a more detailed history of symptoms and prior or concurrent diseases.  
 Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets is important. Concomitant drugs with potential hepatotoxicity should 
be recorded and discontinued unless alternative therapies are not available.  In the 
case of concomitant drugs potentially hepatotoxic, continued use of investigational 
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product should be discussed with the Sponsor's Medical Monitor.  The patient may be 
discontinued from investigational product, if clinically appropriate.  
 Obtaining a history of exposure to environmental chemical agents or herbal 
supplements which may be associated with liver toxicity.  
 Ruling out acute viral hepatitis types A, B, C, D (in those thought to have acute HBV 
infection), and E; autoimmune or alcoholic hepatitis; Wilson's disease, 
hypoxic/ischemic hepatopathy; and biliary tract disease.   
 Investigators should consider testing for Hepatitis E virus when assessing for hepatic 
decompensation as infection with Hepatitis E virus in patients with chronic liver 
diseases such as PBC may rapidly worsen with signs and symptoms similar to drug 
induce liver injury (Kumar 2013) 
 Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin).  
 Seeking hepatology consultation, if the Investigator is not a hepatologist 
7.7. 
Criteria for Study Termination 
The Sponsor (Intercept Pharmaceuticals, Inc.) reserves the right to terminate the study at any 
time.  It is normal procedure to review the emerging clinical and safety data.  As a result of such 
a review or a recommendation by the Data Monitoring Committee (DMC), it may be necessary 
to stop the study before all patients have completed the study.  In addition, the Sponsor may 
terminate the study at an investigational site at any time (eg, Good Clinical Practice [GCP] 
noncompliance or poorly performing sites, as determined by the number of patients enrolled or 
the quality of the study data). 
The Investigator and/or Sponsor (or designee) must notify the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) of discontinuation of a site or the study and the 
reason for doing so. 
Investigators will be informed by the Sponsor as to when the final study visit is to be completed, 
and should then schedule all patients for the end of study (EOS) or end of treatment (EOT) Visit.  
8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Population 
This study will be conducted at approximately 35 international study sites with experience in 
treating patients with PBC with moderate to severe hepatic impairment defined as CP-B and 
CP-C.  Prospective patients will be identified primarily from the hospital and/or physician’s 
database of patients with PBC, or may be referred from other physicians.  Patients may self-refer 
to an Investigator if they become aware of the study through local, national, or international PBC 
patient societies, forums, or networks. 
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8.2. 
Patient Inclusion Criteria 
1. A definite or probable diagnosis of PBC (consistent with American Association for the 
Study of Liver Diseases [AASLD] and European Association for the Study of the Liver 
[EASL] Practice Guidelines [Lindor 2009, EASL 2009]), defined as having ≥2 of the 
following 3 diagnostic factors: 
 History of elevated ALP levels for at least 6 months 
 Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer 
(≤1:80), PBC-specific antibodies (anti-GP210 and/or anti-SP100) and/or 
antibodies against the major M2 components (PDC-E2, 2-oxo-glutaric acid 
dehydrogenase complex)  
 Liver biopsy consistent with PBC (collected at any time prior to Screening) 
2. Evidence of cirrhosis including at least one of the following: 
 Biopsy results consistent with PBC Stage 4  
 Liver stiffness as assessed by TE Value ≥16.9 kPa 
 Clinical evidence in the absence of acute liver failure consistent with cirrhosis 
including: gastroesophageal varices, ascites, radiological evidence of cirrhosis 
(nodular liver or enlargement of portal vein and splenomegaly) 
 Combined low platelet count (<140 000/mm3) with: 
 persistent decrease in serum albumin, or  
 elevation in prothrombin time /INR (not due to antithrombotic agent use), 
or 
 elevated bilirubin (2× ULN) 
3. Satisfy the criteria of the modified CP classification for hepatic impairment during 
Screening: 
 Moderate:  CP-B (Scores 7 to 9) or 
 Severe:  CP-C (Scores 10 to 12) 
4. MELD score of 6 to 24 at Screening 
5. Age ≥18 years 
6. Taking UDCA for at least 12 months (stable dose for ≥3 months) prior to Day 1, or 
unable to tolerate or unresponsive to UDCA (no UDCA for ≥3 months) 
7. Contraception:  Female patients must be postmenopausal, surgically sterile, or if 
premenopausal (and not surgically sterile), be prepared to use ≥1 effective method of 
contraception during the study and for 30 days after the end of treatment visit.  Effective 
methods of contraception are considered to be those listed below: 
 Barrier method, ie, (a) condom (male or female) with spermicide or 
(b) diaphragm with spermicide; or 
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 Intrauterine device; or 
 Vasectomy (partner); or 
 Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection); or 
 Abstinence, if in line with the preferred and usual lifestyle of the patient (where 
abstinence is defined as refraining from heterosexual intercourse)  
8. Must provide written informed consent and agree to comply with the study protocol. 
8.3. 
Patient Exclusion Criteria 
1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6) 
2. History of liver transplant or organ transplant  
3. History of alcohol or drug abuse within 12 months prior to Screening 
4. Current hepatic encephalopathy (as defined by a West Haven score of ≥2 [AASLD, 
EASL 2014]) 
5. History or presence of other concomitant liver diseases including: 
a. Hepatitis C virus infection and RNA positive 
b. Active hepatitis B infection; however, patients who have seroconverted (hepatitis B 
surface antigen and hepatitis B e antigen negative) may be included in this study after 
consultation with the Medical Monitor 
c. Primary sclerosing cholangitis 
d. Alcoholic liver disease 
e. Definite autoimmune liver disease or overlap hepatitis 
f. Gilbert’s Syndrome 
6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function 
prior to randomization 
7. Patients with history or presence of hepatorenal or hepatopulmonary syndrome 
8. Patients with significant active infection (ie spontaneous bacterial peritonitis) 
9. Patients with known or suspected hepatocellular carcinoma 
10. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
11. Participation in another investigational product, biologic, or medical device study within 
30 days prior to Screening.  Participation in a previous study of OCA is allowed with 
3 months washout prior to enrollment in this study 
12. Mental instability or incompetence, such that the validity of informed consent or ability 
to be compliant with the study is uncertain 
13. UDCA naïve (unless contraindicated) 
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8.4. 
Dose Adjustment, Interruption, and Withdrawal from 
Investigational Product or Study 
Investigational product may be temporarily decreased (eg, from 10 mg twice weekly to 5 mg 
twice weekly, or from 5 mg twice weekly to 5 mg once weekly) or temporarily or permanently 
stopped based on tolerability concerns.  Investigational product may be resumed at the 
maintenance dose upon resolution of gastroenteritis or worsening renal function or dehydration if 
there is no evidence of liver injury.  For rechallenge following all other dose interruptions (see 
Table 5), investigational product should be initiated at a lower dose and patients monitored more 
frequently with up-titration considered based on tolerability. 
Adjustments, interruptions, discontinuation, and any rechallenge of investigational product 
should be implemented per the criteria outlined in Table 5.  Patients that discontinue 
investigational product are expected to continue in the study (and follow the regular visit 
schedule, with the exception of PK sampling [trough PK may be required in the event of an AE 
consistent with hepatic injury or decompensation]) until the end of the study, but may withdraw 
consent at any time. 
Table 5: 
Criteria for Dose Adjustment, Interruption, Discontinuation, and 
Rechallenge 
DOSE ADJUSTMENT 
 
 
Criteria 
Action Taken with IP 
Adjustment 
New Onset Severe Pruritus 
Drug holiday or less 
frequent dosing 
Return to original dose regimen if tolerated 
DOSE INTERRUPTION 
 
 
Criteria 
Action Taken with IPa 
Rechallengeb 
If liver biochemistries indicative of 
suspected hepatic injury are identified as 
exceeding upper threshold criteria and 
require immediate interruption (see Part 
A of Table 3)c 
Interrupt immediately 
upon initial observation 
Patient may be rechallenged after a 
minimum of 30 days if fully resolved OR 
stable and approved by the Medical Monitor 
and Investigator. 
 
 
Other liver biochemistries indicative of 
suspected hepatic injury are outside 
upper threshold criteria upon repeat 
testing as defined in Part A of Table 3d 
Interrupt after 
confirmation by repeat 
testing 
Liver biochemistries indicative of 
potential hepatic decompensation in the 
absence of symptoms (see Part B of 
Table 3)e 
Closely monitor until 
normalization or 
stabilization. 
 
If values continue to 
increase relative to the 
baseline value, interrupt 
Clinical events indicative of hepatic 
decompensation (see Part B of Table 4) 
Closely monitor until 
normalization or 
stabilization 
The patient may be rechallenged after a 
minimum of 30 days if fully resolved OR 
stable and approved by the Medical Monitor 
and Investigator. 
 
IP should be re-initiated at a lower dose (or 
lower dose frequency) and titrated per 
Investigator discretion. 
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Gastroenteritis (established severe 
abdominal pain, vomiting, diarrhea for 
more than 4 days) 
Interrupt  
If no evidence of liver injury is detected, IP 
may be restarted at the same dose after 
resolution of intercurrent illness. 
Evidence of worsening of renal function 
or dehydration 
Interrupt  
DOSE DISCONTINUATION 
 
 
Criteria 
Action Taken with IP 
Rechallenge 
If INR increases ≥2.0 in absence of 
clinical symptoms criteria (unless due to 
vitamin K deficiency) f 
Discontinue / 
No Rechallenge 
Discontinue IP permanently and continue to 
return for scheduled study visits for safety 
follow-up.  
 
Continue to return for scheduled study visits 
for safety follow-up. Monitor closely for 
clinical outcomes according to protocol 
assessments. 
If total bilirubin thresholds (Part B of 
Table 3) are observed in the presence of 
clinical symptoms of cholestatic 
hepatitis or hepatic encephalopathyf 
Multi-Organ failure requiring 
hospitalization 
Liver transplantation 
Pregnancy 
Fully resolved = Return to baseline levels or return to within normal limits (WNL). IP = investigational product 
a If patient is unable to be evaluated promptly, study drug must be immediately interrupted. 
b Requires complete documentation of complete resolution or normal/baseline results based on laboratory 
parameters and symptoms.   
c Total bilirubin baseline ≤ULN and ≥3x baseline, baseline >ULN and ≥2x baseline, ALT or AST >3x baseline (and 
>ULN) 
d ALT or AST ≥2x baseline or electrolytes (sodium <130 mEq/L). 
e Total bilirubin baseline ≤ULN and 1.5 mg/dL increase from baseline OR baseline >ULN and 1.0 mg/dL increase 
from baseline; INR >0.3 increase from baseline 
f If INR increases ≥2.0 in the absence of clinical symptoms or if or total bilirubin thresholds OR an INR increase 
from baseline of ≥1.5 are observed in the presence of clinical symptoms of cholestatic hepatitis or hepatic 
encephalopathy. 
8.4.1. 
Other Reasons for Discontinuation of Study or Investigational Product  
The following events are considered appropriate reasons for a patient to discontinue 
investigational product; however, these patients are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
 Patient begins treatment with commercially available OCA. 
 The Investigator or Sponsor considers that it is advisable or in the best interest of the 
patient. 
 The occurrence of clinical or laboratory AEs considered by the Investigator to be 
clinically important safety concerns and related to study drug. 
 Withdrawal of consent  
 Consent may be fully withdrawn (in which case the patient discontinues both 
investigational product and study visits and procedures). 
 Consent may be modified to discontinue study visits but allow semi-annual 
telephone contact. 
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 Consent may be modified to discontinue study visits or semi-annual telephone 
contact but allow continued access to medical records to assess for suspected 
major adverse cardiovascular events (MACE) and liver-related clinical events. 
  Early termination procedures should be conducted if the patient withdraws 
consent (see Section 9.7.13). 
The Investigator is encouraged to contact the Sponsor prior to discontinuing a patient from 
treatment.  The Investigator must notify the Sponsor study monitor by telephone or email as soon 
as possible if any patient prematurely withdraws from the study. 
8.4.1.1. 
Withdrawal of Consent to Continue in the Study  
If the patient decides that it is in his/her best interest to discontinue from the study, he or she may 
withdraw consent.  It is fully understood that all patients volunteer for the study and that they 
may withdraw their consent to continue in the study at any time. 
Early termination procedures should be conducted if the patient withdraws consent (See 
Section 9.7.13). 
A reasonable effort must be made to determine the reason(s) for patient discontinuation.  This 
information and date must be recorded in the appropriate eCRF. 
8.4.1.2. 
Lost to Follow-Up 
Patients will be considered “lost to follow-up” only after documented attempts to reach the 
patient prove unsuccessful.  A reasonable effort (ie, 2 phone calls/messages, no response to 
registered letter) must be made to contact the patient and determine the reason(s) why a patient 
fails to return for a study visit or is lost to follow-up.  This information and date of contact must 
be recorded in the appropriate eCRF. 
8.4.2. 
Patient Discontinuation Notification 
The Investigator must notify the Sponsor as soon as possible if any patient prematurely 
discontinues from the study.  The date when the patient is withdrawn and the primary reason(s) 
for discontinuation must be recorded in the eCRF; additional information may be requested by 
the Sponsor to complete a discontinuation narrative.  This information must be documented in 
the eCRF. 
If a patient is withdrawn from the study early (regardless of the cause), all of the early 
termination (ET)/EOS evaluations are to be performed at the time of withdrawal, to the extent 
possible. 
9. 
TREATMENT OF PATIENTS 
9.1. 
Investigational Product Treatment Regimen 
The term investigational product refers to either OCA (provided as part of this clinical study) or 
placebo.   
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Two treatment groups will be evaluated:  OCA and placebo.  Investigational product will be 
administered orally.  Each dose will be made up of 1 tablet (ie, one OCA 5 mg tablet or one 
OCA 10 mg tablet, or matching placebo).   
Investigational product will be taken orally with water for the duration of the study.  Patients will 
be instructed to begin dosing on Day 1 and are to take investigational product at approximately 
the same time on dosing days.  Patients must be instructed to swallow the tablet whole; they must 
not chew, divide, or crush the tablet. 
At each study visit where the dose of investigational product is administered at the site, all 
assessments, except for the post-dose collection of blood samples for the PK assessment, must be 
completed before administration of investigational product. 
9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.2) 
will be used at the discretion of the usual care provider (or Investigator if also the usual care 
provider).  Relevant information about all concomitant medications (including prescribed, over 
the-counter, or herbal preparations) taken within 30 days of Screening and during the study must 
be recorded in the source documents and eCRF, as well as any dose or dose regimen changes that 
occur during the study.  Concomitant medications should be stable prior to Day 1. 
PBC Specific Therapy 
Investigators will be encouraged to follow guidelines for care based upon local and institutional 
practice patterns and any relevant published practice guidelines.  Throughout the course of the 
study, Investigators are expected to monitor patients’ PBC regimens and, if responsible for usual 
care, may adjust the regimen to achieve locally-appropriate treatment goals.  These goals will be 
individualized, with the understanding that currently applicable PBC guidelines may vary across 
different geographic regions. 
Ideally, patients should generally remain on the baseline PBC therapies throughout the course of 
the study, unless the baseline PBC therapy is no longer considered clinically appropriate by the 
Investigator.  In addition, patients should be reminded to keep taking their blinded 
investigational product. 
9.2.1. 
Drug Interactions 
Bile acid sequestrants (BAS, including cholestyramine and its derivatives, colestipol, 
colesevelam, or other sequestrants) or aluminum hydroxide- or smectite-containing antacids 
should not be taken within 4 hours of taking investigational product (and UDCA if applicable), 
ie, BAS should be administered at minimum 4 hours before or 4 hours after investigational 
product administration. 
OCA taken concomitantly with warfarin may result in decreased INR levels; therefore, INR 
should be monitored and the dosage of warfarin adjusted, as needed during treatment with OCA 
and after cessation of OCA, to maintain the target INR range.  
The effect of OCA on drug metabolizing enzymes has been evaluated in both in vitro and clinical 
studies.  The PK profile of caffeine, a sensitive CYP1A2 substrate probe, showed weak effect of 
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OCA on CYP1A2.  Based on these results, OCA may increase the exposure of narrow 
therapeutic index drugs that are substrates for CYP1A2, such as theophylline and tizanidine. 
Information related to additional drug-drug interaction (DDI) studies is available in the current 
version of the IB.  The aforementioned sections of the IB should be referred to during the course 
of the study, and are accessible to Investigators to help facilitate the assessment of potential 
DDIs with OCA that may be observed in study patients. 
9.2.2. 
Prohibited Medications 
Commercial OCA therapy (if available) is prohibited while on investigational product, and if 
prescribed during the course of the study, the Investigator should be cognizant of the possibility 
of double dosing.  Patients who initiate with commercial OCA therapy must discontinue 
investigational product and are expected to continue through the end of the study (see 
Section 8.4.1).   
9.3. 
Treatment Compliance 
The Investigator should assess the patient’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Patients should be instructed to retain all bottles of investigational product, even if empty, and to 
return them to the Investigator at the indicated visits (Table 1).  The Investigator or designee 
should perform investigational product accountability (ie, count of returned tablets) and, if 
applicable, follow-up with the patient to retrieve any investigational product bottles that have not 
been returned.  
If the Investigator has concerns about a patient’s dosing compliance, he or she should discuss 
this with the patient, assess the reasons for noncompliance and the likelihood that the patient will 
remain noncompliant, and notify the Sponsor accordingly.   
9.4. 
Randomization and Blinding 
9.4.1. 
Methods of Assigning Patients to Treatment Groups 
This study will be conducted in a double-blind, placebo-controlled manner.  Enrolled patients 
who meet all eligibility requirements will be randomized in a 1:1 ratio to 1 of 2 treatment groups:  
placebo or OCA based on a predefined randomization code (generated by Sponsor or designee) 
using an interactive web response system (IWRS), which the Sponsor intends will serve as a 
computer-based patient registration system at Screening and Day 1.   
Randomization will be stratified by CP class (CP-B or CP-C).  Baseline MELD scores will be 
monitored on an ongoing basis to ensure adequate distribution of MELD scores.  The IWRS will 
serve as the investigational product inventory and management system and may be integrated 
with the study database.  
The Investigator or designee will be required to register the patient in the IWRS and may be 
prompted to provide patient data necessary to properly randomize and allocate the patient to 
treatment.  A randomization number will be assigned and investigational product (OCA or 
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placebo) dispensing information will be provided (eg, bottle numbers allocated) while 
maintaining the study blind.   
9.4.2. 
Blinding 
The Sponsor, patients, Investigator, and study site staff will be blinded to the patient’s treatment 
allocation during the patient’s participation in the double-blind phase of the study.     
9.4.3. 
Emergency Unblinding Procedures 
Treatment assignment for individual patients will be made available to the Investigator for 
medical emergency use only (such as unblinding which is necessary in order to treat a serious 
adverse event [SAE] through the IWRS system).  When possible, the Medical Monitor should be 
consulted in the event that a medical emergency necessitates unblinding (ie, in situations where 
knowledge of the blinded treatment assignment is necessary for further medical management of 
the patient).  If it is not reasonable to inform the Medical Monitor in advance of the unblinding, 
the Investigator must promptly document in the patient’s record the rationale for unblinding and 
should subsequently contact the Medical Monitor to explain any premature unblinding of 
treatment assignment.  Procedures for unblinding a patient’s treatment will be provided 
separately to the Investigator.  Similarly, if the Medical Monitor breaks the blind for an 
individual patient for the purpose of evaluating an emergent safety issue, the Medical Monitor 
will document within study documentation the rationale, circumstances, and the person or 
persons being informed about the unblinding. 
The DMC will have access to the IWRS and will be able to unblind individual patients.  Refer to 
Section 15.8 for further details regarding DMC access to blinded and unblinded data.  The DMC 
will document details about any unblinded patient data reviews in the closed session DMC 
minutes, which will be made available to the Sponsor only after the database is locked and the 
study is unblinded.  Cases of premature unblinding, as noted above, will also be reviewed by the 
DMC.  
Access to treatment assignments will also be made available to the designated Intercept staff 
responsible for expedited safety reporting of suspected unexpected serious adverse reactions 
(SUSARs) to the Regulatory Authorities. 
9.5. 
Assignment of Site and Patient Numbers 
9.5.1. 
Site Numbers 
Each study site selected to participate in this study will be assigned a site number by the Sponsor.  
The site number will be used to categorize patient data and to identify the site and/or Investigator 
within study documents.  This number will be recorded in the eCRF. 
9.5.2. 
Patient Numbers 
Patients are assigned using a unique 10-character identifier (AAA-BBBCCC), independent of the 
randomization number. The first 3 digits represent the last 3 digits of the protocol number, 
followed by a hyphen (AAA-). The next 3 digits represent the site number (BBB). The last 
3 digits represent a unique screening number that is assigned in sequential order at each site 
starting with 001 (CCC). 
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9.6. 
Restrictions 
Participation in another investigational product, biologic, or medical device study within 30 days 
prior to Screening and during the course of the study is prohibited.  Previous exposure to OCA 
(as a study participant or received commercial OCA therapy) is allowed provided patients 
haven’t taken OCA within 3 months prior to enrollment in this study. 
9.6.1. 
Fasting Requirement at Study Visits 
All patients must have been fasting for at least 8 hours prior to their Screening Visit and all 
subsequent study visits, as all analytes will be assayed in fasting blood or plasma samples.  
Water is permitted during the fasting period. 
9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visit windows are specified in the Schedule of Study Procedures (Table 1).  Visits should be 
based on Day 1 (not on the prior visit) unless stated otherwise.  For example, Week 6 should 
ideally occur 6 calendar weeks (± 7 days) following Day 1.   
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk, and benefit of the 
study to the patient and will provide him/her with a copy of the informed consent form (ICF).  
The patient will be given sufficient time to consider the study before deciding whether or not to 
participate.  The patient will be informed that participation is voluntary and that her/his future 
medical treatment will not be compromised by participation in the study and that he or she can 
withdraw from the study at any time.  The patient must be willing and able to provide written 
informed consent (on hard copies) before entering the study.  The Investigator or a medically 
qualified designee is responsible for administering and documenting the written informed 
consent of the patient.  The patient will be given a copy of the patient information sheet (PIS) 
and his/her signed and dated informed consent form (ICF).   
9.7.3. 
Assessing Cirrhosis 
Acceptable methods of confirming (via medical history) or assessing cirrhosis for purposes of 
the study are defined as a patient who has documented evidence or presence of one or more of 
the following cirrhosis indicators: 
 Biopsy results consistent with PBC Stage 4 (Ludwig 1978)   
 Liver Stiffness as assessed by TE Value ≥16.9 kPa (Corpechot 2012) 
 The presence of any of the following (unless exclusionary per Section 8.3) in the 
absence of acute liver failure: 
 Gastroesophageal varices 
 Ascites 
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 Radiological evidence of cirrhosis (nodular liver or enlargement of portal vein 
and splenomegaly) 
 Combined low platelet count (<140 000/mm3) with: 
 Persistent decrease in serum albumin, or  
 Elevation in prothrombin time /INR (not due to antithrombotic agent use), or 
 Elevated bilirubin (2× ULN) 
9.7.4. 
Screening Procedures (14 days to 28 days prior to Day 1) 
Informed consent must be obtained from the patient before performing any study-related 
procedures, including Screening procedures.  The Screening Visit assessments must be 
performed ≥14 days but less than 28 days prior to Day 1 to determine whether the patient meets 
all the inclusion criteria and none of the exclusion criteria.  Patients who do not fulfill all 
eligibility criteria will not be enrolled in the study.  Patients may be rescreened after 2 months 
have elapsed from the date of their most recent screening visit procedure; however, all Screening 
procedures (including obtaining informed consent) should be repeated and a new three-digit 
Screening number assigned.   
Screening Visit procedures are as follows: 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits. 
 Collect medical history. 
 Collect PBC history.  
 Verify inclusion and exclusion criteria for eligibility. 
 Perform a physical examination, including height, smoking and alcohol consumption 
history, and current habits for both.  
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record any pretreatment-emergent AEs. 
 Record prior (if within 30 days of Screening) and current concomitant medications. 
 Perform a standard 12-lead electrocardiogram (ECG). 
 Perform assessments for calculation of CP Score (Section 14.1.1) 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Virology Screen (HCV and HBsAg) 
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 Obtain urine sample for urinalysis  
 Perform a urine-based beta human chorionic gonadotropin (β-hCG) pregnancy test in 
females of childbearing potential.  
 Instruct the patient to fast overnight (at least 8 hours) before the next visit (water is 
permitted). 
 Record the visit in IWRS.  
 Perform an ultrasound for HCC surveillance and evaluation of gallbladder status 
(if equipment is unavailable, sites should make every attempt to use available 
community referral sites).  If an ultrasound has been done within 12 months of 
Screening, and a report/adequate data are available, a pretreatment ultrasound at 
Screening is not required.  If the ultrasound cannot be performed at Screening 
(eg, device/technician unavailability, scheduling issues, etc), the procedure may be 
completed anytime within the screening visit window or on Day 1.  Results from the 
screening ultrasound should be reviewed to assess possible exclusion criteria prior to 
randomization. 
9.7.5. 
Day 1 Procedures (Randomization) 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits. 
 Review inclusion and exclusion criteria for eligibility. 
 Perform a physical examination.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant heath care professional (HCP) or non-HCP related office 
visits that have occurred since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record any pretreatment-emergent AEs. 
 Review and record prior concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (Section 13.2.7). 
 Randomize the patient only if s/he meets all inclusion criteria and no exclusion 
criteria. 
 Record the visit in IWRS and dispense investigational product 
 Instruct the patient to begin dosing on the day of the Day 1 Visit.   
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 Obtain urine sample for urinalysis  
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Markers of fibrosis (ELF [HA, P3NP, and TIMP 1]) 
 Fasting PK assessment 
 Bile Acid/C4/FGF-19  
 Perform TE using the Fibroscan® TE device.  If the TE cannot be performed on Day 1 
(eg, device/technician unavailability, scheduling issues, TE data is needed to inform 
cirrhosis assessment, etc.), the procedure may be completed within the Day 1 Visit 
window, (if data is needed for cirrhosis assessment) or as close as possible to the Day 
1 Visit, preferably, after patient eligibility has been confirmed.  Instruct the patient to 
take Day 1 dose on the day of this visit. 
 If ultrasound for gallbladder assessment was not performed at Screening and the 
historic ultrasound is >12 months from Day 1, perform ultrasound. 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to the visit 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.6. 
Week 3 and Week 42 Safety Visit Procedures 
Preferably, the patient will come in to the clinic for this visit.  Alternatively, the site will 
telephone the patient for assessments and a home health nurse will visit to draw safety labs. 
 Verify that patient is dosing as directed. 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits. 
 Review and record prior concomitant medications. 
 Assess and record AEs. 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
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 Assess investigational product compliance, perform investigational product 
accountability. 
 For Week 42 Only:  Assess for dose titration, if eligible. (Refer to Section 7.3) 
 For Week 42 Only:  Dispense investigational product only if there is dose increase 
or as needed.  No new investigational product bottles will be dispensed if there is only 
change in dosing frequency of the same dose level.  Patients are expected to use up 
each investigational product bottle before a new bottle will be dispensed 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Schedule the next visit (Week 6 or Week 48), reiterate dosing instructions, and advise 
the patient: 
For Week 3 Only:   
 Week 6 Visit should occur 3, 4, or 5 days after taking the Week 6 dose, eg, if 
the Week 6 dose is taken on a Sunday, the patient should come in for the Week 6 
Visit within the following Wednesday and Friday (Figure 3). 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to the visit 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
For Week 42 Only: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.7. 
Week 6 Procedures 
Week 6 Visit should occur 3, 4, or 5 days after taking the Week 6 dose, eg, if the Week 6 dose is 
taken on a Sunday, the patient should come in for the Week 6 Visit within the following 
Wednesday and Friday (Figure 3). 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
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 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform a physical examination.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.7). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Bile Acids/C4/FGF-19 
 Fasting PK assessment 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.8. 
Week 9 through Week 48 (Safety Contact) 
Patients should be contacted by telephone/email at Week 9 and every 3 weeks afterward to 
Week 48. 
 Contact patient by phone/email. 
 Review and record prior concomitant medications. 
 Assess and record AEs. 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess investigational product compliance, perform investigational product 
accountability. 
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9.7.9. 
Week 12, Week 24, Week 36 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Perform a physical examination.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.7). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible. (Refer to Section 7.3) 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed.   
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation 
 Markers of fibrosis (ELF [HA, P3NP, and TIMP 1])  
 Bile Acid/C4/FGF-19  
 Fasting PK assessment (Week 36 only) 
 Perform TE using the Fibroscan® TE device.  If the TE cannot be performed on visit 
day (eg, device/technician unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be completed within the visit 
window (if data is needed for cirrhosis assessment) or as close as possible to the visit. 
 Perform an ultrasound for HCC surveillance at Week 24 ONLY (if equipment is 
unavailable, sites should make every attempt to use available community referral 
sites). 
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 Serial PK assessment at Week 12 and 24 ONLY (not done at Week 36); the 
following procedures will be conducted in all patients: 
 30 minutes prior to dosing:  collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hour postdose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at:  1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post dose 
Note:  Patients should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until after the 1-hour sample is 
collected.  A meal replacement drink will be provided following collection of the 1-, 4-, 
and 7-hour PK sample.  No other food or drink (water is permitted) will be allowed until 
after the 9-hour sample collection (see Figure 4).  The 24-hour post-dose sample can be 
obtained upon return to the clinic or by a home health care designee. 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to visits; s/he will dose at the clinic 
for Week 18 and Week 30 visits (if this is in compliance with the established 
dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.10. 
Week 18 and Week 30 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF. 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Perform a physical examination.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
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 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.7). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3). 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed.   
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Bile Acid/C4/FGF-19  
 Serial PK assessment; the following procedures will be conducted in all patients: 
 30 minutes prior to dosing: collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hour postdose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours postdose 
Note:  Patients should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until after the 1-hour sample is 
collected.  A meal replacement drink will be provided following collection of the 1-, 4-, 
and 7-hour PK sample.  No other food or drink (water is permitted) will be allowed until 
after the 9-hour sample collection (see Figure 4).  The 24-hour post-dose sample can be 
obtained upon return to the clinic or by a home health care designee. 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to both visits; s/he will dose at the 
clinic on Week 24 (if this is in compliance with the established dosing frequency), 
and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
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9.7.11. 
Week 48 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Perform a physical examination, including smoking and alcohol consumption history, 
and current habits for both.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform ECG. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.7). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3). 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed. 
 Perform urinalysis  
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Markers of fibrosis (ELF [HA, P3NP, and TIMP 1]) 
 Bile Acids/C4/FGF-19 
 Serial PK assessment; the following procedures will be conducted in all patients: 
 30 minutes prior to dosing: collect predose blood sample 
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 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.   
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hour post dose blood draw, administer meal replacement 
(to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post dose 
Note:  Patients should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until after the 1-hour sample is 
collected.  A meal replacement drink will be provided following collection of the 1-, 4-, 
and 7-hour PK sample.  No other food or drink (water is permitted) will be allowed until 
after the 9-hour sample collection (see Figure 4).  The 24-hour post-dose sample can be 
obtained upon return to the clinic or by a home health care designee. 
 Perform TE using the Fibroscan® TE device.  If the TE cannot be performed on visit 
day (eg, device/technician unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be completed within the visit 
window (if data are needed for cirrhosis assessment) or as close as possible to the 
visit. 
 Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to the visit, and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.12. 
Every 3 Months after Week 48  
Quarterly 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Perform a physical examination, including height, smoking and alcohol consumption 
history, and current habits for both.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
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 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.7). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3 ). 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed. 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to the visit, and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
Patients will complete a TE/ELF (HA, P3NP and TIMP 1) and ultrasound (for HCC 
surveillance) assessment, every 6 months (±2 weeks) after Week 48.  
ECG and urinalysis will be done yearly (±2 weeks) after Week 48.    
9.7.13. 
End of Study/Early Termination/End of Treatment Procedures for Patients That 
Withdraw from Investigational Product or Withdraw Consent 
Patients who discontinue investigational product before Week 48 are expected to continue in the 
study until the end of the study (EOS [when patient terminates the study]) or at the discretion of 
the Sponsor.     
EOT (when patient discontinues investigational product)/ET procedures will be required 
whenever patients discontinue treatment with investigational product (Table 1, Section 9.7.11).  
The EOT/ET Visit (Table 1) and procedures listed below (Table 6) must be performed as close 
as possible to the patient’s last dose of investigational product.  When a patient discontinues or 
interrupts investigational product and continues with regularly scheduled study visits, the EOS 
Visit will be completed as the patient’s final study visit.  The actual investigational product 
discontinuation scenario (Table 6) will determine the sequence of the EOT/ET and EOS Visits 
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and procedures.  In some cases, the EOT/ET Visit and procedures will precede the EOS Visit; in 
others, the EOT/ET and EOS Visits will be combined and performed as close as possible to the 
patient’s last dose of investigational product.  EOT and EOS Visits are encouraged but at no time 
will a missed EOT or EOS visit be considered a protocol deviation. 
When a patient ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (ET) (withdrawal of consent) or discontinuation, an 
EOT/EOS Visit must be performed as near as possible to her/his last dose of investigational 
product and the procedures listed in Table 1 performed.  The purpose of this visit is to conduct 
complete and/or final assessments on or as near as possible to the final day of dosing.  In some 
cases, the patient may discontinue on the day of a scheduled study visit.  In these cases, 
EOT/EOS Visit procedures should be performed in place of the scheduled study visit procedures.  
The data will be recorded as EOT/ET and EOS procedures in the eCRF. 
Table 6: 
Early Discontinuation Scenarios 
 
Investigational 
Product 
Consent 
Study Visit 
Status 
EOT Visita 
EOS 
Visita 
Early 
Termination 
Discontinued 
Withdrawn 
No additional 
visits except 
EOT/EOS 
Combined visit, completed as 
close as possible to last dose of 
investigational product. 
Treatment 
Discontinuationb 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as close as 
possible to last dose 
of investigational 
product. 
Complete 
at final 
study 
visit. 
Discontinued 
Record review 
only 
Record review 
only 
Combined visit, completed as 
close as possible to last dose of 
investigational product. 
Sponsor 
Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit, completed as 
close as possible to last dose of 
investigational product. 
Pregnancy 
Discontinued 
Complete per the above scenarios - Early Termination or Treatment 
Discontinuation 
Lost to 
Follow-Up 
Discontinued 
LTF 
None 
Unable to complete due to LTF 
status 
EOS = end of study; EOT = end of treatment; LTF = lost to follow-up 
a Refer to Section 7.1.2, Schedule of Study Procedures for all procedures and evaluations required at the EOS and 
EOT Visits.  
b Includes initiation of commercially available OCA. 
9.7.14. 
Unscheduled Safety Visit 
The Investigator may schedule an at-clinic Unscheduled/Safety Visit at any time if clinically 
warranted.  Unscheduled and/or repeat assessments, including additional laboratory tests or 
investigations, may be conducted.   
As appropriate, the Medical Monitor should be contacted. 
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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
The investigational product is a white, round, film coated tablet containing OCA 5 mg or 10 mg 
or matching placebo.  The tablets contain the following inactive ingredients:  microcrystalline 
cellulose, sodium starch glycolate, and magnesium stearate. 
10.2. 
Investigational Product Packaging and Labeling 
The packaging and labeling of investigational product supplies will be performed according to 
Good Manufacturing Practice standards by a designated qualified vendor.  All investigational 
product will be provided as tablets for oral administration and provided in high density 
polyethylene bottles with heat induction seals and child resistant closures.  The bottle packaging 
will not reveal any information about the treatment dose contained in the bottle.  Multiple bottles 
may be dispensed to the patient at each visit to provide enough tablets for dosing until the next 
visit. 
The designated investigational product packaging/distribution vendor will also be responsible for 
the distribution of the investigational product to the Investigator. 
10.3. 
Investigational Product Storage 
All OCA tablet strengths provided to clinical study sites in support of clinical studies are to be 
shipped and stored at 15°C to 25°C.  Temperature excursions within the range of 2°C and 30°C 
for no more than a 6-month period are acceptable, and the OCA tablet continues to be suitable 
for use in clinical studies.  Additionally, temperature excursions within the range -20°C to 40°C 
for no more than 7 days are acceptable, and the OCA tablet continues to be suitable for use in 
clinical studies.  
10.4. 
Investigational Product Administration 
Refer to Section 9.1. 
10.5. 
Investigational Product Accountability and Disposal 
The Sponsor’s representative will send investigational product to the study site under appropriate 
storage conditions.  All shipments of investigational product should be unpacked and the 
contents reviewed immediately upon receipt.  If it is not possible to verify the contents 
immediately, they must be stored under the appropriate storage conditions until verification of 
the contents is possible (ideally, within 1 business day from receipt).  The pharmacist or designee 
should verify the investigational product against the shipment documentation.  The pharmacist or 
designee should contact the Sponsor immediately to report any concerns regarding the shipment.  
All investigational product will be provided for use only in this study and is not to be used for 
any other purpose.  The Investigator or designee will maintain a full record of investigational 
product accountability, including records of individual patient dispensing and final return or 
disposition (as directed by the Sponsor).  
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The study monitor, also known as the Clinical Research Associate (CRA), will review 
accountability records against investigational product dispensed and that remaining in stock, 
during on site monitoring visits and when the study is completed, or if it is prematurely 
terminated.  The CRA will retrieve documentation detailing and confirming the return or 
destruction of the investigational product.  If the investigational product is to be returned to the 
Sponsor’s vendor for destruction, the CRA will also prepare the investigational product for 
shipment. 
11. 
OVERVIEW OF ASSESSMENTS 
The assessments supporting the objectives for the study are in Table 7: 
Table 7: 
Table of Assessments 
Primary Objectives 
Assessments 
PK parameters 
OCA and its conjugates glyco-OCA and tauro-OCA, and 
metabolite OCA glucuronide 
Safety and tolerability  
SAEs and TEAEs, physical exam, ECG, vital signs, 
clinical laboratory assessments, discontinuations, pruritus, 
and fatigue 
Secondary Objectives 
Assessments 
Changes in risk scores 
Changes in MELD and in CP Scores and components of 
the CP score and MELD score 
Changes in liver biochemistry and hepatobiliary 
damage  
Total and direct bilirubin, ALP, ALT, AST, GGT, INR, 
creatinine, albumin, platelets 
PD parameters 
FGF-19, C4, and plasma bile acids 
Additional Objectives 
Assessments 
Noninvasive measurements of liver fibrosis, liver 
stiffness and cirrhosis 
TE/ELF (HA, P3NP, and TIMP-1) 
PK/PD relationship 
PK parameters compared to PD parameters and safety and 
tolerability assessments (above) 
Patient-reported outcomes 
Pruritus VAS, PBC-40, EQ-5D-5L, CLDQ 
Clinical events 
Death (all-cause and liver-related), liver transplant, MELD 
score ≥15 (for patients with MELD ≤12 at baseline), 
hospitalization for new onset or recurrence of: variceal 
bleed, hepatic encephalopathy, spontaneous bacterial 
peritonitis, uncontrolled ascites, and HCC. 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
C4 = 7α-hydroxy-4-cholesten-3-one; CLDQ = Chronic Liver Disease Questionnaire; CP = Child-Pugh; ECG = 
electrocardiogram; ELF = enhanced liver fibrosis;  
FGF-19 = fibroblast growth factor-19; GGT = gamma-glutamyl transferase; HA = hyaluronic acid;  
INR = international normalized ratio; MELD = Model End Stage Liver Disease; OCA = obeticholic acid; P3NP = 
procollagen 3 N-terminal peptide; PBC = Primary Biliary Cholangitis;  
PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event; TE = Transient Elastography;  
TEAE = treatment emergent adverse events; TIMP-1 = tissue inhibitor of metalloproteinase 1; VAS = visual 
analog scale 
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12. 
CLINICAL PHARMACOKINETIC ASSESSMENTS 
Pharmacokinetic analyses will be based on the PK population (Section 15.1).  Patients in the PK 
Population with at least one PD assessment after dosing will be included in the combined PK/PD 
analyses.   
12.1. 
Pharmacokinetic Blood Sampling 
Serial and fasting PK assessments will be performed in all patients participating in the study.   
At Day 1, and Weeks 6, 12, 18, 24, 30, 36, and 48, patients will provide fasted blood samples for 
measurement of OCA and its conjugates, glyco-OCA and tauro-OCA, and metabolite OCA 
glucuronide 30 minutes before administration of investigational product (Table 8).  Patients will 
then receive a dose of investigational product with approximately 240 mL of water.   
Week 6 Visit should occur 3, 4, or 5 days after the Week 6 dose (eg, if the Week 6 dose of 
investigational product is taken on a Sunday, the patient should come in for the Week 6 Visit 
between Wednesday and Friday [Figure 3]).   
During the treatment period: 
 Pharmacokinetic fasting samples will be obtained from all patients at Day 1, and 
Weeks 6, 12, 18, 24, 30, 36, and 48 prior to dose administration in accordance with 
Figure 4. 
 Serial PK assessments will be performed in all patients at Weeks 12, 18, 24, 30, and 48.   
Figure 3: 
Week 6 Sampling Schedule 
 
IP = investigational product; PK = pharmacokinetic 
At Weeks 12, 18, 24, 30, and 48, serial PK blood samples will be obtained at 0.5, 0.75, 1, 1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours postdose (Figure 4) for all patients.  The patient will be given 
the option to return to the clinic the following morning for the 24-hour postdose sample or 
samples can be obtained by a home health care designee.  The home health care agency must be 
advised one week in advance of the appointment.   
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Figure 4: 
Pharmacokinetic Sampling Schedule 
 
h = hour; IP = investigational product; PK = pharmacokinetic  
Patients should not drink additional water for 1 hour after taking the dose of investigational 
product and will remain fasted until after the 1-hour sample is collected.  A meal replacement 
drink will be provided following collection of the 1-, 4-, and 7-hour PK sample.  The nutritional 
information of the meal replacement drink should be submitted to and approved by the Sponsor 
in advance.  No other food or drink (water is permitted) will be allowed until after the 9-hour 
sample collection. 
Table 8: 
Acceptable Windows for Pharmacokinetic Sample Collection 
Nominal Sampling Time 
Acceptable Sampling Window 
Before administration of investigational product 
(predose or fasting) 
Within 30 minutes before dosing 
0.5 to 1.5 hours after investigational product 
± 10 minutes 
2 to 2.5 hours after investigational product 
± 20 minutes 
3 to 24 hours after investigational product 
± 30 minutes 
12.2. 
Processing and Handling of Pharmacokinetic Samples 
Whole blood will be collected at each scheduled sample timepoint.  Detailed procedures for the 
collection of blood samples including further processing into plasma will be provided in a 
separate laboratory manual.  The storage and shipment procedures for subsequent bioanalysis, 
will be provided to the investigational site and home health care company in a separate document 
before the study is initiated. 
12.3. 
Bioanalysis 
Plasma concentrations of OCA and its conjugates, glyco-OCA and tauro-OCA, and metabolite 
OCA glucuronide will be determined using a validated liquid-chromatography mass 
spectrometry/mass spectrometry (LC/MS/MS) method.  A detailed description of validation 
information and results from the bioanalytical assay will be provided in separate reports.  These 
samples may be used for evaluation of metabolites of OCA or other concomitant medication, for 
further evaluation of the bioanalytical method, and for analyses that provide information on the 
metabolic pathways used or impacted by OCA. 
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13. 
ASSESSMENT OF SAFETY 
13.1. 
Adverse Events and Serious Adverse Events 
13.1.1. 
Definitions of Adverse Events 
13.1.1.1. Adverse Event  
AEs are defined as any untoward medical occurrence associated with the use of the 
investigational product in humans, whether or not considered related to investigational product.  
An AE, also referred to as an adverse experience, can be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom, or disease temporally associated with any use of 
the investigational product, without any judgment about causality and irrespective of route of 
administration, formulation, or dose, including an overdose.   
AEs include, but are not limited to: (1) a worsening or change in nature, severity, or frequency of 
condition(s) present at the start of the study; (2) patient deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction.  For reporting purposes, pregnancy is not 
considered an AE.  
Patients should be questioned about AEs in a general way, without leading the patient or asking 
about the occurrence of any specific symptom.  The Investigator should attempt to establish a 
diagnosis of the event based on signs, symptoms, and/or other clinical information.  The 
diagnosis and not the individual signs/symptoms should be documented as the AE.  For example, 
if the underlying disease process is a stroke, it would not be appropriate to record the AE by 
describing the symptoms “sudden numbness, dizziness, and difficulty speaking.”  The AE 
medical term of “stroke or cerebrovascular accident” should be recorded as it more accurately 
describes the AE. 
Patients should be instructed to contact the site promptly upon awareness if they develop signs 
and symptoms of potential hepatic decompensation such as:  pale-colored stools, urine color 
from pale to deep amber [dark], nausea, vomiting, abdominal pain, diarrhea, weight loss, fever 
and chills, fatigue, weakness, loss of appetite, confusion, swelling of the legs or abdomen, 
yellowing of the skin or the whites of eyes, and bruising easily. 
13.1.1.2. Serious Adverse Event  
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
 Death 
 Is immediately life threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
 Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
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Events not considered to be SAEs are hospitalizations for: 
 Routine monitoring of the studied indication and not associated with any deterioration 
in condition or AE; 
 Elective treatment for a pre-existing condition that did not worsen; 
 Respite care or observation when there is no AE associated with the hospitalization. 
13.1.1.3. Treatment-Emergent Adverse Event 
A treatment-emergent AE (TEAE) is any event not present before the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
13.1.1.4. Adverse Events of Special Interest  
The following decompensation events are adverse events of special interest; a subset of these are 
also captured as additional efficacy assessments (see Section 14.2.3).   
 Variceal bleeding or recurrent variceal bleeding documented by endoscopy OR 
patient presenting with anemia or melena (hemoglobin drop ≥2 g/dL) and found to 
have varices documented by endoscopy, irrespective of hospitalization or requirement 
of blood transfusion.  
 Gastrointestinal bleeding as a result of gastric or duodenal varices verified by 
endoscopy 
 Hepatic encephalopathy, Grade ≥2 
 New onset ascites requiring treatment 
 Worsening of ascites (requiring increase in drug therapy or requirement of surgical 
procedure such as paracentesis or shunt placement) 
 Refractory ascites -unresponsive to medications, and patient is not a candidate for 
TIPS or shunt and requires large volume paracentesis 
 Hyponatremia (Na ≤125 mEq/L) secondary to ascites 
 Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis- by cell 
count/chemistry) 
 Hepatorenal syndrome Type 1 and Type 2 and Acute Kidney Injury (AKI) 
 Liver failure defined as worsening of liver synthetic function that is persistently worse 
relative to baseline and/or progressive over time: 
 Hepato-pulmonary syndrome 
 Porto-pulmonary syndrome 
 Liver Transplant 
 Increase in MELD scores by 3 points relative to baseline, persistent over time and 
unrelated to vitamin K deficiency related increase in INR 
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 Any liver related event that requires hospitalization and treatment 
13.1.2. 
Relationship to Investigational Product 
The Investigator will document her/his opinion of the relationship of the AE to treatment with 
the investigational product using the criteria outlined in Table 9.  An AE for which there is a 
“reasonable possibility” that the investigational product caused the AE is otherwise referred to as 
suspected adverse reaction (SAR).  “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the investigational product and the AE.   
If the relationship between the AE/SAE and the investigational product is determined to be 
“definite,” “probable,” or “possible” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 
Table 9: 
Relationship of Adverse Events to Investigational Product 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product or in which the investigational product level has been established in 
body fluids or tissue; that follows a known or expected response pattern to the suspected 
investigational product; and that is confirmed by improvement on stopping or reducing the 
dosage of the investigational product, and reappearance of the reaction on repeated exposure. 
Probable 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product; that follows a known or expected response pattern to the suspected 
investigational product; that is confirmed by stopping or reducing the dosage of the 
investigational product; and that could not be reasonably explained by the known 
characteristics of the patient’s clinical state. 
Possible 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product; that follows a known or expected response pattern to the suspected 
investigational product; but that could readily be produced by a number of other factors. 
Unlikely 
An event that does not follow a reasonable temporal sequence from administration of the 
investigational product; that does not follow a known or suspected response pattern to the 
suspected investigational product; and that could reasonably be explained by known 
characteristics of the patient’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
13.1.3. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 10, must be entered on the AE eCRF.  It should be noted that the term 
“severe” used to grade intensity is not synonymous with the term “serious.”  The assessment of 
severity is made regardless of investigational product relationship or of the seriousness of the 
AE. 
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Table 10: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Causing no limitation of usual activities; the patient may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the patient may experience annoying 
discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the patient may experience intolerable 
discomfort or pain. 
13.1.4. 
Reporting of Adverse Events and Serious Adverse Events 
13.1.4.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the patient 
fully completes her/his study participation. 
All AEs, whether believed by the Investigator to be related or unrelated to the investigational 
product, must be documented in the patient’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product.  Redacted medical record source documentation will be requested for all 
SAEs and emergency room visits. 
In addition, the Investigator should contact the study Medical Monitor upon awareness when any 
signs or symptoms of hepatic decompensation are observed in any patient. 
13.1.4.2. Reporting of Serious Adverse Events 
In agreeing to the provisions of this protocol, the Investigator accepts all legal responsibilities for 
immediate reporting of SAEs to the Sponsor.  Immediate reporting implies within 24 hours of 
becoming aware of the occurrence of an SAE. 
All SAEs must be reported to the Sponsor (including suspected liver-related clinical outcome 
events that qualify as serious).  SAEs are reported by entering the SAE data into the study 
specific EDC system.  Entering the SAE data into the EDC system will automatically notify the 
Sponsor of the event.  In the event that the EDC system is inaccessible, an SAE may reported by: 
 E-mail to the SAE email address:  
 
 Fax using a paper SAE report form:  
 
If an SAE is reported by fax, an SAE Report form must also be completed in the EDC system as 
soon as the EDC system is accessible.  At a minimum, the following information should be 
provided at the time of the initial report:   
 Patient number  
 Event term  
 At least 1 criterion classifying the event as serious  
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 Name and title of the reporting individual  
 Causal relationship to the investigational product  
The Investigator will assess whether the event is causally related to the investigational product.  
The Sponsor will also assess whether the event is causally related to the investigational product, 
in addition to assessing the overall safety profile of the investigational product.  The Sponsor will 
notify the appropriate regulatory agencies as well as all participating Investigators of Safety 
Reports/Expedited Safety Reports that occur during the study within the time frames required by 
each regulatory agency.  
Following the initial report, any additional information obtained by the Investigator about the 
SAE must be reported promptly to the Sponsor in the same manner as described above for the 
initial SAE report.  Any supporting source documentation should be faxed to 
 or 
emailed to 
 as soon as possible.   
The Investigator is responsible for submitting information on Safety Reports/Expedited Safety 
Reports received from the Sponsor to her/his local IRB/IEC, as directed by the local country 
requirements.  Documentation of the submissions to IRBs/IEC s must be retained in the 
appropriate study file(s).  As instructed by the Sponsor, Safety Reports/Expedited Safety Reports 
should be retained in the appropriate investigative site study files or with the IB.  
13.1.5. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the EDC represent the official record of all AEs and SAEs reported 
in the study.  The Investigator should comply with requests by the Medical Monitor or other 
Sponsor personnel to record the SAE on the patient’s AE eCRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the Sponsor, the Investigator should 
provide input into the SAE narrative and provide timely information to ensure prompt follow-up 
and closure of the SAE report. 
The Investigator and supporting personnel responsible for patient care should discuss with the 
Medical Monitor any need for supplemental investigations of SAEs.  The results of these 
additional assessments must be reported to the Medical Monitor. 
13.1.6. 
Notification of Post-Treatment SAEs for Patients Who Continue in the Study 
Post-treatment SAEs that occur in patients who remain in the study after investigational product 
has been discontinued must be reported to the Sponsor within 24 hours by following the 
instructions provided in Section 13.1.4.2 . 
SAEs that occur in patients who discontinue investigational product, initiate treatment with 
commercially available Ocaliva, and remain in the study must be reported to the Sponsor within 
24 hours by following the instructions provided in Section 13.1.4.2. 
13.1.7. 
Notification of Post-Study SAEs  
All SAEs that occur within 30 days following discontinuation from the study, whether or not 
they are related to the investigational product, must be reported to the Sponsor within 24 hours 
by following the instructions provided in Section 13.1.4.2. 
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If an Investigator becomes aware of an SAE that may be attributable to the investigational 
product at any time after the end of the study, the Sponsor should be notified immediately 
(ie, within 24 hours) by following the instructions provided in Section 13.1.4.2. 
13.1.8. 
Follow-Up of AEs and SAEs 
All AEs must be followed during the course of the study until the AE resolves, is no longer of 
clinical concern, has stabilized or is otherwise explained, or the patient is lost to follow-up. 
AEs ongoing at the final visit that are deemed to be “possibly, probably, or definitely” related or 
of other clinical significance must be followed for as long as necessary to adequately evaluate 
the safety of the patient or until the event stabilizes, resolves, or is no longer of clinical concern.  
The Investigator must ensure that follow-up includes any supplemental investigations indicated 
to elucidate the nature and/or causality of the AE.  This may include additional laboratory tests 
or investigations, or consultation with other healthcare professionals, as considered clinically 
appropriate by the Investigator. 
Drug-Induced Liver Injury or Disease Progression 
All patients showing possible drug-induced liver injury or disease progression should be 
followed until all abnormalities return to normal or to the baseline state.  Drug-induced liver 
injury may develop or progress even after the causative drug has been stopped.  Results should 
be recorded in the eCRF.  Note that longer follow-up can sometimes reveal an off-drug repetition 
of what had appeared to be drug-induced liver injury, indicating that liver injury was related to 
underlying liver disease. 
Cholecystitis or Pancreatitis 
Patients should be instructed to contact the investigational site if they experience any of the 
following signs and symptoms:  nausea, vomiting, abdominal pain, diarrhea, weight loss, fever 
and chills, worsening or new fatigue, or weakness.  Patients should also be counseled to seek 
immediate medical assistance if they experience persistent severe abdominal pain.   
In the event that cholecystitis and/or pancreatitis is suspected, Investigators should promptly 
bring patients into the clinic to undergo a complete evaluation, including a physical examination, 
and laboratory assessments [ie, amylase and lipase]).  Investigators should refer to standard of 
care guidelines on suspected pancreatitis (Banks 2012, Greenburg 2015).  Diagnosis of acute 
pancreatitis includes 2 of the following:   
 Abdominal pain (acute onset of a persistent, severe, epigastric pain often radiating to 
the back)  
 Serum lipase activity (or amylase) at least 3 times greater than the upper limit of 
normal 
 Characteristic findings of acute pancreatitis on computed tomography or magnetic 
resonance imaging 
To ensure appropriate vigilance, amylase and lipase levels should be monitored monthly for 
3 months after onset of symptoms, irrespective of whether a diagnosis of cholecystitis and or 
pancreatitis is confirmed.  The Investigator should contact the Medical Monitor upon awareness 
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of the above (ie, suspected or confirmed diagnosis).  Results should be recorded promptly in the 
eCRF. 
13.1.9. 
Pregnancy and Follow-Up  
Pregnancies are not considered AEs in and of themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical study, she must discontinue treatment with 
investigational product immediately and the Sponsor must be notified within 24 hours of the 
Investigator’s awareness of the pregnancy by completing the Pregnancy CRF in the EDC system 
and downloading and completing the Pregnancy Report Form.  The Pregnancy Report Form 
must be emailed to 
 or faxed to 
  The patient and 
neonate must be followed for outcome information and/or as considered appropriate by the 
Investigator and Sponsor. 
 
Completing the Pregnancy Report Form is not a substitute for reporting an AE/SAE when and 
AE/SAE has occurred.  In the situation when an AE/SAE has occurred, the AE/SAE reporting 
procedures described in Section 13.1.4 must also be followed. 
13.2. 
Other Safety Parameters 
13.2.1. 
Medical History/Demographics 
A complete medical history will be obtained from the patient at screening.  Demographic 
characteristics (age, gender, race, and ethnicity) will be recorded. 
13.2.2. 
Medical and Surgical Procedures  
Medical and surgical procedures will be recorded at the visits indicated in Table 1. 
13.2.3. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the visits specified in the Schedule of Study Procedures (Table 1).  A basic physical 
examination should be performed, including all body systems pertinent to the patient.  Smoking 
and alcohol consumption history and current habits will be recorded.  Any clinically significant 
abnormality should be reported on the AE eCRF page for findings that appear after consent, and 
on the medical history eCRF for any finding present prior to consent.   
13.2.4. 
Vital Signs and Weight 
Vital signs (oral temperature, sitting heart rate, respiratory rate and sitting blood pressure [BP]) 
and weight will be assessed at indicated visits (Table 1).  When taking heart rate, respiratory rate 
and BP readings, patients should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
13.2.5. 
Electrocardiogram  
Standard ECGs will be collected at indicated visits (Table 1).  The Investigator or designee will 
review the ECG and findings will be recorded in the eCRF as normal, abnormal but not clinically 
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significant, or abnormal and clinically significant.  Any clinically significant abnormalities on 
ECGs recorded after Day 1 will also be documented as AEs and entered on the AE page of the 
eCRF.  
Investigative sites must retain a copy of all ECGs evaluated by the Investigator or designee.  
These ECGs must be clearly labeled with the Patient ID number, date, and time.   
13.2.6. 
Laboratory Assessments 
Patients will be instructed to attend each study visit in a fasted state, preferably in the morning, 
and patients should remain fasted until their blood samples have been collected.  At all visits, the 
Investigator or designee will verify that the patient has fasted for at least 8 hours and record 
fasting status in the source and eCRF.  If the patient reports having eaten (water is permitted) 
within 8 hours, the Investigator or designee will document accordingly in the source and eCRF 
and remind the patient that fasting is required before all study visits. 
Blood samples for serum chemistry, coagulation, and hematology; and urine samples will be 
collected at visits as detailed in the Schedule of Study Procedures (see Table 1).  The number and 
volume of samples to be collected at each visit will be detailed in the laboratory manual. 
Full instructions concerning the number and type of samples to be collected at each visit, the 
required sample volumes, sample collection methods, sample processing, labeling, and shipping 
will be provided in a separate procedural manual.  All necessary collection supplies will be 
provided by the central laboratory and will be appropriately assembled for the specific 
evaluations required at each visit. 
All patients with laboratory tests containing clinically significant abnormal values are to be followed 
regularly until the values return to normal ranges; until a valid reason, other than investigational 
product related AE, is identified; or until further follow-up is deemed medically unnecessary.   
Laboratory samples will be stored for a maximum of up to 1 year after the end of the study 
(depending on stability) in the event that retesting is required, and destroyed after 1 year if not 
analyzed. 
The list of laboratory analytes to be tested is shown in Table 11. 
Table 11: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen, creatinine, aspartate 
aminotransferase [AST, SGOT], alanine aminotransferase 
[ALT, SGPT], ALP, GGT, electrolytes [calcium, chloride, 
potassium, sodium], glucose, total protein, and blood lipids 
(total cholesterol, LDL, HDL and VLDL fractions and 
TG), CPK, magnesium, phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, conjugated (direct) 
bilirubin, total bilirubin, free fatty acids, TFT (TSH, free 
T3 and free T4) 
Hematology 
Hemoglobin, hematocrit, white blood count with 
differential, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, platelets, red blood cell count 
(including MCV, MCH, MCHC) 
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Table 11: 
List of Laboratory Analytes to be Tested (Continued) 
Laboratory Assessment 
Analyte 
Coagulation 
PT, PTT, INR 
Urinalysis; 
Pregnancy 
pH, specific gravity, total protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, 
leucocytes, nitrates; albumin, creatinine, 
albumin/creatinine ratio (if positive); β-hCG 
Markers of Cholecystitis and Pancreatitis 
Amylase and lipase 
Noninvasive measurements of liver fibrosis 
ELF (HA, P3NP, and TIMP-1) 
PK assessments 
OCA (parent and conjugates [glyco and tauro], metabolite 
OCA-glucuronide)  
PD markers 
C4, FGF-19 and plasma bile acids 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hCG = human chorionic 
gonadotropin; C4 = 7α-hydroxy-4-cholesten-3-one; CPK = creatine phosphokinase; ELF = enhanced liver fibrosis; FGF-19 = 
fibroblast growth factor-19; GGT = gamma-glutamyl transferase; HA = hyaluronic acid; HDL = high density lipoprotein; INR 
= international normalized ratio; LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; OCA = obeticholic acid; P3NP = procollagen 
3 N-terminal peptide; PT = Prothrombin time; PTT = partial thromboplastin time; SGOT = Serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase; T3 = triiodothyronine; T4 = thyroxine; TG = triglyceride; TFT = 
thyroid function test; TIMP-1 = tissue inhibitor of metalloproteinase 1; TSH = thyroid stimulating hormone; VLDL = very 
low-density lipoprotein 
Laboratory reference ranges for the study will be based on the laboratory vendor range. 
Urine based β-hCG pregnancy tests will be performed in female patients of childbearing 
potential per protocol specified visits (see Table 1).  If a urine pregnancy test is positive, a serum 
pregnancy test must be performed to confirm the result.  If positive, the Sponsor must be notified 
and the patient will be followed as outlined in Section 13.1.9 until pregnancy outcome.  
INR will be calculated based on prothrombin time value by the central laboratory.  MELD scores 
will be calculated based on creatinine, bilirubin, and INR values, with modification by United 
Network for Organ Sharing.  Total OCA will be calculated based on the sum of OCA, 
glycol-OCA, and tauro-OCA concentrations.  Laboratory analyte results may be used to calculate 
various cardiovascular risk and fibrosis measurement scores. 
13.2.7. 
Patient-Reported Outcomes and Healthcare Resource Use 
Data will be collected to determine the effects of OCA on health-related quality of life.  
Healthcare resource use as well as a general health status assessment (for the purposes of 
generating health utilities) will be used to support subsequent cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Assessments of patient-reported 
outcomes will take place during the visits indicated in Table 1.   
The following patient-reported outcomes will be used to evaluate the effects of OCA compared 
to placebo on improvements in health-related quality of life: 
 PBC-40:  The PBC-40 is a validated disease-specific 40-question quality of life 
questionnaire, which consists of 6 domains:  General Symptoms, Itch, Fatigue, 
Cognitive Function, Social, and Emotional (Jacoby 2005). 
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 EQ-5D-5L:  The EQ-5D-5L consists of 2 sections – the descriptive system and the 
visual analogue scales (VASs).  The descriptive system is organized into 
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  Each dimension has 5 levels:  no problems, slight problems, 
moderate problems, severe problems, and extreme problems.  The VAS records the 
patient’s self-rated health on a 20-cm vertical, line with endpoints labelled “the best 
health you can imagine” and “the worst health you can imagine” (Herdman 2011, 
Oemar 2013). 
 Pruritus VAS:  A VAS will also be used to assess pruritus in individual patients. 
 Chronic Liver Disease Questionnaire:  The CLDQ is a disease-specific health related 
quality of life questionnaire for patients with chronic liver disease.  The questionnaire 
includes 29 items in the following domains: fatigue, activity, emotional function, 
abdominal symptoms, systemic symptoms, and worry).  Each question is answered on 
a scale from 1 (always) to 7 (never) with a higher score corresponding to a better 
quality of life.  The CLDQ produces a summary score and domain scores that 
correlate with the severity of liver disease (Younossi 1999). 
Patients will be asked to complete the questionnaires and initial and date each document.  The 
questionnaires should be filed in the patient’s study records.  These may require transcription to 
the eCRF by study site staff. 
Healthcare resource use will be collected from eCRFs including number, reason for and duration 
of hospitalizations and emergency room visits, number of outpatient physician visits (patient 
reported), and use of concomitant medications.  The purpose is to evaluate the effects of OCA 
compared to placebo on patient-reported outcomes and healthcare resource. 
14. 
EFFICACY ASSESSMENTS 
14.1. 
Biochemical Measures of Disease Severity 
14.1.1. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is calculated and reported within the EDC system 
based on data entered into the eCRF by adding the scores from the 5 factors outlined in Table 12 
and can range from 5-15.  A total score of 5-6 is considered Grade A (mild, well-compensated 
disease); 7-9 is Grade B (moderate, significant functional compromise); and 10 and above is 
Grade C (severe, decompensated disease).  Calculation of the CP Score includes Investigator 
assessments of ascites and hepatic encephalopathy, which may be assessed during the adverse 
event review at the scheduled visits, as well as total bilirubin, serum albumin, and prothrombin 
time, which will populate from the central laboratory.   
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Table 12: 
Child-Pugh Scoring System 
Factor 
Units 
Points 
1 
2 
3 
Serum bilirubin 
μmol/L 
<34 
34-50 
>50 
mg/dL 
<2.0 
2.0-3.0 
>3.0 
Serum albumin 
g/L 
>35 
28-35 
<28 
g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
Seconds prolonged 
0-3 
4-6 
>6 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites 
 
None 
Mild 
Moderate-Severe 
Hepatic encephalopathya 
 
0 
Grade 1 or 2 
Grade 3 or 4 
a Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
 Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves 
 Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
 Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
 Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity  
 (Pugh 1973, Lucey 1997), Vilstrup 2014 
14.1.2. 
Model of End Stage Liver Disease Score 
The MELD scoring system is used to assess the severity of chronic liver disease.  The MELD 
score is useful in assessing patients with significant decompensation, and the MELD score is 
now used by the United Network for Organ Sharing in the US and Eurotransplants to manage the 
organ allocation for liver transplantation.  The threshold for placement on an organ 
transplantation queue varies between regions across the globe.   
An increasing MELD score is associated with increased severity of hepatic dysfunction and 
increased 3-month mortality risk.  The MELD score is derived from the patient’s serum total 
bilirubin, serum creatinine, and INR, as appropriate, to predict survival (Kamath 2007).  MELD 
score will be calculated and reported for visits where these parameters are measured 
(see Table 1). 
14.1.3. 
Changes in Liver Biochemistry and Hepatobiliary Damage 
ALP, ALT, AST, GGT, total and direct bilirubin, INR, creatinine, albumin, platelets will be 
measured according to the frequency listed in Table 1. 
14.2. 
Additional Assessments 
14.2.1. 
Noninvasive Measurements of Liver Stiffness and Fibrosis 
The ELF test assesses: HA, P3NP, and TIMP-1.  Samples will be assessed in patients according 
to the schedules presented in Table 1. 
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The Fibroscan® TE device (Echosens, Paris, France) will be used at all study sites that have the 
equipment to collect hepatic stiffness measurements.  These study sites must have the staff 
trained in the use and data interpretation of the device.  This is a validated and non-invasive 
radiological technique used to assess hepatic fibrosis which will be conducted according to the 
schedule presented in Table 1.   
14.2.2. 
Markers of FXR activation 
Blood samples will be collected in all patients to measure C4, FGF-19, and bile acids.  The 
results of these analyses will be used to assess the PK/PD response of OCA.  Blood samples will 
be assessed in patients according to the schedule presented in Table 1.   
14.2.3. 
Clinical Outcome Events 
Clinical outcome events will be evaluated by an Adjudication Committee (described in 
Section 15.9) to confirm if they meet the criteria to be considered Clinical Outcome Events.  
15. 
STATISTICAL METHODS AND ANALYSES 
Individual patient data obtained from electronic case report forms (eCRFs), central laboratories, 
external sources, and any derived data will be presented in data listings by patient.  All data 
listings that contain an evaluation date will contain a relative study day.  Pre-treatment and on 
treatment study days are numbered relative to the day of the first dose of investigational product 
which is designated as Day 1.   
All output will be incorporated into Microsoft Word rich text format (.rtf) files, sorted and 
labeled according to the International Conference on Harmonisation (ICH) recommendations, 
and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, Baseline, efficacy, and safety 
parameters.   
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) of the parameter will be presented.  Percentage 
calculations will be based on non-missing data, unless otherwise specified.  Percentages are 
rounded to 1 decimal place, unless otherwise specified.   
For continuous variables, the number of patients, mean, standard deviation (SD), standard error 
of the mean (SEM), median, minimum, and maximum values will be presented.  The precision of 
summary statistics, unless otherwise, specified will be as follows:  mean and median to 1 more 
decimal place than the raw data, and SD and SEM to 2 decimal places more than the raw data.  
In general, the decimal places should not exceed 3 decimal places unless appropriate.  
Confidence intervals (CIs) will be provided and will be rounded to 1 decimal place, unless 
otherwise specified. 
Time-to-event data will be summarized using Kaplan-Meier (KM) methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of 
censored observations. 
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There will be no formal hypothesis testing in this study.  However, summary statistics for each 
treatment group will be presented, as well as 95% CIs for the difference between the treatment 
groups. 
15.1. 
Analysis Populations 
The following patient populations will be evaluated and used for presentation and analysis of the 
data: 
 The Intent-to-Treat (ITT) Population will include all randomized patients who receive 
any amount of investigational product (OCA or placebo).  The ITT Population will be 
the primary population used for summarizing efficacy assessments.  
 The Safety Population will include all patients who received at least one dose of 
investigational product (placebo or OCA). The Safety Population will be the primary 
population used for safety analyses.  
 The PK population will include all patients receiving OCA who have adequate 
concentration-time profiles to characterize OCA and its conjugates and must not have 
any major protocol deviations that potentially affect exposure levels. 
15.2. 
Determination of Sample Size 
To reasonably characterize the PK of OCA in patients with hepatic impairment, a 
simulation-based approach estimated a requirement of approximately 20 patients in the OCA 
treatment group assuming a 15% discontinuation rate.  A total of 30 patients is adequate with 
10 patients on placebo to be included as a comparator and 20 patients on OCA.  An additional 
20 patients will be enrolled to support safety and efficacy evaluations.  Therefore, approximately 
50 patients (including at least 20% of patients with CP-C) will be randomized in a 1:1 ratio to 
1 of the 2 treatment groups:  Placebo and OCA.  
15.3. 
Pharmacokinetic Analyses 
The PK Population will be used for analysis of PK parameters, which include plasma OCA 
(parent) and its conjugates (glyco-OCA and tauro-OCA), total OCA, metabolite OCA 
glucuronide, and potentially other conjugates or metabolites not yet identified. 
PK analysis will be based on the PK population.  Values will be calculated using 
non-compartmental methods.  The values will be summarized by active treatment group using 
descriptive statistics.  Full details regarding the planned analyses, methods, and outputs for the 
study will be detailed in the statistical analysis plan (SAP). 
15.4. 
Safety Analyses 
Safety analyses will be conducted using the Safety population.  Safety data, including AEs, AEs 
of special interest including pruritus and hepatic safety, vital signs, ECG, and clinical laboratory 
results will be summarized by treatment group using the Safety Population. 
The incidence of TEAEs and SAEs will be tabulated by system organ class (SOC) and preferred 
term (PT) for each treatment group, and similarly by severity and relationship to treatment.   
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Laboratory parameters, physical examinations including vital signs, and ECGs will be 
summarized by treatment group using descriptive statistics at Baseline and at each scheduled 
post-Baseline visit.  The absolute change from baseline will also be summarized. 
No inferential comparison with formal statistical hypothesis testing will be performed for safety 
endpoints.  
15.4.1. 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA).  Summary 
tables of TEAEs will be provided.   
Each AE summary will be displayed by treatment group.  Summaries that are displayed by SOC 
and PT will be ordered by descending order of incidence of SOC and PT within each system 
organ class.  Summaries of the following types will be presented: 
 Overall summary of TEAEs. 
 Patient incidence of TEAEs and the total number of entries by MedDRA SOC and 
PT.  This summary will be repeated for all subgroups. 
 Patient incidence of TEAEs by MedDRA SOC, PT, and highest severity.  At each 
level of patient summarization, a patient is classified according to the highest severity 
if the patient reported 1 or more events.  AEs with missing severity will be considered 
severe for this summary. 
 Patient incidence of TEAEs by MedDRA SOC, PT, and closest relationship to 
investigational product (Related/Not Related).  Related AEs are those with 
relationships reported as “Definite,” “Probable,” or “Possible,” and unrelated AEs are 
those with relationships reported as “Unlikely” or “Not Related.”  At each level of 
patient summarization, a patient is classified according to the closest relationship if 
the patient reported 1 or more events.  AEs with a missing relationship will be 
considered related for this summary. 
 Patient incidence of serious TEAEs and the total number of entries by MedDRA SOC 
and PT. 
 Patient incidence of TEAEs leading to investigational product withdrawal or study 
discontinuation by MedDRA SOC and PT.  This is a subset of the AEs where Action 
Taken with Study Treatment is checked as “Drug Withdrawn” or where “Patient 
Discontinued from Study” is checked. 
The following listings will be presented by treatment group and patient: 
 All adverse events. 
 Serious adverse events (This is a subset of the AEs where serious is marked as 
“Yes”). 
 Severe adverse events (This is a subset of AEs where severity is marked as “Severe”). 
 Related adverse events (This is a subset of the AEs where relationship marked as 
“Definite,” “Probable,” or “Possible”). 
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 Adverse events leading to Study Drug Withdrawal or Study Discontinuation (This is a 
subset of the AEs where Action Taken with Study Treatment is checked as “Drug 
Withdrawn” or where “Patient Discontinued from Study” is checked). 
 Adverse events leading to death (This is a subset of the AEs where the corresponding 
AE number is specified on the Death eCRF). 
Adverse events of special interest as defined in Section 13.1.1.4 will be summarized for each 
treatment group.   
15.4.2. 
Clinical Laboratory Evaluations 
Laboratory parameters will be summarized in standard international (SI) system of units by 
treatment group using descriptive statistics at Baseline and at each on-study evaluation.  Re-test 
or unscheduled results will not be summarized but will be included in the data listings.  The 
change from Baseline will also be summarized.  Baseline is defined as the mean of all available 
evaluations prior to treatment.   
In addition, shift tables (ie, low-normal-high at Baseline versus low-normal-high at post Baseline 
visit in a 3-by-3 contingency table) from Baseline to worst value, last value, and at each 
scheduled post-Baseline visit will be provided for hematology and serum chemistry by treatment 
group to assess changes in laboratory values from Baseline to each on-study evaluation.   
15.4.3. 
Additional Safety Analysis 
Vital Signs and Weight 
The results and change from Baseline to each on-study evaluation visit will be summarized by 
treatment group for weight, oral temperature, sitting heart rate, respiratory rate and sitting blood 
pressure. 
Electrocardiograms 
Electrocardiogram (ECG) results will be summarized at each on-study visit descriptively, 
including the number and percentage of patients with normal, abnormal not clinically significant, 
and abnormal clinically significant results at Baseline and each on-study evaluation. 
15.4.4. 
Adverse Events of Special Interest 
Pruritus: Treatment-emergent pruritus, defined as any PT including “Prur,” will be summarized 
separately by the MedDRA SOC, treatment group, and PT as a subset of all TEAEs.  This 
summary will be repeated for patients with “new or worsened” pruritus events, as defined as 
follows: 
 Mild, moderate, or severe treatment-emergent pruritus events in patients with no 
pruritus at Baseline, or 
 Worsening of the severity of the Baseline condition in patients with pruritus at 
Baseline. 
Baseline pruritus is defined as the Investigator’s rating of severity as collected on the PBC 
Disease History eCRF.  Patients whose Baseline severity is severe will be counted as worsening 
if an AE of pruritus with severe is recorded. 
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An analysis of treatment-emergent pruritus event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  Each individual patient year on study will be derived as the last 
known date during the study minus the first dose date plus 1 divided by 365.25 days/year.   
In order to explore the relationship between pruritus and the investigational product, the 
following time-to-event analyses will be performed: 
 Time to first onset of treatment-emergent pruritus  
 The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 
 Patients who never reported an AE of pruritus will be censored at the date of last 
contact. 
 Time to onset of the first moderate or severe treatment-emergent pruritus 
 The time to the start of the first moderate or severe pruritus will be calculated by 
date of onset of the first moderate or severe pruritus – date of first dose of 
investigational product +1. 
 Patients who never reported a moderate or severe AE of pruritus will be censored 
at the date of completion or discontinuation. 
 Time to onset of the first severe treatment-emergent pruritus 
 The time to the start of the first severe pruritus will be calculated by date of onset 
of the first severe pruritus – date of first dose of investigational product +1. 
 Patients who never reported a severe AE of pruritus will be censored at the date of 
completion or discontinuation. 
The analysis of time to first onset of treatment-emergent pruritus AE, time to onset of the first 
moderate or severe treatment-emergent pruritus, and onset of the first severe treatment-emergent 
pruritus will include the number of patients with pruritus (first onset, first moderate or severe, 
first severe), the number of patients without pruritus (censored), and the minimum and maximum 
times in days.  KM estimates will be calculated by treatment group.  The tabulation will include 
the KM estimate methodology using 25th, 50th (median), and 75th percentiles of the medians and 
corresponding with associated 2-sided 95% confidence intervals (CIs), if the medians can be 
estimated as well as percentage of censored observations. 
Fatigue: Treatment-emergent fatigue is defined as any PT which includes “Fatigue.”  New or 
worsened treatment-emergent fatigue is defined as follows: 
 Any mild, moderate, or severe treatment-emergent fatigue events in patients with no 
fatigue at Baseline, or 
 Worsening of the severity of the Baseline condition in patients with fatigue at 
Baseline. 
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Baseline fatigue is defined as the Investigator’s rating of severity as collected on the PBC 
Disease History eCRF.  Patients whose Baseline severity is severe will be counted as worsening 
if an AE of fatigue with severe is recorded. 
An analysis of treatment-emergent fatigue event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  Each individual patient year on study will be derived as the last 
known date during the study minus the first dose date plus 1 divided by 365.25 days/year.   
In order to explore the relationship between fatigue and the investigational product, the following 
time-to-event analyses will be performed: 
 Time to first onset of treatment-emergent fatigue  
 The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 
 Patients who never reported an AE of fatigue will be censored at the date of last 
contact. 
 Time to onset of the first moderate or severe treatment-emergent fatigue 
 The time to the start of the first moderate or severe fatigue will be calculated by 
date of onset of the first moderate or severe fatigue – date of first dose of 
investigational product +1. 
 Patients who never reported a moderate or severe AE of fatigue will be censored 
at the date of last contact. 
 Time to onset of the first severe treatment-emergent fatigue 
 The time to the start of the first severe fatigue will be calculated by date of onset 
of the first severe fatigue – date of first dose of investigational product +1. 
 Patients who never reported a severe AE of fatigue will be censored at the data of 
last contact. 
The analysis of time to first onset of treatment-emergent fatigue AE, time to onset of the first 
moderate or severe treatment-emergent fatigue, and onset of the first severe treatment-emergent 
fatigue will include the number of patients with pruritus (first onset, first moderate or severe, 
first severe), the number of patients without fatigue (censored), and the minimum and maximum 
times in days.  KM estimates will be calculated by treatment group.  The quartiles, including the 
median time-to-event and their respective 2-sided 95% CIs, will be presented.  KM estimates 
will be plotted as a “survival curve” for each treatment group. 
15.5. 
Efficacy Analyses 
This study does not plan to test a formal hypothesis for any efficacy endpoint.   
The endpoints of efficacy assessments are change in total and direct bilirubin, INR, creatinine, 
albumin, platelets, ALP, ALT, AST, and GGT from baseline to Week 48 (end of the study), 
change from baseline to Week 48 in CP score and components of the CP score, and change from 
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baseline to Week 48 in MELD and components of the MELD score.  Analyses of change from 
Baseline to Week 48 (end of study) will be modelled between treatment groups using ANCOVA 
model with change from Baseline as the dependent variable, treatment group and randomization 
stratification factor as fixed effects and the baseline value as a covariate.  The same analysis will 
be carried out using percentage change from Baseline as the dependent variable. 
Analyses of change from Baseline to Week 48 (end of study) will be modelled between 
treatment groups using ANCOVA model with change from Baseline as the dependent variable, 
treatment group and randomization stratification factor as fixed effects and the baseline value as 
a covariate.  The same analysis will be carried out using percentage change from Baseline as the 
dependent variable. 
Summary statistics of the laboratory values will be provided by treatment group.  The results, 
change from Baseline, and percentage change from Baseline values, as well as estimates of 
least-square (LS) means, standard errors (StdErr), and 2-sided 95% CIs, will be presented by 
treatment group.  Estimates of the mean difference between treatment groups, the StdErr of the 
difference, and 2-sided 95% CI of the difference will also be presented.   
Risk Scores: Changes from baseline in the MELD score and in CP score, C4, FGF-19 and 
plasma bile acids will be summarized and analyzed using the Wilcoxon Rank Sum Test.  The 
median differences and 95% CI of the median differences between treatment groups will be 
constructed using Hodges-Lehmann estimate.  If the median differences between treatments are 
not symmetrical around the median, the Sign Test may be used. 
Shifts in MELD scores from Baseline will be reported by visit using the following categories:  
<10, 10 to <12, 12 to <13, 13 to <14, 14 to <15, and ≥15.   
CP class will be presented in shift tables showing the shift from baseline to each scheduled 
post-baseline visit by the count and percentage of patients within each shift classification. 
Individual factors will be presented in a listing. 
15.6. 
Additional Efficacy Analyses 
Analyses of changes in liver stiffness (TE) and liver fibrosis (ELF [HA, P3NP, and TIMP-1]) 
will be summarized and analyzed using the same methodology specified for the key secondary 
analyses of change in bilirubin. 
The following clinical endpoints will be captured in the study: 
 Time to death (all cause) 
 Time to liver-related death 
 Time to liver transplant 
 MELD score ≥15 (for patients with MELD ≤12 at baseline) 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
 Time to variceal bleed 
 Time to hepatic encephalopathy (as defined by a West Haven score of ≥2) 
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 Time to spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 Time to uncontrolled ascites (diuretic resistant ascites requiring therapeutic 
paracentesis at a frequency of at least twice in a month). 
The incidence and time to first occurrence of any above listed clinical events will be summarized 
by treatment group using the log rank test stratified by the randomization stratification factor.  
KM estimates of the distribution of the time-to-event will be tabulated and graphed by treatment 
group.  The tabulation will include the KM methodology using 25th, 50th (median), and 75th 
percentiles with associated 2-sided 95% confidence intervals (CIs), as well as percentage of 
censored observations.  The number and percent of patients censored and with events will be 
presented.  The hazard ratio and 2-sided 95% CI will be estimated based on a Cox regression 
model stratified by randomization strata.  
In addition, the incidence and time to each of the above clinical events, and the incidence and 
time to occurrence of hepatocellular carcinoma (HCC) will be summarized by treatment group 
using the same methods as defined above.  
Full details regarding additional efficacy analyses will be detailed in the SAP. 
15.7. 
Handling of Missing Data 
Missing data will be assumed to be missing at random.  No data will be imputed. 
15.8. 
Data Monitoring Committee 
An independent DMC includes hepatologists, pharmaceutical physicians, 
epidemiology/cardiology expert(s), and statistician(s) not involved in the study as Investigators, 
adjudication committee members, or consultants.  The DMC will have oversight of the study 
conduct as defined by the DMC charter.  All members will have considerable experience with 
clinical study conduct and DMCs.  Any candidate found to have a conflict of interest or whose 
name is listed on the Food and Drug Administration (FDA) debarment list will not be offered 
membership.  Conflicts of interest will be assessed regularly, and if members are found to have a 
new conflict of interest they will be replaced. 
The DMC will meet approximately quarterly at scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review safety and efficacy data in order to ensure the safe and 
proper treatment of patients.  Based on review of these data, the DMC will advise the Sponsor on 
the validity and scientific merit of continuing the study. 
Written minutes of both the open and closed DMC sessions will be prepared.  The closed 
minutes will be made available to the appointed Sponsor representatives only after the database 
is locked.  
Data listings provided to the DMC do not contain individual patient treatment information; 
however, the DMC will have access to the database and may unblind individual patient data as 
appropriate.  Summary tables reviewed by the DMC during closed sessions will include an 
overall column containing information regarding all patients and separate treatment columns 
with ‘dummy’ labels, ie, the actual treatment groups are used, but are not identified.  Data 
reviewed during the meetings will include, at a minimum, disposition, demographics, exposure, 
clinical laboratory results, MedDRA-coded AEs, and AEs leading to early withdrawal of 
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investigational product.  At each meeting, detailed narratives of interval SAEs (including events 
resulting in death) are reviewed by the DMC in addition to a cumulative list of all SAEs. 
The DMC may agree to adjust meeting frequency based upon actual and projected safety and 
efficacy data availability.  Adjustments to or stopping of the protocol defined doses may be 
considered based on DMC evaluation of OCA safety and tolerability. 
All Investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DMC relating to patient safety, which alter the 
conduct of this study.  The Investigators will inform the patients of such actions and the protocol, 
PIS, and ICF will be revised, as appropriate. 
15.9. 
Adjudication Committees 
All suspected liver-related clinical events, major adverse cardiovascular events 
(MACE)/expanded MACE, and drug-related hepatic injury events that occur after administration 
of the first dose of investigational product will be reviewed by the following blinded adjudication 
committees, depending on event type, before inclusion in any analysis.  The 3 committees and 
event types they are responsible for adjudicating are as follows: 
 Cardiovascular Adjudication Committee (CAC):  Adjudicates all suspected MACE, 
including all deaths 
 Hepatic Outcomes Committee:  Adjudicates all deaths and suspected liver-related 
outcomes 
 Hepatic Safety Committee:  Adjudicates all suspected drug-related hepatic injury 
events 
Each adjudication committee will have a charter that documents the reporting of events by the 
study site, definition of the suspected events to be adjudicated, supply of source documentation 
to the committee, entire data flow and process from committee membership, review of the events 
by the committee, reporting of the final assessment, and the working procedures of the 
committee.   
The adjudication committee members will include experts with relevant adjudication experience; 
they will not be involved in the study as Investigators, DMC members, or consultants.  Any 
candidate found to have a conflict or whose name is listed on the FDA debarment list is not 
offered membership.  Conflicts of interest are assessed regularly, and if members are found to 
have a new conflict of interest they will be replaced. 
The adjudication of suspected events will be based on available source documentation, including 
but not limited to individual clinical study data, hospital records, histology, discharge summaries, 
and/or death certificates.  The adjudication committees will not receive any individual patient 
treatment or site-specific information.  The assessment of events will be conducted in 
compliance with study-specific procedures, manuals, GCP, and all other applicable regulatory 
requirements, including the archiving of essential documents. 
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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
Study records at each site will be monitored at regular intervals by a representative of the 
Sponsor, the CRA.  The role of the CRA is to aid the Investigator in the maintenance and 
documentation of complete, accurate, legible, well organized and easily retrievable data.  In 
addition, the CRA will ensure the Investigator's understanding of all applicable regulations 
concerning the clinical evaluation of the investigational product and will ensure an understanding 
of the protocol, reporting responsibilities and the validity of the data.  This will include ensuring 
that full and appropriate essential documentation is available. 
In order to perform this role, the CRA must perform source data verification and as such must be 
given access to the patient’s primary source documentation (eg, paper or electronic medical 
records such as consent to participate in the study, visit dates, screening and randomization 
numbers, demographic information, medical history, disease history, physical examination, vital 
signs, laboratory assessments [copy of laboratory reports], AEs, concomitant medications, dates 
of dispensing investigational product, ECGs, etc) that support data entries in the eCRF.  The 
eCRF must be completed promptly after each visit to allow the progress and results of the study 
to be closely followed by the Medical Monitor. 
The Investigator may exercise judgment in allowing the CRA access to particular sections of the 
patient's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
16.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IEC/IRB, and/or 
regulatory agencies to conduct one or more site audits during or after the study and agrees to 
allow access to all study-related documentation and information and be available for discussion 
about the study.   
17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the eCRF or ultimately 
transferred into the database to ensure accuracy and completeness.   
Training sessions, regular monitoring of the study at the study site by the Sponsor or designated 
personnel (eg, CRA), instruction manuals, data verification, cross checking, and data audits will 
be performed to ensure quality of all study data.  Investigators’ meetings and/or onsite study 
initiations will be performed to prepare Investigators and other study site personnel for 
appropriate collection of study data. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit.   
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18. 
ETHICS 
18.1. 
Ethics Review 
The final study protocol, including the final version of the PIS-ICF and/or other patient 
information, must be approved or given a favorable opinion in writing by an IRB/IEC as 
appropriate.  The Investigator must submit written IRB/IEC approval to Intercept before he or 
she can enroll any patient into the study.  The Investigator is responsible for providing the IB and 
any other available safety information and information about payments and compensation 
available to study patients to the IRB/IEC for review. 
The Investigator is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements.  A favorable opinion on amendments will be obtained prior 
to implementation, unless the amendment is necessary to reduce immediate risk to study 
participants.  In addition, the IRB/IEC must approve all advertising used to recruit patients for 
the study.  The protocol must be reapproved by the IRB/ IEC upon receipt of amendments and 
annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product, 
according to local regulations and guidelines.  The Sponsor will provide this information to the 
Investigator. 
Progress reports and notifications of SARs will be provided to the IRB/IEC according to local 
regulations and guidelines.  Investigators or the Sponsor or its designee will provide reports to 
the IRB/IEC as requested, as a minimum annually, and after the study is complete. 
18.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki, “(64th World Medical Association [WMA] General Assembly, 
Fortaleza, Brazil, October 2013),”and are consistent with ICH/GCP, applicable regulatory 
requirements and the Sponsor’s policies. 
18.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the patient is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Patients 
must also be notified that they are free to discontinue from the study at any time.  The patient 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The patient’s signed and dated consent form must be obtained before conducting any study 
procedures. 
The Investigator(s) must maintain the original, signed ICF. A copy of the ICF must be given to 
the patient. 
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18.4. 
Patient Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the patient will be 
regarded as confidential and confidentiality of all patients will be maintained.  Monitors 
(eg, CRA, Medical Monitor), auditors and inspectors will require access to a patient’s medical 
notes for the purpose of source document verification but the patient’s confidentiality will be 
maintained at all times.  An agreement for disclosure of any such information will be obtained in 
writing and is included in the statement of informed consent.  The study data shall not be 
disclosed to a third party (with the exception of auditors and/or regulatory authorities) without 
the written consent of the Sponsor.  All data shall be secured against unauthorized access. 
The Investigator will maintain a list of patient’s names and identifying information (eg, patient’s 
hospital number, unique patient number).  This list will not be collected by the Sponsor. 
The PIS-ICF will explain that study data will be stored in a computer database, maintaining 
confidentiality in accordance with national data protection legislation.  All data computer 
processed by the Sponsor or designee will be identified by unique patient number/randomization 
code/site number, only.   
When personal data on patients are stored or processed by computer, the data must be protected 
to prevent disclosure to unauthorized third parties.  The pertinent sections of the data protection 
laws in the country in which the protocol is being conducted will be complied with in full. 
The PIS-ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, regulatory authorities, or IEC/IRBs may require direct access to parts of the hospital or 
study site records relevant to the study, including patient’s medical history. 
19. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the patients for the duration of the study.  If the Investigator 
is not present in the study site during the assessment, he or she will leave instructions for the 
study site staff and a telephone number where he or she can be reached. 
Named physician(s) will be responsible for the medical follow-up of patients, as applicable. 
19.1. 
Adverse Event Reporting 
The Investigator is responsible for recording AEs reported by the patient or discovered by any 
other means during the study.  In agreeing to the provisions of this protocol, the Investigator 
accepts all legal responsibilities for immediate reporting of SAEs to the Sponsor. 
19.2. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any significant way without 
proper notification to the Sponsor (or designee).  Only the Sponsor may amend the protocol.  
Any change in study conduct considered necessary by the Investigator will be made only after 
consultation with the Sponsor, who will then issue a formal protocol amendment to implement 
the change and obtain regulatory approval.  The only exception is when the Investigator 
considers a patient’s safety to be compromised if immediate action is not taken. 
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19.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
 Approved PIS-ICF (all versions) 
 IRB/IEC approvals (of protocol/amendments, patient questionnaires, etc)  
 Form FDA 1572  
 Current medical license of Investigators 
 Curriculum vitae of Investigators 
 Laboratory certification and reference ranges 
 Financial disclosure forms 
19.4. 
Ethics Review (IRB/IEC) 
Please see Section 18.1 for the Investigator’s responsibilities regarding ethics review. 
19.5. 
Archiving and Record Retention 
The Investigator should retain all essential documents and correspondence relating to this study 
in the Investigator Site File (ISF).  Any study documents stored elsewhere should have their 
location referenced in the ISF table of contents or in a note to file. 
All documents relating to the study including the ISF itself, source documents and patient 
medical files (retained per country specific regulations), completed study patient log and 
confidential patient identification list will be retained by the Investigator until at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the Sponsor.  In the event that storage of records 
becomes a problem at any time during this period, the Sponsor should be consulted for 
assistance.  At the end of the minimum period, the Investigator should obtain written 
authorization from the Sponsor before the destruction of any records.  The Investigator will 
notify the Sponsor if ownership of documents or responsibility for the study site is transferred.  
The Sponsor will inform Investigators should it become aware of any changes in storage 
requirements. 
20. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it Sponsors consistent 
with the Declaration of Helsinki.  Consistent with the recommendations of the editors of several 
leading medical journals, the International Committee of Medical Journal Editors (ICMJE), 
authorship of publications resulting from Intercept sponsored studies should fairly recognize the 
activities of those that have made a significant contribution to the study (http://www.icmje.org).  
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Thus, it is anticipated that authorship will reflect the contribution made by the Sponsor 
personnel, the Investigators and others involved, such as statisticians.   
In recent years, issues about conflicts of interest and accuracy of the study data have been raised 
in the medical press.  Accordingly, the Sponsor has developed publication guidelines for clinical 
studies that are appropriate for this study.  Key issues include the following: 
 Clinical Trial Registries (eg, www.clinicaltrials.gov, www.clinicaltrialsregister.eu):  
A description of the study and relevant design elements (eg, basic design, objectives 
and endpoints, sample size, study population, and key inclusion/exclusion criteria) 
and results will be published online in a manner consistent with applicable regulatory 
guidelines. 
 Overview:  Investigators, reviewers and editors will have the right to audit the data to 
verify its accuracy. 
 Responsibility:  Each Investigator is responsible for the accuracy and completeness of 
all data from her/his site.  The Sponsor (or its representatives) is responsible for the 
accuracy of the data entered into the study databases and the analyses conducted. 
 Data Management:  The Sponsor will establish data management and SAP.  The 
Investigators will have the opportunity to provide input into the plans.  The 
Investigators will have the right to review the audit reports and data resolution 
decisions prior to the establishment of a clean file.  The Investigators will have the 
right to appoint appropriately qualified auditors, with GCP experience, to audit the 
Sponsor’s data prior to the establishment of a clean file.  The Investigators must 
provide adequate notice (at least 2 months) to the Sponsor of their intention to audit a 
study.  The audit should be conducted in a timely manner to allow the resolution of 
discrepancies before a clean file is established.  The Investigators will bear all the 
costs for the conduct of audits that they initiate, except those related to the resolution 
of data queries which the Sponsor will bear.  Such audits must be conducted in such a 
manner as to minimize the time to create the clean file. 
 Authorship:  Intercept, in collaboration with the Investigators, will establish the 
appropriate authorship and responsibility for drafting study documents in accordance 
with the principles of the ICMJE.  All manuscripts will be reviewed and agreed upon 
before submission for publication by all authors.   
 Single Center Publication and Additional Publications:  This is a multicenter study 
and is designed to be published with complete data from all the study sites.  Single 
center publications are therefore not considered appropriate.  Any such publications 
should clearly state that the data are “extracted” from a multicenter study and that the 
study was not intended, or statistically powered, for data presentation by a single 
study site.   
 Intercept Review of External Manuscripts:  Consistent with this, Investigators must 
submit any drafts of any publications or presentations that may arise from this study 
to the Sponsor for review and approval and to ensure consistency with the policy in 
this protocol at least 30 days prior to submission for publication or presentation.  The 
Sponsor will have the right to request appropriate modification to correct facts and to 
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Confidential and Proprietary    
represent its, or the Publication Committee’s, opinion if these differ with the proposed 
publication.  
 Confidentiality:  Investigators will conduct all interactions with the company and 
with third parties consistent with the executed confidentiality agreements.  While 
publication, by intention, presents the critical scientific data in a public forum, some 
information (such as future plans, results of preclinical studies or chemical formulae) 
may still need to remain confidential. 
 Medical Journal Review:  Upon request, all pertinent study data and information will 
be made available as supplemental information for journal editors and reviewers to 
evaluate and audit, eg, protocol and amendments, data tabulations, etc.  Arrangements 
will be made to maintain the confidentiality of such supplemental information. 
Arrangements will also be made to maintain the confidentiality of the identity of 
journal reviewers.  Records will be maintained of which documents and datasets were 
reviewed. 
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21. 
LIST OF REFERENCES 
Banks O, Bollen T, Dervenis C, et al.  Classification of acute pancreatitis-2012:  revision of the 
Atlanta classification and definitions by international consensus.  Gut. 2013; 62:102-111. 
Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Digestive and Liver Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin ME, Gish RG, et al. Changing Nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Gastroenterology. 2015b;149(6):1627-9. 
Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: From 'cirrhosis' to 
'cholangitis'. Hepatology. 2015c;62(5):1620-2. 
Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of 
liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 
2012;56(1):198-208. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51(2):237-67. 
Greenburg J., Hsu J., Bawazeer M., et al.  Clinical Practice Guideline:  Management of acute 
pancreatitis.  Can J Surg. 2016; 59 (2):128-140. 
Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European 
Association for the Study of the Liver and the American Association for the Study of Liver 
Diseases. J Hepatol. 2014 Sep;61(3):642-59. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-36. 
Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the PBC-40, a 
disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 
2005;54(11):1622-9. 
Kamath PS, Kim WR. The model for end-stage liver disease (MELD). Hepatology. 2007 
Mar;45(3):797-805. 
Kim WR, Lindor KD, Locke GR, et al. Epidemiology and natural history of primary biliary 
cirrhosis in a US community. Gastroenterol. 2000;119:1631-36. 
Kumar A, Saraswat VA. Hepatitis E and Acute-on-Chronic Liver Failure. Journal of clinical and 
experimental hepatology. 2013 Sep;3(3):225-30. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis: AASLD Practice 
Guidelines. Hepatology. 2009;50(1):291-308. 
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver 
transplant waiting list: a report of a national conference organized by the American Society of 
Transplant Physicians and the American Association for the Study of Liver Diseases. Liver 
Transpl Surg. 1997;3(6):628-37. 
Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis 
(syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol. 
1978;379(2):103-12. 
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Oemar M, Janssen B. EQ-5D-5L User Guide: Basic Information on how to use the EQ-5D-5L 
instrument. 2013 October;Version 2.0:1-28. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-72. 
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding 
oesophageal varices. Br J Surg. 1973;60(8):646-9. 
Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 
Practice Guideline by the American Association for the Study of Liver Diseases and the 
European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35. 
Younossi ZM, Guyatt G, Kiwi M, et al. Development of a disease specific questionnaire to 
measure health related quality of life in patients with chronic disease. Gut. 1999;45(2):295-300. 
 
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APPENDIX A. SUMMARY OF CHANGES:  PROTOCOL 747-401 VERSION 2 (DATED 22 MAY 2017) 
Please note that Protocol 747 401 Version 1 was generated to specifically address US FDA post-marketing requirements but 
was not submitted to other Regulatory/Competent Authorities or Ethics Committees due to ongoing negotiations. The changes 
in Version 2 were incorporated based on FDA review of Version 1 of the protocol.  In general: 
 Background information was included to estimate the exposure difference between healthy subjects and patients with 
moderate hepatic impairment to support the rationale for dose selection (Section 5.4.2) 
 Additional PK sampling times were added to adequately characterize the PK of OCA and its active metabolites at 
steady-state in patients with moderate and severe impairment when dosing weekly to biweekly (Section 12) 
 The period between screening and Day 1 was extended to at least 14 days to establish a baseline for serum biomarkers with 
at least two samples two weeks apart (Schedule of Study Procedures, Section 9.7.4) 
 The Week 3 contact Visit by email/telephone was changed to a Safety Visit to assess evidence of early hepatotoxicity 
(Schedule of Study Procedures, Section 9.7.6) 
 Guidelines were added to assess patients for evidence of hepatotoxicity at each visit (Section 8.4.1.2). 
The table below includes substantial revisions made to Protocol 747-401 under Version 2.  Revised text in Version 2 is indicated in 
bold font, and the text deleted from Version 1 is crossed out in the table below.  (Minor/editorial changes and non-substantial changes 
are not listed individually in the summary table below). 
Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
Title Page 
(For FDA Review Only) 
EudraCT Number: 2017-001762-13 
Added  
EudraCT 
Number 
STUDY 
PERSONNEL 
CONTACT 
INFORMATION 
Emergency Contact Information 
Medical Monitor - 24-hour Emergency Reporting 
Contact: 
 MD, Medical Director, 
Drug Safety,  
Intercept Pharmaceuticals, Inc. 
Mobile: 
  
Medical Monitor  
Primary 
Contact: 
 MD, Medical Director, Ph
Intercept Pharmaceuticals, Inc. (Intercept) 
Telephone: 
  
Email: 
 
Updated 
contact list. 
Page 312 of 603
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PPD
PPD
PPD
PPD


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Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
Telephon
e: 
  
Email: 
 
Or if Not Available: 
Contact: 
, MD, PhD,  
Intercept Pharmaceuticals, Inc. 
Telephon
e: 
 
SAE Contact Information 
SAE Fax: 
 
SAE email address 
 
Telephone 
 
 
Clinical Operations and Project Management 
Contact: 
 VP, Clinical 
Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 
 
 
 
 
 
SAE Fax: 
 
SAE Email: 
 
 
 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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PPD
PPD
PPD


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 3: 0 4 Ja n 2 0 1 8  
 
Pa ge 9 5  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d Te xt ( Ve rsi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
 
T he st u d y is pla n ne d t o ha ve a p pr o xi matel y 2 0  
i n vesti gati o nal sites, gl o ball y 
T he st u d y is pla n ne d t o ha ve a p pr o xi matel y 3 5  
i n vesti gati o nal sites, gl o ball y 
U p date d site 
n u m bers.  
S y n o psis, St u d y 
Peri o d, 7. 1. 3, 
St u d y D urati o n  
St u d ie d Peri o d: T he st u d y will i ncl u de a 1 4-da y scree ni n g 
peri o d a n d a 4 8 -wee k d o u ble -bli n d pri mar y  treat me nt 
peri o d.  F oll o wi n g c o m pleti o n of t he W ee k 4 8 visit, 
patie nts will re mai n o n bli n de d i n vesti gati o nal pr o d uct a n d 
be see n at re g ular i nter vals u ntil all patie nts c o m ple te t he 
pri mar y treat me nt  peri o d at w hic h p oi nt all  patie nts will 
tra nsiti o n t o a n o pe n -la bel l o n g-ter m safet y e xte nsi o n 
( L T S E). 
St u d y  Peri o d:  P atie nts  will recei ve d o u ble-bli n d tre at me nt 
f or at le ast 4 8  wee ks.  P atie nts w h o h a ve c o m plete d t heir 
4 8 -wee k d o u ble bli n d tre at me nt peri o d will c o nti n ue 
d o u ble bli n d tre at me nt u ntil all r a n d o mize d p atie nts h a ve 
c o m plete d t heir p artici p ati o n i n t he 4 8 -wee k  treat me nt 
peri o d a n d t he d at a b ase f or  t hat peri o d is l oc ke d 
( a p pr o xi m atel y 3 ye ars).  Patie nts will t he n be gi ve n t he 
o pti o n  t o g o o n  o pe n -la bel tre at me nt. 
U p date d 
descri pti o n of 
st u d y peri o d. 
S y n o psis, 
O bjecti ves 6. 1 
Pri mar y 
O bjecti ves; 6. 2 
Sec o n dar y 
O bjecti ves, 6. 3, 
A d diti o nal 
O bjecti ves,  
:  I n patie nts wit h M o derate t o Se vere P B C: 
• 
T o e val uate t he p har mac o ki netics ( P K) of O C A a n d its 
c o nj u gates, gl yc o -O C A, ta ur o -O C A, a n d O C A gl uc ur o ni de  
 
Li ver bi oc he mistr y i ncl u di n g t otal bilir u bi n  
 
… as partate a mi n otra nsferase [ A S T], a n d 
ga m ma gl uta m yl tra nsa mi nase [ G G T  
 
 
 
Bi o mar kers of bile aci d s y nt h esis a n d 
h o me ostasis i ncl u di n g fi br o blast gr o wt h fact or 
1 9 ( F G F 1 9), 7 α h y dr o x y - 4-c h oleste n - 3-o ne 
( C 4), a n d plas ma a n d fecal bile aci ds  
 
T o assess t he P K/ P har mac o d y na mic ( P D) relati o ns hi p 
of O C A o n:  
 
A L P, t otal bilir u bi n, a n d a mi n otra nsferases  
 
Bile aci d h o me ostasis  
 
Safet y a n d t olera bilit y (e g pr urit us) 
 
 
• T o e val uate t he p har mac o ki netics ( P K) of O C A a n d its 
c o nj u gates, gl yc o -O C A, ta ur o -O C A, a n d met a b olite  O C A 
gl uc ur o ni de c o m p are d wit h pl ace b o  
 
Li ver bi oc he mistr y i ncl u di n g t otal a n d direct  
bilir u bi n  
 
… as partate a mi n otra nsferase [ A S T], a n d ga m ma 
gl uta m yl tra nsa mi nase [ G G T],), i nter n ati o n al 
n or m alize d r ati o (I N R), cre ati ni ne, al b u mi n, 
pl atelets    
 
Bi o mar kers of bile aci d s y nt hesis a n d 
h o me ostasis i ncl u di n g fi br o blast gr o wt h fact or 
1 9 ( F G F 1 9), 7 α h y dr o x y - 4-c h oleste n - 3-o ne 
( C 4), a n d plas ma bile aci ds 
 
T o assess t he P K/ P har mac o d y na mic ( P D) relati o ns hi p of 
O C A wit h : 
 
P K p ar a meters c o m p are d t o P D P ar a meters a n d 
S afet y a n d T oler a bilit y assess me nts ( a b o ve)    
 
Clarifie d 
st u d y 
o bjecti ves.  
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Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
• 
To assess clinical outcomes consistent with end-stage 
liver disease 
• 
To assess patient reported outcomes (Pruritus Visual 
Analogue Scale [VAS], PBC-40, EQ 5D-5L, Chronic 
Liver Disease Questionnaire [CLDQ]) 
• 
To assess clinical events consistent with end-stage liver 
disease 
Synopsis, 
Methodology 
and Section 7.1. 
Overall Study 
Design 
Patients will be screened for up to ≤14 days… 
Patients will be screened ≥14 days but not more than 
28 days… 
Extended to 
14 days to 
satisfy PMR 
for 2 baseline 
measurement
s. 
Synopsis,  
Double-Blind 
Treatment 
Period, 7.1, 
Overall Study 
Design 
Double-Blind Primary Treatment Period 
… (ie, Day 1 through Week 48), clinic visits will occur 
approximately every 6 weeks for the assessment of safety, 
tolerability, PK, and PD (trough).  At each visit, trough PK 
assessments will be performed in all patients participating 
in the study.  Serial PK sampling will be performed at 
Week 12 and only after a patient uptitrates.  Following 
completion of the Week 48 visit, patients will remain on 
blinded investigational product and be seen at regular visits 
every 3 months until all patients complete the 48 week 
primary treatment period. 
…  Double-Blind Treatment Period:  …(ie, Day 1 through 
Week 48), an initial safety visit will occur at Week 3.  
After the Week 6, subsequent clinic visits will occur 
approximately every 6 weeks for the assessment of safety, 
tolerability, PK, and PD.  At each visit (except screening 
and Week 3), fasting PK assessments will be performed in 
all patients participating in the study.  Serial PK sampling 
will be performed at Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week double-blind 
treatment period will continue double blind treatment 
until all randomized patients have completed their 48-
week treatment period and the database for that period is 
locked.  Patients will then be given the option to go on 
open-label treatment.   
Updated 
description of 
study period. 
Synopsis, Long -
term Open Label 
Extension Phase 
Long -term Open Label Extension Phase 
Once all patients have completed the double-blind 48 week 
primary treatment period, patients will have the option to 
continue into an open-label long term safety extension and 
all patients will receive OCA.  Visits in the LTSE will 
occur every 3 months for up to 5 years.  Patients on placebo 
during the primary treatment period will initiate study 
medication at 5-mg OCA once weekly and follow the 
dosing regimen based on their CP score.  Patients on OCA 
Section deleted. 
Updated 
description of 
study. 
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Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
during the primary treatment period will continue the dose 
that they are on once unblinded. 
Synopsis and 
Section 7.1.1, 
Study Design 
Diagram 
 
EOS = end of study; EOT = end of treatment, OCA = obeticholic acid 
*Initial dose titration of investigational product may occur at the Week 12 
Visit, or any study visit … 
 
Note: Initial dose titration of investigational product may be considered as 
early as the Week 12 visit, or any study visit thereafter for patients on all 
dosing regimens, based on …. 
Patients who complete Week 48 will continue double-blind treatment 
until all randomized patients have completed their participation in the 
48-week treatment period and the database for that period is locked. 
Updated 
study 
diagram. 
Synopsis, 
Dosing Regimen, 
Section,  7.3 
(Table 2) 
All patients will initiate investigational product once 
weekly with 5 -mg OCA or matching placebo.  Starting at 
Week 12, safety and tolerability of investigational product 
will be evaluated and, if tolerated, the patient can increase 
the dose to the next dose level as described below: 
• At Week 12, if investigational product is tolerated and 
laboratory assessments from the Week 6 visit do not 
indicate a safety concern, the patient will change the 
dosing frequency to 5 mg twice weekly, at least 3 days 
apart.   
 Following an additional 6 weeks of treatment, if 
investigational product is tolerated, patients may be up-
titrated to OCA 10 mg twice weekly at least 3 days 
apart, the maximum dose for patients with CP-C.  
 Following an additional 6 weeks of treatment, if 
tolerated, Patients with CP-B may titrate to a maximum 
dose of OCA 5 mg once daily, the maximum dose for 
patients with CP-B.  
All patients will initiate investigational product once weekly 
with 5 mg OCA or matching placebo.  Titration may be 
considered as early as the Week 12 Visit.  Following visit 
procedures at Week 12, if the investigational product is 
tolerated and laboratory assessments do not indicate a safety 
concern, the patient may up-titrate to OCA 5 mg twice 
weekly and may start the higher dose regimen no earlier 
than 2 days after they took their last dose.  Dosing will 
then occur at least 3 days apart.  Every 6 weeks thereafter, 
based on safety and tolerability assessments, patients can 
be considered for further up titration as described below.  
At each titration visit, the patient may start the higher 
dose regimen no earlier than 2 days after the prior dose. 
Patients with CP-B may titrate to a maximum dose of OCA 
5 mg once daily. 
 
Patients with CP-C may titrate to a maximum dose of 
OCA 10 mg twice weekly at least 3 days apart.  
 
Updated table 
for clarity. 
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Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
• 
If, during the course of the study, a patient transitions 
from CP- B to CP-C, or vice versa, the maximal dose 
for the new CP classification would apply. 
 
Planned OCA or Matching Placebo Dosing Regimen by 
Child-Pugh Score 
 
Child-Pugh B 
(Moderate Hepatic 
Impairment) 
Child-Pugh C 
(Severe Hepatic 
Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting Dose 
a (Day 1) 
5 mg 
once 
weekly 
matching 
placebo 
5 mg 
once 
weekly 
matching 
placebo 
Titration 1b 
(≥Week 12) 
5 mg 
twice 
weeklyc 
matching 
placebo 
5 mg 
twice 
weeklyc 
matching 
placebo 
Titration 2b 
(≥6 weeks 
after Titration 
1) 
10 mg 
twice 
weeklyc 
matching 
placebo 
10 mg 
twice 
weeklyc 
matching 
placebo 
Titration 3b 
(≥6 weeks 
after Titration 
2) 
5 mg 
once 
daily 
matching 
placebo 
NA 
matching 
placebo 
 
 
aStarting dose based on patient’s Child-Pugh Score at Screening. 
bPlanned titration regimen is shown; however, the titration of dose and/or 
frequency is dependent on patient tolerability and/or changes in Child-
Pugh Score at any time during the study. 
cDosing per the twice weekly schedule must be at least 3 days apart. 
 
Child-Pugh B 
(Moderate Hepatic 
Impairment) 
Child-Pugh C 
(Severe Hepatic 
Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting Dose 
(Day 1) 
5 mg 
once 
weekly 
matching 
placebo 
5 mg once 
weekly 
matching 
placebo 
Titration 1a  
5 mg 
twice 
weeklyb 
matching 
placebo 
5 mg 
twice 
weeklyc 
matching 
placebo 
Titration 2a  
10 mg 
twice 
weeklyb 
matching 
placebo 
10 mg 
twice 
weeklyc 
matching 
placebo 
Titration 3a  
5 mg 
once 
daily 
matching 
placebo 
NA 
NA 
 
aPlanned titration regimen is shown; however, the titration of dose 
and/or frequency is dependent on patient tolerability and/or changes in 
Child-Pugh Score at any time during the study 
bDosing per the twice weekly schedule must be at least 3 days apart. 
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Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
(insertion) 
If, during the course of the study, a patient transitions 
from CP- B to CP-C, or vice versa, the maximal dose for 
the new CP classification would apply.   If a patient 
demonstrates an improvement to CP-A, they should 
follow the dosing regimen for patients with CP-A. 
 
Over the course of the study, a patient’s CP category may 
change.  When a patient demonstrates a change in CP 
category, dosing should be reassessed and modified if 
appropriate.  Changes to the dosing regimen are not 
mandatory and should be based on clinical judgment and 
change in CP score.  The titration steps for CP-B and CP-C 
patients are identical with exception of the maximum allowed 
dose.  Therefore, if a patient changes CP class from B to C, or 
vice versa, the maximal dose for the new regimen will apply.  
If a patient improves to CP-A during the study, the maximal 
CP-B dose will still apply.  If a patient has not yet reached the 
maximal dose, the appropriate titration regimen should be 
followed.  
 
 
 
a Once a patient begins dosing with the new dosing regimen, 
titration should occur as described for the planned dosing 
regimen.  
b 
Dosing per the twice weekly schedule must be at least 3 
days apart. 
Added to 
provide 
more 
information 
on dosing. 
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Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 3: 0 4 Ja n 2 0 1 8  
 
Pa ge 1 0 0  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d Te xt ( Ve rsi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
S y n o psis a n d 
Secti o n 8. 2, Ke y 
I ncl usi o n 
Criteria  
2.  E vi de nce of cirr h osis i ncl u di n g at least o ne of t he 
f oll o wi n g: 
 Bi o ps y i n dicati n g cirr h osis or a me dical hist or y wit h 
hist ol o gical e vi de nce of cirr h osis   
 Cli nical e vi de nce c o nsiste nt wit h cirr h osis i ncl u di n g: 
es o p ha geal  varices, ascites, e nce p hal o pat h y,  or p ortal 
h y perte nsi o n  
   Li ver stiff ness as assesse d b y T E of > 1 6. 9 k Pa  
 
 
 
 
 
 
 
 
 
 
6.  A ge ≥1 8 years  
7.  Ta ki n g U D C A f or at least 1 2 m o nt hs (sta ble d ose f or 
≥3 m o nt hs) pri or t o Da y 1, or u na ble t o t olerate U D C A 
( n o U D C A f or ≥3 m o nt hs)  
8.  C o ntrace pti o n:  Fe male patie nts m ust be 
p ost me n o pa usal, s ur gicall y sterile, or if pre me n o pa usal 
(a n d n ot s ur gicall y sterile), be pre pare d t o use ≥1 
effecti ve met h o d of c o ntrace pti o n d uri n g t he st u d y a n d 
f or 3 0 da ys after t he e n d of treat me nt visit.  Effecti ve 
met h o ds of c o ntrace pti o n are c o nsi dere d t o be t h ose 
liste d bel o w: 
 
Barrier met h o d, ie, (a) c o n d o m ( male or fe male) 
wit h s p er mici de or  ( b) dia p hra g m, wit h 
s per mici de; or  
 
I ntra uteri ne de vice; or  
2.  E vi de nce of cirr h osis i ncl u di n g at least o ne of t he 
f oll o wi n g: 
 Bi o ps y res ults c o nsiste nt wit h P B C  St a ge 4   
 Li ver stiff ness as assesse d b y T E Me di a n V al ue 
≥1 6. 9  k Pa  
 Cli nical e vi de nce i n t he a bse nce of ac ute li ver f ail ure 
c o nsiste nt wit h cirr h osis i ncl u di n g: g astr oes o p h a ge al  
varices, ascites, r a di ol o gic al e vi de nce of cirr h osis 
( n o d ul ar li ver or e nl ar ge me nt of p ortal vei n a n d 
s ple n o me g al y) 
 C o m bi ne d l o w pl atelet c o u nt ( < 1 4 0 0 0 0/ m m 3) wit h 
 persiste nt decre ase i n ser u m al b u mi n, or  
 ele v ati o n i n pr ot hr o m bi n ti me/I N R ( n ot d ue t o 
a ntit hr o m b otic a ge nt use), or  
 ele v ate d bilir u bi n ( 2 × U L N)  
 
6.  Ta ki n g U D C A f or at leas t 1 2 m o nt hs (sta ble d ose f or 
≥3  m o nt hs) pri or t o Da y 1, or u na ble t o t olerate or 
u nres p o nsi ve t o  U D C A ( n o U D C A f or ≥3 m o nt hs)  
 
 
Pr o vi de d 
m ore details 
re gar di n g 
i ncl usi o n 
re q uire me nts.  
O nl y liste d 
i ncl usi o ns 
directl y 
relate d t o 
P B C i n 
s y n o psis.   
Ot her cri teria 
were delete d 
fr o m 
s y n o psis b ut 
re mai n i n t he 
mai n b o d y.  
O nl y criteria 
wit h c ha n ges 
are prese nte d 
i n t his S O C. 
T he f ull 
i ncl usi o n/ 
e xcl usi o n list 
is i n t he b o d y 
of t he 
pr ot oc ol.  
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Key Change 
 
Vasectomy (partner), or  
 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection, or 
 
Abstinence, if in line with the preferred and usual 
lifestyle of the patient (where abstinence is defined 
as refraining from heterosexual intercourse) 
9. Must provide written informed consent and agree to 
comply with the study protocol. 
Synopsis and 
Section 8.3, Key 
Exclusion 
Criteria 
4. History or presence …: 
 
Hepatitis C virus infection RNA positive 
5. 
In the opinion of the Investigator, fluctuating or 
rapidly deteriorating hepatic function during the 
Screening period 
6. Patients with history or presence of hepatorenal or 
hepatopulmonary syndrome 
7. Patients with significant active infection (ie 
spontaneous bacterial peritonitis) 
8. Patients with known or suspected hepatocellular 
carcinoma 
9. History of known or suspected clinically significant 
hypersensitivity to OCA or any of its components 
10. Participation in another investigational product, 
biologic, or medical device study within 30 days prior 
to Screening.  Participation in a previous study of OCA 
is allowed with 3 months washout prior to enrollment 
in this study 
4. Hepatic encephalopathy (as defined by a West Haven 
score of ≥2) 
5. 
History or presence …: 
 
Hepatitis C virus infection and RNA positive 
6. In the opinion of the Investigator, fluctuating or rapidly 
deteriorating hepatic function prior to randomization 
Added 
additional 
key exclusion 
criteria #4.  
Other criteria 
were deleted 
from 
synopsis but 
remain in the 
main body.  
Only criteria 
with changes 
are presented 
in this SOC. 
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Key Change 
11. Mental instability or incompetence, such that the 
validity of informed consent or ability to be compliant 
with the study is uncertain 
12. UDCA naïve (unless contraindicated). 
Synopsis, 
Duration of 
Treatment 
The study will include a 14-day screening period and a 48 
week double -blind primary treatment period.   Following 
completion of the Week 48 visit, patients will remain on 
blinded investigational product and be seen at regular visits 
every 3 months until all patients complete the double-blind 
48 week primary treatment period.  Hence, depending on 
the rate of patient enrollment, patients will be exposed to 
investigational product for a minimum of 1 year up to 
approximately 2 years during the blinded period.  
Following completion of the blinded period, Patients will 
have the option to continue into an extension during which 
they will receive open label treatment and be seen at regular 
visits every 3 months for up to 5 years.  
Patients who have completed their 48-week double blind 
treatment period will continue double blind treatment 
until all randomized patients have completed their 
participation in the 48-week treatment period and the 
database for that period is locked (approximately 
3 years).  Patients will then be given the option to go on 
open-label treatment.    
Updated 
description of 
study. 
Synopsis, 
Criteria for 
Evaluation and 
11, Overview of 
Assessments, 
Table 5, 
Additional 
Objectives 
PD Parameters;   
plasma, fecal 
bile acids 
PK 
Plasma 
concentrations 
of OCA and its 
conjugates, 
glyco-OCA, 
tauro-OCA; and 
metabolite OCA 
glucuronide 
Clarified 
study 
parameter for 
evaluation. 
Changes in MELD and in CP score  
 
Changes in MELD and in CP score and 
components of the CP score 
 
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Key Change 
PD parameters 
fecal bile acids 
PK/PD parameters 
bile acids 
Markers of inflammation 
IL-6, hs-CRP, 
TNF-α, IgM, 
IgA, IgG, CK 
18 M30, and 
others as 
determined 
during course 
of study.   
 
IL-6, hs-CRP, 
TNF-α, IgM, IgA, 
IgG, CK 18 M30,  
PK/PD relationship of OCA and liver 
biochemistry 
OCA and its 
conjugates, 
glyco-OCA 
tauro-OCA; 
and OCA 
glucuronide 
PK/PD relationship 
PK parameters 
compared to PD 
Parameters and 
Safety and 
Tolerability 
assessments 
(above) 
PK/PD relationship of OCA and bile acid 
homeostasis 
Bile acids 
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Key Change 
Clinical Outcomes 
Incidence and 
time to first 
occurrence of 
any of the 
following:  all-
cause 
mortality, 
liver-related 
events 
resulting in 
death, hepatic 
failure leading 
to liver 
transplant, 
variceal bleed, 
hepatic 
encephalopath
y, spontaneous 
bacterial 
peritonitis, 
ascites, 
hepatocellular 
carcinoma 
Clinical Events 
Death (all-cause 
and liver-related), 
liver transplant, 
Model of end stage 
liver disease 
(MELD) score ≥15 
(for patients with 
MELD ≤12 at 
baseline), 
Hospitalization for 
new onset or 
recurrence of: 
variceal bleed, 
hepatic 
encephalopathy, 
spontaneous 
bacterial peritonitis, 
Uncontrolled 
ascites, and HCC. 
Synopsis, 
Statistical 
Methods, Safety 
Analyses 
The absolute change from baseline will also be 
summarized.  No inferential comparison of safety endpoints 
will be performed. 
The absolute change from baseline will also be summarized.  
No inferential comparison with formal statistical hypothesis 
testing will be performed for safety endpoints. 
Clarified 
statistical 
methods. 
Synopsis, 
Statistical 
Methods, 
Additional 
Efficacy 
Analyses 
The following clinical outcomes will be captured in the 
study: 
 
All-cause mortality 
 
Liver related death 
 
Liver transplant 
The following endpoints consistent with end-stage liver 
disease will be captured in the study: 
 
Time to death (all cause) 
 
Time to liver-related death 
 
Time to liver transplant 
Clarified 
statistical 
methods. 
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Key Change 
 
Variceal bleed 
 
Hepatic encephalopathy 
 
Bacterial peritonitis 
 
Ascites 
 
Hepatocellular carcinoma 
 
 
 
 
 
 
 
 
 
 
The incidence and time to first occurrence of any of the 
above listed clinical outcomes will be summarized ….The 
tabulation will include the KM estimate of the medians and 
corresponding 95% confidence intervals (CIs), if the 
medians can be estimated.  … The hazard ratio and 95% CI 
will be estimated based on a Cox regression model 
stratified by randomization strata. 
In addition, the incidence and time to each of the above 
outcomes  will be summarized by treatment group using the 
same methods as defined above.   
 
Model of end stage liver disease (MELD) 
score ≥15 (for patients with MELD ≤12 at 
baseline) 
 
Hospitalization (as defined by a stay of 
24 hours or greater) for new onset or 
recurrence of: 
 
Time to variceal bleed 
 
Time to hepatic encephalopathy (as 
defined by a West Haven score of ≥2) 
 
Time to spontaneous bacterial peritonitis 
(confirmed by diagnostic paracentesis) 
 
Time to uncontrolled ascites (diuretic 
resistant ascites requiring therapeutic 
paracentesis at a frequency of at least twice 
in a month) 
The incidence and time to first occurrence of the above listed 
clinical outcomes will be summarized ….The tabulation will 
include the KM methodology using 25th, 50th (median), and 
75th percentiles with associated 2-sided 95% confidence 
intervals (CIs), as well as percentage of censored 
observations.  ….  The hazard ratio and 2-sided 95% CI will 
be estimated based on a Cox regression model stratified by 
randomization strata. 
In addition, the incidence and time to each of the above 
clinical events, and the incidence and time to occurrence 
of hepatocellular carcinoma (HCC) will be summarized by 
treatment group using the same methods as defined above. 
 
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Key Change 
Synopsis and 
Section 15.2, 
Sample Size, 
To reasonably characterize the PK of OCA in patients with 
hepatic impairment, a simulation-based approach estimated 
a requirement of approximately 20 patients per OCA 
treatment group assuming a 15% discontinuation rate.  Ten 
patients on placebo will be included as a comparator.  The 
assessment was based on 80% powering for the 90% 
confidence interval of the geometric mean ratio of Total 
OCA (sum of OCA, glyco OCA, and tauro OCA). 
To reasonably characterize the PK of OCA in patients with 
hepatic impairment, a simulation based approach estimated a 
requirement of approximately 20 patients in the OCA 
treatment group assuming a 15% discontinuation rate.  Ten 
patients on placebo will be included as a comparator.  An 
additional 20 patients will be enrolled to support safety 
and efficacy evaluations.  Therefore, approximately 
50 patients (including at least 20% of patients with CP-C) 
will be randomized. 
 
5.2,  Nonclinical 
Experience with 
Obeticholic Acid 
Insertion 
Intercept Pharmaceuticals, Inc. (the Sponsor) has 
completed a standard battery of nonclinical safety 
pharmacology and toxicology studies.  No major 
nonclinical safety effects have been seen other than 
pharmacologic hepatic effects observed at high doses.  
These pharmacologic hepatic effects are consistent with 
the detergent effects of a bile acid at exceedingly high 
hepatocellular exposure. 
Added 
section to 
briefly 
address 
nonclinical 
studies. 
5.3, Clinical 
Development of 
Obeticholic Acid 
As of 31 Jan 2016, approximately 1726 patients have 
received at least 1 dose of OCA.  Of these, 844 were 
healthy volunteers, 458 patients had PBC, 330 patients had 
nonalcoholic steatohepatitis, 41 patients had diabetes 
mellitus/ nonalcoholic fatty liver disease, 33 patients had 
alcoholic cirrhosis/portal hypertension, and 20 patients had 
primary sclerosing cholangitis (PSC). 
As of 31 Jan 2017, approximately 2186 patients have 
received at least 1 dose of OCA.  Of these, 844 were healthy 
volunteers, 525 patients had PBC, 686 patients had 
nonalcoholic steatohepatitis (NASH), 41 patients had 
diabetes mellitus/ nonalcoholic fatty liver disease (NAFLD), 
33 patients had alcoholic cirrhosis/portal hypertension, 
52 patients had primary sclerosing cholangitis (PSC), and 
5 patients had biliary atresia. 
Updated 
numbers of 
patients who 
have received 
OCA. 
5.4, 
 
Rationale 
for Study Design 
and Dose for 
Investigational 
Product 
 
5.4  Rationale for Study Design and Dose for 
Investigational Product 
Inserted new 
header for 
clarity  
5.4.1, Rationale 
for Study Design 
Patients with moderate or severe hepatic impairment (Child 
Pugh B or C) will constitute approximately 20% of the 
patients included in the ongoing clinical outcomes Study 
747 302 which was specifically designed to confirm clinical 
benefit across the spectrum of disease including patients 
The 747-401 study is specifically designed to confirm 
clinical benefit across the spectrum of disease including 
patients with hepatic impairment.  Data collected from Study 
747 401 will serve as a bridge to the 747-302 study. 
Clarified the 
intent of the 
401 study. 
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Key Change 
with hepatic impairment.  Data collected from Study 747 
401 will serve as a bridge between the two studies. 
5.4.2, Rationale 
for Obeticholic 
Acid Dose and 
Duration 
Results from the hepatic impairment study (747-103) 
indicate that plasma exposure increases, in comparison to 
subjects with normal liver function, with increasing severity 
of impairment as classified by Child Pugh A (CP A), CP B 
or Child Pugh C (CP C) scores by 1.4-, 8.0-, and 13 fold, 
respectively.  No apparent impact on the overall safety 
profiles were observed in this study.  Liver exposure, 
however, modestly increased by 1.1-, 1.5, and 1.7-fold, 
respectively, as shown in simulations using a physiologic 
PK model developed to characterize OCA and its 
conjugates.  Together, the results from these analyses 
suggest that the doses of OCA administered to patients with 
moderate or severe hepatic impairment should be modestly 
lower than those for patients with normal hepatic function 
to achieve similar hepatic exposure. 
 
 
 
(insertion) 
 
 
 
 
 
 
 
 
 
 
 
Simulations using a physiologic PK model predicted changes in 
systemic and liver OCA concentrations associated with changes 
in the severity of hepatic impairment (CP Score).  Model 
simulations predicted that for mild (Child-Pugh A [CP-A]), 
moderate (Child-Pugh B [CP-B]), and severe (Child-Pugh C 
[CP-C]) hepatic impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to patients with normal 
hepatic function, whereas total OCA liver concentrations 
increase 1.1-, 1.5-, and 1.7-fold, respectively.  Because the liver is 
the primary site of action for the safety and efficacy of OCA, it is 
important to account for the differences in systemic and liver 
exposure when assessing effective doses.  It is also important to 
note that while hepatically impaired (CP-B and C) patients 
treated with OCA in Phase 1 and 2 studies experienced plasma 
OCA exposures >10-fold higher than those in healthy patients, 
no apparent impact on the overall safety profile was observed, 
consistent with only a modest increase in liver exposure of OCA 
associated with hepatic impairment.  Together, the results from 
these analyses suggest that the doses of OCA administered to 
patients with moderate or severe hepatic impairment should be 
modestly lower than those for patients with normal hepatic 
function to achieve similar hepatic exposure.    
Therefore, the current FDA-approved prescribing information 
for OCA includes a modified dosing regimen in patients with 
moderate and severe hepatic impairment that is designed to 
achieve liver exposures in these patients that would be similar to 
non-hepatically impaired patients through initiation at a lower 
Added 
rationale for 
OCA dosing 
in hepatically 
impaired 
patients. 
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Key Change 
 
Therefore, a modified dosing regimen is recommended for 
OCA in patients with moderate and severe hepatic 
impairment that is designed to initiate doses to achieve 
plasma exposures levels of OCA similar to those without 
hepatic impairment or CP-A.  After which, subjects may 
then titrate their doses upwards to achieve liver exposures 
that would be similar in both patient populations.  This 
modified dosing regimen was selected based on the 
established safety and tolerability of OCA in subjects with 
PBC, along with PK/PD modeling and simulations.  
Patients will initiate dosing at OCA 5 mg once weekly.  
Starting at Week 12, if the prior dose regimen was 
tolerated, the patients will increase the dosing frequency to 
5 mg twice weekly (at least 3 days apart).  After 6 weeks, a 
second titration may occur to OCA 10 mg twice weekly as 
long as tolerated.  Patients classified as CP B may further 
titrate their dose upwards to OCA 5 mg once daily after 
6 weeks on the OCA 10 mg twice weekly regimen. 
dose (5 mg OCA once-weekly) followed by gradual up-titration 
(Section 7.3).   
The dosing regimen in this study follows the FDA-approved 
prescribing information, with the exception of the maximum 
allowed dose in patients with moderate impairment.  While the 
prescribing information allows for a maximum dose of 10 mg 
twice weekly for patients with moderate impairment, the 
protocol allows for a maximum dose of 5 mg once daily.  The 
choice of 5 mg once daily is supported by the estimated steady-
state liver and plasma exposure of total OCA for patients with 
moderate hepatic impairment receiving a 5 mg once daily dose 
relative to healthy patients receiving a 10 mg dose.  A maximum 
allowed dose of 5 mg once daily in patients with moderate 
hepatic impairment is estimated to achieve liver exposure 
similar to non-hepatically impaired patients receiving a 10 mg 
daily dose and maximize efficacy in this patient population. 
 
7.1.2, Schedule 
of Study 
Procedures 
Schedule of Study Procedures (Double-Blind Treatment 
Period) 
Schedule of Study Procedures 
Updated 
procedures to 
match 
updated study 
design. 
7.1.2, Schedule 
of Study 
Procedures, Visit 
Windows 
≤-1 to -14 days 
-28 to -14 days 
Updated 
procedures to 
match 
updated study 
design. 
7.1.2, Schedule 
of Study 
Procedures, Visit 
Weeks Row 
Week 3: Safety Contact 
Week 48 
Under Long-Term Treatment 
Week 3 
Week 48/ET/EOS/EOT 
Every 3 months 
Week 3 
telephone/em
ail contact 
visit now a 
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Key Change 
laboratory 
safety visit. 
7.1.2, Schedule 
of Study 
Procedures 
(Insertion) 
 
Dose Titration 
IL-6, hs-CRP, TNF-α, IgM, IgG, IgA, CK-18-M30, others 
as determined during course of study 
Fecal PK Analysis 
TE Fibroscan® 
ELF 
MELD 
PK trough Collection 
Column: Long-Term Treatment 
Procedures: Medical and Surgical Procedures 
Dose Titration Assessment 
Markers of Inflammation: IL-6, hs CRP, TNF-α, IgM, IgG, 
IgA, CK-18-M30 
 
 
 
TE/ELF (HA, P3NP, and TIMP 1) 
PK Fasting Collection 
Updated 
procedures to 
match 
updated study 
design 
7.1.2, Table 1, 
Schedule of 
Study 
Procedures 
Footnotes 
a 
Patients should be contacted by telephone/email every 
3 weeks (±1 week) between clinic visits starting at Week 3 
and continuing to Week 48 to assess for AEs, concomitant 
medications, and verify that s/he is dosing as directed. 
b 
Visits should be based on Day 1. 
c 
The patient should be instructed to fast overnight (at 
least 8 hours) prior to each visit.  Fasting is required prior to 
all study visits (except Screening Visit 1) but water is 
permitted. 
d 
Medical history performed at Screening only.    
e 
The yearly physical exam will also include an 
assessment of smoking and alcohol consumption history 
and current habits for both.  Height will only be collected at 
Day 1 and Week 48.    
f 
Child-Pugh Score will be calculated based on ascites 
assessment, hepatic encephalopathy grade, and central 
laboratory evaluations per the Child-Pugh scoring system 
noted in the eCRF. 
g 
The EQ-5D-5L Quality of Life questionnaire is 
validated for use in multiple languages. If a validated 
aVisit schedule should be based on Day 1.  Day 1 visit 
must occur at least 2 weeks after screening visit. 
bPatients should be contacted by telephone/email every 
3 weeks (±1 week) between clinic visits starting at Week 9 
and continuing to Week 48 to assess for AEs, concomitant 
medications, medical/surgical procedures, and verify that 
s/he is dosing as directed. 
c Preferably, the patient comes in to the clinic for this 
visit.  Alternatively, site will telephone the patient for 
assessments and home health nurse will visit to draw 
safety labs. 
d Visit should occur 3, 4, or 5 days after taking the Week 6 
dose. 
e 
The patient should be instructed to fast overnight (at least 
8 hours) prior to each visit.  Fasting is required prior to all 
study visits, including screening, but water is permitted. 
f Height and assessment of smoking and alcohol 
consumption history and current habits will be assessed at 
Screening and Week 48.   Assessment of smoking and 
Updated 
procedures to 
match 
updated study 
design 
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Key Change 
translation is not available in the local language required for 
a specific study patient, the data from that questionnaire 
will not be collected.  The CLDQ measures change over 
time in patients with chronic liver disease.  
h 
Patients will be instructed to begin dosing on the Day 1 
visit after completing all study assessments. (ie, on Day 1).  
Patients will be instructed to take investigational product at 
approximately the same time of day.  Patients must be 
instructed to swallow the tablet whole; they must not chew, 
divide, or crush the tablet. 
i 
Initial dose titration of investigational product may 
occur at the Week 12 Visit, or any study visit thereafter for 
patients on all dosing regimens, based on CP score, 
tolerability and safety laboratory tests from the previous 
visit.  Subsequent dose titration(s) may occur no earlier than 
6 weeks after the previous dose titration and will be based 
on tolerability and CP score. 
j 
Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry and at every 
visit.  If positive, a confirmatory blood test must be 
performed at the central laboratory.  If the confirmatory 
blood test is also positive, the patient may not continue in 
the study.  (Additional testing may be conducted where 
required, regionally) 
alcohol consumption history and current habits will be 
assessed quarterly after Week 48. 
g 
Child-Pugh Score will be calculated based on ascites 
assessment, hepatic encephalopathy grade, and central 
laboratory evaluations per the Child-Pugh scoring system 
noted in the eCRF. 
h 
The EQ-5D-5L Quality of Life questionnaire is validated 
for use in multiple languages. If a validated translation is not 
available in the local language required for a specific study 
patient, the questionnaire will not be collected.  The CLDQ 
measures change over time in patients with chronic liver 
disease.  
i 
New investigational product bottles will be dispensed 
if the patient is titrated. Unless up-titrated, patients are 
expected to use up each investigational product bottle 
before a new bottle will be dispensed.  No new bottles will 
be dispensed if dose frequency is changed.  Patients will be 
instructed to begin dosing on Day 1, after completing all 
study assessments.  Patients will be instructed to take 
investigational product at approximately the same time of 
day.  Patients must be instructed to swallow the tablet whole; 
they must not chew, divide, or crush the tablet. 
j 
Dose titration of investigational product may occur 
starting after the Week 12 Visit, or any study visit thereafter 
for patients on all dosing regimens, based on CP score, 
tolerability and safety laboratory tests from the previous visit.  
Subsequent dose titration(s) may occur no earlier than 
6 weeks after the previous dose titration and will be based on 
tolerability and CP score.   
k Urine β-hCG pregnancy tests must be performed in females 
of childbearing potential prior to entry and at every visit 
(except Week 3).  If positive, a confirmatory blood test must 
be performed at the central laboratory.  If the confirmatory 
blood test is also positive, the patient may not continue in the 
study.  (Additional testing may be conducted where required, 
regionally). 
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l The patient will be given the option to return to the 
clinic the following morning for the 24-hour postdose 
sample or samples can be obtained by a home health care 
designee.  Patients who are discontinued from 
investigational product prior to completion of the study 
are encouraged to continue to follow the regular visit 
schedule, with the exception of PK sampling.   
m The noninvasive radiological liver fibrosis 
measurement devices (such as, FibroScan® device 
[Echosens; Paris, France]) will be used at all study sites to 
collect hepatic stiffness measurements. 
n Patients will complete a TE/ELF and ultrasound 
assessment, every 6 months (±2 weeks) after Week 48. 
O ECG and urine dipstick will be done yearly 
(±2 weeks) after Week 48 Visit. 
p 
Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds:  Unless HCC has already been confirmed by 
biopsy, a second confirmatory image (eg, MRI) should be 
obtained to confirm suspected HCC. 
7.1.3, Study 
Duration 
The study will include a 14-day screening period and a 
48 week double-blind primary treatment period.  Following 
completion of the primary treatment period, patients will 
remain on blinded investigational product and be seen at 
regular intervals until all patients complete the primary 
treatment period (Figure 1).  Patients will have the option to 
continue into an open-label LTSE after all patients have 
completed the Week 48 procedures in which they will 
receive open-label treatment and be seen at regular visits 
every 3 months for up to 5 years. 
Patients will receive double-blind treatment for at least 
48 weeks.  Patients who have completed their 48-week 
double blind treatment period will continue double blind 
treatment until all randomized patients have completed 
their 48-week treatment period and the database for that 
period is locked (approximately 3 years).  Patients will 
then be given the option to go on open-label treatment. 
Updated 
description of 
study period. 
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7.3, Planned 
Dosing Regimen 
All patients will initiate investigational product once 
weekly with 5-mg OCA or matching placebo.  Starting at 
Week 12, safety and tolerability of investigational product 
will be evaluated and, if tolerated, the patient can increase 
the dose to the next dose level as described below 
(Table 2): 
• 
At Week 12, if investigational product is tolerated and 
laboratory assessments from the Week 6 visit do not 
indicate a safety concern, the patient will change the dosing 
frequency to 5 mg twice weekly, at least 3 days apart.  
 
Following an additional 6 weeks of treatment, if 
investigational product is tolerated, patients may be up 
titrated to OCA 10 mg twice weekly at least 3 days apart, 
the maximum dose for patients with CP-C 
 
 
Following an additional 6 weeks of treatment, if 
tolerated, patients with CP-B may titrate to a maximum 
dose of OCA 5 mg once daily, the maximum dose for 
patients with CP-B. 
 
All patients will initiate investigational product once weekly 
with 5-mg OCA or matching placebo.   Titration may be 
considered as early as the Week 12 visit.  Following visit 
procedures at Week 12, if the investigational product is 
tolerated and laboratory assessments do not indicate a safety 
concern, the patient will up-titrate to OCA 5 mg twice 
weekly and may start the higher dose regimen no earlier 
than 2 days after they took their last dose.  Dosing will 
then occur at least 3 days apart.  Every 6 weeks thereafter, 
based on safety and tolerability assessments, patients can 
be considered for further up titration as described below 
(Table 3).  At each titration visit, the patient may start the 
higher dose regimen no earlier than 2 days after the prior 
dose. 
 
Patients with CP-C may titrate to a maximum dose of OCA 
10 mg twice weekly at least 3 days apart.  
Patients with CP-B may titrate to a maximum dose of OCA 
5 mg once daily. 
Clarified 
dosing 
regimen. 
7.4, Dose 
Adjustment 
Criteria, 
Scheduled Dose 
Titration 
The first dose titration for any patient may occur no earlier 
than 12 weeks following initiation of OCA or matching 
placebo. 
After initiation of OCA or matching placebo, titration may 
be considered as early as the Week 12 visit.   
Clarified 
dosing 
regimen. 
7.4.1, Pre-
Titration 
Tolerability 
Assessment 
Requirements 
Tolerability of investigational product must be assessed 
prior to titrating a patient to a higher dose.  A review of 
AEs and available safety laboratory results (eg, chemistry, 
hematology, and coagulation) obtained within 
approximately 6 weeks of the up-titration visit must be 
performed as part of the investigational product tolerability 
assessment, prior to any planned up-titration in 
investigational product (eg, Week 6, laboratory results 
should be reviewed prior to titration at Week 12).  If for any 
reason, laboratory results are not available at the time of the 
Tolerability of investigational product must be assessed prior 
to titrating a patient to a higher dose.  To determine if a 
patient is eligible for a dose up-titration refer to 
Section 7.3 
Clarified 
dosing 
regimen. 
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Key Change 
planned up titration visit, additional laboratory samples 
must be obtained and reviewed, prior to up titrating the 
patient to a higher dose. 7.3 
To be eligible for a dose up-titration, patients should not be 
experiencing significant AEs that are suspected to be 
related to investigational product (eg, severe pruritus) or 
displaying other symptoms that may indicate intolerability 
of investigational product. 
7.4.2., Safety 
Criteria for 
Adjustment or 
Stopping Doses 
 
Investigational product may be temporarily decreased (eg, 
by decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability concerns.  The 
dose of investigational product should be resumed to the 
maintenance dose in a blinded manner once the issues 
relating to the lack of tolerability are resolved.   
Subjects who discontinue investigational product are 
expected to continue in the study (and follow the regular 
visit schedule) until the end of the study, and the study will 
only terminate at the time. 
 
This 
information 
has been 
incorporated 
into Section 
8.4, which 
was renamed  
8.4. Dose 
Adjustment, 
Interruption, 
and 
Withdrawal 
from 
Investigation
al Product or 
Study and 
additional 
text was 
added.  
8.4,  Dose 
Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
8.4  Patient Withdrawal Criteria 
 
(Insertion) 
Dose Adjustment, Interruption, and Withdrawal from 
Investigational Product or Study 
Investigational product may be temporarily decreased 
(eg, by decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability concerns.  The 
dose of investigational product should be resumed to the 
maintenance dose in a blinded manner once the issues 
relating to the lack of tolerability are resolved.   
Section 
revised to 
integrate 
withdrawal 
criteria in one 
section of 
protocol.  
Text was 
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Key Change 
Patients who are discontinued from investigational 
product prior to completion of the study are encouraged 
to continue to follow the regular visit schedule, with the 
exception of PK sampling, but may withdraw consent at 
any time. 
previously in 
Section 7.4.2. 
8.4.1. 
Reasons 
for Additional 
Monitoring or 
Mandatory 
Interruption of 
Investigational 
Product 
8.4.1. 
Reasons for Mandatory Discontinuation of 
Investigational Product 
Moved to 8.4.2 
 
 
8.4.1. 
Reasons for Additional Monitoring or Mandatory 
Interruption of Investigational Product 
Heading text 
updated.  
8.4.1.1, Reasons 
for Additional 
Monitoring 
Related to Liver 
Chemistries 
8.4.1.1. Pregnancy 
8.4.1.1. Reasons for Additional Monitoring Related to 
Liver Chemistries 
Patients who develop ALT or AST >2x baseline (and 
>ULN) or total bilirubin >1.5x baseline (and >ULN) 
should have repeat testing within 48 to 72 hours to 
confirm values.  Patients with persistent elevations (eg, 
additional lab testing per Investigator discretion) should 
be closely monitored.  Concomitant elevations in total 
bilirubin or INR with persistent increases in ALT or AST 
should also be closely monitored. 
Pregnancy 
moved to 
Section 
8.4.1.3.  New 
Section with 
text added. 
8.4.1.2. Reasons 
for 
Investigational 
Product 
Interruption 
Related to 
Elevated Liver 
Chemistries 
(Insertion) 
8.4.1.2. Reasons for Investigational Product Interruption 
Related to Elevated Liver Chemistries 
Development of any of the following clinical laboratory 
values, without explanation, during the study mandates 
investigational product interruption: 
• 
AST and/or ALT >3× baseline (and >ULN) 
• 
Total bilirubin >2× baseline (and >ULN) 
Repeat testing within 48 to 72 hours to confirm the 
abnormalities and to determine if they are increasing or 
decreasing should be performed.  Detailed adverse event 
information should also be collected, and the patient 
should be investigated for possible causes of the liver 
chemistry changes, as appropriate.  The Investigator 
New Section 
added to meet 
PMR 
requirements. 
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Key Change 
should obtain a history of concomitant medications 
(including nonprescription medications and herbal and 
dietary supplement preparations) and other possible 
causes of liver enzyme and bilirubin increases.  Any 
potentially hepatotoxic medications should be identified 
and discontinued if advisable.  
If symptoms persist or repeat testing shows AST or ALT 
>3× baseline (and >ULN) or total bilirubin >2× baseline 
(and >ULN), patients should be followed as clinically 
indicated depending on other laboratory and clinical signs 
and symptoms.   
For the purposes of this protocol, if the above referenced 
significant elevation in liver enzyme or bilirubin levels 
resolve following interruption of investigational product 
and no other cause for the elevation is identified, the 
elevations should be assumed to be related to 
investigational product and investigational product 
should be discontinued.  If the liver enzyme or bilirubin 
levels do not resolve following interruption of 
investigational product and no other cause for the 
elevation is identified, it may be assumed that the 
elevations were due to disease progression and the patient 
may be re-challenged following a discussion between the 
Investigator or designee and the Sponsor. 
Elevation of liver enzymes or bilirubin is based on 
comparison to baseline values defined as the mean of all 
available Screening and Day 0 values, which are the mean 
of all available evaluations prior to the first 
administration of investigational product.  At least 2 of 
these samples will be obtained a minimum of 2 weeks 
apart during the Screening period.  Elevations that occur 
gradually over the course of the study may be indicative 
of disease progression and should be assessed as clinically 
appropriate.  Liver enzyme and bilirubin elevations that 
occur over a shorter time, such as within a 6-month 
period, should be evaluated for drug-induced liver injury 
as provided in the guidelines below. 
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Key Change 
If at any time a patient develops signs or symptoms of 
hepatotoxicity such as new onset fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>7%) in combination with 
elevations in liver enzymes, investigational product should 
be interrupted and liver enzymes monitored until signs or 
symptoms resolve.  
Patients who develop evidence of severe drug-induced 
liver injury that is suspected to be causally related to the 
investigational product should be discontinued from 
investigational product and should not be rechallenged.  
Severe drug-induced liver injury includes, but is not 
limited to, functional hepatic impairment, as indicated by 
rising bilirubin or INR that cannot be explained by 
progression of disease.  Natural progression of the 
underlying condition and other causal factors such as a 
common bile duct stone or development of other 
concurrent liver disease should be considered before the 
investigational product is permanently discontinued.  
If after all investigations and actions outlined above have 
been completed, the investigator determines that the 
elevations in liver biochemistries are considered not 
related to investigational product, the Sponsor must be 
contacted before investigational product can be 
reinitiated.  Follow-up procedures for patients resuming 
treatment, including laboratory evaluations and physical 
examinations, must be performed after a maximum of 2 
weeks of retreatment.  Results must be reported to the site 
as soon as possible so the Investigator can determine if it 
appropriate for the patient is to continue treatment.   
The Medical Monitor must be contacted in all cases of 
persistent liver biochemistry elevations. 
All hepatic injury events, regardless of relationship to 
investigational product, will be adjudicated by the 
Hepatic Safety Committee (see Section 15.9) 
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Key Change 
8.4.1.3, 
Pregnancy 
(Insertion) 
Whenever the site is notified of a possible pregnancy, the 
patient should be asked to come in for an unscheduled visit 
to perform a serum pregnancy test.  If a female patient 
becomes pregnant, the patient must stop taking 
investigational product immediately and be withdrawn from 
the study… 
8.4.1.3. Pregnancy 
If a female patient becomes pregnant, she must interrupt 
treatment with investigational product immediately, but 
should continue with the study visit schedule.  As 
described in Section 13.1.10 pregnancy is not considered 
an AE for reporting purposes.  The patient may restart 
investigational product when she is no longer pregnant or 
breastfeeding (if applicable) at the discretion of the 
Investigator and after discussion with the Medical 
Monitor as described in Section 13.1.10).  New baseline 
procedures should include pregnancy testing. 
Was Section 
8.4.1.1 
8.4.2,  Reasons 
for Mandatory 
Discontinuation 
of 
Investigational 
Product 
8.4.2. 
Other Reasons for Discontinuation of 
Investigational Product or Study Termination 
8.4.2. 
Reasons for Mandatory Discontinuation of 
Investigational Product 
Patients who undergo a liver transplant during the course 
of the study must discontinue investigational product and 
discontinue the study visit schedule.  However, these 
patients should be encouraged to consent to the 
semiannual telephone contact and/or continued record 
review only to allow for secondary outcome events data to 
be collected. 
Now Section 
8.4.3 and text 
added. 
 
8.4.2.3. Elevated Liver Enzymes 
Section deleted. 
Information 
in 8.4.1.2 
now covers 
this. 
8.4.3,  Other 
Reasons for 
Discontinuation 
of 
Investigational 
Product or Study 
Termination   
 
Subjects who discontinue investigational product are 
expected to continue in the study until the end of the study 
or at the discretion of the Sponsor.  If a patient experiences 
a suspected clinical outcomes event, he or she should 
continue the regular visit schedule and continue taking 
investigational product as long as the Investigator assesses 
it as safe.   
Early termination procedures should only be conducted if 
the patient withdraws consent (See Section 9.7.14).   
8.4.3. 
Other Reasons for Discontinuation of 
Investigational Product or Study Termination 
The following events are considered appropriate reasons for a 
patient to discontinue investigational product; however, 
these patients are expected to continue in the study until 
study termination (or at the discretion of the Sponsor): 
• 
Patient begins treatment with commercially available 
OCA. 
• 
The Investigator or Sponsor considers that it is 
advisable or in the best interest of the patient. 
Was Section 
8.4.2 and 
additional 
text added. 
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Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 3: 0 4 Ja n 2 0 1 8  
 
Pa ge 1 1 8  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d Te xt ( Ve rsi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
It is a gree d t hat, f or reas o na ble ca use, eit her t he 
I n vesti gat or or t he S p o ns or, ma y ter mi nate t his st u d y. 
T he f oll o wi n g e ve nts are c o nsi dere d a p pr o priate reas o ns f or 
a s u bject t o disc o nti n ue fr o m t he s t u d y: 
• 
T he occ urre nce of cli nic al or l a b or at or y A Es 
c o nsi dere d b y t he I n vesti g at or t o be cli nic all y i m p ort a nt 
s afet y c o ncer ns a n d rel ate d t o st u d y dr u g. 
• 
Wit h dr a w al of c o nse nt  
 
C o nse nt m a y be f ull y wit h dr a w n (i n w hic h c ase 
t he p atie nt disc o nti n ues b ot h i n vesti g ati o n al 
pr o d uct a n d st u d y visits a n d pr oce d ures).  
 
C o nse nt m a y be m o difie d t o disc o nti n ue st u d y 
visits b ut all o w se mi -a n n u al tele p h o ne c o nt act.  
 
C o nse nt m a y be m o difie d t o disc o nti n ue st u d y 
visits or se mi -a n n u al tele p h o ne c o nt act b ut all o w 
c o nti n ue d access t o me dic al rec or ds t o assess f or 
s us pecte d m aj or a d verse c ar di o v asc ul ar e ve nts 
( M A C E) a n d li ver-rel ate d cli nic al o utc o mes.  
 
E arl y ter mi n ati o n pr oce d ures s h o ul d be 
c o n d ucte d if t he p atie nt wit h dr a ws c o nse nt ( See 
Secti o n 9. 7 . 1 2) 
8. 4. 3. 1.
 
Wit h dra wal 
of C o nse nt t o 
C o nti n ue i n t he 
St u d y  
8. 4. 3. 1.  Wit h dra wal of C o nse nt  
…  t heir c o nse nt t o c o nti n ue i n t he st u d y at a n y ti me 
(I nserti o n) 
A reas o na ble eff ort m ust be ma de t o …  
8. 4. 3. 1.  Wit h dr a w al of C o nse nt t o C o nti n ue i n t he St u d y  
 
E arl y ter mi n ati o n pr oce d ures s h o ul d be c o n d ucte d if t he 
p atie nt wit h dr a ws c o nse nt ( See Secti o n 9. 7. 1 2 ). 
A d de d m ore 
i nf or mati o n 
re gar di n g 
wit h dra wal 
fr o m st u d y. 
8. 4. 3. 2.  L ost t o 
F oll o w -U p  
8. 4. 2. 2.  L ost t o F ol l o w-U p  
If a patie nt fails t o ret ur n t o t he cli nic f or a st u d y visit, a n d 
t he I n vesti gat or ceases t o ha ve c o ntact wit h t he patie nt, he 
or s he  will be wit h dra w n fr o m t he st u d y . 
8. 4. 3. 2.  L ost t o F oll o w -U p  
P atie nts will be  c o nsi dere d “l ost t o f oll o w u p ” o nl y a fter 
d oc u me nte d atte m pts t o re ac h t he p atie nt pr o ve 
u ns uccessf ul.   
U p date d te xt.  
8. 4. 4,  Patie nt 
Disc o nti n uati o n 
N otificati o n  
8. 4. 3. 
Patie nt Disc o nti n uati o n N otificati o n  
T he I n vesti gat or m ust n otif y t he S p o ns or as s o o n as 
p ossi ble if a n y patie nt pre mat urel y disc o nti n ues fr o m t he 
st u d y.  T he date w he n t he patie nt is wit h dra w n a n d t he 
8. 4. 4 . 
Patie nt Disc o nti n uati o n N otificati o n  
T he I n vesti gat or m ust n otif y t he S p o ns or as s o o n  as p ossi ble 
if a n y patie nt pre mat urel y disc o nti n ues fr o m t he st u d y.  T he 
date w he n t he patie nt is wit h dra w n a n d t he pri mar y reas o n(s) 
Clarifie d te xt.  
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primary reason(s) for discontinuation must be recorded in 
the eCRF; additional information may be requested by the 
Sponsor to complete a discontinuation narrative.  Patients 
will be considered “lost to follow up” only after reasonable, 
documented attempts to reach the patient prove 
unsuccessful.  In all cases, a reasonable effort must be made 
to determine the reason(s) that a patient fails to return for 
required study visits or discontinues from the study.  This 
information must be documented in the eCRF. 
for discontinuation must be recorded in the eCRF; additional 
information may be requested by the Sponsor to complete a 
discontinuation narrative.  This information must be 
documented in the eCRF. 
9.2, Concomitant 
Medications 
Patients must follow the medication restrictions outlined in 
the inclusion and exclusion criteria (Section ) during the 
study. 
Concomitant medications will be used at the discretion of 
the usual care provider (or Investigator if also the usual care 
provider).  … taken prior to (ie, within 30 days of 
Screening) and …  Concomitant medications should be 
stable prior to Day 1 (ie no change in dosing within 
3 months of screening). 
Concomitant medications (other than prohibited 
concomitant medications listed in Section 9.2.2) will be 
used at the discretion of the usual care provider (or 
Investigator if also the usual care provider).  … taken within 
30 days of Screening and during the study must be recorded 
in the source documents and …  Concomitant medications 
should be stable prior to Day 1. 
Clarified use 
of 
concomitant 
meds. 
9.2.1, Drug 
Interactions 
Patients taking bile acid sequestrants (BAS, including 
cholestyramine and its derivatives, colestipol, colesevelam, 
or other sequestrants) or aluminum hydroxide- or smectite-
containing antacids should be instructed to stagger their 
dosing of investigational product and UDCA, ensuring at 
least 4 hours between doses of the BAS and/or these 
antacids and the investigational product (and UDCA; ie, 
BAS should be administered at minimum 4 hours before or 
4 hours after investigational product administration). 
Bile acid sequestrants (BAS, including cholestyramine and its 
derivatives, colestipol, colesevelam, or other sequestrants) or 
aluminum hydroxide- or smectite-containing antacids should 
not be taken within 4 hours of taking investigational 
product (and UDCA if applicable), ie, BAS should be 
administered at minimum 4 hours before or 4 hours after 
investigational product administration).   
Clarified use 
of 
concomitant 
meds. 
9.2.2, Prohibited 
Medications 
Patients who continue with commercial OCA therapy must 
discontinue investigational product and are expected to 
continue through the end of the study (see Section 8.4.2).  
Fibric acid derivatives (fibrates) and other medication 
intended to lower blood triglyceride levels are also 
prohibited while on investigational product.) 
Patients who continue with commercial OCA therapy must 
discontinue investigational product and are expected to 
continue through the end of the study (see Section 8.4.3).   
Some patient 
may be 
expected to 
be on 
fibrates. 
9.4.2, Blinding 
The patients, Investigator, and study site staff will be 
blinded to… 
The Sponsor, patients, Investigator, and study site staff will 
be blinded to… 
 
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Key Change 
9.6, Restrictions 
Participation in another investigational product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the study is prohibited.   
Participation in another investigational product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the study is prohibited.  Previous 
exposure to OCA (as a study participant or received 
commercial OCA therapy) is allowed within 3 months 
prior to enrollment in this study 
Updated to 
include 
patients who 
may be on 
prescribed 
OCA and 
who received 
investigationa
l OCA as 
study 
participants. 
9.7.1, Visit 
Procedures 
(Insertion) 
Visit windows are specified in the Schedule of Study 
Procedures (Table 1). 
Added text 
pointing to 
visit windows 
for study 
procedures. 
9.7.2, Informed 
Consent 
Procedures 
…The patient must be willing and able to provide written 
informed consent (on hard copies or on electronic devices 
such as iPads) before entering the study.   
The patient must be willing and able to provide written 
informed consent (on hard copies) before entering the study.   
Updated 
language. 
9.7.3, Assessing 
Cirrhosis 
To determine which dosing regimen patients should follow, 
cirrhosis should be assessed by the Investigator at 
Screening Visit 1.  Acceptable methods of confirming (via 
medical history) or assessing cirrhosis for purposes of the 
study are defined as a patient who has documented 
evidence or presence of one or more of the following 
cirrhosis indicators: 
 
varices 
 
Patients will be dosed according to their CP Score 
calculated in the eCRF (see Section 14.1.1 and Table 12). 
Cirrhosis status should be reassessed as clinically indicated 
throughout the study.  Any change in cirrhosis status will 
necessitate re-evaluation of the dosing regimen. 
Acceptable methods of confirming (via medical history) or 
assessing cirrhosis for purposes of the study are defined as a 
patient who has documented evidence or presence of one or 
more of the following cirrhosis indicators: 
 
 
Gastroesophageal varices 
Clarified 
assessment 
instructions. 
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Key Change 
9.7.4, Screening 
Procedures 
Screening Procedures (-1 day to 14 days prior to Day 1) 
Screening Procedures (14 days to 28 days prior to Day 1) 
Updated 
procedures to 
match 
updated 
protocol 
design. 
The Screening Visit assessments must be performed within 
≤14 days prior to Day 1 to… 
The Screening Visit assessments must be performed ≥14 days 
prior to Day 1 to… 
The patient is to review and sign the ICF 
 
• 
Verify that the patient has fasted for at least 8 hours. 
 
Record fasting status in the source and eCRF 
 
If the patient reports having eaten within 
8 hours, document accordingly in the source and 
eCRF and remind the patient that fasting is 
required prior to all study visits 
• 
Obtain blood samples for serum chemistry, 
hematology, and coagulation tests. 
 
• 
Perform a physical examination. 
Perform a physical examination, including smoking and 
alcohol consumption history, and current habits for both. 
(Insertion) 
• 
Record the visit in IWRS 
 
Perform TE using the Fibroscan® TE device.  If TE has 
been done within 3 months of Day 1 and a 
report/adequate data are available, a pretreatment TE at 
Day 1 is not required.  If the TE cannot be performed on 
Day 1 (eg, device/technician unavailability, scheduling 
issues, TE data is needed to inform cirrhosis assessment, 
etc.), the procedure may be completed within the Day 1 
Visit window, (if data is needed for cirrhosis 
assessment) or as close as possible to the Day 1 Visit, 
preferably, after patient eligibility has been confirmed.  
Instruct the patient to take Day 1 dose on the day of this 
visit. 
 
 
Perform TE using the Fibroscan® TE device.  If the TE 
cannot be performed on Day 1 (eg, device/technician 
unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be 
completed within the Day 1 Visit window, (if data is 
needed for cirrhosis assessment) or as close as possible to 
the Day 1 Visit, preferably, after patient eligibility has 
been confirmed.  Instruct the patient to take Day 1 dose on 
the day of this visit. 
 
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Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 3: 0 4 Ja n 2 0 1 8  
 
Pa ge 1 2 2  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d Te xt ( Ve rsi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
• 
Pr o vi de kits a n d i nstr ucti o ns f or c ollecti o n of st o ol 
s peci me ns at h o me pri or t o t he Da y 1 visit 
 
Perf or m a n ultras o u n d f or H C C s ur veilla nce (if e q ui p me nt 
is u na vaila ble, sites s h o ul d ma ke e ver y atte m pt t o use 
a vaila ble c o m m u nit y referral sites).  If a n ultras o u n d has 
bee n d o ne wit hi n 1 2 m o nt hs of Scree ni n g, a n d a 
re p ort/a de q uate data are a vaila ble, a pretreat me nt 
ultras o u n d at Scree ni n g is n ot re q uire d.  If t he ultras o u n d 
ca n n ot be perf or me d at Scree ni n g (e g, de vice/tec h nicia n 
u na vaila bilit y, sc he d uli n g iss ues, etc), t he pr oce d ure ma y 
be c o m plete d a n yti me wit hi n t he scree ni n g visit wi n d o w 
or o n Da y 0.  Res ults fr o m t he scree ni n g ultras o u n d s h o ul d 
be re vie we d t o assess p ossi ble e xcl usi o n criteria pri or t o 
ra n d o mizati o n. 
 
Clarifie d 
sa m pli n g 
pr oce d ures.  
9. 7. 5, Da y 1 
Pr oce d ures  
 O btai n bl o o d sa m ples f or  mar kers of i nfla m mati o n  
 E L F (i ncl u di n g  H A, P 3 N P, a n d TI M P -1)  
 Tr o u g h  P K assess me nt  
Mar kers of i nfla m mati o n a n d fi br osis (I L -6, hs -C R P, T N F -α, 
I g M, I g G, I g A, C K - 8-M 3 0, H A, P 3 N P, a n d TI M P 1)  
F asti n g  P K assess me nt  
Clarifie d 
sa m pli n g 
pr oce d ures  
…, after patie nt eli gi bilit y has bee n c o nfir me d  
… after patie nt eli gi bilit y has bee n c o nfir me d.  
I nstr uct t he 
p atie nt t o t a ke D a y 1 d ose o n t he d a y of t his visit. 
Clarifie d 
pr oce d ures  
• 
Rec or d t he visit i n I W R S a n d dis pe nse i n vesti gati o nal 
pr o d uct  
 
I nstr uct t he patie nt t o be gi n d osi n g o n t he da y.  
 
 
 
( Sec o n d t o last b ullet)  …t he pr oce d ure ma y be c o m plete d 
wit hi n t he Da y 1 visit wi n d o w, (if data is nee de d f or 
cirr h osis assess me nt) or as cl ose as p ossi ble t o t he Da y 1 
visit, prefera bl y, after patie nt eli gi bilit y has bee n c o nfir me d.  
 
Rec or d t he visit i n I W R S a n d dis pe nse i n vesti gati o nal 
pr o d uct  
 I nstr uct t he patie nt t o be gi n d osi n g o n t he da y of t he 
D a y 1 visit.  
 
…t he  pr oce d ure  ma y  be  c o m plete d  wit hi n  t he  Da y  1  visit 
wi n d o w, (if data is nee de d f or cirr h osis assess me nt) or as cl ose 
as  p ossi ble  t o  t he  Da y  1  visit,  prefera bl y,  after  patie nt 
eli gi bilit y has bee n c o nfir me d.  I nstr uct t he p atie nt t o t a ke 
D a y 1 d ose o n t he d a y of t his visit.  
U p date d 
pr oce d ures t o 
matc h 
u p date d 
pr ot oc ol 
desi g n.  
Pa ge 3 4 1 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 3: 0 4 Ja n 2 0 1 8  
 
Pa ge 1 2 3  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d Te xt ( Ve rsi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
9. 7. 6, Wee k 3 
Safet y Visit 
Pr oce d ures  
Wee k 3 (Safet y  C o ntact)  
Wee k 3  Safet y  Visit Pr oce d ures  
U p date d 
pr oce d ures t o 
matc h 
u p date d 
pr ot oc ol 
desi g n per 
P M R 
re q uire me nts. 
Patie nts s h o ul d be c o ntacte d b y tele p h o ne at Wee k 3 t o 
assess f or A Es a n d verif y t hat s/ he  is d osi n g as directe d. 
• 
C o ntact  patie nt b y p h o ne/e mail . 
Prefer a bl y, t he p atie nt will c o me i n t o t he cli nic f or t his 
visit.  Alter n ati vel y, t he site will tele p h o ne t he p atie nt f or 
assess me nts a n d a h o me he alt h n urse will visit t o dr a w 
s afet y l a bs.  
Verif y t h at p atie nt is d osi n g as directe d. 
• 
Verif y t h at t he patie nt  h as f aste d f or at le ast 8  h o urs.  
 Rec or d f asti n g st at us i n t he s o urce a n d e C R F  
• If t he p atie nt re p orts h a vi n g e ate n wit hi n 8 h o urs, 
d oc u me nt acc or di n gl y i n t he s o urce a n d e C R F a n d 
re mi n d t he p atie nt t h at f asti n g is re q uire d pri or t o all 
st u d y visits. 
• Re vie w a n d rec or d pri or c o nc o mit a nt me dic ati o ns.  
• Assess a n d rec or d A Es.  
• Re vie w a n d rec or d a n y n o n -st u d y rel ate d me dic al or 
s ur gic al tre at me nt pr oce d ures a n d a n y me dic all y 
rele v a nt H C P or n o n -H C P rel ate d office visits t h at 
h a ve occ urre d si nce t he pre vi o us st u d y visit.  
• Assess i n vesti g ati o n al pr o d uct c o m pli a nce, perf or m 
i n vesti g ati o n al pr o d uct acc o unt a bilit y  
 
• O bt ai n bl o o d s a m ples f or  
 Ser u m c he mistr y, he m at ol o g y, a n d c o a g ul ati o n  
 
Sc he d ule t he ne xt visit, reiter ate d osi n g i nstr ucti o ns, a n d 
a d vise t he p atie nt:  
 
Wee k 6 visit s h o ul d occ ur 3, 4, or 5 d a ys after t a ki n g t he 
Wee k 6 d ose, e g if t he Wee k 6 d ose is t a ke n o n a S u n d a y, 
t he p atie nt s h o ul d c o me i n f or t he Wee k 6 visit wit hi n t he 
f oll o wi n g We d nes d a y a n d Fri d a y ( Fi g ure 2). 
 
•   
 
N O T t o t a ke i n vesti g ati o n al pr o d uct o n t he m or ni n g 
of t he ne xt visit, a n d  
Pa ge 3 4 2 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 3: 0 4 Ja n 2 0 1 8  
 
Pa ge 1 2 4  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d Te xt ( Ve rsi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
 
T o bri n g t he i n vesti g ati o n al pr o d uct b ottle(s); s/ he 
will d ose at t he cli nic (if t his is i n c o m pli a nce wit h 
t he est a blis he d d osi n g fre q ue nc y), a n d 
 
T o f ast o ver ni g ht ( at le ast 8 h o urs) pri or t o t he ne xt 
visit.  F asti n g is re q uire d pri or t o all st u d y visits, b ut 
w ater is per mitte d.  
9. 7. 8, Wee k 9 
t hr o u g h Wee k 4 8 
( Safet y C o ntact) 
(I nserti o n) 
P atie nts s h o ul d be c o nt acte d b y tele p h o ne/e m ail at Wee k 
9 a n d e ver y 3 wee ks after w ar d t o Wee k 4 8 . 
• 
C o nt act p atie nt b y p h o ne/e m ail.  
• 
Re vie w a n d rec or d pri or c o nc o mit a nt me dic ati o ns.  
• 
Assess a n d rec or d A Es.  
• 
Re vie w a n d rec or d a n y n o n -st u d y rel ate d me dic al or 
s ur gic al tre at me nt pr oce d ures a n d a n y me dic all y 
rele v a nt H C P or n o n -H C P rel ate d office visits t h at 
h a ve occ urre d si nce t he pre vi o us st u d y visit.  
• 
Assess i n vesti g ati o n al pr o d uct c o m pli a nce, perf or m 
i n vesti g ati o n al pr o d uct acc o u nt a bilit y. 
Secti o n 
a d de d t o 
pr o vi de 
g ui da nce f or 
tele p h o ne/e m
ail safet y 
c o ntact. 
9. 7. 9 ,  Wee k 1 2, 
Wee k 2 4, W ee k 
3 6 Pr oce d ures  
Wee k 1 2 Pr oce d ures  
 
 
 
 
 
 
 
 
 
O btai n bl o o d sa m ples f or mar kers of i nfla m mati o n 
 
E L F (i ncl u di n g H A, P 3 N P, a n d TI M P -1)  
 
C 4, a n d F G F -1 9, bile aci ds  
 
Tr o u g h  P K assess me nt  
 
Wee k 1 2, Wee k 2 4, Wee k 3 6  Pr oce d ures  
• 
Assess i n vesti g ati o n al pr o d uct c o m pli a nce, perf or m 
i n vesti g ati o n al pr o d uct acc o u nt a bilit y 
• 
Dis pe nse i n vesti g ati o n al pr o d uct o nl y if t here is d ose  
i ncre ase or as nee de d. N o ne w i n vesti g ati o n al pr o d uct 
b ottles will be dis pe nse d if t here is o nl y c h a n ge i n 
d osi n g fre q ue nc y of t he s a me d ose le vel. P atie nts are 
e x pecte d t o use u p e ac h i n vesti g ati o n al pr o d uct b ottle 
bef ore a ne w b ottle will be dis pe nse d.  
• 
Assess f or d ose titr ati o n,  if eli gi ble. ( Refer t o 
Secti o n  7. 3)  
 O btai n bl o o d sa m ples f or  
 
Ser u m c he mistr y, he m at ol o g y, a n d c o a g ul ati o n   
 
M ar kers of I nfl a m m ati o n (I L -6, hs -C R P, T N F -α, 
I g M, I g G, I g A, C K-1 8 -M 3 0)  
 
Bile Aci d / C 4/ F G F-1 9  
U p date d 
pr oce d ures t o 
matc h 
u p date d 
pr ot oc ol 
desi g n.  
Pa ge 3 4 3 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 3: 0 4 Ja n 2 0 1 8  
 
Pa ge 1 2 5  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d Te xt ( Ve rsi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
 
F asti n g P K assess me n t 
• 
Perf or m a uri ne -b ase d β -h C G pre g n a nc y test i n 
fe m ales of c hil d be ari n g p ote nti al. 
 
Perf or m T E usi n g t he Fi br osc a n ® T E de vice.  If t he 
T E c a n n ot be perf or me d o n visit d a y (e g, 
de vice/tec h nici a n u n a v ail a bilit y, sc he d uli n g iss ues, 
T E d at a is nee de d t o i nf or m cirr h osis assess me nt, 
etc.), t he pr oce d ure m a y be c o m plete d wit hi n t he 
visit wi n d o w (if d at a is nee de d f or cirr h osis 
assess me nt) or as cl ose as p ossi ble t o t he visit.  
• 
Serial P K assess me nt; t he  f oll o wi n g pr oce d ures will be 
c o n d ucte d i n all patie nts  
• 
Serial P K assess me nt at Wee k 1 2 a n d 2 4 O N L Y ( n ot 
d o ne at Wee k 3 6  a n d Wee k 4 2 ); t he f oll o wi n g pr oce d ures 
will be c o n d ucte d i n all patie nts  
U p date d 
pr oce d ures t o 
matc h 
u p date d 
pr ot oc ol 
desi g n.  
9. 7. 9,  Wee k 1 2, 
Wee k 2 4, W ee k 
3 6 Pr oce d ures  
N ote:  Patie nts s h o ul d n ot  c o ns u me a n y f o o d f or t he 
d urati o n of t he 6- h o ur P K assess me nts e xce pt t he meal 
re place me nt dri n k.   
N ote:  Patie nts s h o ul d o nl y c o ns u me me al f oll o wi n g t he 
4- h o ur a n d 7 - h o ur P K assess me nt ti mes (see Fi g ure 3).    
A d de d m ore 
sa m pli n g 
ti mes. 
I nserti o n 
 
Perf or m a n ultras o u n d f or H C C s ur veilla nce at Wee k 2 4 
O N L Y  (if e q ui p me nt is u na vaila ble, sites s h o ul d ma ke 
e ver y atte m pt t o use a vaila ble c o m m u nit y referral sites).  
 
 
• 
Assess t he patie nt’s s u p pl y of i n vesti gati o nal pr o d uct 
t o e ns ure a n a de q uate a m o u nt. 
delete d  
Delete d f or 
clarit y. 
9. 7. 1 0   Wee k 1 8 
a n d W ee k 3 0 
Pr oce d ures  
 
 
 
 
 
A d de d t he f oll o wi n g pr oce d ure:  
• 
Dis pe nse i n vesti g ati o n al pr o d uct o nl y if t here is d ose 
i ncre ase or as nee de d. N o ne w I P b ottles will be dis pe nse d 
if t here is o nl y c h a n ge i n d osi n g fre q ue nc y of t he s a me 
d ose le vel. P atie nts are e x pecte d t o use u p e ac h I P b ottle 
bef ore a ne w b ottle will be dis pe nse d.   
Secti o n 
mer ge d i nt o 
9. 7. 8, 
a d diti o nal P K 
assess me nts 
a d de d per 
Pa ge 3 4 4 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 3: 0 4 Ja n 2 0 1 8  
 
Pa ge 1 2 6  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d Te xt ( Ve rsi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
 O btai n bl o o d sa m ples f or mar kers of i nfla m mati o n 
 
E L F (i ncl u di n g H A, P 3 N P, a n d TI M P -1)  
 
C 4, a n d F G F -1 9, bile aci ds  
 
Tr o u g h  P K assess me nt  
 
 
 
 
 
 
 
 
 
C ollect bl o o d sa m ples at: 1. 5, 2, 2. 5, 3, 4, 5, 6 h o urs 
p ost d ose  
 O btai n bl o o d sa m ples f or 
 
Ser u m c he mistr y, he m at ol o g y, a n d c o a g ul ati o n  
 
M ar kers of i nfl a m m ati o n a n d fi br osis (I L 6, 
hs -C R P, T N F α, I g M, I g G, I g A, C K 1 8 M 3 0, 
E L F [ H A, P 3 N P, a n d TI M P 1])  
 
F asti n g P K assess me nt  
 
Bile Aci d/ C 4/ F G F -1 9  
• 
Serial P K assess me nt at Wee k 1 2 a n d 2 4 O N L Y ( n ot 
d o ne at Wee k 3 6) ; t he f oll o wi n g pr oce d ures will be 
c o n d ucte d i n all patie nts:  
 
 
 
C ollect bl o o d sa m ples at: 1. 5, 2, 2. 5, 3, 4, 5, 6 7, 8, 9, 
a n d 2 4  h o urs p ost d ose  
P M R 
re q uire me nts. 
N ote:  Patie nts s h o ul d n ot  c o ns u me a n y f o o d f or t he 
d urati o n of t he 6- h o u r P K assess me nts e xce pt t he meal 
re place me nt dri n k.   
N ote:  Patie nts s h o ul d o nl y c o ns u me a me al f oll o wi n g t he 
4- h o ur a n d 7 - h o ur P K assess me nt ti mes  (see Fi g ure 3).   
A d de d m ore 
sa m pli n g 
ti mes. 
9. 7. 1 0, Wee k 2 4 
Pr oce d ures  
9. 7. 1 0, Wee k 2 4 Pr oce d ures  
delete d  
I nc or p orate d 
i nt o Secti o n 
9. 7. 8  
9. 7. 1 1 , Wee k 4 8 
Pr oce d ures  
9. 7. 1 2 
9. 7. 1 0, Wee k 4 8 Pr oce d ures  
U p date d 
la n g ua ge. 
• 
Perf or m a p h ysical e xa mi nati o n,  
• 
Perf or m a p h ysical e xa mi nati o n, i ncl u di n g s m o ki n g a n d 
alc o h ol c o ns u m pti o n hist or y, a n d c urre nt h a bits f or b ot h  
Clarif y st u d y 
pr oce d ures.  
Pa ge 3 4 5 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 3: 0 4 Ja n 2 0 1 8  
 
Pa ge 1 2 7  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d Te xt ( Ve rsi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
(I nserti o n) 
• 
Assess i n vesti g ati o n al pr o d uct c o m pli a nce, perf or m 
i n vesti g ati o n al pr o d uct acc o u nt a bilit y. 
• 
Dis pe nse i n vesti g ati o n al pr o d uct o nl y if t here is d ose 
i ncre ase or as nee de d.  N o ne w i n vesti g ati o n al 
pr o d uct b ottles will be dis pe nse d if t here is o nl y 
c h a n ge i n d osi n g fre q ue nc y of t he s a me d ose le vel.  
P atie nts are e x pecte d t o use u p e ac h i n vesti g ati o n al 
pr o d uct b ottle bef ore a ne w b ottle will be dis pe nse d . 
• 
Assess f or d ose titr ati o n, if eli gi ble (r efer t o 
Secti o n  7. 3)  
 
Perf or m a n ultr as o u n d f or H C C s ur veill a nce (if 
e q ui p me nt is u n a v ail a ble, sites s h o ul d m a ke e ver y 
atte m pt t o use a v ail a ble c o m m u nit y referr al sites).  
 
Clarif y st u d y 
pr oce d ures.  
O btai n bl o o d sa m ples f or mar kers of i nfla m mati o n 
  
E L F (i ncl u di n g H A, P 3 N P, a n d TI M P-1)  
 
C 4, a n d F G F -1 9, bile aci ds  
 
Tr o u g h  P K assess me nt  
 
• 
Perf or m uri n al ysis ( di pstic k)  
 
O btai n bl o o d sa m ples f or  
 
Ser u m c he mistr y, he m at ol o g y, a n d c o a g ul ati o n  
 
M ar kers of i nfl a m m ati o n a n d fi br osis (I L 6, hs -
C R P, T N F α, I g M, I g G, I g A, C K 1 8 M 3 0, E L F 
[ H A, P 3 N P, a n d TI M P 1]) 
 
F asti n g P K assess me nt  
 
Bile Aci d/ C 4/ F G F -1 9  
Clarif y st u d y 
pr oce d ures.  
• 
Serial P K assess me nt; will o nl y  be c o n d ucte d i n 
patie nts w h o are u ptitrati n g t o t he ne xt d ose le vel.  
• 
Serial P K assess me nt; t he f oll o wi n g pr oce d ures will be 
c o n d ucte d i n all  patie nts.  
U p date d 
la n g ua ge. 
 
 
I m me diatel y f oll o wi n g 1 hr p ost d ose bl o o d dra w, 
a d mi nister meal re pla ce me nt (t o be c o ns u me d wit hi n 
5 – 1 0  mi n utes)  
A d de d m ore 
sa m pli n g 
ti mes. 
Pa ge 3 4 6 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 3: 0 4 Ja n 2 0 1 8  
 
Pa ge 1 2 8  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d Te xt ( Ve rsi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
 C ollect bl o o d sa m ples at: 1. 5, 2, 2. 5, 3, 4, 5, 6, 7, 8, 9, 
a n d 2 4 h o urs p ost d ose.   
N ote:  Patie nts s h o ul d n ot  c o ns u me a n y f o o d f or t he 
d urati o n of t he 6- h o ur P K assess me nts e xce pt t he meal 
re place me nt dri n k.   
N ote:  Patie nts s h o ul d o nl y c o ns u me me al f oll o wi n g t he 
4- h o ur a n d 7- h o ur P K assess me nt ti mes (see Fi g ure 3) .   
A d de d m ore 
sa m pli n g 
ti mes. 
Perf or m T E usi n g t he Fi br osca n ® T E de vice.   
Perf or m T E usi n g t he Fi br osca n ® T E de vice.  If t he T E 
c a n n ot be perf or me d o n visit d a y (e g, de vice/tec h nici a n 
u n a v ail a bilit y, sc he d uli n g iss ues, T E d at a is nee de d t o 
i nf or m cirr h osis assess me nt, etc.), t he pr oce d ure m a y be 
c o m plete d wit hi n t he visit wi n d o w (if d at a is nee de d f or 
cirr h osis assess me nt ) or as cl ose as p ossi ble t o t he visit. 
Clarifie d 
pr oce d ural 
i nstr ucti o ns. 
• 
Assess t he patie nt’s s u p pl y of i n vesti gati o nal pr o d uct 
t o e ns ure a n a de q uate a m o u nt.   
 
Clarifie d 
pr oce d ural 
i nstr ucti o ns 
• 
Sc he d ule t he f oll o w-u p  visit a n d a d vise t he patie nt : 
• 
Sc he d ule t he ne xt visit , reiter ate d osi n g i nstr ucti o ns, 
a n d a d vise t he patie nt:  
 N O T t o t a ke i n vesti g ati o n al pr o d uct o n t he m or ni n g 
of t he ne xt visit, a n d  
 T o bri n g t he i n vesti g ati o n al pr o d uct b ottle(s); s/ he 
will d ose at t he cli nic (if t his is i n c o m pli a nce wit h t he 
est a blis he d d osi n g fre q ue nc y), a n d  
 T o f ast o ver ni g ht ( at le ast 8 h o urs) pri or t o t he ne xt 
visit.  F asti n g is re q uire d pri or t o all st u d y visits, b ut 
w ater is per mitte d . 
Clarif y st u d y 
pr oce d ures.  
9. 7. 1 2 , E ver y 3 
M o nt hs after 
Wee k 4 8  
9 . 7. 13 
Patie nts w h o ha ve c o m plete d t heir 4 8 -wee k d o u ble -bli n d 
treat me nt peri o d will c o nti n ue d o u ble bli n d treat me nt u ntil 
all ra n d o mize d patie nts ha ve c o m plete d t heir partici pati o n 
i n t he pri mar y treat me nt peri o d a n d t he data base is 
l oc ke d …. a n d s h o ul d n ot e xcee d t he i n dicate d ma xi mal 
d ose a n d fre q ue nc y i n dicate d f or t heir C P cate g or y.   
9. 7. 1 1.  E ver y 3 M o nt hs after Wee k 4 8  
Q u arterl y  
 
Verif y t h at t he p a tie nt h as f aste d f or at le ast 8 h o urs.  
 
Rec or d f asti n g st at us i n t he s o urce a n d e C R F  
 
If t he p atie nt re p orts h a vi n g e ate n wit hi n 
8 h o urs, d oc u me nt acc or di n gl y i n t he s o urce a n d 
Clarifie d 
dis pe nsi n g 
i nstr ucti o ns. 
Pa ge 3 4 7 of 6 0 3


Protocol 747-401 
Version 3: 04 Jan 2018
Page 129
 
Confidential and Proprietary    
Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
Patients will then have the option to continue into an open-
label LTSE. 
 
 
eCRF and remind the patient that fasting is 
required prior to all study visits, but water is 
permitted. 
 
Perform a physical examination, including smoking 
and alcohol consumption history, and current habits 
for both.  
 
Review and record any non-study related medical or 
surgical treatment procedures and any medically 
relevant HCP or non-HCP related office visits that 
have occurred since the previous study visit. 
 
Assess and record vital signs (oral temperature, 
sitting heart rate, respiratory rate, and sitting blood 
pressure). 
 
Assess and record AEs. 
 
Review and record concomitant medications. 
 
Perform assessments for calculation of CP Score 
(Section 14.1.1). 
 
Administer Quality of Life and Patient 
questionnaires (see Section 13.2.6). 
 
Assess investigational product compliance, perform 
investigational product accountability. 
 
Dispense investigational product only if there is dose 
increase or as needed.  No new investigational 
product bottles will be dispensed if there is only 
change in dosing frequency of the same dose level.  
Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed. 
 
Assess for dose titration, if eligible (refer to 
Section 7.3 ). 
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 
Perform urinalysis (dipstick) 
 
Perform a urine-based β-hCG pregnancy test in 
females of childbearing potential. 
 
Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 
Schedule the next visit, reiterate dosing instructions, 
and advise the patient: 
 
NOT to take investigational product on the 
morning of the next visit, and  
 
To bring the investigational product bottle(s); s/he 
will dose at the clinic (if this is in compliance with 
the established dosing frequency), and 
 
To fast overnight (at least 8 hours) prior to the next 
visit.  Fasting is required prior to all study visits, 
but water is permitted. 
Patients will complete a TE/ELF (HA, P3NP and TIMP 1) 
and ultrasound (for HCC surveillance) assessment, every 
6 months (±2 weeks) after Week 48. 
ECG will be done yearly (±2 weeks) after Week 48. 
9.7.13,  End of 
Study/Early 
Termination 
Procedures for 
Patients that 
Withdraw from 
Investigational 
Product or 
9.1.14;   End of Treatment/Early Termination Procedures 
for Patients that Withdraw from Investigational Product or 
Withdraw Consent … 
Patients who discontinue investigational product before are 
expected to continue … 
 
EOT/ET procedures will be required whenever patients 
discontinue treatment with investigational product 
 
9.7.12. . End of Study/Early Termination/End of Treatment 
Procedures for Patients that Withdraw from Investigational 
Product or Withdraw Consent … 
Patients who discontinue investigational product before 
Week 48 are expected to continue ... 
 
EOT (when subject discontinues investigational product)/ET 
procedures will be required whenever patients discontinue 
treatment with investigational product (Table 1, 
Section 9.7.10) 
Clarified 
procedures. 
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Key Change 
Withdraw 
Consent 
 
When a patient discontinues investigational product but 
continues with regularly scheduled study visits, the EOS 
Visit will be completed as the patient’s final study visit. 
 
 
(Insertion) 
 
 
When a patient discontinues or interrupts investigational 
product and continues with regularly scheduled study visits, 
the EOS Visit will be completed as the patient’s final study 
visit. 
 
 
EOT and EOS visits are encouraged but at no time will a 
missed EOT or EOS visit be considered a protocol 
deviation. 
9.7.13,  Table 5, 
row 5 
Treatment Interruption  
Interrupted Retained Regular 
Visit Schedule 
Complete as close as possible to last dose 
of investigational product Complete at final study visit 
Deleted  
Removed to 
reduce 
confusion 
10.3, 
Investigational 
Product Storage 
Investigational product should be stored in the containers in 
which they are received from the Sponsor’s supplier, at 
15ºC to 25ºC. 
All OCA tablet strengths provided to clinical trial sites in 
support of clinical studies are to be shipped and stored at 
15°C to 25°C.  Temperature excursions within the range 
of 2°C and 30°C for no more than a 6-month period are 
acceptable, and the OCA tablet continues to be suitable 
for use in clinical studies.   Additionally, temperature 
excursions within the range -20°C to 40°C for no more 
than 7 days are acceptable, and the OCA tablet continues 
to be suitable for use in clinical studies. 
Updated 
storage 
conditions 
per the 
Investigator’s 
Brochure. 
12, 12.1, 
Pharmacokinetic 
Blood Sampling 
 
Subjects with at least one PD assessment after dosing will 
be included in the combined PK/PD analyses 
 
Serial and trough PK assessments will be performed in all 
patients participating in the study. 
 
 
At each visit, patients will provide… 
 
 
Patients in the PK Population with at least one PD 
assessment after dosing will be included in the combined 
PK/PD analyses 
Serial and fasting PK assessments will be performed in all 
patients participating in the study. 
 
At Day 1, and Weeks 6, 12, 18, 24, 30, 36, and 48, patients 
will provide… 
Specific dates 
are required 
to obtain 
optimum PK 
results 
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Key Change 
(Insertion) 
 
Week 6 visit should occur 3, 4, or 5 days after the Week 6 
dose, (eg if the Week 6 dose of drug is taken on a Sunday, 
the patient should come in for the Week 6 visit between 
Wednesday and Friday [Figure 2]). 
(Insertion) 
 
…serial PK blood samples will be obtained at 0.5, 0.75, 1, 
1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose… 
 
Figure 2: 
Week 6 Sampling Schedule 
  
IP = investigational product; PK = pharmacokinetic 
At Weeks 12, 18, 24, 30, and 48, Serial PK blood samples 
will be obtained at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9 
and 24 hours postdose (Figure 3) for all patients.  The 
patient will be given the option to return to the clinic the 
following morning for the 24-hour postdose sample or 
samples can be obtained by a home health care designee.  
The home health care agency must be advised one week in 
advance of the appointment.   
Added 
diagram and 
language to 
clarify PK 
sampling 
procedures. 
(Insertion) 
Figure 3: 
Pharmacokinetic Sampling Schedule 
 
OCA = obeticholic acid; PK = pharmacokinetic 
Added 
diagram and 
language to 
clarify PK 
sampling 
procedures. 
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Key Change 
12.1, 
Pharmacokinetic 
Blood Sampling 
 
Table 7: Pharmacokinetic Sampling Schedule 
 
 
Replaced 
with other 
Figures 2 and 
3. 
During the double-blind treatment period and double-blind 
LTSE: 
• 
Pharmacokinetic trough samples will be obtained from 
all patients at all visits prior to dose administration in 
accordance with Table 7. 
• 
Serial PK assessments will be performed in all patients 
at Week 12.  Thereafter, PK assessments will be conducted 
at every titration visit in those patients who were eligible 
and uptitrated their dose.  Sample collection for fecal 
analysis will occur concurrent with serial PK sampling 
visits only.   
During the treatment period: 
• 
Pharmacokinetic fasting samples will be obtained from 
all patients at Weeks 6, 12, 18, 24, 30, 36, and 48 prior to 
dose administration in accordance with Figure 3. 
• 
Serial PK assessments will be performed in all patients 
at Weeks 12, 18, 24, 30, and 48.   
Clarify PK 
sampling and 
collection 
procedures. 
12.2,  Processing 
and Handling of 
Pharmacokinetic 
Samples 
The storage and shipment procedures for subsequent 
bioanalysis will be provided to the investigational site and 
in a separate document before the study is initiated. 
The storage and shipment procedures for subsequent 
bioanalysis will be provided to the investigational site and 
home health care company in a separate document before 
the study is initiated. 
Added option 
of using 
home health 
care service. 
13, Assessment 
of Safety 
Safety will be monitored and assessed by AEs/SAEs, 
medical history, physical examination, vital signs 
measurements, ECG results, and clinical laboratory 
assessments.  
Safety will be assessed in terms of AEs.  All AEs, whether 
observed by the investigator, reported by the patient, noted 
from laboratory findings, or identified by other means, will 
be recorded from the time the patient signs his/her consent 
deleted 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
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Key Change 
form (s)until the patient completes study participation (final 
Follow Up Visit). 
Recording AEs/SAEs in the electronic data capture (EDC) 
system is the method for reporting AEs/SAEs.  It is 
therefore imperative, that AEs/SAEs are recorded into the 
EDC. 
13.1.1.3.
 
Treatment-
Emergent 
Adverse Event 
 
13.1.1.2 
A treatment-emergent AE (TEAE) is any event not present 
before the initiation of the investigational product or any 
event already present that worsens in either intensity or 
frequency following exposure to the investigational 
product. 
Moved to Section 13.1.3. Recording Adverse Event 
Severity 
 
Safety 
information 
updated to 
match 
Protocol 
747-302.   
 
 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
13.1.3.1. Severity 
of Pruritus (as an 
Adverse Event) 
To ensure consistency in reporting, the following guidelines 
for assessing severity of pruritus should be used for AE 
reporting.  As pruritus is a patientive symptom, clinical 
judgment should be used to determine its severity and 
management Table 10 
Table 10 deleted. 
 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
13.1.4.1.
 
Reporting of 
Adverse Events 
(Insertion) 
….  Redacted medical record source documentation will 
be requested for all SAEs and emergency room visits. 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
13.1.4.2.
 
Reporting of 
• 
Telephone:  
 
If an SAE is reported by telephone or fax, … 
If an SAE is reported by fax, … 
Number no 
longer in use. 
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Key Change 
Serious Adverse 
Events 
 
 
 
 
13.1.5.1.
 
Potential 
Clinical 
Outcome Events 
 
The events listed below will be initially assessed by the 
Investigator to determine if they are Potential Clinical 
Outcome Events.  These events will be evaluated by an 
Adjudication Committee (described in Section 15.9) to 
confirm if they meet the criteria to be considered Clinical 
Outcome Events.  
Potential Clinical Outcome Events: 
Hospitalization for clinical complications of cirrhosis. 
Given that the Potential Clinical Outcome Events could also 
meet the criteria of a SUSAR, which would necessitate 
unblinding for expedited reporting, the Sponsor will not 
expeditiously report suspected Potential Clinical Outcome 
events in order to retain the study blind and preserve the 
integrity of the clinical outcomes endpoint.  These events 
will be selected as a “potential study event” on the Adverse 
Event eCRF and will be submitted for adjudication to the 
Adjudication Committee as described in Section 15.9. 
 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
13.1.7.
 
Notification 
of Post-
Treatment SAEs 
for Patients Who 
Continue in the 
Study 
13.1.7. Notification of Post-Study SAEs  
If an Investigator becomes aware of an SAE that may be 
attributable to the investigational product at any time after 
the end of the study, the Sponsor should be notified 
immediately (ie, within 24 hours) by following the 
instructions provided in Section 13.1.4.2 
13.1.7. Notification of Post-Treatment SAEs for Patients 
Who Continue in the Study 
Post-treatment SAEs that occur in patients who remain in 
the study after investigational product has been 
discontinued must be reported to the Sponsor within 
24 hours by following the instructions provided in 
Section 13.1.4.2. 
SAEs that occur in patients who discontinue 
investigational product, initiate treatment with 
commercially available Ocaliva, and remain in the study 
must be reported to the Sponsor within 24 hours by 
following the instructions provided in Section 13.1.4.2. 
Safety 
information 
updated to 
match 
Protocol 
747-302.  
Deleted text 
is already in 
Section 
13.1.8. 
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13.1.8.
 
Notification 
of Post--Study 
SAEs  
 
(Insertion) 
13.1.8. Notification of Post-Study SAEs  
All SAEs that occur within 30 days following 
discontinuation from the study, whether or not they are 
related to the investigational product, must be reported to 
the Sponsor within 24 hours by following the instructions 
provided in Section 13.1.4.2. 
 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
13.1.8.
 
Notification 
of Post-
Treatment SAEs 
for Subjects Who 
Continue in the 
Study 
13.1.8. Notification of Post-Treatment SAEs for Subjects 
Who Continue in the Study 
Post-treatment SAEs that occur in subjects who remain in 
the study after investigational product has been 
discontinued must be reported to the Sponsor within 24 
hours by following the instructions provided in 
Section 13.1.4.2 
Moved to 13.1.7 
Safety 
information 
updated to 
match 
Protocol 
747-302 9 
(moved to 
13.1.7). 
13.1.10, 
Pregnancy and 
Follow-up 
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant 
while she is enrolled in the clinical study, she must 
discontinue investigational product immediately and the 
Sponsor must be notified within 24 hours of the 
Investigator’s learning of the pregnancy by completing. 
In the situation that the EDC is not functioning, the Medical 
Monitor should be notified by telephone.  The investigator 
remains responsible for entering the pregnancy information 
into the EDC when the EDC becomes functional. 
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant 
while she is enrolled in the clinical study, she must interrupt 
treatment with investigational product immediately (see 
Section) and the Sponsor must be notified within 24 hours of 
the Investigator’s awareness of the pregnancy by completing 
the Pregnancy CRF in the EDC system and downloading 
and completing the Pregnancy Report Form.  The 
Pregnancy Report Form must be emailed to 
 or faxed to 
   
The patient and neonate must be followed for outcome 
information and/or as considered appropriate by the 
Investigator and Sponsor. 
The patient may restart investigational product when she 
is no longer pregnant or breastfeeding (if applicable) at 
the discretion of the Investigator and after discussion with 
the Medical Monitor.  The patient must have a negative 
pregnancy test before restarting investigational product.  
If a patient’s pregnancy is terminated early (planned or 
unplanned), she must have termination of the pregnancy 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
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confirmed by a serum β-hCG test before restarting 
investigational product. 
13.2.2, Physical 
Examination 
13.2.1 
(Insertion) 
13.2.2 
A basic physical examination… Smoking and alcohol 
consumption history and current habits will be 
recorded…. 
Clarified 
assessments 
13.2.5, 
Laboratory 
Assessments 
For visits that require fasting, the Investigator or designee 
will verify that the patient has fasted for at least 8 hours …   
At all visits (except screening), the Investigator or designee 
will verify that the patient has fasted for at least 8 hours… 
Clarified visit 
procedures 
Blood samples for serum chemistry, coagulation, and 
hematology will be collected at every visit… 
Blood samples for serum chemistry, coagulation, and 
hematology and urine samples will be collected at visits… 
Clarified 
what samples 
will be 
collected. 
13.2.5, 
Laboratory 
Assessments, 
Table 9 
 
Added the following labs: 
 
Serum Chemistry 
 
CPK, TFT (TSH, free T3 and free T4) 
 
Urinalysis (dipstick) 
 
Pregnancy 
 
Noninvasive measurement… 
 
ELF (HA, P3NP, and TIMP-1), TE 
Updated lab 
tests to be 
performed. 
Biomarkers of Hepatic Fibrosis and/or Inflammation;  IL-6, 
hs-CRP, TNF-α, IgM, IgA, IgG, CK 18 M30, and others as 
determined during course of study 
Markers of Inflammation; IL-6, hs-CRP, TNF-α, IgM, IgA, 
IgG, CK-18-M30 
Clarified 
assessments 
Genetics;  DNA including single-nucleotide 
polymorphisms that may be involved in PBC; RNA 
deleted 
No longer 
doing this 
analysis. 
13.2.5, 
Laboratory 
Assessments 
(Insertion) 
PD markers: C4, FGF-19 and plasma bile acids 
Added new 
row  
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Key Change 
13.2.5, 
Laboratory 
Assessments 
(Insertion) 
Laboratory reference ranges for the study will be based 
on the laboratory vendor range. 
Added to 
satisfy PMR 
request. 
14.1.1, Child-
Pugh Score, 
Table 10 
Factor 
Unit
s 
Points 
Deletion 
 
 
 
 
Encephalopathy now 0 
Simplified 
CP scoring 
procedure. 
1 
2 
3 
Serum bilirubin 
μmo
l/L 
<3
5 
35-50 
>50 
Serum albumin 
g/L 
>3
5 
28-35 
<28 
Hepatic encephalopathy 
 
No 
 
 
14.2.1,  Markers 
of Inflammation, 
Apoptosis and 
Necrosis 
Blood samples for analytes including hs-CRP, IgM, TNF-α, 
and cytokeratin-18, neoepitope M30. 
Blood samples for analytes including IL-6, hs-CRP, IgA, 
IgG, IgM, TNF-α, and cytokeratin-18, neoepitope M30. 
Added 
additional 
markers. 
15.4, Safety 
Analyses 
No inferential comparison of safety endpoints will be 
performed.  All safety comparisons will be descriptive. 
No inferential comparison with formal statistical hypothesis 
testing will be performed for safety endpoints. 
Clarified 
statistical 
analyses. 
15.4.3, Adverse 
Events of Special 
Interest 
…  The quartiles, including the median time-to-event and 
their respective 2-sided 95% CIs, will be presented.  KM 
estimates will be plotted as a “survival curve” for each 
treatment group. 
…  The tabulation will include the KM estimate 
methodology using 25th, 50th (median), and 75th percentiles 
of the medians and corresponding with associated 2-sided 
95% confidence intervals (CIs), if the medians can be 
estimated as well as percentage of censored observations. 
Clarified 
statistical 
analyses. 
15.5, Efficacy 
Analyses, 4th 
paragraph 
…  The results, change from Baseline, and percentage 
change from Baseline values, as well as estimates of least-
square (LS) means, standard errors (StdErr), and 95% CIs, 
will be presented by treatment group.  Estimates of the 
mean difference between treatment groups, the StdErr of 
the difference, and 95% CI of the difference will also be 
presented.  No formal hypothesis testing will be performed. 
The results, change from Baseline, and percentage change 
from Baseline values, as well as estimates of least-square 
(LS) means, standard errors (StdErr), and 2-sided 95% CIs, 
will be presented by treatment group.  Estimates of the mean 
difference between treatment groups, the StdErr of the 
difference, and 2-sided 95% CI of the difference will also be 
presented 
Clarified 
statistical 
analyses. 
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Key Change 
15.6, Additional 
Efficacy 
Analyses 
The following clinical outcomes will be captured in the 
study: 
• 
All cause mortality 
• 
Liver related death 
• 
Liver transplant 
• 
Variceal bleed 
• 
Hepatic encephalopathy 
• 
Bacterial peritonitis 
• 
Ascites 
• 
Hepatocellular carcinoma 
The following clinical endpoints will be captured in the 
study : 
• 
Time to death (all-cause ) 
• Time to liver-related death 
• Time to hepatic failure leading to liver transplant 
•  Model of end stage liver disease (MELD) score ≥15 
(for patients with MELD ≤12 at baseline) 
• Hospitalization (as defined by a stay of 24 hours or 
greater) for new onset or recurrence of: 
 
Time to variceal bleed 
 
Time to hepatic encephalopathy (as defined by 
a West Haven score of ≥2) 
 
Time to spontaneous bacterial peritonitis 
(confirmed by diagnostic paracentesis) 
• Time to uncontrolled ascites (diuretic resistant ascites 
requiring therapeutic paracentesis at a frequency of at 
least twice in a month). 
 
The incidence and time to first occurrence of any above listed 
clinical events will be summarized by treatment group using 
the log rank test stratified by the randomization stratification 
factor.  KM estimates of the distribution of the time-to-event 
will be tabulated and graphed by treatment group.  The 
tabulation will include the KM methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% 
confidence intervals (CIs), as well as percentage of censored 
observations.  The number and percent of patients censored 
and with events will be presented.  The hazard ratio and 2-
Clarified 
statistical 
endpoints. 
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Key Change 
sided 95% CI will be estimated based on a Cox regression 
model stratified by randomization strata.  
In addition, the incidence and time to each of the above 
clinical events, and the incidence and time to occurrence 
of hepatocellular carcinoma (HCC) will be summarized 
by treatment group using the same methods as defined 
above. 
 
18.3, Written 
Informed 
Consent 
(Insertion) 
The Investigator(s) must maintain the original, signed 
ICF. A copy of the ICF must be given to the patient. 
Updated 
language. 
21, List of 
References 
(Insertion) 
Hepatic encephalopathy in chronic liver disease: 2014 
practice guideline by the European Association for the 
Study of the Liver and the American Association for the 
Study of Liver Diseases. J Hepatol 2014 Sep;61(3):642-59. 
Kamath PS, Kim WR. The model for end-stage liver 
disease (MELD). Hepatology 2007 Mar;45(3):797-805. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl-
chenodeoxycholic acid (6-ECDCA), a potent and selective 
FXR agonist endowed with anticholestatic activity. J Med 
Chem. 2002 Aug 15;45(17):3569-72. 
Added new 
references  
Appendix A, List 
of Study 747-401 
Outcome Events 
Some of the specified clinical endpoints will also by 
definition (see Section 13.1) qualify as Serious Adverse 
Events (SAEs).  The sponsor must be notified of any SAEs 
within 24 hours of the site becoming aware of the event 
(see Section 13.1.4).  The Sponsor is responsible for 
regulatory reporting of SAEs including expeditious 
reporting of SAEs that are considered related to the 
investigational product and considered Unexpected by 
regulatory standards as defined in the Investigational 
Brochure. 
 
This is 
covered in 
the main text. 
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Key Change 
The Sponsor may consider the following lists of events to 
be exempt from expeditious regulatory reporting but will 
continue to report them in a non-expeditious manner: 
Potential Clinical Outcome Events: 
Liver-related events resulting in death 
Hepatic failure leading to liver transplant 
Variceal bleed 
Hepatic encephalopathy 
Spontaneous bacterial peritonitis 
Ascites 
Hepatocellular carcinoma 
 
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APPENDIX B. SUMMARY OF CHANGES:  PROTOCOL 747-401 VERSION 3 (DATED  
04 JAN 2018) 
Protocol 747-401 was revised to include the following information: 
 The Introduction was revised to highlight the need for close monitoring specifically in patients with clinical evidence of 
hepatic decompensation and other complications due to advanced cirrhosis.  Reference is made to sections describing 
specific criteria for investigational product adjustment, interruption, or discontinuation based on adverse events or 
laboratory values. This language also emphasizes the need for careful observation and evaluation of the entire clinical 
picture over and above system-generated alerts and flags for lab values.   
 Dosing regimens were updated to modify dosing to one regimen for patients with moderate and severe hepatic impairment 
(eg, same for CP-B and CP-C), not to exceed 10 mg twice weekly, to align with label dosing guidelines.  Titration is now 
only based on tolerability and not CP score. 
 Reference to an option for open-label treatment was removed.  An open-label extension will be considered only after 
review of blinded safety and PK data from the double-blind treatment period.  For clarity, reference to the Long-Term 
Extension was changed to Double-Blind Extension; visits during this period remain the same. 
 Protocol was updated with discontinuation criteria for decompensation events and biochemical thresholds.  A plan for 
monitoring and drug-induced liver injury algorithm has been included to ensure careful monitoring and drug 
interruption/discontinuation.  Analysis of decompensation events as adverse events of interest has been added.  
Additionally, “Close Observation” per FDA Guidance for Industry on Drug Induced Liver Injury” has been clearly defined 
in the protocol to ensure that patients who experience a potential DILI undergo a full evaluation. 
 Guidance was added that patients should be instructed to contact the site promptly upon awareness if they develop signs 
and symptoms of potential hepatic decompensation such as:  pale-colored stools, urine color from pale to deep amber 
[dark], nausea, vomiting, abdominal pain, diarrhea, weight loss, fever and chills, fatigue, weakness, loss of appetite, 
confusion, swelling of the legs or abdomen, yellowing of the skin or the whites of eyes, and bruising easily. 
 Guidance was added that the Investigator should contact the study Medical Monitor upon awareness when any signs and 
symptoms of hepatic decompensation are observed in any patient. 
 Guidance was added for monitoring amylase and lipase levels in patients with suspected acute pancreatitis.  
 Gallbladder assessments were added at Screening or Day 1. 
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Summary of Changes 
The following revisions were made to the protocol in Protocol Version 3.  Revised and new text in Version 3 is indicated in bold font, 
and the text deleted from Protocol Version 2 is crossed out in the table below.  Minor/editorial changes are not listed individually in 
the summary table below. 
 
 
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Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Sponsor’s Approval 
of the Protocol 
 PhD  
 
 
 
 
  
Vice President, Clinical Development 
Intercept Pharmaceuticals, Inc. 
 PhD  
 
 
 
 
  
Sr Vice President, Clinical Development 
Intercept Pharmaceuticals, Inc. 
Signatory’s title changed. 
Study Personnel 
Contact Information 
Medical Monitor  
Primary Contact: 
 MD 
Medical Director, Pharmacovigilance, 
Intercept Pharmaceuticals, Inc. (Intercept) 
Telephone: 
 
Email: 
 
SAE Fax:
 
SAE Email: 
 
Medical Monitor  
Primary Contact: 
, DO, MSPH 
Senior Medical Director, Intercept 
Pharmaceuticals, Inc. (Intercept) 
 
Secondary Contact: 
 MD 
Senior Medical Director, Intercept 
Pharmaceuticals, Inc. (Intercept) 
 
 
24-Hour Telephone: 
 
 
SAE Fax:
 
SAE Email: 
 
Change in personnel. 
Synopsis, Study 
Period; Section 7.1.3, 
Study Duration 
Study Period:  Patients will receive double-blind 
treatment for at least 48 weeks.  Patients who have 
completed their 48-week double blind treatment period 
will continue double-blind treatment until all 
randomized patients have completed their participation 
in the 48-week treatment period and the database for that 
period is locked (approximately 3 years).  Patients will 
then be given the option to go on open-label treatment. 
Study Period:  Patients will receive double-blind 
treatment for at least 48 weeks.  Patients who have 
completed their 48-week double blind treatment period 
will continue double-blind treatment until all 
randomized patients have completed their participation 
in the 48-week treatment period and the database for 
that period is locked (approximately 3 years).  An 
open-label extension study in which all patients 
receive OCA will be considered following review of 
blinded safety and PK data. 
An open-label extension will 
only be considered only after 
review of blinded safety and PK 
data from the double-blind 
treatment period.   
Synopsis, Phase of 
Development 
Phase 4 
Phase 4:  US, Canada, and the EU 
Phase 3b:  All other regions 
Study is only considered a 
Phase 4 in regions where 
Ocaliva has received regulatory 
approval. 
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PPD
PPD
PPD
PPD
PPD
PPD
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Synopsis, Additional 
Objectives; Section 
6.3, Additional 
Objectives 
Additional Objectives: 
 
To evaluate the effect of OCA treatment compared 
to placebo on: 
 
Markers of inflammation 
 
Noninvasive markers of liver fibrosis 
(Enhanced Liver Fibrosis [ELF]™ score) 
  
Noninvasive measurement of liver stiffness 
(transient elastography [TE]) 
Additional Objectives: 
 
To evaluate the effect of OCA treatment compared 
to placebo on: 
 
Noninvasive markers of liver fibrosis 
(Enhanced Liver Fibrosis [ELF]™ score) 
 
Noninvasive measurement of liver stiffness 
(transient elastography [TE]) 
Samples were removed to 
simplify the study design. 
Synopsis, Double-
Blind Treatment 
Period; Section 7.1, 
Overall Study Design 
Double-Blind Treatment Period:  During the 48-week 
treatment period (ie, Day 1 through Week 48), an initial 
safety visit will occur at Week 3.  After the Week 6 
Visit, subsequent clinic visits will occur approximately 
every 6 weeks for the assessment of safety, tolerability, 
PK, and PD.  At each visit (except screening and Week 
3), fasting PK assessments will be performed in all 
patients participating in the study.  Serial PK sampling 
will be performed at Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week double blind 
treatment period will continue double blind treatment 
until all randomized patients have completed their 48-
week treatment period and the database for that period is 
locked.  Patients will then be given the option to go on 
open-label treatment. 
Double-Blind Treatment Period:  During the 48-week 
treatment period (ie, Day 1 through Week 48), an initial 
safety visit will occur at Week 3.  After the Week 6 
Visit, subsequent clinic visits will occur approximately 
every 6 weeks for the assessment of safety, tolerability, 
PK, and PD.  Titration may be considered as early as 
the Week 12 Visit.  Fasting PK assessments will be 
performed in all patients participating in the study on 
Day 1, Week 6, and Week 36.  Serial PK sampling 
(which also includes a fasted PK assessment) will be 
performed at Week 12, 18, 24, 30, and 48.  
Patients who have completed their 48-week double 
blind treatment period will continue double blind 
treatment until all randomized patients have completed 
their 48-week treatment period and the database for 
that period is locked.  An open-label extension study 
in which all patients receive OCA will be considered 
following review of blinded safety and PK data.   
Clarification for sites needed to 
clarify Fasted and Serial PK 
assessment timepoints. 
 
An open-label extension will 
only be considered only after 
review of blinded safety and PK 
data from the double-blind 
treatment period.   
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Synopsis, Study 
Design Diagram; 
Section 7.1.1 Study 
Design Diagram 
 
OCA = obeticholic acid, PBC = primary biliary 
cholangitis 
Notes: Initial dose titration of investigational product 
may be considered as early as the Week 12 
Visit, or any study visit thereafter for patients on 
all dosing regimens, based on tolerability and 
safety laboratory tests from the previous visit.  
Subsequent dose titration(s) may occur no 
earlier than 6 weeks after the previous dose 
titration and will be based on tolerability and CP 
score.   
Patients who complete Week 48 will continue 
double-blind treatment until all randomized 
patients have completed their participation in the 
48-week treatment period and the database for 
that period is locked. 
 
OCA = obeticholic acid, PBC = primary biliary 
cholangitis 
Notes: Initial dose titration of investigational product 
may be considered as early as the Week 12 
Visit, or any study visit thereafter for patients 
on all dosing regimens, based on tolerability 
and safety laboratory tests from the previous 
visit.  Subsequent dose titration(s) may occur 
no earlier than 6 weeks after the previous dose 
titration and will be based on tolerability.   
Patients who complete Week 48 will continue 
double-blind treatment until all randomized 
patients have completed their participation in 
the 48-week treatment period and the database 
for that period is locked. 
Clarification of extension 
period needed to ensure it is not 
confused with an open-label 
extension. 
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Synopsis, Dosing 
Regimen; Section 7.3 
Planned Dosing 
Regimen 
… 
Dosing will then occur at least 3 days apart.  Every 6 
weeks thereafter, based on safety and tolerability 
assessments, patients can be considered for further up 
titration as described below.  At each titration visit, the 
patient may start the higher dose regimen no earlier than 
2 days after the prior dose. 
Patients with CP-B may titrate to a maximum dose of 
OCA 5 mg once daily. 
Patients with CP-C may titrate to a maximum dose of 
OCA 10 mg twice weekly at least 3 days apart. 
If, during the course of the study, a patient transitions 
from CP- B to CP-C, or vice versa, the maximal dose for 
the new CP classification would apply. 
Planned OCA or Matching Placebo Dosing Regimen by 
Child-Pugh Score 
 
Child-Pugh B 
(Moderate 
Hepatic 
Impairment) 
Child-Pugh C 
(Severe Hepatic 
Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting 
Dose (Day 
1) 
5 mg 
once 
weekl
y 
matchin
g 
placebo 
5 mg 
once 
weekl
y 
matchin
g 
placebo 
Titration 
1a  
5 mg 
twice 
weekl
yb 
matchin
g 
placebo 
5 mg 
twice 
weekl
yb 
matchin
g 
placebo 
Titration 
2a  
10 mg 
twice 
weekl
yb 
matchin
g 
placebo 
10 mg 
twice 
weekl
yb 
matchin
g 
placebo 
… 
Dosing will then occur at least 3 days apart.  Every 6 
weeks thereafter, based on tolerability assessments, 
patients can be considered for further up titration as 
described below.  At each titration visit, the patient 
may start the higher dose regimen no earlier than 2 
days after the prior dose. 
Patients may titrate to a maximum dose of OCA 10 
mg twice weekly at least 3 days apart.  
Planned OCA or Matching Placebo Dosing Regimen 
 
Child-Pugh B and Child-Pugh C 
(Moderate and Severe Hepatic 
Impairment) 
 
Treatment Group 
 
OCA 
Placebo 
Starting 
Dose (Day 
1) 
5 mg once 
weekly 
matching 
placebo once 
weekly 
Titration 
1a  
5 mg twice 
weeklyb 
matching 
placebo twice 
weeklyb 
Titration 
2a  
10 mg twice 
weeklyb 
matching 
placebo twice 
weeklyb 
a Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
patient tolerability. 
b Dosing per the twice weekly schedule must be at 
least 3 days apart. 
 
Per FDA request to align dosing 
with label dosing guidelines for 
CP-B and CP-C patients. 
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Titration 
3a  
5 mg 
once 
daily 
matchin
g 
placebo 
NA 
NA 
a Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
patient tolerability and/or changes in Child-Pugh Score 
at any time during the study. 
b Dosing per the twice weekly schedule must be at least 
3 days apart. 
Over the course of the study, a patient’s CP category 
may change.  When a patient demonstrates a change in 
CP category, dosing should be reassessed and modified 
if appropriate.  Changes to the dosing regimen are not 
mandatory and should be based on clinical judgment and 
change in CP score.  The titration steps for CP-B and 
CP-C patients are identical with exception of the 
maximum allowed dose.  Therefore, if a patient changes 
CP class from B to C, or vice versa, the maximal dose 
for the new regimen will apply.  If a patient improves to 
CP-A during the study, the maximal CP-B dose will still 
apply.  If a patient has not yet reached the maximal dose, 
the appropriate titration regimen should be followed.  
Maximum Dose for OCA or Matching Placebo for 
Changes in Child-Pugh Category 
 
a Once a patient begins dosing with the new dosing 
regimen, titration should occur as described for the 
planned dosing regimen.  
b Dosing per the twice weekly schedule must be at least 
3 days apart. 
Synopsis, Key 
Inclusion Criteria; 
Section 8.2, Patient 
Inclusion Criteria 
3. 
Satisfy the criteria of the modified CP classification 
for hepatic impairment during Screening (ie, within 14 
days before the first dose of investigational product): 
3. 
Satisfy the criteria of the modified CP 
classification for hepatic impairment during Screening  
Correction 
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Synopsis, Key 
Exclusion Criteria; 
Section 8.3, Patient 
Exclusion Criteria 
4.   Hepatic encephalopathy (as defined by a West 
Haven score of ≥2) 
4.   Current hepatic encephalopathy (as defined by a 
West Haven score of ≥2) 
Correction 
Synopsis, Key 
Exclusion Criteria 
5. 
History or presence of other concomitant liver 
diseases including: 
• 
Hepatitis C virus infection and RNA positive 
• 
Active hepatitis B infection; however, patients who 
have seroconverted (hepatitis B surface antigen and 
hepatitis B antigen negative) may be included in this 
study after consultation with the medical monitor 
5. 
History or presence of other concomitant liver 
diseases including: 
• 
Hepatitis C virus infection and RNA positive 
• 
Active hepatitis B infection; however, patients 
who have seroconverted (hepatitis B surface antigen 
and hepatitis B e antigen negative) may be included in 
this study after consultation with the Medical Monitor 
Correction 
Synopsis, Duration of 
Treatment 
Patients who have completed their 48-week double blind 
treatment period will continue double blind treatment 
until all randomized patients have completed their 
participation in the 48-week treatment period and the 
database for that period is locked (approximately 3 
years).  Patients will then be given the option to go on 
open-label treatment. 
Patients who have completed their 48-week double 
blind treatment period will continue double blind 
treatment until all randomized patients have completed 
their participation in the 48-week treatment period and 
the database for that period is locked (approximately 3 
years).  An open-label extension study in which all 
patients receive OCA will be considered following 
review of blinded safety and PK data. 
An open-label extension will 
only be considered only after 
review of blinded safety and PK 
data from the double-blind 
treatment period.   
Synopsis, Criteria for 
Evaluation; Section 
11, Overview of 
Assessments, Table 7 
Secondary Objectives 
Assessments 
Changes in risk scores 
Changes in MELD and in 
CP score and components 
of the CP score 
Changes in liver 
biochemistry and 
hepatobiliary damage  
Total and direct bilirubin, 
ALP, ALT, AST, GGT, 
INR, creatinine, albumin, 
platelets 
PD parameters 
FGF-19, C4, and plasma 
bile acids 
Additional Objectives 
Assessments 
Markers of 
inflammation 
IL-6, hs-CRP, TNF-α, 
IgM, IgA, IgG, 
CK-18-M30  
Noninvasive 
measurements of liver 
fibrosis, liver stiffness 
and cirrhosis 
TE and ELF (HA, P3NP, 
and TIMP-1) 
Secondary 
Objectives 
Assessments 
Changes in risk scores 
Changes in MELD and in 
CP scores and 
components of the CP 
score and MELD score 
Changes in liver 
biochemistry and 
hepatobiliary damage  
Total and direct bilirubin, 
ALP, ALT, AST, GGT, 
INR, creatinine, albumin, 
platelets 
PD parameters 
FGF-19, C4, and plasma 
bile acids 
Additional 
Objectives 
Assessments 
Noninvasive 
measurements of liver 
fibrosis, liver stiffness 
and cirrhosis 
TE and ELF (HA, P3NP, 
and TIMP-1) 
 
Risk score assessment clarified.  
 
Markers of inflammation were 
removed to simplify the study 
design. 
 
 
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Section 14.1.1, Child-
Pugh Score 
Factor 
Units 
Points 
1 
2 
3 
Serum 
bilirubin 
μmol/L 
<35 
35-50 
>50 
mg/dL 
<2.0 
2.0-
3.0 
>3.0 
 
Factor 
Units 
Points 
1 
2 
3 
Serum 
bilirubin 
μmol/L 
<34 
34-50 
>50 
mg/dL 
<2.0 
2.0-
3.0 
>3.0 
 
Error correction 
Synopsis, Safety 
Analyses; Section 
15.4, Safety Analysis 
Safety analyses will be conducted using the Safety 
population.  Safety data, including AEs, vital signs, 
electrocardiogram, and clinical laboratory results will be 
summarized by treatment group.   
Safety analyses will be conducted using the Safety 
population.  Safety data, including AEs, AEs of special 
interest including pruritus and hepatic safety, vital 
signs, electrocardiogram, and clinical laboratory results 
will be summarized by treatment group.   
Per FDA request 
Synopsis, Additional 
Efficacy Analyses; 
Section 15.6, 
Additional Efficacy 
Analyses 
Analyses of changes in liver stiffness and ELF, 
cytokeratin-and TIMP-1, and markers of inflammation 
will be summarized and analyzed using the same 
methodology specified for the secondary analyses of 
change in bilirubin. 
 
Analyses of changes in liver stiffness (TE) and liver 
fibrosis (ELF [HA, P3NP, and TIMP-1]), will be 
summarized and analyzed using the same methodology 
specified for the secondary analyses of change in 
bilirubin. 
 
Correction 
Synopsis, Sample 
Size Justification; 
Section 15.2, 
Determination of 
Sample Size 
To reasonably characterize the PK of OCA in patients 
with hepatic impairment, a simulation-based approach 
estimated a requirement of approximately 20 patients in 
the OCA treatment group assuming a 15% 
discontinuation rate.  Ten patients on placebo will be 
included as a comparator.  An additional 20 patients will 
be enrolled to support safety and efficacy evaluations.  
Therefore, approximately 50 patients (including at least 
20% of patients with CP-C) will be randomized.  
 
To reasonably characterize the PK of OCA in patients 
with hepatic impairment, a simulation based approach 
estimated a requirement of approximately 20 patients in 
the OCA treatment group assuming a 15% 
discontinuation rate.  A total of 30 patients is 
adequate with 10 patients on placebo to be included as 
a comparator and 20 patients on OCA.  An additional 
20 patients will be enrolled to support safety and 
efficacy evaluations.  Therefore, approximately 50 
patients (including at least 20% of patients with CP-C) 
will be randomized in a 1:1 ratio to 1 of the 2 
treatment groups:  Placebo and OCA. 
Clarification. 
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Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 5.1, 
Overview of Disease 
State and OCA 
In May 2016, the US Food and Drug Administration 
(FDA) granted accelerated approval for OCA (marketed 
as Ocaliva), for the treatment of patients with PBC in 
combination with UDCA in adults with an inadequate 
response to UDCA or as monotherapy in adults unable 
to tolerate UDCA.  In December 2016, the European 
Commission granted conditional approval for Ocaliva 
for the same indication. 
In May 2016, the US Food and Drug Administration 
(FDA) granted accelerated approval for OCA 
(marketed as Ocaliva), for the treatment of patients 
with PBC in combination with UDCA in adults with an 
inadequate response to UDCA or as monotherapy in 
adults unable to tolerate UDCA.  In December 2016, 
the European Commission granted conditional approval 
for Ocaliva for the same indication, and in May 2017 
Ocaliva received approval from Health Canada.  
Study 747-401 is considered a Phase 4 study in 
regions where OCA has received regulatory 
approval for PBC (ie, in the US, Canada, and the 
EU).  In all other regions, this study is considered 
Phase 3b. 
Ocaliva has been approved in 
Canada since last version of 
protocol. 
Study is only considered a 
Phase 4 in regions where 
Ocaliva has received regulatory 
approval. 
Section 5.3, Clinical 
Development of 
Obeticholic Acid 
As of 31 Jan 2017, approximately 2186 patients have 
received at least 1 dose of OCA.  Of these, 844 were 
healthy volunteers, 525 patients had PBC, 686 patients 
had nonalcoholic steatohepatitis (NASH), 41 patients 
had diabetes mellitus/ nonalcoholic fatty liver disease 
(NAFLD), 33 patients had alcoholic cirrhosis/portal 
hypertension, 52 patients had primary sclerosing 
cholangitis (PSC), and 5 patients had biliary atresia. 
As of 13 Oct 2017, approximately 2690 subjects have 
received at least 1 dose of OCA.  Of these, 844 were 
healthy volunteers, 552 patients had PBC, 1141 
patients had nonalcoholic steatohepatitis (NASH), 41 
patients had diabetes mellitus/ nonalcoholic fatty liver 
disease (NAFLD), 33 patients had alcoholic 
cirrhosis/portal hypertension, 73 patients had primary 
sclerosing cholangitis (PSC), and 6 patients had biliary 
atresia. 
Updated exposure numbers 
available 
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5.4.2, Rationale for 
Obeticholic Acid 
Dose and Duration 
Therefore, the current FDA-approved prescribing 
information for OCA includes a modified dosing 
regimen in patients with moderate and severe hepatic 
impairment that is designed to achieve liver exposures in 
these patients that would be similar to non-hepatically 
impaired patients through initiation at a lower dose (5 
mg OCA once-weekly) followed by gradual up-titration 
(Section 7.3).   
The dosing regimen in this study follows the FDA-
approved prescribing information, with the exception of 
the maximum allowed dose in patients with moderate 
impairment.  While the prescribing information allows 
for a maximum dose of 10 mg twice weekly for patients 
with moderate impairment, the protocol allows for a 
maximum dose of 5 mg once daily.  The choice of 5 mg 
once daily is supported by the estimated steady-state 
liver and plasma exposure of total OCA for patients with 
moderate hepatic impairment receiving a 5 mg once 
daily dose relative to healthy patients receiving a 10 mg 
dose.  A maximum allowed dose of 5 mg once daily in 
patients with moderate hepatic impairment is estimated 
to achieve liver exposure similar to non-hepatically 
impaired patients receiving a 10 mg daily dose and 
maximize efficacy in this patient population. 
Therefore, the current FDA-approved prescribing 
information for OCA includes a modified dosing 
regimen in patients with moderate and severe hepatic 
impairment that is designed to achieve liver exposures 
in these patients that would be similar to 
non-hepatically impaired patients through initiation at a 
lower dose (5 mg OCA once-weekly) followed by 
gradual up-titration (Section 7.3).   
 
Text no longer applicable since 
all dosing regimens will follow 
FDA-approved prescribing 
information. 
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Section 5.5, 
Importance of 
Monitoring Disease 
Progression 
New Section 
Given PBC is a chronic, progressive liver disease, it 
is important that patients with PBC are closely 
monitored to ensure early identification of 
decompensation and/or liver injury.  More extensive 
safety monitoring and appropriate dosing 
adjustments, interruptions, and discontinuations 
will be implemented to improve patient oversight 
and safety.  Investigators, together with the 
Sponsor’s Medical Monitor, will consistently and 
frequently assess individual patients to determine 
on an ongoing basis the totality of a patient’s clinical 
profile, which includes careful evaluation of signs 
and symptoms of potential hepatic injury and/or 
decompensation coupled with rules-based 
laboratory monitoring. 
Patients will be monitored for potential hepatic 
injury and/or decompensation.  Criteria for 
implementing dosing adjustments, interruptions, or 
discontinuations, and close monitoring procedures 
postdose-adjustment are described in Section 8.4 
and Section 7.6.  The more extensive monitoring is 
important given the elevated risk of decompensation 
and potential for higher hepatic exposure to OCA in 
this population. 
Language added to generate 
Investigator awareness of the 
disease progression trajectory 
and unpredictable nature of 
progression in patients at high 
risk, as well as incorporation of 
language regarding altered bile 
acid and OCA PK and drug 
exposure in patients with 
hepatic impairment and the 
need for close vigilance to 
identify potential liver toxicity 
or decompensation. 
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Section 5.6, Summary 
of Known Potential 
Risks with 
Investigational 
Product 
The primary AE shown to be related to OCA is pruritus.  
Pruritus has also been observed in clinical studies with 
OCA in other indications, as well as in healthy patients, 
but with a much lower frequency than that observed in 
patients with PBC. 
Consistent with the dose-limiting hepatic toxicities 
observed in the non-clinical studies and the chemical 
characteristics of OCA as a bile acid and detergent, 
dose-related but reversible and asymptomatic increases 
in ALT and AST were observed in healthy volunteers 
treated with multiple doses of OCA starting at the 100 
mg dose (Study 747-102).   
In patients with chronic liver disease such as PBC, 
hepatobiliary findings including increased transaminases 
and bilirubin and signs or symptoms of hepatic 
decompensation such as development of jaundice were 
observed.  These findings were seen more frequently 
with doses of OCA 10 mg once daily to OCA 50 mg 
once daily (up to 5x the highest recommended dose).  In 
addition, cholecystitis, including acute cholecystitis, was 
reported in association with treatment with OCA. 
Lipoprotein changes have also been observed with OCA 
dosing, including a decrease in high density lipoprotein 
(HDLc) and an increase in low density lipoprotein 
(LDLc).  Notably, in patients with PBC, the decrease in 
mean HDLc levels occurred early and stabilized within 3 
months after which time levels generally remained 
constant over the course of treatment.  The average 
levels of HDLc remained within normal limits.  
Commensurate with decreases in HDLc, decreases in 
total cholesterol were observed in patients with PBC, 
while LDLc concentrations remained comparable to 
baseline and placebo in OCA treated patients with the 
exception of a modest transient and early rise after 
initiation of treatment. 
Based on previous PK and short-term studies in patients 
with hepatic impairment, increased systemic exposure 
was not associated with an apparent change in the safety 
profile of OCA as assessed by the incidence and severity 
of AEs or by changes in clinical laboratory tests.  
Hepatotoxicity has been associated with increased liver 
concentrations of OCA.  Hepatic impairment does not 
The rate of progression and risk of decompensation 
is variable and may be rapid in certain patients, 
necessitating closer surveillance of patients at risk.   
Clinical Data 
In two Phase 2 studies and a Phase 3 study 
evaluating OCA in the treatment of subjects with 
PBC, hepatic adverse events were observed in 
subjects receiving doses of OCA ranging from the 
maximum approved dose of 10 mg once daily to 50 
mg (5 times the highest recommended dose).   
Recent safety findings in NASH clinical trials 
include 2 cases of hepatic decompensation reported 
as SUSARs, 1 of which resulted in death.  Both cases 
involved numerous confounding factors that make 
evaluation of association with treatment difficult.  
Details for both events are provided in the 
Investigator’s Brochure Addendum 1 to Version 
Number: 16 (31 March 2017), Effective Date: 02 
October 2017. 
The primary AE shown to be related to OCA is 
pruritus.  Pruritus has also been observed in clinical 
studies with OCA in other indications, as well as in 
healthy subjects, with the highest frequency 
observed in subjects with PBC.  The incidence and 
severity of pruritus have been shown to be dose 
dependent, but there is no evidence of association 
with stage or progression of underlying disease. 
Changes in lipid profiles have also been observed 
with OCA dosing, including an increase in 
low-density lipoprotein (LDL) cholesterol and a 
decrease in high-density lipoprotein (HDL) 
cholesterol.  The clinical significance of these lipid 
findings remains unclear and is being studied 
further. 
Independent data monitoring committees (DMCs) 
have performed detailed reviews of several studies 
including the Phase 3, clinical outcomes study in 
PBC (747-302) and the Phase 3, pivotal study in 
NASH with fibrosis (747-303).  The DMC reviewed 
data (unmasked for PBC and unblinded by 
Updated in relations to other 
revisions made per FDA 
request. 
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affect the ability of OCA to activate FXR in the intestine 
and the liver. 
Refer to the Investigator’s Brochure (IB) for additional 
information regarding the known potential risks with the 
investigational product. 
treatment group for NASH with a total of 
approximately 1000 subjects) in closed sessions, 
which excluded participation of the Sponsor.  Based 
on these reviews, the DMC recommended that both 
studies continue without modification. 
Post-Marketing Cases in PBC 
As of September 2017, greater than 3000 patients 
have received Ocaliva in the post-marketing 
setting.  In patients with moderate to severe hepatic 
impairment (Child-Pugh B and C), liver 
decompensation, liver failure, and death have been 
reported when Ocaliva was dosed up to 7 times the 
recommended once weekly starting dose for such 
patients.  Based on the initial medical assessment of 
these cases, which included patients having 
undergone liver transplant, there was insufficient 
evidence suggesting a causal relationship between 
higher than recommended dosing and the reported 
adverse events. However, Intercept 
Pharmaceuticals, Inc. (the Sponsor) continues to 
assess the potential association between adverse 
events, including deaths, and the higher than 
recommended dosing of Ocaliva observed in PBC 
patients with moderate to severe hepatic 
impairment (Child-Pugh B and C) through ongoing 
post-marketing pharmacovigilance activities. 
Signs and symptoms reported in patients 
experiencing liver-related adverse events who 
received Ocaliva include:  increases in bilirubin and 
other liver enzymes, new or worsening pruritus, 
new or worsening fatigue, vague neuropsychiatric 
symptoms (such as dysphoria), abdominal pain, 
nausea, vomiting, diarrhea, dehydration, jaundice, 
and liver decompensation. 
Refer to the IB for additional information regarding the 
known potential risks with the investigational product. 
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
Treatment Period (Weeks) 
Long-Term 
Safety 
Extension 
Double-Blind Treatment Period 
(Weeks)b 
Double-
Blind 
Extension 
Clarification 
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Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
Insertion 
Week 42 Visit added with assessments to match 
Week 3 Visit plus assesments to assess for dose 
titration and dispense IP. 
Correction 
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1, 
Screening, Day 1 
Insertion 
Gallbladder assessment (ultrasound) 
Gathering additional data at 
Screening may be beneficial in 
identifying at risk populations 
(eg, to assist with the causality 
of potential 
gallbladder/pancreatic 
complications).  
Insertion 
Footnotes added  
r 
If an ultrasound has been done within 12 
months of Screening, and a report/adequate data 
are available, a pretreatment ultrasound at 
Screening is not required. 
s 
If ultrasound for gallbladder assessment was 
not performed at Screening and the historic 
ultrasound is >12 months from Day 1, perform 
ultrasound. 
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
Markers of Inflammation: IL-6, hs-CRP, TNF-α, IgM, 
IgG, IgA, CK-18-M30 
Deletion 
Samples were removed to 
simplify the study design. 
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
Insertion 
Amylase and Lipase:  Sample to be collected if the 
patient experiences acute pancreatitis or 
cholecystitis. 
Per FDA request. 
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
PK Fasting Collection 
Removed for Weeks 12, 18, 24, 30, and 48/ET/EOS/EOT 
Deletion 
Clarification for sites needed to 
clarify Fasted and Serial PK 
assessment timepoints.  Serial 
PK is fasted, so indicating both 
types of assessments for these 
days was redundant.   
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
Insertion  
Footnote added to Serum 
Chemistry/Hematology/Coagulation 
l MELD values will be calculated based on serum 
chemistry coagulation values at each visit. 
Clarification. 
Section 7.4, 
Monitoring and 
Management of 
Potential Hepatic 
Injury and/or 
Disease Progression 
New Section 
Given the chronic nature of PBC, it is important to 
monitor for potential hepatic injury, disease 
progression and/or hepatic decompensation.  Child-
Pugh and MELD scores will be reviewed at each 
visit where labs are drawn (Table 1).  In addition, 
adverse events, signs and symptoms of potential 
hepatic injury or decompensation, and laboratory 
values will also be reviewed at regular intervals as 
described in Section 7.1.2.  Based on biochemical 
and clinical assessments, the investigational product 
Extensive safety monitoring 
and dosing adjustments, 
interruptions, or 
discontinuations are required 
given the elevated risk of 
decompensation and higher 
hepatic exposure to OCA in this 
population. It is important that 
Investigators construct an entire 
clinical picture, which includes 
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may be interrupted or discontinued per criteria 
discussed in Section 7.4.2 and Section 7.4.3, and 
close monitoring procedures will be implemented 
(refer to Section 7.6). 
not only rules based monitoring 
but careful evaluation of signs 
and symptoms of potential 
decompensation and diagnostic 
dilemmas. 
Section 7.4.1, Signs 
and Symptoms of 
Potential Hepatic 
Injury or 
Decompensation 
New Section 
Patients should be instructed to contact study 
personnel if they notice any of the following signs 
and symptoms or have healthcare interactions 
outside of the study setting  
Signs and Symptoms of Hepatic Injury or 
Decompensation: 
 
Specific signs and symptoms of liver 
impairment:  yellowing of the skin or 
the whites of eyes, pale-colored stools, 
urine color change from pale to deep 
amber [dark] (reflecting impaired 
bilirubin metabolism) 
 
More general signs and symptoms of 
ascites and encephalopathy:  
confusion, swelling of the legs or 
abdomen 
 
Non-specific signs and symptoms of 
impaired health:  nausea, vomiting, 
abdominal pain, diarrhea, weight loss, 
fever and chills, worsening or new 
fatigue, weakness, loss of appetite 
 
Significant intercurrent illnesses such 
as gastroenteritis may exacerbate 
hepatic injury or decompensation (eg, 
established severe abdominal pain, 
vomiting, and diarrhea for more than 
4 days) and should be an indication 
for prompt investigational product 
interruption and complete patient 
evaluation 
Other Symptoms: 
Per FDA request. 
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 
Worsening of renal function or likely 
dehydration 
Healthcare Provider (HCP) Interactions: 
 
Visits to primary HCP or referral to 
any specialist for any new symptoms 
(other than ongoing care for stable 
comorbidities) 
 
New medications or changes to 
current medications prescribed from 
HCP or any new over the counter 
medications or herbal supplements  
 
Laboratory procedures or 
assessments performed by an HCP  
Signs and symptoms for potential hepatic injury or 
decompensation should be followed by (1) 
evaluation of liver biochemistry for suspected drug-
induced liver injury (DILI) or potential hepatic 
decompensation (Section 7.4.2), (2) assessment of 
clinical events for potential hepatic decompensation 
(Section 7.4.3), (3) triggering of close monitoring or 
investigational product interruption/discontinuation 
per criteria (Section 8.4), (4) documentation in the 
AE eCRF or the SAE eCRFs (Section 13.1), and (5) 
contact with the Medical Monitor. 
Section 7.4.2, Liver 
Biochemistry 
Assessments for 
Potential Hepatic 
Injury or Hepatic 
Decompensation 
New Section 
Liver biochemistry will be assessed to evaluate 
biochemical triggers that will prompt an immediate 
reevaluation of patients for potential hepatic injury 
or hepatic decompensation.  These assessments will 
be performed at: 
 
Each protocol-specified visit (Table 1)  
 
Unscheduled visits as needed in the 
event of signs or symptoms of 
suspected hepatic injury or 
decompensation or if laboratory 
alerts have been triggered 
It is important that the laboratory assessments be 
completed as required and that the central 
Per FDA request. 
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laboratory be used for assessments whenever 
possible.  In the event that a patient cannot return 
to the clinic for a scheduled or unscheduled visit, or 
there is an event that triggers a need for an 
immediate assessment, the use of a local lab is 
permissible at the discretion of the Investigator. In 
these cases, the Investigator will obtain the 
laboratory results and the laboratory normal 
ranges. 
The process for assessing criteria is presented in 
Figure 2, and the specific threshold(s) for each 
laboratory analyte to trigger mandatory repeat 
testing and, potentially, a complete patient 
evaluation (depending on the repeat result) are 
summarized in Table 3. 
Figure 2: 
DILI Management Algorithm 
 
 
DILI = drug-induced liver injury; IP = Investigational Product 
NOTE Other laboratory criteria include:  ALT, AST, total bilirubin, INR, and 
electrolytes (sodium). 
Table 3 
Liver Laboratory Criteria for 
Monitoring of Suspected Hepatic 
Injury or Potential Hepatic 
Decompensation and Criteria for 
Interruption or Discontinuation 
of Investigational Product 
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It should be noted that it is difficult to recognize 
every potential marker of hepatic or renal 
deterioration.  There is no substitute for good 
medical judgment.  Investigators will be reminded 
to be cautious and mindful in their evaluation of 
patients’ symptoms, signs, and laboratory results.  
However, for example, a single abnormal laboratory 
analyte result may be artefactual; accordingly, 
Investigators will be allowed to implement an 
alternate follow-up procedure if considered 
appropriate based on their medical judgement, but 
only after documented agreement with the 
Sponsor’s Medical Monitor. 
7.4.3, Clinical 
Criteria for 
Monitoring for 
Potential Hepatic 
Decompensation 
New Section 
Patients will be monitored for potential hepatic 
decompensation events throughout the study.  
Clinical criteria for monitoring these events and the 
interruption/discontinuation of investigational 
product is summarized in Table 4. 
Investigational product should be discontinued 
permanently if the patient received a liver 
transplant or experiences multi-organ failure as 
defined in Table 4, Part A.  Patients should continue 
to return for scheduled study visits for safety follow 
up.  
Patients who experience other potential hepatic 
decompensation events defined in Table 4, Part B 
should be closely monitored until normalization or 
stabilization.  Patients may be rechallenged after a 
minimum of 30 days if fully resolved OR stable and 
approved by the Medical Monitor and Investigator. 
 
Table 4  Clinical Criteria for Monitoring Potential 
Hepatic Decompensation Events and Interruption / 
Discontinuation of Investigational Product   
Per FDA request. 
7.5, Dose Titration 
Criteria 
Dose Adjustment Criteria 
Dose titration may follow the scheduled dosing regimens 
described in Section 7.3 or occur due to tolerability 
concerns or as a result of changes in a patient’s CP 
Score. 
Dose titrations may involve increases or decreases in 
dosing frequency and are dependent on tolerability (as 
Dose Titration Criteria 
Dose titration may follow the scheduled dosing 
regimens described in Section 7.3 or occur due to 
tolerability concerns. 
Dose titrations may involve increases or decreases in 
dosing frequency and are dependent on tolerability (as 
assessed by a review of AEs and safety laboratory 
Updates made to reflect 
titration for dosing per label 
dosing guidelines. 
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assessed by a review of AEs and safety laboratory 
results).  In general, down-titration may be done in 
response to tolerability concerns and can occur at any 
time.  Up-titration will be done per protocol based on 
tolerability, as assessed by the Investigator based on 
response, or following resolution of a tolerability 
concern that previously led to down-titration.  
Up-titrations may only occur to the maximum dose and 
frequency indicated for each dosing regimen as defined 
in Section 7.3. 
Scheduled Dose Titration - After initiation of OCA or 
matching placebo, titration may be considered as early 
as the Week 12 Visit.  Subsequent titrations in dose or 
dosing frequency for patients may occur no earlier than 
6 weeks following an up-titration. 
Tolerability Dose Titration - Investigators may 
decrease the dosing frequency or dose as considered 
clinically appropriate (eg, tolerability) 
Dose Titration due to Change in CP Score – Over the 
course of the study, a patient’s CP category may change.  
When a patient demonstrates a change in CP category 
(as assessed per Table 12), dosing should be reassessed 
and modified if appropriate (Table 2).  Changes to the 
dosing regimen are not mandatory and should be based 
on clinical judgment and change in CP score.  The 
titration steps for CP-B and CP-C patients are identical 
with exception of the maximum allowed dose.  
Therefore, if a patient changes CP class from B to C, or 
vice versa, the maximal dose for the new regimen will 
apply (Table 2).  If a patient improves to CP-A during 
the study, the maximal CP-B dose will still apply.  If a 
patient has not yet reached the maximal dose, the 
appropriate titration regimen (Table 2) should be 
followed.  
Table 3: 
Maximum Daily dose based on 
change in Child-Pugh Category 
results).  In general, down-titration may be done in 
response to tolerability concerns and can occur at any 
time.  Up-titration will be done per protocol based on 
tolerability, as assessed by the Investigator based on 
response, or following resolution of a tolerability 
concern that previously led to down-titration.  
Up-titrations may only occur to the maximum dose and 
frequency indicated as defined in Section 7.3. 
Scheduled Dose Titration - After initiation of OCA or 
matching placebo, titration may be considered as early 
as the Week 12 Visit.  Subsequent titrations in dose for 
patients may occur no earlier than 6 weeks following 
an up-titration. 
Tolerability Dose Titration - Investigators may 
decrease the dosing frequency or dose as considered 
clinically appropriate (eg, tolerability). 
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a  Once a patient begins dosing with the new dosing 
regimen, titration should occur as described for that 
dosing regimen in Section 7.3 .  
b Dosing per the twice weekly schedule must be at least 
3 days apart. 
CP Scores will be calculated at all study visits (except 
Week 3).  While PBC-specific versions of CP scores are 
available, this study will use the standard calculation 
(Pugh 1973, Lucey 1997).  All associated visit data 
(including central laboratory results) should be entered 
into the electronic case report form (eCRF) in a timely 
fashion to confirm that the patient’s CP Score has not 
changed.  If a change in CP Score is observed 
independent of a study visit, the patient should be 
contacted via phone to discuss the need for a dosing 
modification and should be asked to return to the 
investigative site as soon as possible if a new bottle of 
investigational product is required to be dispensed. 
Section 7.6, Close 
Observation 
New Section 
If investigational product is interrupted or 
discontinued as described in Section 8.4, patients 
should be closely monitored (contacted by the site a 
minimum of every 2 weeks and scheduled visits 
every 6 weeks; if returning to the site for a 
scheduled visit is not feasible, use of a local lab may 
be permissible at the Investigator's discretion).  At a 
minimum, the following assessments should be 
conducted at each study visit:   
 
Physical exam and thorough review of 
patient reported signs and symptoms,  
 
Liver biochemistry (including ALP, 
ALT, AST, GGT, total and 
conjugated bilirubin, creatinine, and 
Per FDA request. 
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albumin), prothrombin time 
(PT)/INR, serum electrolytes, and 
assessment of Child Pugh (only if the 
patient is at the study site) and MELD 
scores.  
In addition, a trough pharmacokinetic sample for 
assessment of OCA serum drug levels and its major 
metabolites should be obtained in any patient who 
develops an AE that is indicative of or consistent 
with hepatic injury or decompensation.  
The following additional monitoring procedures 
should be performed for events of potential hepatic 
injury (per FDA Guidance for Industry on Drug 
Induced Liver Injury) or suspected hepatic 
decompensation based on criteria described in 
Section 7.4.1, Section 7.4.2, Section 7.4.3.  These 
cases need to be discussed with the Sponsor's 
Medical Monitor: 
 
Repeating liver biochemistry and 
function tests as described in Section 
7.4.2.  Frequency of retesting can 
decrease to once a week or less if 
abnormalities stabilize or the study 
drug has been discontinued and the 
patient is asymptomatic, as clinically 
indicated.  
 
Obtaining a more detailed history of 
symptoms and prior or concurrent 
diseases.  
 
Obtaining a history of concomitant 
drug use (including nonprescription 
medications and herbal and dietary 
supplement preparations), alcohol 
use, recreational drug use, and special 
diets is important. Concomitant drugs 
with potential hepatotoxicity should 
be recorded and discontinued unless 
alternative therapies are not 
available.  In the case of concomitant 
drugs potentially hepatotoxic, 
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continued use of investigational 
product should be discussed with the 
Sponsor's Medical Monitor.  The 
patient may be discontinued from 
investigational product, if clinically 
appropriate.  
 
Obtaining a history of exposure to 
environmental chemical agents or 
herbal supplements which may be 
associated with liver toxicity.  
 
Ruling out acute viral hepatitis types 
A, B, C, D (in those thought to have 
acute HBV infection), and E; 
autoimmune or alcoholic hepatitis; 
Wilson's disease, hypoxic/ischemic 
hepatopathy; and biliary tract 
disease.   
 
Investigators should consider testing 
for Hepatitis E virus when assessing 
for hepatic decompensation as 
infection with Hepatitis E virus in 
patients with chronic liver diseases 
such as PBC may rapidly worsen with 
signs and symptoms similar to drug 
induce liver injury (Kumar 2013) 
 
Obtaining additional tests to evaluate 
liver function, as appropriate (e.g., 
INR, direct bilirubin).  
 
Seeking hepatology consultation, if 
the Investigator is not a hepatologist 
Section 8.4, Dose 
Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
Investigational product may be temporarily decreased 
(eg, by decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability concerns.  
The dose of investigational product should be resumed 
to the maintenance dose in a blinded manner once the 
issues relating to the lack of tolerability are resolved.   
Patients who are discontinued from investigational 
product prior to completion of the study are encouraged 
Investigational product may be temporarily decreased 
(eg, from 10 mg twice weekly to 5 mg twice weekly, 
or from 5 mg twice weekly to 5 mg once weekly) or 
temporarily or permanently stopped based on 
tolerability concerns.  Investigational product may be 
resumed at the maintenance dose upon resolution of 
gastroenteritis or worsening renal function or 
dehydration if there is no evidence of liver injury.  
Per FDA request. 
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to continue to follow the regular visit schedule, with the 
exception of PK sampling, but may withdraw consent at 
any time. 
For rechallenge following all other dose 
interruptions (see Table 5), investigational product 
should be initiated at a lower dose and patients 
monitored more frequently with up-titration 
considered based on tolerability. 
Adjustments, interruptions, discontinuation, and 
any rechallenge of investigational product should be 
implemented per the criteria outlined in Table 5.  
Patients that discontinue investigational product are 
expected to continue in the study (and follow the 
regular visit schedule, with the exception of PK 
sampling [trough PK may be required in the event of 
an AE consistent with hepatic injury or 
decompensation]) until the end of the study, but may 
withdraw consent at any time. 
Table 5  Criteria for Dose Adjustment, 
Interruption, Discontinuation, and Rechallenge 
8.4.1, Reasons for 
Additional 
Monitoring of 
Mandatory 
Interruption of 
Investigational 
Product; 8.4.1.1, 
Reasons for 
Additional 
Monitoring Related to 
Liver Chemistries; 
8.4.1.2, Reasons for 
Investigational 
Product Interruption 
Related to Elevated 
Liver Chemistries; 
8.4.1.3, Pregnancy; 
8.4.2., Reasons for 
Mandatory 
Discontinuation of 
Investigational 
Product 
8.4.1. 
Reasons for Additional Monitoring or 
Mandatory Interruption of Investigational Product 
8.4.1.1. Reasons for Additional Monitoring Related to 
Liver Chemistries 
Patients who develop ALT or AST >2× baseline (and 
>ULN) or total bilirubin >1.5× baseline (and >ULN) 
should have repeat testing within 48 to 72 hours to 
confirm values.  Patients with persistent elevations (eg, 
additional lab testing per Investigator discretion) should 
be closely monitored.  Concomitant elevations in total 
bilirubin or INR with persistent increases in ALT or 
AST should also be closely monitored. 
8.4.1.2. Reasons for Investigational Product 
Interruption Related to Elevated Liver Chemistries 
Development of any of the following clinical laboratory 
values, without explanation, during the study mandates 
investigational product interruption: 
• 
AST and/or ALT >3× baseline (and >ULN) 
• 
Total bilirubin >2× baseline (and >ULN) 
Repeat testing within 48 to 72 hours to confirm the 
abnormalities and to determine if they are increasing or 
decreasing should be performed.  Detailed adverse event 
information should also be collected, and the patient 
should be investigated for possible causes of the liver 
Deletion 
Replaced by text in in other 
sections added per FDA 
request. 
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chemistry changes, as appropriate.  The Investigator 
should obtain a history of concomitant medications 
(including nonprescription medications and herbal and 
dietary supplement preparations) and other possible 
causes of liver enzyme and bilirubin increases.  Any 
potentially hepatotoxic medications should be identified 
and discontinued if advisable.  
If symptoms persist or repeat testing shows AST or ALT 
>3× baseline (and >ULN) or total bilirubin >2× baseline 
(and >ULN), patients should be followed as clinically 
indicated depending on other laboratory and clinical 
signs and symptoms.   
For the purposes of this protocol, if the above referenced 
significant elevation in liver enzyme or bilirubin levels 
resolve following interruption of investigational product 
and no other cause for the elevation is identified, the 
elevations should be assumed to be related to 
investigational product and investigational product 
should be discontinued.  If the liver enzyme or bilirubin 
levels do not resolve following interruption of 
investigational product and no other cause for the 
elevation is identified, it may be assumed that the 
elevations were due to disease progression and the 
patient may be re-challenged following a discussion 
between the Investigator or designee and the Sponsor. 
Elevation of liver enzymes or bilirubin is based on 
comparison to baseline values defined as the mean of all 
available Screening and Day 1 values, which are the 
mean of all available evaluations prior to the first 
administration of investigational product.  At least 2 of 
these samples will be obtained a minimum of 2 weeks 
apart during the Screening period.  Elevations that occur 
gradually over the course of the study may be indicative 
of disease progression and should be assessed as 
clinically appropriate.  Liver enzyme and bilirubin 
elevations that occur over a shorter time, such as within 
a 6-month period, should be evaluated for drug-induced 
liver injury as provided in the guidelines below. 
If at any time a patient develops signs or symptoms of 
hepatotoxicity such as new onset fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>7%) in combination with 
elevations in liver enzymes, investigational product 
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should be interrupted and liver enzymes monitored until 
signs or symptoms resolve.  
Patients who develop evidence of severe drug-induced 
liver injury that is suspected to be causally related to the 
investigational product should be discontinued from 
investigational product and should not be rechallenged.  
Severe drug-induced liver injury includes, but is not 
limited to, functional hepatic impairment, as indicated 
by rising bilirubin or INR that cannot be explained by 
progression of disease.  Natural progression of the 
underlying condition and other causal factors such as a 
common bile duct stone or development of other 
concurrent liver disease should be considered before the 
investigational product is permanently discontinued.  
If after all investigations and actions outlined above 
have been completed, the investigator determines that 
the elevations in liver biochemistries are considered not 
related to investigational product, the Sponsor must be 
contacted before investigational product can be 
reinitiated.  Follow-up procedures for patients resuming 
treatment, including laboratory evaluations and physical 
examinations, must be performed after a maximum of 2 
weeks of retreatment.  Results must be reported to the 
site as soon as possible so the Investigator can determine 
if it is appropriate for the patient to continue treatment.   
The Medical Monitor must be contacted in all cases of 
persistent liver biochemistry elevations. 
All hepatic injury events, regardless of relationship to 
investigational product, will be adjudicated by the 
Hepatic Safety Committee (see Section 15.9). 
8.4.1.3. Pregnancy 
If a female patient becomes pregnant, she must interrupt 
treatment with investigational product immediately, but 
should continue with the study visit schedule.  As 
described in Section 13.1.9 pregnancy is not considered 
an AE for reporting purposes.  The patient may restart 
investigational product when she is no longer pregnant 
or breastfeeding (if applicable) at the discretion of the 
Investigator and after discussion with the Medical 
Monitor as described in Section 13.1.9).  New baseline 
procedures should include pregnancy testing. 
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8.4.2. 
Reasons for Mandatory Discontinuation of 
Investigational Product 
Patients who undergo a liver transplant during the course 
of the study must discontinue investigational product 
and discontinue the study visit schedule.  However, 
these patients should be encouraged to consent to the 
semiannual telephone contact and/or continued record 
review only to allow for secondary outcome events data 
to be collected. 
Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 9.5.2., Patient 
Numbers 
Patients will be identified by a unique 6-digit number, 
independent of the randomization number.  The first 3 
digits will represent the site number and the last three 
digits will represent the Screening number. 
Patients are assigned using a unique 10-character 
identifier (AAA-BBBCCC), independent of the 
randomization number. The first 3 digits represent the 
last 3 digits of the protocol number, followed by a 
hyphen (AAA-). The next 3 digits represent the site 
number (BBB). The last 3 digits represent a unique 
screening number that is assigned in sequential 
order at each site starting with 001 (CCC). 
Update per current practice. 
Section 9.7.2, 
Informed Consent 
Procedures 
The Investigator or designee will explain the nature, 
purpose, possible risk, and benefit of the study to the 
patient and will provide him/her with a copy of the 
informed consent form (ICF).  The patient will be given 
sufficient time to consider the study before deciding 
whether or not to participate.  The patient will be 
informed that participation is voluntary and that her/his 
future medical treatment will not be compromised by 
participation in the study and that he or she can 
withdraw from the study at any time.  The patient must 
be willing and able to provide written informed consent 
(on hard copies) before entering the study.  The 
Investigator or a medically qualified designee is 
responsible for administering and documenting the 
written informed consent of the patient.  The patient will 
be given a copy of the patient information sheet (PIS) 
and his/her signed and dated consent form.  Patients will 
also be provided a separate ICF before providing blood 
samples for genetic analysis and must be willing and 
able to provide consent as described above. 
The Investigator or designee will explain the nature, 
purpose, possible risk, and benefit of the study to the 
patient and will provide him/her with a copy of the 
informed consent form (ICF).  The patient will be 
given sufficient time to consider the study before 
deciding whether or not to participate.  The patient will 
be informed that participation is voluntary and that 
her/his future medical treatment will not be 
compromised by participation in the study and that he 
or she can withdraw from the study at any time.  The 
patient must be willing and able to provide written 
informed consent (on hard copies) before entering the 
study.  The Investigator or a medically qualified 
designee is responsible for administering and 
documenting the written informed consent of the 
patient.  The patient will be given a copy of the patient 
information sheet (PIS) and his/her signed and dated 
informed consent form (ICF).   
Correction.  There is no 
separate ICF for this study. 
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Section 9.7.4, 
Screening Procedures 
(14 Days to 28 Days 
prior to Day 1) 
 
Insertion 
 
Perform an ultrasound for HCC surveillance 
and evaluation of gallbladder status (if 
equipment is unavailable, sites should make 
every attempt to use available community 
referral sites).  If… 
Gathering additional data at 
Screening may be beneficial in 
identifying at risk populations 
(eg, to assist with the causality 
of potential 
gallbladder/pancreatic 
complications). 
Section 9.7.5, Day 1 
Procedures 
(Randomization) 
 
Obtain blood samples for 
o 
Serum chemistry, hematology, and 
coagulation  
o 
Markers of inflammation and 
fibrosis (IL-6, hs-CRP, TNF-α, IgM, 
IgG, IgA, CK-18-M30, ELF [HA, 
P3NP, and TIMP 1]) 
o 
Fasting PK assessment 
o 
Bile Acid/C4/FGF-19  
 
Perform TE using the Fibroscan® TE device.  
If the TE cannot be performed on Day 1 (eg, 
device/technician unavailability, scheduling 
issues, TE data is needed to inform cirrhosis 
assessment, etc.), the procedure may be 
completed within the Day 1 Visit window, (if 
data is needed for cirrhosis assessment) or as 
close as possible to the Day 1 Visit, 
preferably, after patient eligibility has been 
confirmed.  Instruct the patient to take Day 1 
dose on the day of this visit. 
 
… 
 
Obtain blood samples for 
o 
Serum chemistry, hematology, and 
coagulation  
o 
Markers of fibrosis (ELF [HA, 
P3NP, and TIMP 1]) 
o 
Fasting PK assessment 
o 
Bile Acid/C4/FGF-19  
 
Perform TE using the Fibroscan® TE device.  
If the TE cannot be performed on Day 1 (eg, 
device/technician unavailability, scheduling 
issues, TE data is needed to inform cirrhosis 
assessment, etc.), the procedure may be 
completed within the Day 1 Visit window, (if 
data is needed for cirrhosis assessment) or as 
close as possible to the Day 1 Visit, 
preferably, after patient eligibility has been 
confirmed.  Instruct the patient to take Day 1 
dose on the day of this visit. 
 
If ultrasound for gallbladder assessment 
was not performed at Screening and the 
historic ultrasound is >12 months from 
Day 1, perform ultrasound. 
Markers of inflammation were 
removed to simplify the study 
design. 
 
Gathering additional data at 
Screening may be beneficial in 
identifying at risk populations 
(eg, to assist with the causality 
of potential 
gallbladder/pancreatic 
complications). 
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Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 9.7.5, Day 1 
Procedures 
(Randomization); 
Section 9.7.11, Week 
48 Procedures; 
9.7.12, Every 3 
Months after Week 
48 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
 
NOT to take investigational product 
on the morning of the next visit, and  
 
To bring the investigational product 
bottle(s); s/he will dose at the clinic 
(if this is in compliance with the 
established dosing frequency), and 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
required prior to all study visits, but 
water is permitted. 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
 
NOT to take investigational 
product on the morning of the next 
visit, and  
 
To bring the investigational 
product bottle(s) to the visit 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
required prior to all study visits, but 
water is permitted. 
Correction.  Patients will only 
be dosed in the clinic on visits 
with Serial PK. 
Section 9.7.6, Week 3 
and Week 42 Safety 
Visit Procedures 
Insertions. 
Week 3 and Week 42 Safety Visit Procedures 
… 
• 
Assess investigational product compliance, 
perform investigational product accountability. 
• 
For Week 42 Only:  Assess for dose titration, if 
eligible. (Refer to Section 7.3) 
• 
For Week 42 Only:  Dispense investigational 
product only if there is dose increase or as needed.  
No new investigational product bottles will be 
dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are 
expected to use up each investigational product 
bottle before a new bottle will be dispensed 
 
• 
Obtain blood samples for 
- 
Serum chemistry, hematology, and 
coagulation  
• 
Schedule the next visit (Week 6 or Week 48), 
reiterate dosing instructions, and advise the patient: 
For Week 3 Only:   
- 
Week 6 Visit should occur 3, 4, or 5 days after 
taking the Week 6 dose, eg, if the Week 6 dose is taken 
Correction to add Week 42 
visit.  Additional clarifications 
needed to distinguish certain 
assessments from Week 3.  
Clarification on which visits 
will have in-clinic dosing. 
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on a Sunday, the patient should come in for the Week 6 
Visit within the following Wednesday and Friday 
(Figure 3). 
- 
NOT to take investigational product on the 
morning of the next visit, and  
- 
To bring the investigational product bottle(s) to 
the visit 
- 
To fast overnight (at least 8 hours) prior to the 
next visit.  Fasting is required prior to all study 
visits, but water is permitted. 
For Week 42 Only: 
- 
NOT to take investigational product on the 
morning of the next visit, and  
- 
To bring the investigational product bottle(s); s/he 
will dose at the clinic (if this is in compliance with the 
established dosing frequency), and 
- 
To fast overnight (at least 8 hours) prior to the 
next visit.  Fasting is required prior to all study visits, 
but water is permitted. 
Section 9.7.7, Week 6 
Procedures 
Insertion 
Week 6 Visit should occur 3, 4, or 5 days after 
taking the Week 6 dose, eg, if the Week 6 dose is 
taken on a Sunday, the patient should come in for 
the Week 6 Visit within the following Wednesday 
and Friday (Figure 3). 
Clarification. 
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Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 9.7.9, Week 
12, Week 24, Week 
36 Procedures 
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation 
 
Markers of inflammation and 
fibrosis (IL-6, hs-CRP, TNF-α, IgM, 
IgG, IgA, CK-18-M30, ELF [HA, 
P3NP, and TIMP 1])  
 
Bile Acid/C4/FGF-19  
 
Fasting PK assessment 
… 
 
Serial PK assessment at Week 12 and 24 
ONLY (not done at Week 36 and 
Week 42); the following procedures will 
be conducted in all patients: 
 
30 minutes prior to dosing: collect 
predose blood sample 
 
Dispense/Administer investigational 
product from the double-blind bottle 
(collected from the patient upon 
arrival for this visit) with 240 mL (8 
oz.) of water.  Instruct the patient to 
swallow the tablet whole; s/he must 
not chew, divide, or crush the tablet.    
 
Collect blood samples at: 30 min, 45 
min, 1 hour postdose 
 
Immediately following 1 hour 
postdose blood draw, administer 
meal replacement drink (to be 
consumed within 5 – 10 minutes)  
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation 
 
Markers of fibrosis (ELF [HA, 
P3NP, and TIMP 1])  
 
Bile Acid/C4/FGF-19  
 
Fasting PK assessment (Week 36 
only) 
… 
 
Serial PK assessment at Week 12 and 24 
ONLY (not done at Week 36); the 
following procedures will be conducted 
in all patients: 
 
30 minutes prior to dosing: collect 
predose blood sample 
 
Dispense/Administer 
investigational product from the 
double-blind bottle (collected from 
the patient upon arrival for this 
visit) with 240 mL (8 oz.) of water.  
Instruct the patient to swallow the 
tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 
Collect blood samples at: 30 min, 
45 min, 1 hour postdose 
 
Immediately following 1 hour 
postdose blood draw, administer 
meal replacement drink (to be 
consumed within 5 – 10 minutes)  
Markers of inflammation were 
removed to simplify the study 
design. 
 
Clarification of serial and 
fasting PK assessments. 
 
Clarification of water and meal 
restrictions on visit day. 
 
Clarification of which visits 
have in-clinic dosing. 
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 
Collect blood samples at: 1.5, 2, 2.5, 
3, 4, 5, 6, 7, 8, 9, and 24 hours 
postdose 
Note:  Patients should only consume a meal 
following the 4-hour and 7-hour PK 
assessment times (see Figure 4).  Patients 
should not drink any water until at least one 
hour postdose. 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
 
NOT to take investigational product 
on the morning of the next visit, and  
 
To bring the investigational product 
bottle(s); s/he will dose at the clinic 
(if this is in compliance with the 
established dosing frequency), and 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
required prior to all study visits, but 
water is permitted. 
 
 
Collect blood samples at: 1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours 
postdose 
Note:  Patients should not drink additional water for 
1 hour after taking the dose of investigational 
product and will remain fasted until after the 
1-hour sample is collected.  A meal replacement 
drink will be provided following collection of the 1-, 
4-, and 7-hour PK sample.  No other food or drink 
(water is permitted) will be allowed until after the 
9-hour sample collection (see Figure 4).  The 24-
hour post-dose sample can be obtained upon return 
to the clinic or by a home health care designee. 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
 
NOT to take investigational 
product on the morning of the next 
visit, and  
 
To bring the investigational 
product bottle(s) to visits; s/he will 
dose at the clinic for Week 18 and 
Week 30 visits (if this is in 
compliance with the established 
dosing frequency), and 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
required prior to all study visits, but 
water is permitted. 
Section 9.7.10, Week 
18 and Week 30 
Procedures 
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation  
 
Bile Acid/C4/FGF-19  
 
Fasting PK assessment 
… 
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation  
 
Bile Acid/C4/FGF-19  
… 
Fasting PK removed; serial PK 
on this visit is fasted. 
 
Clarification of water and meal 
restrictions on visit day 
 
Clarification on which visits 
will have in-clinic dosing. 
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 
Serial PK assessment; the following 
procedures will be conducted in all 
patients: 
 
30 minutes prior to dosing:  collect 
predose blood sample 
 
Dispense/Administer investigational 
product from the double-blind bottle 
(collected from the patient upon 
arrival for this visit) with 240 mL (8 
oz.) of water.  Instruct the patient to 
swallow the tablet whole; s/he must 
not chew, divide, or crush the tablet.    
 
Collect blood samples at: 30 min, 45 
min, 1 hour postdose 
 
Immediately following 1 hour 
postdose blood draw, administer 
meal replacement drink (to be 
consumed within 5 – 10 minutes)  
 
Collect blood samples at:  1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours 
post dose 
Note:  Patients should only consume a meal following 
the 4-hour and 7-hour PK assessment times (see Figure 
4).  Patients should not drink any water until at least one 
hour postdose. 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
 
NOT to take investigational product 
on the morning of the next visit, and  
 
To bring the investigational product 
bottle(s); s/he will dose at the clinic 
(if this is in compliance with the 
established dosing frequency), and 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
 
Serial PK assessment; the following 
procedures will be conducted in all 
patients: 
 
30 minutes prior to dosing: collect 
predose blood sample 
 
Dispense/Administer 
investigational product from the 
double-blind bottle (collected from 
the patient upon arrival for this 
visit) with 240 mL (8 oz.) of water.  
Instruct the patient to swallow the 
tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 
Collect blood samples at: 30 min, 
45 min, 1 hour postdose 
 
Immediately following 1 hour 
postdose blood draw, administer 
meal replacement drink (to be 
consumed within 5 – 10 minutes)  
 
Collect blood samples at: 1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours 
postdose 
Note:  Patients should not drink additional 
water for 1 hour after taking the dose of 
investigational product and will remain 
fasted until after the 1-hour sample is 
collected.  A meal replacement drink will 
be provided following collection of the 1-, 
4-, and 7-hour PK sample.  No other food 
or drink (water is permitted) will be 
allowed until after the 9-hour sample 
collection (see Figure 4).  The 24-hour 
post-dose sample can be obtained upon 
return to the clinic or by a home health 
care designee. 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
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required prior to all study visits, but 
water is permitted. 
 
NOT to take investigational 
product on the morning of the next 
visit, and  
 
To bring the investigational 
product bottle(s) to both visits; 
s/he will dose at the clinic on 
Week 24 (if this is in compliance 
with the established dosing 
frequency), and 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
required prior to all study visits, but 
water is permitted. 
9.7.11, Week 48 
Procedures 
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation  
 
Markers of inflammation and 
fibrosis (IL-6, hs-CRP, TNF-α, IgM, 
IgG, IgA, CK-18-M30, ELF [HA, 
P3NP, and TIMP 1]) 
 
Fasting PK assessment 
 
Bile Acids/C4/FGF-19 
 
Serial PK assessment; the following 
procedures will be conducted in all 
patients: 
 
30 minutes prior to dosing: collect 
predose blood sample 
 
Dispense/Administer investigational 
product from the double-blind bottle 
(collected from the patient upon 
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation  
 
Markers of fibrosis (ELF [HA, 
P3NP, and TIMP 1]) 
 
Bile Acids/C4/FGF-19 
 
Serial PK assessment; the following 
procedures will be conducted in all 
patients: 
 
30 minutes prior to dosing: collect 
predose blood sample 
 
Dispense/Administer 
investigational product from the 
double-blind bottle (collected from 
the patient upon arrival for this 
visit) with 240 mL (8 oz.) of water.   
 
Collect blood samples at: 30 min, 
45 min, 1 hour postdose 
Markers of inflammation were 
removed to simplify the study 
design. 
 
Fasting PK removed; serial PK 
on this visit is fasted. 
 
Clarification of water and meal 
restrictions on visit day 
 
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arrival for this visit) with 240 mL (8 
oz.) of water.   
 
Collect blood samples at: 30 min, 45 
min, 1 hour postdose 
 
Immediately following 1 hour post 
dose blood draw, administer meal 
replacement (to be consumed within 
5 – 10 minutes)  
 
Collect blood samples at: 1.5, 2, 2.5, 
3, 4, 5, 6, 7, 8, 9, and 24 hours post 
dose 
Note:  Patients should only consume meal 
following the 4-hour and 7-hour PK 
assessment times (see Figure 4).  Patients 
should not drink any water until at least one 
hour post dose 
 
Immediately following 1 hour post 
dose blood draw, administer meal 
replacement (to be consumed 
within 5 – 10 minutes)  
 
Collect blood samples at: 1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours 
post dose 
Note:  Patients should not drink additional 
water for 1 hour after taking the dose of 
investigational product and will remain 
fasted until after the 1-hour sample is 
collected.  A meal replacement drink will 
be provided following collection of the 1-, 
4-, and 7-hour PK sample.  No other food 
or drink (water is permitted) will be 
allowed until after the 9-hour sample 
collection (see Figure 4).  The 24-hour 
post-dose sample can be obtained upon 
return to the clinic or by a home health 
care designee. 
Section 12.1, 
Pharmacokinetic 
Blood Sampling 
… 
Week 6 Visit should occur 3, 4, or 5 days after the Week 
6 dose (eg, if the Week 6 dose of investigational product 
is taken on a Sunday, the patient should come in for the 
Week 6 Visit between Wednesday and Friday [Figure 
2]).   
… 
Patients should not drink additional water for 1 hour 
after taking the dose of investigational product and will 
remain fasted until after the 1-hour sample is collected.  
A meal will be provided following collection of the 1-, 
4-, and 7-hour PK sample; the meal will be a meal 
… 
Week 6 Visit should occur 3, 4, or 5 days after the 
Week 6 dose (eg, if the Week 6 dose of investigational 
product is taken on a Sunday, the patient should come 
in for the Week 6 Visit between Wednesday and Friday 
[Figure 3]).   
… 
During the treatment period: 
 
Pharmacokinetic fasting samples will 
be obtained from all patients at Day 1, 
and Weeks 6, 12, 18, 24, 30, 36, and 48 
Clarifications. 
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replacement drink with nutrition information that has 
been submitted to and approved by the Sponsor in 
advance.  No other food or drink (water is permitted) 
will be allowed until after the 7-hour sample collection. 
During the treatment period: 
 
Pharmacokinetic fasting samples will be 
obtained from all patients at Weeks 6, 12, 
18, 24, 30, 36, and 48 prior to dose 
administration in accordance with Figure 
3. 
 
Serial PK assessments will be performed 
in all patients at Weeks 12, 18, 24, 30, 
and 48.   
 
prior to dose administration in 
accordance with Figure 4. 
 
Serial PK assessments will be performed
in all patients at Weeks 12, 18, 24, 30, 
and 48.   
Patients should not drink additional water for 1 hour 
after taking the dose of investigational product and will 
remain fasted until after the 1-hour sample is collected.  
A meal replacement drink will be provided following 
collection of the 1-, 4-, and 7-hour PK sample.  The 
nutritional information of the meal replacement 
drink should be submitted to and approved by the 
Sponsor in advance.  No other food or drink (water is 
permitted) will be allowed until after the 9-hour sample 
collection. 
Section 13.1.1.1, 
Adverse Event 
Insertion 
Patients should be instructed to contact the site 
promptly upon awareness if they develop signs and 
symptoms of potential hepatic decompensation such 
as:  pale-colored stools, urine color from pale to 
deep amber [dark], nausea, vomiting, abdominal 
pain, diarrhea, weight loss, fever and chills, fatigue, 
weakness, loss of appetite, confusion, swelling of the 
legs or abdomen, yellowing of the skin or the whites 
of eyes, and bruising easily. 
Given this is an at risk 
population, patients should be 
reminded to contact the 
Investigator or study 
coordinator in case they 
experience side effects or any 
other medical concerns and be 
aware of the signs and 
symptoms of potential hepatic 
decompensation. 
Section 13.1.1.4, 
Adverse Events of 
Special Interest 
Insertion 
The following decompensation events are adverse 
events of special interest; a subset of these are also 
captured as additional efficacy assessments (see 
Section 14.2.3).   
 
Variceal bleeding or recurrent 
variceal bleeding documented by 
endoscopy OR patient presenting with 
anemia or melena (hemoglobin drop 
≥2 gm/dL) and found to have varices 
documented by endoscopy, 
Per FDA request. 
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irrespective of hospitalization or 
requirement of blood transfusion.  
 
Gastrointestinal bleeding as a result 
of gastric or duodenal varices verified 
by endoscopy 
 
Hepatic encephalopathy, Grade ≥2 
 
New onset ascites requiring treatment 
 
Worsening of ascites (requiring 
increase in drug therapy or 
requirement of surgical procedure 
such as paracentesis or shunt 
placement) 
 
Refractory ascites -unresponsive to 
medications, and patient is not a 
candidate for TIPS or shunt and 
requires large volume paracentesis 
 
Hyponatremia (Na ≤125 mEq/L) 
secondary to ascites 
 
Spontaneous bacterial peritonitis 
(confirmed by diagnostic paracentesis- 
by cell count/chemistry) 
 
Hepatorenal syndrome Type 1 and 
Type 2 and Acute Kidney Injury 
(AKI) 
 
Liver failure defined as worsening of 
liver synthetic function that is 
persistently worse relative to baseline 
and/or progressive over time: 
 
Hepato-pulmonary syndrome 
 
Porto-pulmonary syndrome 
 
Liver Transplant 
 
Increase in MELD scores by 3 
points relative to baseline, 
persistent over time and 
unrelated to vitamin K deficiency 
related increase in INR 
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 
Any liver related event that 
requires hospitalization and 
treatment 
Section 13.1.4.1, 
Reporting of Adverse 
Events 
Insertion 
In addition, the Investigator should contact the 
study Medical Monitor upon awareness when any 
signs or symptoms of hepatic decompensation are 
observed in any patient. 
Enhanced communication of 
the Investigator and Medical 
Monitor in the event of signs or 
symptoms of hepatic 
decompensation. 
Section 13.1.8, 
Follow-Up of 
Adverse Events and 
Serious Adverse 
Events 
AEs ongoing at the final visit that are deemed to be 
“possibly, probably, or definitely” related or of other 
clinical significance must be followed for as long as 
necessary to adequately evaluate the safety of the patient 
or until the event stabilizes, resolves, or is no longer of 
clinical concern.  If resolved, a resolution date for the 
AE should be documented on the eCRF.  The 
Investigator must ensure that follow-up includes any 
supplemental investigations indicated to elucidate the 
nature and/or causality of the AE.  This may include 
additional laboratory tests or investigations, or 
consultation with other healthcare professionals, as 
considered clinically appropriate by the Investigator. 
All patients showing possible drug-induced liver injury 
should be followed until all abnormalities return to 
normal or to the baseline state.  Drug-induced liver 
injury may develop or progress even after the causative 
drug has been stopped.  Results should be recorded in 
the eCRF.  Note that longer follow-up can sometimes 
reveal an off-drug repetition of what had appeared to be 
drug-induced liver injury, indicating that liver injury was 
related to underlying liver disease. 
 
AEs ongoing at the final visit that are deemed to be 
“possibly, probably, or definitely” related or of other 
clinical significance must be followed for as long as 
necessary to adequately evaluate the safety of the 
patient or until the event stabilizes, resolves, or is no 
longer of clinical concern.  The Investigator must 
ensure that follow up includes any supplemental 
investigations indicated to elucidate the nature and/or 
causality of the AE.  This may include additional 
laboratory tests or investigations, or consultation with 
other healthcare professionals, as considered clinically 
appropriate by the Investigator. 
 
Drug-Induced Liver Injury or Disease Progression 
All patients showing possible drug-induced liver injury 
or disease progression should be followed until all 
abnormalities return to normal or to the baseline state.  
Drug-induced liver injury may develop or progress 
even after the causative drug has been stopped.  Results 
should be recorded in the eCRF.  Note that longer 
follow-up can sometimes reveal an off-drug repetition 
of what had appeared to be drug-induced liver injury, 
indicating that liver injury was related to underlying 
liver disease. 
Cholecystitis or Pancreatitis 
Patients should be instructed to contact the 
investigational site if they experience any of the 
following signs and symptoms:  nausea, vomiting, 
abdominal pain, diarrhea, weight loss, fever and 
chills, worsening or new fatigue, or weakness.  
Patients should also be counseled to seek immediate 
medical assistance if they experience persistent 
severe abdominal pain.   
In the event that cholecystitis and/or pancreatitis is 
suspected, Investigators should  promptly bring 
patients into the clinic to undergo a complete 
Increased monitoring per 
standard of care if a patient is 
diagnosed or develops 
symptoms consistent with 
pancreatitis. 
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evaluation, including a physical examination, and 
laboratory assessments [ie, amylase and lipase]).  
Investigators should refer to standard of care 
guidelines on suspected pancreatitis (Banks 2012, 
Greenburg 2015).  Diagnosis of acute pancreatitis 
includes 2 of the following:   
• 
Abdominal pain (acute onset of a persistent, 
severe, epigastric pain often radiating to the back)  
• 
Serum lipase activity (or amylase) at least 3 
times greater than the upper limit of normal 
• 
Characteristic findings of acute pancreatitis on 
computed tomography or magnetic resonance 
imaging 
To ensure appropriate vigilance, amylase and lipase 
levels should be monitored monthly for 3 months 
after onset of symptoms, irrespective of whether a 
diagnosis of cholecystitis and or pancreatitis is 
confirmed.  The Investigator should contact the 
Medical Monitor upon awareness of the above (ie, 
suspected or confirmed diagnosis).  Results should be 
recorded promptly in the eCRF. 
Section 13.1.9, 
Pregnancy and 
Follow-Up 
Pregnancies are not considered AEs in and of 
themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical 
study, she must interrupt treatment with investigational 
product immediately (see Section 8.4.1.3) and the 
Sponsor must be notified within 24 hours of the 
Investigator’s awareness of the pregnancy by completing 
the Pregnancy CRF in the EDC system and downloading 
and completing the Pregnancy Report Form.  The 
Pregnancy Report Form must be emailed to 
 or faxed to 
.  
The patient and neonate must be followed for outcome 
information and/or as considered appropriate by the 
Investigator and Sponsor. 
The patient may restart investigational product when she 
is no longer pregnant or breastfeeding (if applicable) at 
the discretion of the Investigator and after discussion 
with the Medical Monitor.  The patient must have a 
negative pregnancy test before restarting investigational 
product.  If a patient’s pregnancy is terminated early 
(planned or unplanned), she must have termination of 
the pregnancy confirmed by a serum β-hCG test before 
restarting investigational product. 
Pregnancies are not considered AEs in and of 
themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical 
study, she must discontinue treatment with 
investigational product immediately and the Sponsor 
must be notified within 24 hours of the Investigator’s 
awareness of the pregnancy by completing the 
Pregnancy CRF in the EDC system and downloading 
and completing the Pregnancy Report Form.  The 
Pregnancy Report Form must be emailed to 
 or faxed to 
  The patient and neonate must be 
followed for outcome information and/or as considered 
appropriate by the Investigator and Sponsor. 
 
Per new study-specific safety 
updates, pregnancy will require 
discontinuation and no option 
to restart. 
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Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 13.2.2., 
Medical and Surgical 
Procedures 
New Section  
Medical and surgical procedures will be recorded 
at the visits indicated in Table 1. 
Section added for consistently 
with Schedule of Events. 
Section 13.2.5, 
Electrocardiogram 
Investigative sites must retain a copy of all ECGs 
evaluated by the Investigator or designee.  These ECGs 
must be clearly labeled with the Patient ID number, date, 
and time.  Full instructions will be provided for 
forwarding the ECGs for central reading. 
Investigative sites must retain a copy of all ECGs 
evaluated by the Investigator or designee.  These 
ECGs must be clearly labeled with the Patient ID 
number, date, and time.   
Correction. 
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Section 13.2.6, 
Laboratory 
Assessments 
Table 9  List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen, 
creatinine, direct bilirubin, total 
bilirubin, aspartate 
aminotransferase [AST, 
SGOT], alanine 
aminotransferase [ALT, 
SGPT], ALP, GGT, 
electrolytes [calcium, chloride, 
potassium, sodium], glucose, 
total protein, and blood lipids 
(total cholesterol, LDL, HDL 
and VLDL fractions and TG), 
CPK, magnesium, phosphorus, 
bicarbonate, unconjugated 
(indirect) bilirubin, conjugated 
(direct) bilirubin, free fatty 
acids, TFT (TSH, free T3 and 
free T4) 
Hematology 
Hemoglobin, hematocrit, white 
blood count with differential, 
neutrophils, lymphocytes, 
monocytes, eosinophils, 
basophils, platelets, red blood 
cell count (including MCV, 
MCH, MCHC) 
Coagulation 
PT, PTT, INR 
Urinalysis (dipstick) 
pH, specific gravity, total 
protein, glucose, ketones, 
bilirubin, blood, microscopic 
exam, urobilinogen, albumin, 
creatine, leucocytes, nitrates, 
albumin/creatine ratio (if 
positive), pregnancy 
Markers of Inflammation  
IL-6, hs-CRP, TNF-α, IgM, 
IgA, IgG, CK-18-M30 
Noninvasive 
measurements of liver 
fibrosis, liver stiffness and 
cirrhosis 
ELF (HA, P3NP, and TIMP-1) 
TE 
PK assessments 
OCA (parent and conjugates 
[glyco and tauro], metabolite 
OCA-glucuronide)  
Table 11  List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea 
nitrogen, creatinine, direct 
bilirubin, total bilirubin, 
aspartate aminotransferase 
[AST, SGOT], alanine 
aminotransferase [ALT, 
SGPT], ALP, GGT, 
electrolytes [calcium, 
chloride, potassium, 
sodium], glucose, total 
protein, and blood lipids 
(total cholesterol, LDL, HDL 
and VLDL fractions and 
TG), CPK, magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) 
bilirubin, conjugated (direct) 
bilirubin, total bilirubin, 
free fatty acids, TFT (TSH, 
free T3 and free T4) 
Hematology 
Hemoglobin, hematocrit, 
white blood count with 
differential, neutrophils, 
lymphocytes, monocytes, 
eosinophils, basophils, 
platelets, red blood cell count 
(including MCV, MCH, 
MCHC) 
Coagulation 
PT, PTT, INR 
Urinalysis (dipstick) 
pH, specific gravity, total 
protein, glucose, ketones, 
bilirubin, blood, microscopic 
exam, urobilinogen, 
leucocytes, nitrates; 
albumin, creatinine, 
albumin/creatinine ratio (if 
positive); β-hCG 
Markers of 
Cholecystitis and 
Pancreatitis 
Amylase and lipase 
Markers of inflammation 
samples were removed to 
simplify the study design. 
Amylase and lipase added per 
FDA request. 
Total OCA calculation update 
is a correction. 
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Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
PD markers 
C4, FGF-19 and plasma bile 
acids 
 
… 
INR will be calculated based on prothrombin time value 
by the central laboratory.  MELD scores will be calculated 
based on creatinine, bilirubin, Na, and INR values, with 
modification by United Network for Organ Sharing.  Total 
OCA will be calculated based on OCA, tauro-OCA, glyco 
OCA, and metabolite OCA glucuronide concentrations.  
Laboratory analyte results may be used to calculate 
various cardiovascular risk and fibrosis measurement 
scores. 
Noninvasive 
measurements of liver 
fibrosis 
ELF (HA, P3NP, and TIMP-
1) 
PK assessments 
OCA (parent and conjugates 
[glyco and tauro], metabolite 
OCA-glucuronide)  
PD markers 
C4, FGF-19 and plasma bile 
acids 
… 
NR will be calculated based on prothrombin time 
value by the central laboratory.  MELD scores will be 
calculated based on creatinine, bilirubin, and INR 
values, with modification by United Network for 
Organ Sharing.  Total OCA will be calculated based 
on the sum of OCA, glyco-OCA, and tauro-OCA 
concentrations.  Laboratory analyte results may be 
used to calculate various cardiovascular risk and 
fibrosis measurement scores. 
Section 14.1.1, 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is calculated 
and reported within the EDC system based on data entered 
into the eCRF by adding the scores from the 5 factors 
outlined in Table 12 and can range from 5-15.  A total 
score of 5-6 is considered Grade A (mild, well-
compensated disease); 7-9 is Grade B (moderate, 
significant functional compromise); and 10 and above is 
Grade C (severe, decompensated disease).  Calculation of 
the CP Score includes Investigator assessments of ascites 
and hepatic encephalopathy, which may be assessed 
during the adverse event review at the scheduled visits, as 
well as total bilirubin, serum albumin, and prothrombin 
time, which will populate from the central laboratory.  
Investigators will be responsible for determining the 
appropriate dosing regimen based on the CP score ( and ).  
Any change in CP Score will necessitate re evaluation of 
the dosing regimen. 
Child-Pugh Score (Pugh 1973, Lucey 1997) is 
calculated and reported within the EDC system based 
on data entered into the eCRF by adding the scores 
from the 5 factors outlined in Table 12 and can range 
from 5-15.  A total score of 5-6 is considered Grade A 
(mild, well-compensated disease); 7-9 is Grade B 
(moderate, significant functional compromise); and 10 
and above is Grade C (severe, decompensated 
disease).  Calculation of the CP Score includes 
Investigator assessments of ascites and hepatic 
encephalopathy, which may be assessed during the 
adverse event review at the scheduled visits, as well as 
total bilirubin, serum albumin, and prothrombin time, 
which will populate from the central laboratory.   
 
Per new dosing guidelines, CP 
score will not determine dosing 
regimen. 
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Revised Text (Version 3) 
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Reasons / 
Justification for Change 
Section 14.1.2, 
Model of End Stage 
Liver Disease Score 
An increasing MELD score is associated with increased 
severity of hepatic dysfunction and increased 3-month 
mortality risk.  The MELD score is derived from the 
patient’s serum total bilirubin, serum creatinine, and INR, 
as appropriate, to predict survival and is calculated 
according to the following formula (Kamath 2007): 
MELD = 3.78×ln[serum bilirubin (mg/dL)] + 
11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43  
MELD score will be calculated and reported in whole 
numbers according to the frequency listed in Table 1. 
An increasing MELD score is associated with 
increased severity of hepatic dysfunction and 
increased 3-month mortality risk.  The MELD score is 
derived from the patient’s serum total bilirubin, serum 
creatinine, and INR, as appropriate, to predict survival 
(Kamath 2007).  MELD score will be calculated and 
reported for visits where these parameters are 
measured (see Table 1). 
Text clarified since calculation 
is not performed by the site. 
Section 14.2.1, 
Markers of 
Inflammation, 
Apoptosis and 
Necrosis 
Markers of Inflammation, Apoptosis and Necrosis 
Blood samples for analytes including IL-6, hs-CRP, IgA, 
IgG, IgM, TNF-α, cytokeratin-18 neoepitope M30.  
Assessments will be performed according to the schedules 
presented in . 
Deletion 
Markers of inflammation were 
removed to simplify the study 
design. 
Section 15.3, 
Pharmacokinetic 
Analyses 
PK analysis will based on the PK population.  Values will 
be calculated using non-compartmental methods.  The 
values will be summarized by active treatment group 
using descriptive statistics. 
 
PK analysis will be based on the PK population.  
Values will be calculated using non-compartmental 
methods.  The values will be summarized by active 
treatment group using descriptive statistics.  Full 
details regarding the planned analyses, methods, 
and outputs for the study will be detailed in the 
SAP. 
Clarification. 
Section 15.4, Safety 
Analyses 
Laboratory parameters, physical examinations including 
vital signs, and ECGs will be summarized by treatment 
group using descriptive statistics at Baseline and at each 
scheduled post-Baseline visit.  The absolute change from 
baseline will also be summarized. 
CP scores will be summarized by treatment group at 
Baseline and at each post-Baseline visit. 
No inferential comparison with formal statistical 
hypothesis testing will be performed for safety endpoints.  
 
Laboratory parameters, physical examinations 
including vital signs, and ECGs will be summarized 
by treatment group using descriptive statistics at 
Baseline and at each scheduled post-Baseline visit.  
The absolute change from baseline will also be 
summarized. 
No inferential comparison with formal statistical 
hypothesis testing will be performed for safety 
endpoints.  
 
Correction. 
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Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 15.4.1, 
Adverse Events 
Insertion 
Adverse events of special interest as defined in 
Section 13.1.1.4 will be summarized for each 
treatment group.   
Per FDA request. 
Section 15.4.2, 
Clinical Laboratory 
Evaluations 
Laboratory parameters will be summarized in standard 
international (SI) system of units by treatment group using 
descriptive statistics at Baseline and at each on-study 
evaluation.  Re-test or unscheduled results will not be 
summarized but will be included in the data listings.  The 
change from Baseline will also be summarized.  Baseline 
is defined as the mean of all available evaluations prior to 
treatment.   
In addition, shift tables (ie, low-normal-high at Baseline 
versus low-normal-high at post Baseline visit in a 3-by-3 
contingency table) from Baseline to worst value, last 
value, and at each scheduled post-Baseline visit will be 
provided for hematology and serum chemistry by 
treatment group to assess changes in laboratory values 
from Baseline to each on-study evaluation.   
Vital Signs and Weight 
The results and change from Baseline to each on-study 
evaluation visit will be summarized by treatment group for 
weight, oral temperature, sitting heart rate, respiratory rate 
and sitting blood pressure. 
Electrocardiograms 
Electrocardiogram (ECG) results will be summarized at 
each on-study visit descriptively, including the number 
and percentage of patients with normal, abnormal not 
clinically significant, and abnormal clinically significant 
results at Baseline and each on-study evaluation. 
Laboratory parameters will be summarized in standard 
international (SI) system of units by treatment group 
using descriptive statistics at Baseline and at each on-
study evaluation.  Re-test or unscheduled results will 
not be summarized but will be included in the data 
listings.  The change from Baseline will also be 
summarized.  Baseline is defined as the mean of all 
available evaluations prior to treatment.   
In addition, shift tables (ie, low-normal-high at 
Baseline versus low-normal-high at post Baseline visit 
in a 3-by-3 contingency table) from Baseline to worst 
value, last value, and at each scheduled post-Baseline 
visit will be provided for hematology and serum 
chemistry by treatment group to assess changes in 
laboratory values from Baseline to each on-study 
evaluation.   
 
Correction.  Moved to separate 
section since not laboratory 
evaluations. 
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Section 
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Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 15.4.3, 
Additional Safety 
Analysis 
New Section 
Vital Signs and Weight 
The results and change from Baseline to each on-
study evaluation visit will be summarized by 
treatment group for weight, oral temperature, 
sitting heart rate, respiratory rate and sitting blood 
pressure. 
Electrocardiograms 
Electrocardiogram (ECG) results will be 
summarized at each on-study visit descriptively, 
including the number and percentage of patients 
with normal, abnormal not clinically significant, 
and abnormal clinically significant results at 
Baseline and each on-study evaluation. 
Separate section created per 
above deletion. 
Section 15.5, 
Efficacy Analyses 
Risk Scores: Changes from baseline in the MELD score 
and in CP score will be summarized and analyzed using 
the Wilcoxon Rank Sum Test.  The median differences 
and 95% CI of the median differences between treatment 
groups will be constructed using Hodges-Lehmann 
estimate.  If the median differences between treatments 
are not symmetrical around the median, the Sign Test may 
be used. 
Risk Scores: Changes from baseline in the MELD 
score and in CP score, C4, FGF-19 and plasma bile 
acids will be summarized and analyzed using the 
Wilcoxon Rank Sum Test.  The median differences 
and 95% CI of the median differences between 
treatment groups will be constructed using Hodges-
Lehmann estimate.  If the median differences between 
treatments are not symmetrical around the median, the 
Sign Test may be used. 
Clarification. 
Section 15.6, 
Additional Efficacy 
Analyses 
Analyses of changes in liver stiffness and ELF, cytokeratin-and 
TIMP-1, and markers of inflammation will be summarized and 
analyzed using the same methodology specified for the key 
secondary analyses of change in bilirubin. 
… 
Analyses of changes in liver stiffness (TE) and liver fibrosis 
(ELF [HA, P3NP, and TIMP-1]) will be summarized and 
analyzed using the same methodology specified for the key 
secondary analyses of change in bilirubin. 
… 
Full details regarding additional efficacy analyses will be 
detailed in the SAP. 
Clarification 
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Revised Text (Version 3) 
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Reasons / 
Justification for Change 
Section 21, List of 
references 
Insertion 
Banks O, Bollen T, Dervenis C, et al.  Classification 
of acute pancreatitis-2012:  revision of the Atlanta 
classification and definitions by international 
consensus.  Gut. 2013; 62:102-111. 
… 
Greenburg J., Hsu J., Bawazeer M., et al.  Clinical 
Practice Guideline:  Management of acute 
pancreatitis.  Can J Surg. 2016; 59 (2):128-140. 
… 
Kumar A, Saraswat VA. Hepatitis E and Acute-on-
Chronic Liver Failure. Journal of clinical and 
experimental hepatology. 2013 Sep;3(3):225-30. 
… 
Vilstrup H, Amodio P, Bajaj J, et al. Hepatic 
encephalopathy in chronic liver disease: 2014 
Practice Guideline by the American Association for 
the Study of Liver Diseases and the European 
Association for the Study of the Liver. Hepatology. 
2014 Aug;60(2):715-35. 
New references added per 
added cited content. 
 
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1. 
TITLE PAGE 
 
 
Clinical Study Protocol 747-401 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Pharmacokinetics and Safety of Obeticholic Acid in Patients with Primary 
Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
 
 
Version 4:  15 Feb 2019 
 
EudraCT Number: 2017-001762-13 
 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
USA 
 
TEL:  +1 858 652 6800 
 
 
CONFIDENTIAL 
The information contained herein is the property of Intercept Pharmaceuticals, Inc. and may not 
be reproduced, published, or disclosed to others without written authorization of Intercept 
Pharmaceuticals, Inc. 
 
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Protocol 747-401 
Version4: 15 Feb2019 
Pa e2 
SPONSOR'S APPROVAL OF THE PROTOCOL 
Reviewed and Approved by: 
 PhD 
Sr Vice President, Clinical Development 
Intercept Pharmaceuticals, Inc. 
Confidential and Proprietary 
Date 
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INVESTIGATOR’S AGREEMENT 
 
I have received and read the current version of the Investigator’s Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-401.  Having fully considered all the information available, 
I agree that it is ethically justifiable to give OCA to selected patients according to this protocol. 
I understand that all information concerning OCA supplied to me by the Sponsor, Intercept 
Pharmaceuticals, Inc., and/or its agents in connection with this study and not previously 
published is confidential information.  This includes the IB, clinical study protocol, case report 
forms (CRF), and any other preclinical and clinical data provided by the Sponsor. 
I understand that no data are to be made public or published without prior knowledge and written 
approval by the Sponsor. 
By my signature below, I hereby attest that I have read, understood and agreed to abide by all the 
conditions, instructions and restrictions contained in Protocol 747-401 and in accordance with 
Good Clinical Practice (CPMP/ICH/135/95), the Declaration of Helsinki, and all regulatory 
requirements for protection of human patients in clinical studies and privacy requirements for the 
protection of individual and company data. 
I acknowledge that the Sponsor of the study has the right to discontinue the study at any time. 
 
 
 
 
 
 
Investigator’s Name (Printed) 
 
 
 
 
 
 
Investigator’s Signature 
 
Date 
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STUDY PERSONNEL CONTACT INFORMATION 
Medical Monitor  
Primary Contact: 
 
Senior Medical Director, Clinical Division  
Syneos Health 
  
 
Secondary Contact: 
 DO, MSPH 
Senior Medical Director 
Intercept Pharmaceuticals, Inc. (Intercept) 
 
 
24-Hour Telephone: 
 
 
SAE Fax: 
 
SAE Email: 
 
 
 
 
 
 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product: 
Obeticholic Acid 
Name of Active Ingredient: 
Obeticholic acid (OCA); 6α-ethyl-chenodeoxycholic acid; (6-ECDCA) 
Title of Study:  
A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating the Pharmacokinetics and Safety 
of Obeticholic Acid in Patients with Primary Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
Investigators and/or Study Center(s):  
The study is planned to have approximately 50 investigational sites, globally. 
Study Period:  Patients will receive double-blind treatment for at 
least 48 weeks.  Patients who have completed their 48-week 
double blind treatment period will continue double-blind 
treatment until all randomized patients have completed their 
participation in the 48-week treatment period and the database for 
that period is locked (approximately 3 years).  An open-label 
extension study in which all patients receive OCA will be 
considered following review of blinded safety and PK data. 
Phase of Development:   
Phase 4:  US, Canada, and the EU 
Phase 3b:  All other regions 
 
Objectives:   
Primary Objective: 
 
To evaluate the pharmacokinetics (PK) of OCA and its conjugates, glyco-OCA and tauro-OCA, and 
metabolite OCA glucuronide compared with placebo 
 
To evaluate the safety and tolerability of OCA treatment compared with placebo 
Secondary Objectives:  
 
To evaluate the effect of OCA treatment compared to placebo on:  
 
The model of end stage liver disease (MELD) score and its components 
 
Child-Pugh (CP) score and its components 
 
Liver biochemistry including total and direct bilirubin, alkaline phosphatase (ALP), and 
aminotransferases (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and gamma 
glutamyl transaminase [GGT]), international normalized ratio (INR), creatinine, albumin, platelets 
 
Biomarkers of bile acid synthesis and homeostasis including fibroblast growth factor 19 (FGF-19), 
7α-hydroxy-4-cholesten-3-one (C4), and plasma bile acids 
Additional Objectives: 
 
To evaluate the effect of OCA treatment compared to placebo on: 
 
Noninvasive markers of liver fibrosis (Enhanced Liver Fibrosis [ELF]™ score) 
  
Noninvasive measurement of liver stiffness (transient elastography [TE]) 
 
To assess the PK/Pharmacodynamic (PD) relationship of OCA with: 
 
PK parameters compared to PD parameters and safety and tolerability assessments 
 
To assess patient reported outcomes (Pruritus Visual Analogue Scale [VAS], PBC-40, EQ 5D-5L, Chronic 
Liver Disease Questionnaire [CLDQ]) 
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 
To assess clinical events consistent with end-stage liver disease 
 
Death (all-cause) 
 
Liver transplant 
 
MELD score ≥15 (for patients with MELD ≤12 at baseline)  
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
variceal bleed, hepatic encephalopathy (as defined by a West Haven score of ≥2), spontaneous 
bacterial peritonitis 
 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
 
Hepatocellular carcinoma (HCC) 
Methodology:  This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the PK and 
safety of OCA treatment in patients with primary biliary cholangitis (PBC) and moderate to severe hepatic 
impairment defined as Child-Pugh B (CP-B) (moderate) and Child-Pugh C (CP-C) (severe) including a broad 
distribution of MELD scores (ranging from 6 to 24).  Approximately 50 patients (including at least 20% of 
patients with CP-C) will be enrolled in the study.  Patients will be screened ≥14 days but not more than 28 days 
prior to entering the study (Day 1).  Patients who meet all eligibility requirements will be randomized in a 
1:1 ratio to one of two treatment groups:  Placebo or OCA.  Randomization will be stratified by CP class.  
Baseline MELD scores will be monitored on an ongoing basis to ensure adequate distribution of MELD scores.   
Following completion of safety assessments and laboratory specimen collection, blinded investigational product 
will be dispensed with instruction to begin dosing the same day (Day 1) at OCA 5 mg or placebo once weekly.  
Double-Blind Treatment Period:  During the 48-week treatment period (ie, Day 1 through Week 48), an initial 
safety visit will occur at Week 3.  After the Week 6 Visit, subsequent clinic visits will occur approximately 
every 6 weeks for the assessment of safety, tolerability, PK, and PD.  Titration may be considered as early as the 
Week 12 Visit.  Fasting PK assessments will be performed in all patients participating in the study on Day 1, 
Week 6, and Week 36.  Serial PK sampling (which also includes a fasted PK assessment) will be performed at 
Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week double blind treatment period will continue double-blind treatment 
until all randomized patients have completed their 48-week treatment period and the database for that period is 
locked.  An open-label extension study in which all patients receive OCA will be considered following review 
of blinded safety and PK data.   
Study Design Diagram 
OCA = obeticholic acid, PBC = primary biliary cholangitis 
Notes: Initial dose titration of investigational product may be considered as early as the Week 12 Visit, or any study visit 
thereafter for patients on all dosing regimens, based on tolerability and safety laboratory tests from the previous 
visit.  Subsequent dose titration(s) may occur no earlier than 6 weeks after the previous dose titration and will be 
based on tolerability.   
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Patients who complete Week 48 will continue double-blind treatment until all randomized patients have completed 
their participation in the 48-week treatment period and the database for that period is locked. 
Dosing Regimen:   
All patients will initiate investigational product once weekly with 5 mg OCA or matching placebo.  Titration 
may be considered as early as the Week 12 Visit.  Following visit procedures at Week 12, if the investigational 
product is tolerated and laboratory assessments do not indicate a safety concern, the patient may up-titrate to 
OCA 5 mg twice weekly and may start the higher dose regimen no earlier than 2 days after they took their last 
dose.  Dosing will then occur at least 3 days apart.  Every 6 weeks thereafter, based on tolerability assessments, 
patients can be considered for further up titration as described below.  At each titration visit, the patient may 
start the higher dose regimen no earlier than 2 days after the prior dose. 
 
Patients may titrate to a maximum dose of OCA 10 mg twice weekly at least 3 days apart.  
Planned OCA or Matching Placebo Dosing Regimen 
 
Child-Pugh B and Child-Pugh C 
(Moderate and Severe Hepatic Impairment) 
 
Treatment Group 
 
OCA 
Placebo 
Starting Dose (Day 1) 
5 mg once weekly 
matching placebo once weekly 
Titration 1a  
5 mg twice weeklyb 
matching placebo twice weeklyb  
Titration 2a  
10 mg twice weeklyb 
matching placebo twice weeklyb 
a Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on patient tolerability. 
b Dosing per the twice weekly schedule must be at least 3 days apart. 
 
Number of Patients (planned):  Approximately 50 patients will be enrolled in this study. 
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Diagnosis and Main Criteria for Inclusion: 
Key Inclusion Criteria 
1. A definite or probable diagnosis of PBC (consistent with American Association for the Study of Liver 
Diseases [AASLD] and European Association for the Study of the Liver [EASL] Practice Guidelines, 
defined as having ≥2 of the following 3 diagnostic factors: 
 
History of elevated ALP levels for at least 6 months 
 
Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer (≤1:80), 
PBC-specific antibodies (anti-GP210 and/or anti-SP100) and/or antibodies against the major M2 
components (PDC-E2, 2-oxo-glutaric acid dehydrogenase complex)  
 
Liver biopsy consistent with PBC (collected at any time prior to Screening) 
2. Evidence of cirrhosis including at least one of the following: 
 
Biopsy results consistent with PBC Stage 4  
 
Liver stiffness as assessed by TE Value ≥16.9kPa 
 
Clinical evidence in the absence of acute liver failure consistent with cirrhosis including: 
gastroesophageal varices, ascites, radiological evidence of cirrhosis (nodular liver or enlargement 
of portal vein and splenomegaly) 
 
Combined low platelet count (<140 000/mm3) with 
 
persistent decrease in serum albumin, or  
 
elevation in prothrombin time/INR (not due to antithrombotic agent use), or 
 
elevated bilirubin (2× ULN) 
3. Satisfy the criteria of the modified CP classification for hepatic impairment during Screening: 
 
Moderate:  CP-B (Scores 7 to 9) or 
 
Severe:  CP-C (Scores 10 to12) 
4. MELD score of 6 to 24 at Screening 
5. Taking UDCA for at least 12 months (stable dose for ≥3 months) prior to Day 1, or unable to tolerate or 
unresponsive to UDCA (no UDCA for ≥3 months)  
Key Exclusion Criteria 
1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6) 
2. History of liver transplant or organ transplant 
3. History of alcohol or drug abuse within 12 months prior to Screening 
4. Current hepatic encephalopathy (as defined by a West Haven score of ≥2) 
5. History or presence of other concomitant liver diseases including: 
 
Hepatitis C virus infection and RNA positive 
 
Active hepatitis B infection; however, patients who have seroconverted (hepatitis B surface 
antigen and hepatitis B e antigen negative) may be included in this study after consultation with 
the Medical Monitor 
 
Primary sclerosing cholangitis 
 
Alcoholic liver disease 
 
Definite autoimmune liver disease or overlap hepatitis 
 
Gilbert’s Syndrome 
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6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function prior to 
randomization 
Investigational Product, Dosage and Mode of Administration:  
OCA 5 mg or OCA 10 mg tablets, oral administration 
Placebo tablets, matched in size and appearance to OCA tablets, oral administration 
Duration of Treatment:   
Patients who have completed their 48-week double blind treatment period will continue double blind treatment 
until all randomized patients have completed their participation in the 48-week treatment period and the 
database for that period is locked (approximately 3 years).  An open-label extension study in which all patients 
receive OCA will be considered following review of blinded safety and PK data. 
Criteria for Evaluation: 
Primary Objectives 
Assessments 
PK parameters 
OCA and its conjugates, glyco-OCA and tauro-OCA, and 
metabolite OCA glucuronide 
Safety and tolerability  
SAEs and TEAEs, physical exam, ECG, vital signs, clinical 
laboratory assessments, discontinuations, pruritus, and fatigue 
Secondary Objectives 
Assessments 
Changes in risk scores 
Changes in MELD and in CP scores and components of the 
CP score and MELD score 
Changes in liver biochemistry and hepatobiliary 
damage  
Total and direct bilirubin, ALP, ALT, AST, GGT, INR, 
creatinine, albumin, platelets 
PD parameters 
FGF-19, C4, and plasma bile acids 
Additional Objectives 
Assessments 
Noninvasive measurements of liver fibrosis, liver 
stiffness and cirrhosis 
TE and ELF (HA, P3NP, and TIMP-1) 
PK/PD relationship 
PK parameters compared to PD parameters and safety and 
tolerability assessments (above) 
Patient-reported outcomes 
Pruritus VAS, PBC-40, EQ-5D-5L, CLDQ 
Clinical events 
Death (all-cause and liver-related), liver transplant, MELD 
score ≥15 (for patients with MELD ≤12 at baseline), 
hospitalization for new onset or recurrence of: variceal bleed, 
hepatic encephalopathy, spontaneous bacterial peritonitis, 
uncontrolled ascites, and HCC. 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
C4 = 7α-hydroxy-4-cholesten-3-one; CLDQ = Chronic Liver Disease Questionnaire; CP = Child-Pugh; ECG = 
electrocardiogram; ELF = enhanced liver fibrosis; FGF-19 = fibroblast growth factor-19; GGT = gamma-glutamyl 
transferase; HA = hyaluronic acid; INR = international normalized ratio;  MELD = Model End Stage Liver Disease; OCA = 
obeticholic acid; P3NP = procollagen 3 N-terminal peptide; PBC = Primary Biliary Cholangitis; PD = pharmacodynamic; 
PK = pharmacokinetic; SAE = serious adverse event; TE = Transient Elastography; TEAE = treatment emergent adverse 
events; TIMP-1 = tissue inhibitor of metalloproteinase 1; VAS = visual analog scale 
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Statistical Methods: 
Analysis Populations: 
The following patient populations will be evaluated and used for presentation and analysis of the data: 
 
The Intent-to-Treat (ITT) Population will include all randomized patients who receive any amount of 
investigational product (OCA or placebo).  The ITT Population will be the primary population used for 
summarizing efficacy assessments.  
 
The Safety Population will include all patients who received at least one dose of investigational product 
(placebo or OCA). The Safety Population will be the primary population used for safety analyses.  
 
The PK Population will include all patients receiving OCA who have adequate concentration-time 
profiles to characterize OCA and its conjugates and must not have any major protocol deviations that 
potentially affect exposure levels.   
Pharmacokinetic Analyses: 
The PK Population will be used for analysis of PK parameters, which include plasma OCA (parent) and its 
conjugates (glyco-OCA and tauro-OCA), total OCA, metabolite OCA glucuronide, and potentially other 
conjugates or metabolites not yet identified. 
Values will be calculated using non-compartmental methods.  The values will be summarized by active 
treatment group using descriptive statistics.  
Safety Analyses: 
Safety analyses will be conducted using the Safety population.  Safety data, including AEs, AEs of special 
interest including pruritus and hepatic safety, vital signs, electrocardiogram, and clinical laboratory results will 
be summarized by treatment group.  The incidence of treatment-emergent AEs (TEAEs) and serious AEs 
(SAEs) will be tabulated by system organ class and preferred term for each treatment group, and similarly by 
severity and relationship to treatment.  Laboratory parameters, physical examinations including vital signs, and 
electrocardiograms will be summarized by treatment group using descriptive statistics at Baseline and at each 
scheduled post-Baseline visit.  The absolute change from baseline will also be summarized.  No inferential 
comparison with formal statistical hypothesis testing will be performed for safety endpoints. 
Efficacy Analyses: 
This study does not plan to conduct a formal hypothesis testing for any efficacy endpoint.   
The endpoints of efficacy assessments are change in total and direct bilirubin, INR, creatinine, albumin, 
platelets, ALP, ALT, AST, and GGT from baseline to Week 48 (end of the study), change from baseline to 
Week 48 in CP score and components of the CP score, and change from baseline to Week 48 in MELD and 
components of the MELD score.  Analyses of change from Baseline to Week 48 (end of study) will be modelled 
between treatment groups using ANCOVA model with change from Baseline as the dependent variable, 
treatment group and randomization stratification factor as fixed effects and the baseline values as covariates.  
The same analysis will be carried out using percentage change from Baseline as the dependent variable. 
Additional Efficacy Analyses 
Analyses of changes in liver stiffness (TE) and liver fibrosis (ELF [HA, P3NP, and TIMP-1]) will be 
summarized and analyzed using the same methodology specified for the secondary analyses of change in 
bilirubin. 
The following endpoints consistent with end-stage liver disease will be captured in the study: 
 
Time to death (all cause) 
 
Time to liver-related death 
 
Time to liver transplant 
 
MELD score ≥15 (for patients with MELD ≤12 at baseline) 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of: 
 
Time to variceal bleed 
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 
Time to hepatic encephalopathy (as defined by a West Haven score of ≥2) 
 
Time to spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 
Time to uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
The incidence and time to first occurrence of any of the above listed clinical events will be summarized by 
treatment group using the log rank test stratified by the randomization stratification factor.  Kaplan-Meier (KM) 
estimates of the distribution of the time-to-event will be tabulated and graphed by treatment group.  The 
tabulation will include the KM methodology using 25th, 50th (median), and 75th percentiles with associated 
2-sided 95% confidence intervals (CIs), as well as percentage of censored observations.  The number and 
percent of patients censored and with events will be presented.  The hazard ratio and 2-sided 95% CI will be 
estimated based on a Cox regression model stratified by randomization strata.  
In addition, the incidence and time to each of the above clinical events, and the incidence and time to occurrence 
of HCC will be summarized by treatment group using the same methods as defined above.   
Sample Size Justification: 
To reasonably characterize the PK of OCA in patients with hepatic impairment, a simulation based approach 
estimated a requirement of approximately 20 patients in the OCA treatment group assuming a 15% 
discontinuation rate.  A total of 30 patients is adequate with 10 patients on placebo to be included as a 
comparator and 20 patients on OCA.  An additional 20 patients will be enrolled to support safety and efficacy 
evaluations.  Therefore, approximately 50 patients (including at least 20% of patients with CP-C) will be 
randomized in a 1:1 ratio to 1 of 2 treatment groups:  Placebo and OCA. 
 
 
 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Overview of Disease State and OCA ..........................................................................21 
5.2. 
Nonclinical Experience with Obeticholic Acid ..........................................................21 
5.3. 
Clinical Development of Obeticholic Acid ................................................................21 
5.4. 
Rationale for Study Design and Dose for Investigational Product .............................23 
5.4.1. 
Rationale for Study Design .........................................................................................23 
5.4.2. 
Rationale for Obeticholic Acid Dose and Duration ....................................................23 
5.4.3. 
Rationale for Population Chosen ................................................................................24 
5.4.4. 
Rationale for Control Group .......................................................................................24 
5.5. 
Importance of Monitoring of Disease Progression .....................................................24 
5.6. 
Summary of Known Potential Risks with Investigational Product ............................25 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................26 
6.1. 
Primary Objectives .....................................................................................................26 
6.2. 
Secondary Objectives .................................................................................................26 
6.3. 
Additional Objectives .................................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.1.1. 
Study Design Diagram ................................................................................................28 
7.1.2. 
Schedule of Study Procedures ....................................................................................29 
7.1.3. 
Study Duration ............................................................................................................32 
7.2. 
Number of Patients .....................................................................................................32 
7.3. 
Planned Dosing Regimen ...........................................................................................32 
7.4. 
Monitoring and Management of Potential Hepatic Injury and/or Disease 
Progression .................................................................................................................32 
7.4.1. 
Signs and Symptoms of Potential Hepatic Injury or Decompensation .......................33 
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7.4.2. 
Liver Biochemistry Assessments for Potential Hepatic Injury or Hepatic 
Decompensation .........................................................................................................33 
7.4.3. 
Clinical Criteria for Monitoring for Potential Hepatic Decompensation ...................36 
7.5. 
Dose Titration Criteria ................................................................................................37 
7.5.1. 
Pre-Titration Tolerability Assessment Requirements .................................................38 
7.6. 
Close Observation .......................................................................................................38 
7.7. 
Criteria for Study Termination ...................................................................................39 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................39 
8.1. 
Patient Population .......................................................................................................39 
8.2. 
Patient Inclusion Criteria ............................................................................................40 
8.3. 
Patient Exclusion Criteria ...........................................................................................41 
8.4. 
Dose Adjustment, Interruption, and Withdrawal from Investigational 
Product or Study .........................................................................................................42 
8.4.1. 
Other Reasons for Discontinuation of Study or Investigational Product ...................43 
8.4.1.1. 
Withdrawal of Consent to Continue in the Study .......................................................44 
8.4.1.2. 
Lost to Follow-Up.......................................................................................................44 
8.4.2. 
Patient Discontinuation Notification ..........................................................................44 
9. 
TREATMENT OF PATIENTS ..................................................................................45 
9.1. 
Investigational Product Treatment Regimen ..............................................................45 
9.2. 
Concomitant Medications ...........................................................................................45 
9.2.1. 
Drug Interactions ........................................................................................................45 
9.2.2. 
Prohibited Medications ...............................................................................................46 
9.3. 
Treatment Compliance ................................................................................................46 
9.4. 
Randomization and Blinding ......................................................................................46 
9.4.1. 
Methods of Assigning Patients to Treatment Groups .................................................46 
9.4.2. 
Blinding ......................................................................................................................47 
9.4.3. 
Emergency Unblinding Procedures ............................................................................47 
9.5. 
Assignment of Site and Patient Numbers ...................................................................47 
9.5.1. 
Site Numbers ..............................................................................................................47 
9.5.2. 
Patient Numbers ..........................................................................................................48 
9.6. 
Restrictions .................................................................................................................48 
9.6.1. 
Fasting Requirement at Study Visits ..........................................................................48 
9.7. 
Visit Procedures ..........................................................................................................48 
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9.7.1. 
Visit Windows ............................................................................................................48 
9.7.2. 
Informed Consent Procedures.....................................................................................48 
9.7.3. 
Assessing Cirrhosis .....................................................................................................48 
9.7.4. 
Screening Procedures (14 days to 28 days prior to Day 1).........................................49 
9.7.5. 
Day 1 Procedures (Randomization) ............................................................................50 
9.7.6. 
Week 3 and Week 42 Safety Visit Procedures ...........................................................51 
9.7.7. 
Week 6 Procedures .....................................................................................................52 
9.7.8. 
Week 9 through Week 48 (Safety Contact) ................................................................53 
9.7.9. 
Week 12, Week 24, Week 36 Procedures ...................................................................54 
9.7.10. 
Week 18 and Week 30 Procedures .............................................................................55 
9.7.11. 
Week 48 Procedures ...................................................................................................57 
9.7.12. 
Every 3 Months after Week 48 ...................................................................................58 
9.7.13. 
End of Study/Early Termination/End of Treatment Procedures for Patients 
That Withdraw from Investigational Product or Withdraw Consent ..........................59 
9.7.14. 
Unscheduled Safety Visit ...........................................................................................61 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............61 
10.1. 
Investigational Product ...............................................................................................61 
10.2. 
Investigational Product Packaging and Labeling .......................................................61 
10.3. 
Investigational Product Storage ..................................................................................61 
10.4. 
Investigational Product Administration ......................................................................61 
10.5. 
Investigational Product Accountability and Disposal .................................................61 
11. 
OVERVIEW OF ASSESSMENTS ............................................................................62 
12. 
CLINICAL PHARMACOKINETIC ASSESSMENTS .............................................63 
12.1. 
Pharmacokinetic Blood Sampling ..............................................................................63 
12.2. 
Processing and Handling of Pharmacokinetic Samples ..............................................65 
12.3. 
Bioanalysis ..................................................................................................................65 
13. 
ASSESSMENT OF SAFETY .....................................................................................65 
13.1. 
Adverse Events and Serious Adverse Events .............................................................65 
13.1.1. 
Definitions of Adverse Events ....................................................................................65 
13.1.1.1. 
Adverse Event .............................................................................................................65 
13.1.1.2. 
Serious Adverse Event ................................................................................................66 
13.1.1.3. 
Treatment-Emergent Adverse Event ..........................................................................66 
13.1.1.4. 
Adverse Events of Special Interest .............................................................................66 
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13.1.2. 
Relationship to Investigational Product ......................................................................67 
13.1.3. 
Recording Adverse Event Severity .............................................................................68 
13.1.4. 
Reporting of Adverse Events and Serious Adverse Events ........................................68 
13.1.4.1. 
Reporting of Adverse Events ......................................................................................68 
13.1.4.2. 
Reporting of Serious Adverse Events .........................................................................69 
13.1.5. 
Additional Investigator Responsibilities for SAEs .....................................................70 
13.1.6. 
Notification of Post-Treatment SAEs for Patients Who Continue in the Study .........70 
13.1.7. 
Notification of Post-Study SAEs ................................................................................70 
13.1.8. 
Follow-Up of AEs and SAEs ......................................................................................70 
13.1.9. 
Pregnancy and Follow-Up ..........................................................................................71 
13.2. 
Other Safety Parameters .............................................................................................72 
13.2.1. 
Medical History/Demographics ..................................................................................72 
13.2.2. 
Medical and Surgical Procedures ...............................................................................72 
13.2.3. 
Physical Examination .................................................................................................72 
13.2.4. 
Vital Signs and Weight ...............................................................................................72 
13.2.5. 
Electrocardiogram .......................................................................................................72 
13.2.6. 
Laboratory Assessments .............................................................................................72 
13.2.7. 
Patient-Reported Outcomes and Healthcare Resource Use ........................................74 
14. 
EFFICACY ASSESSMENTS ....................................................................................75 
14.1. 
Biochemical Measures of Disease Severity ................................................................75 
14.1.1. 
Child-Pugh Score ........................................................................................................75 
14.1.2. 
Model of End Stage Liver Disease Score ...................................................................76 
14.1.3. 
Changes in Liver Biochemistry and Hepatobiliary Damage ......................................76 
14.2. 
Additional Assessments ..............................................................................................76 
14.2.1. 
Noninvasive Measurements of Liver Stiffness and Fibrosis ......................................76 
14.2.2. 
Markers of FXR activation .........................................................................................76 
14.2.3. 
Clinical Outcome Events ............................................................................................76 
15. 
STATISTICAL METHODS AND ANALYSES .......................................................76 
15.1. 
Analysis Populations ..................................................................................................77 
15.2. 
Determination of Sample Size ....................................................................................77 
15.3. 
Pharmacokinetic Analyses ..........................................................................................78 
15.4. 
Safety Analyses ..........................................................................................................78 
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15.4.1. 
Adverse Events ...........................................................................................................78 
15.4.2. 
Clinical Laboratory Evaluations .................................................................................79 
15.4.3. 
Additional Safety Analysis .........................................................................................80 
15.4.4. 
Adverse Events of Special Interest .............................................................................80 
15.5. 
Efficacy Analyses .......................................................................................................82 
15.6. 
Additional Efficacy Analyses .....................................................................................83 
15.7. 
Handling of Missing Data ...........................................................................................84 
15.8. 
Data Monitoring Committee .......................................................................................84 
15.9. 
Adjudication Committees ...........................................................................................84 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................85 
16.1. 
Study Monitoring ........................................................................................................85 
16.2. 
Audits and Inspections ................................................................................................86 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................86 
18. 
ETHICS ......................................................................................................................86 
18.1. 
Ethics Review .............................................................................................................86 
18.2. 
Ethical Conduct of the Study ......................................................................................87 
18.3. 
Written Informed Consent ..........................................................................................87 
18.4. 
Patient Confidentiality and Data Protection ...............................................................87 
19. 
INVESTIGATOR OBLIGATIONS ...........................................................................88 
19.1. 
Adverse Event Reporting ............................................................................................88 
19.2. 
Protocol Deviations ....................................................................................................88 
19.3. 
Regulatory Documentation .........................................................................................88 
19.4. 
Ethics Review (IRB/IEC) ...........................................................................................88 
19.5. 
Archiving and Record Retention ................................................................................88 
20. 
PUBLICATION POLICY ..........................................................................................89 
21. 
LIST OF REFERENCES ............................................................................................91 
APPENDIX A. SUMMARY OF CHANGES:  PROTOCOL 747-401 VERSION 2 
(DATED 22 MAY 2017) ..................................................................................93 
APPENDIX B. 
SUMMARY OF CHANGES:  PROTOCOL 747-401 VERSION 3 
(DATED  04 JAN 2018) .................................................................................142 
APPENDIX C. 
SUMMARY OF CHANGES:  PROTOCOL 747-401 VERSION 4 
(DATED 15 FEB 2019) ..................................................................................188 
 
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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................29 
Table 2: 
Planned OCA or Matching Placebo Dosing Regimen ................................................32 
Table 3: 
Liver Laboratory Criteria for Monitoring of Suspected Hepatic Injury or 
Potential Hepatic Decompensation and Criteria for Interruption or 
Discontinuation of Investigational Product ................................................................35 
Table 4: 
Clinical Criteria for Monitoring Potential Hepatic Decompensation Events 
and Interruption / Discontinuation of Investigational Product ...................................37 
Table 5: 
Criteria for Dose Adjustment, Interruption, Discontinuation, and 
Rechallenge .................................................................................................................42 
Table 6: 
Early Discontinuation Scenarios .................................................................................60 
Table 7: 
Table of Assessments .................................................................................................62 
Table 8: 
Acceptable Windows for Pharmacokinetic Sample Collection ..................................65 
Table 9: 
Relationship of Adverse Events to Investigational Product .......................................68 
Table 10: Severity of Adverse Events ........................................................................................68 
Table 11: List of Laboratory Analytes to be Tested ...................................................................73 
Table 12: Child-Pugh Scoring System ........................................................................................75 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................28 
Figure 2: 
DILI Management Algorithm .....................................................................................34 
Figure 3: 
Week 6 Sampling Schedule ........................................................................................64 
Figure 4: 
Pharmacokinetic Sampling Schedule .........................................................................64 
  
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this protocol. 
Abbreviation or Specialist Term 
Explanation 
6-ECDCA 
6α-ethyl chenodeoxycholic acid (also known as INT-747) 
AASLD 
American Association for the Study of Liver Diseases  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMA 
antimitochondrial antibody 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
β-hCG 
beta human chorionic gonadotropin 
BAS 
bile acid sequestrants 
BP 
blood pressure 
C4 
7α-hydroxy-4-cholesten-3-one 
CAC 
Cardiovascular Adjudication Committee 
CI 
confidence interval 
CLDQ 
Chronic Liver Disease Questionnaire 
CRA 
Clinical Research Associate 
CP 
Child-Pugh 
eCRF 
electronic case report form 
DDI 
drug-drug interaction 
DMC 
Data Monitoring Committee 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
enhanced liver fibrosis 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
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Abbreviation or Specialist Term 
Explanation 
glyco-OCA 
glycine 6α-ethyl chenodeoxycholic acid 
HCC 
hepatocellular carcinoma 
HCP 
health care professional 
HDL 
high-density lipoprotein 
IB 
Investigational Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio  
IRB 
Institutional Review Board 
ISF 
Investigator site file 
ITT 
intent-to-treat  
IWRS 
interactive web response system 
KM 
Kaplan-Meier 
LDL 
low-density lipoprotein 
LTSE 
long-term safety extension 
LS 
least squares 
MACE 
major adverse cardiovascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model of end stage liver disease  
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cholangitis (also known as primary biliary 
cirrhosis) 
PIS 
patient information sheet 
PK 
pharmacokinetic 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
SD 
standard deviation 
SEM 
standard error of the mean 
SI 
standard international system of units 
SOC 
system organ class 
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Abbreviation or Specialist Term 
Explanation 
StdErr 
standard error 
SUSAR 
suspected unexpected serious adverse reaction 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
the Sponsor 
Intercept Pharmaceuticals, Inc. 
TIPS 
transjugular intrahepatic portosystemic shunt 
UDCA 
ursodeoxycholic acid 
UK 
United Kingdom  
ULN 
upper limit of normal 
US 
United States (of America) 
VAS 
visual analogue scale 
VLDL 
very low-density lipoprotein 
 
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5. 
INTRODUCTION 
5.1. 
Overview of Disease State and OCA 
Primary biliary cholangitis (PBC, also known as primary biliary cirrhosis [Beuers 2015a, 
Beuers 2015b, Beuers 2015c]) is a serious, life-threatening, cholestatic liver disease of unknown 
etiology that, without treatment, frequently progresses to hepatic fibrosis and eventual cirrhosis, 
hepatic decompensation, and necessitates liver transplantation or results in death.  PBC is a rare 
disease with reported prevalence in the US of 40.2/100 000 (Kim 2000).  PBC disproportionately 
affects women approximately 10:1 and is typically diagnosed in patients between 40 to 70 years 
of age.   
Historically, the only approved drug therapy for PBC has been the bile acid, ursodeoxycholic 
acid (UDCA), a physiological constituent of human bile (Lindor 2009).  While UDCA therapy 
had a marked effect on the treatment of PBC, up to 50% of patients showed a suboptimal 
response or no response to UDCA.  Such patients were at significantly increased risk of a poor 
clinical outcome due to PBC disease progression.   
Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist and modified bile acid derived 
from the primary human bile acid chenodeoxycholic acid (CDCA) (Pellicciari 2002), was 
developed for the treatment of PBC and to provide patients who have an inadequate response to 
or poor tolerance of UDCA a novel treatment option that was safe and effective.   
In May 2016, the US Food and Drug Administration (FDA) granted accelerated approval for 
OCA (marketed as Ocaliva), for the treatment of patients with PBC in combination with UDCA 
in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate 
UDCA.  In December 2016, the European Commission granted conditional approval for Ocaliva 
for the same indication, and in May 2017 Ocaliva received approval from Health Canada.  Since 
then, other countries have received approval (eg, Australia and Switzerland).  Study 747-401 is 
considered a Phase 4 study in regions where OCA has received regulatory approval for PBC; in 
all other regions, this study is considered Phase 3b. 
5.2. 
Nonclinical Experience with Obeticholic Acid 
Intercept Pharmaceuticals, Inc. (the Sponsor) has completed a standard battery of nonclinical 
safety pharmacology and toxicology studies.  No major nonclinical safety effects have been seen 
other than pharmacologic hepatic effects observed at high doses.  These pharmacologic hepatic 
effects are consistent with the detergent effects of a bile acid at exceedingly high hepatocellular 
exposure. 
5.3. 
Clinical Development of Obeticholic Acid 
As of 28 October 2018, approximately 3470 subjects have received ≥ 1 dose of OCA.  This 
estimation includes subjects from blinded ongoing studies.  Of these 3470 subjects, 888 were 
healthy volunteers, 580 subjects had PBC, 72 subjects had PSC, 6 subjects had biliary atresia, 
41 subjects had diabetes mellitus/ nonalcoholic fatty liver disease (NAFLD), 1914 subjects had 
NASH, and 33 subjects had portal hypertension due to alcoholic cirrhosis. 
Overall, the pharmacokinetic (PK) profile of OCA is consistent with that expected of a bile acid.  
Phase 1 studies demonstrated that OCA is rapidly absorbed and extensively conjugated with 
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glycine and taurine to form glyco-OCA and tauro-OCA, respectively.  OCA and its conjugates 
are primarily eliminated via biliary excretion, and plasma concentration time profiles 
demonstrated multiple peaking with prolonged exposure, indicative of enterohepatic circulation.  
Plasma concentrations of OCA and its conjugates spike shortly after meals, consistent with gall 
bladder emptying into the duodenum as expected of a bile acid. 
The OCA clinical development PBC program was based on a wide range of studies in PBC 
patients and healthy volunteers.  The clinical pharmacology studies supported the proposed 
dosing regimen:  10 mg fixed dose and a titration regimen starting at OCA 5 mg with titration to 
10 mg based on clinical and biochemical response.  The clinical program included a pivotal 
Phase 3 clinical study (747-301) and two Phase 2 clinical studies (747-201 and 747-202), which 
formed the primary basis of approval of OCA. 
Study 747-201 (59 patients) evaluated 2 doses of OCA (10 mg and 50 mg) given as monotherapy 
versus placebo.  Statistically significant and clinically relevant relative and absolute reductions 
from Baseline in alkaline phosphatase (ALP) were achieved with both doses of OCA versus 
placebo (p <0.0001).  Mean relative ALP reductions were 45% (OCA 10 mg) and 38% 
(OCA 50 mg) compared to an increase of 0.4% with placebo.  Further, significant improvements 
in gamma-glutamyl transferase (GGT) and in conjugated bilirubin were observed with both 
doses compared with placebo (p <0.05).  OCA also resulted in decreased circulating alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) levels. 
Study 747-202 (165 patients) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in patients on a stable therapeutic dose of UDCA.  Overall, the data from 747-202 were 
consistent with Study 747-201.  Statistically significant and clinically meaningful relative and 
absolute reductions in ALP were achieved with all 3 doses of OCA versus placebo (p <0.0001).  
Mean ALP reductions from baseline ranged from 21% to 25% compared to 3% with placebo.  
Improvements were also seen in GGT and ALT levels and in conjugated bilirubin levels. 
Study 747-301 (216 patients) was a Phase 3, double-blind, placebo-controlled, parallel-group 
study followed by a long-term safety extension (LTSE) using OCA in patients with PBC.  The 
primary endpoint for Study 747-301 was a composite endpoint based on the proportion of 
patients reaching specific criteria for ALP and bilirubin (ALP <1.67x upper limit of normal 
[ULN] with a ≥15% reduction and bilirubin ≤ULN).  Both OCA treatment groups met the 
primary endpoint of achieving a reduction in ALP to <1.67x ULN with a ≥15% reduction from 
baseline and a normal bilirubin level after 12 months of therapy.  The placebo group experienced 
a least squares (LS) mean decrease in ALP from baseline of 5%, compared to a significant LS 
mean decrease of 39% in the OCA 10 mg dose group and 33% in the OCA titration group (both 
OCA dose groups p <0.0001 versus placebo). 
The LTSE phases of both Phase 2 studies and the pivotal Phase 3 study support the long-term 
safety of OCA and demonstrate a durable therapeutic response.   
Study 747-302 is an ongoing randomized, double-blind, placebo-controlled clinical outcomes 
study, designed to confirm the clinical benefit of OCA treatment in patients with PBC.  This 
study is inclusive of patients with early to advanced stage PBC. 
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5.4. 
Rationale for Study Design and Dose for Investigational Product 
5.4.1. 
Rationale for Study Design 
There are limited clinical data available to support the use of OCA in patients with PBC with 
moderate to severe hepatic impairment.  The current recommended dosing of such patients is 
based on modeled systemic and hepatic concentrations.  Therefore, Study 747-401 is specifically 
designed to characterize the PK, safety, and efficacy of OCA in this patient population. 
PK and safety parameters will be evaluated as the primary objectives and efficacy parameters 
will be evaluated as secondary and additional objectives.  While the prognostic utility of ALP 
has been established by the Global PBC study group, increasing levels of bilirubin are more 
relevant to understanding the progression of end stage liver disease.  Consistently, bilirubin is a 
key marker of advancing disease as characterized by the Global PBC study group as well as its 
incorporation into model of end stage liver disease (MELD), Child-Pugh (CP), and Mayo risk 
scores.  As such, the potential of OCA to stabilize bilirubin levels will be evaluated. 
In order to generate data for the patient population in a timely fashion, Study 747-401 is 
designed with a relatively short-term, 1-year double-blind treatment period to gather primarily 
PK and safety data.  Therefore, the study will not formally test the long-term efficacy of OCA on 
clinical outcomes.   
Although Study 747-401 is not designed to formally evaluate clinical outcomes, these data will 
be collected and assessed as an additional objective.  Given the importance of evaluating clinical 
outcomes in patients with the most advanced form of the disease, these events will be 
prospectively adjudicated consistent with the procedures implemented in ongoing PBC studies.  
This will allow for a more robust meta-evaluation of clinical outcomes in patients with moderate 
to severe hepatic impairment following the completion of both studies.  
Study 747-302 is specifically designed to confirm clinical benefit across the spectrum of disease 
including patients with hepatic impairment.  Data collected from Study 747-401 will serve as a 
bridge to the 747-302 study. 
Taken together, data from this study will complement the data from Study 747-302 and offer the 
opportunity to better inform the benefit risk profile and appropriate treatment of 
hepatically-impaired patients.  
5.4.2. 
Rationale for Obeticholic Acid Dose and Duration 
Simulations using a physiologic PK model predicted changes in systemic and liver OCA 
concentrations associated with changes in the severity of hepatic impairment (CP Score).  Model 
simulations predicted that for mild (Child-Pugh A [CP-A]), moderate (Child-Pugh B [CP-B]), 
and severe (Child-Pugh C [CP-C]) hepatic impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to patients with normal hepatic function, whereas total 
OCA liver concentrations increase 1.1-, 1.5-, and 1.7-fold, respectively.  Because the liver is the 
primary site of action for the safety and efficacy of OCA, it is important to account for the 
differences in systemic and liver exposure when assessing effective doses.  It is also important to 
note that while hepatically impaired (CP-B and C) patients treated with OCA in Phase 1 and 
2 studies experienced plasma OCA exposures >10-fold higher than those in healthy patients, no 
apparent impact on the overall safety profile was observed, consistent with only a modest 
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increase in liver exposure of OCA associated with hepatic impairment.  Together, the results 
from these analyses suggest that the doses of OCA administered to patients with moderate or 
severe hepatic impairment should be modestly lower than those for patients with normal hepatic 
function to achieve similar hepatic exposure.    
Therefore, the current FDA-approved prescribing information for OCA includes a modified 
dosing regimen in patients with moderate and severe hepatic impairment that is designed to 
achieve liver exposures in these patients that would be similar to non-hepatically impaired 
patients through initiation at a lower dose (5 mg OCA once-weekly) followed by gradual 
up-titration (Section 7.3).   
5.4.3. 
Rationale for Population Chosen 
Patients with PBC and moderate or severe hepatic impairment, based on CP score and varying 
levels of MELD, are the targeted population for this study as OCA has been studied primarily in 
early to moderate stages of liver impairment in patients with PBC.  There is a great need to 
extend therapies to PBC patients with more advanced liver impairment.  Given the unmet 
medical need and observed efficacy, safety and tolerability profile of OCA in early and moderate 
PBC, evaluating the effects of OCA in a late stage population is warranted. 
5.4.4. 
Rationale for Control Group  
The use of a randomized placebo control group added to established standard of care provides 
the best scientific evidence of efficacy and safety.  The use of a placebo control provides a 
concurrent comparator group, accounting for not only a placebo effect but continued standard of 
care.  The use of a placebo control is critical to assess the safety and tolerability of OCA but also 
as a comparator for the high rate of clinical events which are expected in this advanced 
population.  
5.5. 
Importance of Monitoring of Disease Progression 
Given PBC is a chronic, progressive liver disease, it is important that patients with PBC are 
closely monitored to ensure early identification of decompensation and/or liver injury.  More 
extensive safety monitoring and appropriate dosing adjustments, interruptions, and 
discontinuations will be implemented to improve patient oversight and safety.  Investigators, 
together with the Sponsor’s Medical Monitor, will consistently and frequently assess individual 
patients to determine on an ongoing basis the totality of a patient’s clinical profile, which 
includes careful evaluation of signs and symptoms of potential hepatic injury and/or 
decompensation coupled with rules-based laboratory monitoring. 
Patients will be monitored for potential hepatic injury and/or decompensation.  Criteria for 
implementing dosing adjustments, interruptions, or discontinuations, and close monitoring 
procedures postdose-adjustment are described in Section 8.4 and Section 7.6.  The more 
extensive monitoring is important given the elevated risk of decompensation and potential for 
higher hepatic exposure to OCA in this population. 
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5.6. 
Summary of Known Potential Risks with Investigational Product 
The rate of progression and risk of decompensation is variable and may be rapid in certain 
patients, necessitating closer surveillance of patients at risk.   
Clinical Data 
In two Phase 2 studies and a Phase 3 study evaluating OCA in the treatment of subjects with 
PBC, hepatic adverse events were observed in subjects receiving doses of OCA ranging from the 
maximum approved dose of 10 mg once daily to 50 mg (5 times the highest recommended dose).   
Ongoing NASH clinical trials include reports of hepatic decompensation assessed as suspected 
unexpected serious adverse reactions (SUSARs).  Data remain blinded.  Additional details of 
these SUSARs are provided in the IB Version Number: 18 (31 January 2019). 
The primary AE shown to be related to OCA is pruritus.  Pruritus has also been observed in 
clinical studies with OCA in other indications, as well as in healthy subjects, with the highest 
frequency observed in subjects with PBC.  The incidence and severity of pruritus have been 
shown to be dose dependent, but there is no evidence of association with stage or progression of 
underlying disease. 
Changes in lipid profiles have also been observed with OCA dosing, including an increase in 
low-density lipoprotein (LDL) cholesterol and a decrease in high-density lipoprotein (HDL) 
cholesterol.  The clinical significance of these lipid findings remains unclear and is being studied 
further. 
An independent data monitoring committee (DMC) has performed detailed reviews of ongoing 
studies of obeticholic acid, including the Phase 3/4, clinical outcomes study in PBC (747-302), 
this Phase 4 PK and safety study in patients with PBC (747-401), the Phase 3, pivotal study in 
NASH with fibrosis (747-303), and the Phase 3 study in NASH with cirrhosis (747-304).  The 
DMC will continue to review data quarterly and will provide oversight of the above-mentioned 
studies throughout the course of the development program.  Additional details are provided in IB 
Version Number: 18 (31 January 2019). 
Post-Marketing Cases in PBC 
As of October 2018, greater than 4200 patients have received Ocaliva in the post-marketing 
setting.  In patients with moderate to severe hepatic impairment (Child-Pugh B and C), liver 
decompensation, liver failure, and death have been reported when Ocaliva was dosed up to 
7 times the recommended once weekly starting dose for such patients.  Based on the initial 
medical assessment of these cases, which included patients having undergone liver transplant, 
there was insufficient evidence suggesting a causal relationship between higher than 
recommended dosing and the reported adverse events. However, Intercept Pharmaceuticals, Inc. 
(the Sponsor) continues to assess the potential association between adverse events, including 
deaths, and the higher than recommended dosing of Ocaliva observed in PBC patients with 
moderate to severe hepatic impairment (Child-Pugh B and C) through ongoing post-marketing 
pharmacovigilance activities. 
Signs and symptoms reported in patients experiencing liver-related adverse events who received 
Ocaliva include:  increases in bilirubin and other liver enzymes, new or worsening pruritus, new 
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or worsening fatigue, vague neuropsychiatric symptoms (such as dysphoria), abdominal pain, 
nausea, vomiting, diarrhea, dehydration, jaundice, and liver decompensation. 
Refer to the IB for additional information regarding the known potential risks with the 
investigational product. 
6. 
STUDY OBJECTIVES AND PURPOSE 
The study will be conducted in patients with PBC and moderate to severe hepatic impairment 
defined as CP-B and CP-C with MELD scores ranging from 6 to 24. 
6.1. 
Primary Objectives 
 To evaluate the PK of OCA and its conjugates, glyco-OCA and tauro-OCA, and OCA 
metabolite glucuronide compared with placebo 
 To evaluate the safety and tolerability of OCA treatment compared with placebo 
6.2. 
Secondary Objectives 
 To evaluate the effect of OCA treatment compared to placebo on:  
 The MELD score and its components 
 CP score and its components 
 Liver biochemistry including total and direct bilirubin, alkaline phosphatase 
(ALP), and aminotransferases (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], and gamma glutamyl transaminase [GGT]), international 
normalized ratio (INR), creatinine, albumin, platelets 
 Biomarkers of bile acid synthesis and homeostasis including fibroblast growth 
factor 19 (FGF-19), 7α-hydroxy-4-cholesten-3-one (C4), and plasma bile acids 
6.3. 
Additional Objectives 
 To evaluate the effect of OCA treatment compared to placebo on: 
 Noninvasive markers of liver fibrosis (Enhanced Liver Fibrosis [ELF]™score) 
 Noninvasive measurement of liver stiffness (transient elastography [TE]) 
 To assess the PK/Pharmacodynamic (PD) relationship of OCA with: 
 PK parameters compared to PD parameters and safety and tolerability 
assessments 
 To assess patient reported outcomes (Pruritus Visual Analogue Scale [VAS], PBC-40, 
EQ 5D-5L, Chronic Liver Disease Questionnaire [CLDQ] 
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 To assess clinical events consistent with end-stage liver disease 
 Death (all cause) 
 Liver transplant 
 MELD score ≥15 (for patients with MELD ≤12 at baseline) 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: variceal bleed, hepatic encephalopathy (as defined by a West 
Haven score of ≥2), spontaneous bacterial peritonitis 
 Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis 
at a frequency of at least twice in a month) 
 Hepatocellular carcinoma (HCC) 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This Phase 4, randomized, double-blind, placebo-controlled study will evaluate the PK and 
safety of OCA treatment in patients with PBC and moderate to severe hepatic impairment 
defined as CP-B and CP-C including a broad distribution of MELD scores (ranging from 6 to 
24).  Approximately 50 patients (including at least 20% of patients with CP-C) will be enrolled 
in the study.  Patients will be screened ≥14 days but not more than 28 days prior to entering the 
study (Day 1).  Patients who meet all eligibility requirements will be randomized in a 1:1 ratio to 
1 of 2 treatment groups:  Placebo or OCA.  Randomization will be stratified by CP class.  
Baseline MELD scores will be monitored on an ongoing basis to ensure adequate distribution of 
MELD scores. 
Following completion of safety assessments and laboratory specimen collection, blinded 
investigational product will be dispensed with instruction to begin dosing the same day (Day 1) 
at OCA 5 mg or placebo once weekly.   
Double-Blind Treatment Period:  During the 48-week treatment period, an initial safety visit 
will occur at Week 3.  After the Week 6 Visit, subsequent clinic visits will occur approximately 
every 6 weeks for the assessment of safety, tolerability, PK, and PD. Titration may be considered 
as early as the Week 12 Visit (see Section 7.3).  Fasting PK assessments will be performed in all 
patients participating in the study on Day 1, Week 6, and Week 36.  Serial PK sampling (which 
also includes a fasted PK assessment) will be performed at Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week, double-blind treatment period will continue 
double-blind treatment until all randomized patients have completed their 48-week treatment 
period and the database for that period is locked.  An open-label extension study in which all 
patients receive OCA will be considered following review of blinded safety and PK data. 
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7.1.1. 
Study Design Diagram 
Figure 1: 
Study Design  
 
OCA = obeticholic acid, PBC = primary biliary cholangitis 
Notes:  Initial dose titration of investigational product may be considered as early as the Week 12 Visit, or any study 
visit thereafter for patients on all dosing regimens, based on tolerability and safety laboratory tests from the 
previous visit.  Subsequent dose titration(s) may occur no earlier than 6 weeks after the previous dose titration 
and will be based on tolerability. 
Patients who complete Week 48 will continue double-blind treatment until all randomized patients have 
completed their participation in the 48-week treatment period and the database for that period is locked. 
 
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures  
 
 
Double-Blind Treatment Period (Weeks)b 
Double-Blind 
Extension 
Screening 
Day 1a 
3c 
6d 
12 
18 
24 
30 
36 
42c 
48/ ET/ 
EOS/EOT 
Every 3 
months 
Visit Window  
(+/-) 
-28 to -14 
days 
 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±2 wks 
Fast ≥8 h Prior to Visite 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/PBC History 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examf 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Vital Signs and Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Medical and Surgical Procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessments for Child-Pugh 
Scoreg 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Patient Questionnaires (Pruritus 
VAS, PBC-40, EQ- 5D-5L, and 
CLDQ)h 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Randomization/Treatment 
Assigned 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense IPi 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dose Titration Assessmentj 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
IP Accountability/ 
Compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 1: 
Schedule of Study Procedures (Continued) 
 
 
Double-Blind Treatment Period (Weeks)b 
Double-Blind 
Extension 
Screening 
Day 1a 
3c 
6d 
12 
18 
24 
30 
36 
42c  
48/ ET/ 
EOS/EOT 
Every 3 
months 
Visit Window  
(+/-) 
-28 to -14 
days 
 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±2 wks 
Urinalysis  
X 
X 
 
 
 
 
 
 
 
 
X 
Xp 
Urine-based β-hCG Pregnancy 
Testk 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Virology (HCV/HBsAg) 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry/Hematology/ 
Coagulationl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase and Lipase 
Sample to be collected if the patient experiences acute pancreatitis or cholecystitis. 
PK Fasting Collection 
 
X 
 
X 
 
 
 
 
X 
 
 
 
PK Serial Collectionm 
 
 
 
 
X 
X 
X 
X 
 
 
X 
 
PD Markers: Bile 
Acid/C4/FGF-19 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
TE/ELF (HA, P3NP, and 
TIMP-1)n 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Xo 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
X 
Xp 
Hepatic Ultrasoundq 
Xr 
Xs 
 
 
 
 
X 
 
 
 
X 
Xo 
Gallbladder assessment 
(ultrasound) 
Xr 
Xs 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; eCRF = electronic case report form; C4 = 7α hydroxy-4-cholesten-3-one; CLDQ = Chronic Liver Disease Questionnaire; ELF = enhanced liver fibrosis; ET = 
Early Termination; EOS = End of study; EOT = End of Treatment; ; FGF-19 = fibroblast growth factor-19; HA = hyaluronic acid; HCV = Hepatitis C virus; IP = Investigational 
Product; P3NP = procollagen 3 N-terminal peptide;  PBC = primary biliary cirrhosis; PK = pharmacokinetics; TE = transient elastography; wk(s) = week(s), TIMP-1 = tissue 
inhibitor of metalloproteinase ; VAS = Visual Analogue Scale. 
a Visit schedule should be based on Day 1.  Day 1 visit must occur at least 2 weeks after screening visit. 
b Patients should be contacted by telephone/email every 3 weeks (±1 week) between clinic visits starting at Week 9 and continuing to Week 48 to assess for AEs, concomitant 
medications, medical/surgical procedures, and verify that s/he is dosing as directed. (see Section 9.7.8). 
c Preferably, the patient comes in to the clinic for this visit.  Alternatively, site will telephone the patient for assessments and a home health nurse will visit to draw safety labs. 
d Visit should occur 3, 4, or 5 days after taking the Week 6 dose. 
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e The patient should be instructed to fast overnight (at least 8 hours) prior to each visit.  Fasting is required prior to all study visits, including screening, but water is permitted. 
f Height and assessment of smoking and alcohol consumption history and current habits will be assessed at Screening and Week 48.  Assessment of smoking and alcohol 
consumption history and current habits will be assessed quarterly after Week 48.    
g Child-Pugh Score will be calculated based on ascites assessment, hepatic encephalopathy grade, and central laboratory evaluations per the Child-Pugh scoring system noted in the 
eCRF. 
h The EQ-5D-5L Quality of Life questionnaire is validated for use in multiple languages. If a validated translation is not available in the local language required for a specific 
study patient, the questionnaire will not be collected.  The CLDQ measures change over time in patients with chronic liver disease.  
i New investigational product bottles will be dispensed if the patient is up-titrated. Unless up-titrated, patients are expected to use up each investigational product bottle before a 
new bottle will be dispensed.  No new bottles will be dispensed if dose frequency is changed.  Patients will be instructed to begin dosing on Day 1, after completing all study 
assessments.  Patients will be instructed to take investigational product at approximately the same time of day.  Patients must be instructed to swallow the tablet whole; they must 
not chew, divide, or crush the tablet. 
j  
Dose titration of investigational product may occur starting after the Week 12 Visit, or any study visit thereafter for patients on all dosing regimens, based on tolerability and 
safety laboratory tests from the previous visit.  Subsequent dose titration(s) may occur no earlier than 6 weeks after the previous dose titration and will be based on tolerability.   
k Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry and at every visit (except Week 3).  If positive, a confirmatory blood test must 
be performed at the central laboratory.  If the confirmatory blood test is also positive, the patient may not continue in the study.  (Additional testing may be conducted where 
required, regionally). 
l MELD values will be calculated based on serum chemistry and coagulation values at each visit. 
m The patient will be given the option to return to the clinic the following morning for the 24-hour postdose PK sample or samples can be obtained by a home health care designee. 
Patients who are discontinued from investigational product prior to completion of the study are encouraged to continue to follow the regular visit schedule, with the exception of 
PK sampling.   
n The noninvasive radiological liver fibrosis measurement devices (such as, FibroScan® device [Echosens; Paris, France]) will be used at all study sites to collect hepatic stiffness 
measurements.   
o Patients will complete a TE/ELF and ultrasound assessment, every 6 months (±2 weeks) after Week 48. 
p ECG and urinalysis will be done yearly (±2 weeks) after Week 48 Visit.  
q Ultrasound will be conducted to enhance HCC surveillance.  For all on study (eg, post-Day 1) ultrasounds:  Unless HCC has already been confirmed by biopsy, a second 
 
confirmatory image (eg, MRI) should be obtained to confirm suspected HCC.   
r If an ultrasound has been done within 12 months of Screening, and a report/adequate data are available, a pretreatment ultrasound at Screening is not required. 
s If ultrasound for gallbladder assessment was not performed at Screening and the historic ultrasound is >12 months from Day 1, perform ultrasound. 
 
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7.1.3. 
Study Duration 
Patients will receive double-blind treatment for at least 48 weeks.  Patients who have completed 
their 48-week, double-blind treatment period will continue double-blind treatment until all 
randomized patients have completed their 48-week treatment period and the database for that 
period is locked (approximately 3 years).    An open-label extension study in which all patients 
receive OCA will be considered following review of blinded safety and PK data. 
7.2. 
Number of Patients 
Approximately 50 patients will be enrolled in this study. 
7.3. 
Planned Dosing Regimen 
All patients will initiate investigational product once weekly with OCA 5 mg or matching 
placebo (Table 2).  Titration may be considered as early as the Week 12 Visit.  Following visit 
procedures at Week 12, if the investigational product is tolerated and laboratory assessments do 
not indicate a safety concern, the patient may up-titrate to OCA 5 mg twice weekly and may start 
the higher dose regimen no earlier than 2 days after they took their last dose.  Dosing will then 
occur at least 3 days apart.  Every 6 weeks thereafter, based on tolerability assessments, patients 
can be considered for further up titration as described below (Table 2).  At each titration visit, the 
patient may start the higher dose regimen no earlier than 2 days after the prior dose. 
Patients may titrate to a maximum dose of OCA 10 mg twice weekly at least 3 days apart.  
Table 2: 
Planned OCA or Matching Placebo Dosing Regimen 
 
Child-Pugh B and Child-Pugh C 
(Moderate and Severe Hepatic Impairment) 
Treatment Group 
OCA 
Placebo 
Starting Dose (Day 1) 
5 mg once weekly 
matching placebo once weekly 
Titration 1a  
5 mg twice weeklyb 
matching placebo twice weeklyb 
Titration 2a  
10 mg twice weeklyb 
matching placebo twice weeklyb 
a Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on patient 
tolerability. 
b Dosing per the twice weekly schedule must be at least 3 days apart. 
7.4. 
Monitoring and Management of Potential Hepatic Injury and/or 
Disease Progression 
Given the chronic nature of PBC, it is important to monitor for potential hepatic injury, disease 
progression and/or hepatic decompensation.  Child-Pugh and MELD scores will be reviewed at 
each visit where labs are drawn (Table 1).  In addition, adverse events, signs and symptoms of 
potential hepatic injury or decompensation, and laboratory values will also be reviewed at 
regular intervals as described in Section 7.1.2.  Based on biochemical and clinical assessments, 
the investigational product may be interrupted or discontinued per criteria discussed in 
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Section 7.4.2 and Section 7.4.3, and close monitoring procedures will be implemented (refer to 
Section 7.6). 
7.4.1. 
Signs and Symptoms of Potential Hepatic Injury or Decompensation 
Patients should be instructed to contact study personnel if they notice any of the following signs 
and symptoms or have healthcare interactions outside of the study setting  
Signs and Symptoms of Hepatic Injury or Decompensation: 
 Specific signs and symptoms of liver impairment:  yellowing of the skin or the whites 
of eyes, pale-colored stools, urine color change from pale to deep amber [dark] 
(reflecting impaired bilirubin metabolism) 
 More general signs and symptoms of ascites and encephalopathy:  confusion, 
swelling of the legs or abdomen 
 Non-specific signs and symptoms of impaired health:  nausea, vomiting, abdominal 
pain, diarrhea, weight loss, fever and chills, worsening or new fatigue, weakness, loss 
of appetite 
 Significant intercurrent illnesses such as gastroenteritis may exacerbate hepatic injury 
or decompensation (eg, established severe abdominal pain, vomiting, and diarrhea for 
more than 4 days) and should be an indication for prompt investigational product 
interruption and complete patient evaluation 
Other Symptoms: 
 Worsening of renal function or likely dehydration 
Healthcare Provider (HCP) Interactions: 
 Visits to primary HCP or referral to any specialist for any new symptoms (other than 
ongoing care for stable comorbidities) 
 New medications or changes to current medications prescribed from HCP or any new 
over the counter medications or herbal supplements  
 Laboratory procedures or assessments performed by an HCP  
Signs and symptoms for potential hepatic injury or decompensation should be followed by (1) 
evaluation of liver biochemistry for suspected drug-induced liver injury (DILI) or potential 
hepatic decompensation (Section 7.4.2), (2) assessment of clinical events for potential hepatic 
decompensation (Section 7.4.3), (3) triggering of close monitoring or investigational product 
interruption/discontinuation per criteria (Section 8.4), (4) documentation in the AE eCRF or the 
SAE eCRFs (Section 13.1), and (5) contact with the Medical Monitor. 
7.4.2. 
Liver Biochemistry Assessments for Potential Hepatic Injury or Hepatic 
Decompensation 
Liver biochemistry will be assessed to evaluate biochemical triggers that will prompt an 
immediate reevaluation of patients for potential hepatic injury or hepatic decompensation.  These 
assessments will be performed at: 
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 Each protocol-specified visit (Table 1)  
 Unscheduled visits as needed in the event of signs or symptoms of suspected hepatic 
injury or decompensation or if laboratory alerts have been triggered 
It is important that the laboratory assessments be completed as required and that the central 
laboratory be used for assessments whenever possible.  In the event that a patient cannot return 
to the clinic for a scheduled or unscheduled visit, or there is an event that triggers a need for an 
immediate assessment, the use of a local lab is permissible at the discretion of the Investigator. In 
these cases, the Investigator will obtain the laboratory results and the laboratory normal ranges. 
The process for assessing criteria is presented in Figure 2, and the specific threshold(s) for each 
laboratory analyte to trigger mandatory repeat testing and, potentially, a complete patient 
evaluation (depending on the repeat result) are summarized in Table 3. 
Figure 2: 
DILI Management Algorithm 
  
DILI = drug-induced liver injury; IP = Investigational Product 
NOTE 
Other laboratory criteria include:  ALT, AST, total bilirubin, INR, and electrolytes (sodium). 
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Table 3: 
Liver Laboratory Criteria for Monitoring of Suspected Hepatic Injury or 
Potential Hepatic Decompensation and Criteria for Interruption or 
Discontinuation of Investigational Product 
Laboratory Criteria for Monitoring Suspected Hepatic Injury 
Laboratory Parameter 
Action Taken 
Rechallenging Criteria 
Total Bilirubin 
 
If a patient interrupts IP, they may be 
rechallenged after a minimum of 30 days if 
fully resolved OR stable and approved by 
the Medical Monitor and Investigator. 
Baseline ≤ULN and ≥3x baseline 
Interrupt IP 
Baseline >ULN and ≥2x Baseline 
Interrupt IP 
ALT or AST 
 
>3x baseline (and >ULN) 
Interrupt IP 
≥2x baseline 
Repeat Test in 2 to 3 days, 
interrupt IP if still elevated 
Electrolytesa 
 
Sodium <130 mEq/L 
Repeat Test in 2 to 3 days, 
interrupt IP if still below limit 
 Laboratory Criteria for Monitoring Potential Hepatic Decompensation (Absence of Clinical Symptoms) 
Total Bilirubin 
Closely monitor until 
normalization or stabilization. 
 
If values continue to increase 
relative to the baseline value, 
interrupt IP. 
The patient may be rechallenged after a 
minimum of 30 days if fully resolved OR 
stable and approved by the Medical Monitor 
and Investigator. 
 
. 
If laboratory values do not normalize, IP 
should not be restarted. 
Baseline ≤ULN and 1.5 mg/dL increase 
from baseline 
Baseline >ULN and 1.0 mg/dL increase 
from baseline 
INRb 
 
 
>0.3 increase from baseline 
Closely monitor until 
normalization or stabilization. 
 
If values continue to increase 
relative to the baseline value, 
interrupt IP. 
The patient may be rechallenged after a 
minimum of 30 days if fully resolved OR 
stable and approved by the Medical Monitor 
and Investigator. 
 
If laboratory values do not normalize, IP 
should not be restarted. 
≥2.0 unless due to vitamin K deficiency 
Discontinue IP permanently  
Continue to return for scheduled study visits 
for safety follow up. Monitor closely for 
clinical outcomes per protocol. 
Laboratory Criteria for Monitoring Potential Hepatic Decompensation in the Presence of Clinical Symptoms  
Total bilirubin thresholds defined in Part B 
OR an INR increase from baseline of ≥1.5 
are observed in the presence of clinical 
symptoms of cholestatic hepatitis or hepatic 
encephalopathyc  
Discontinue IP permanently 
Continue to return for scheduled study visits 
for safety follow up. Monitor closely for 
clinical outcomes per protocol. 
IP = investigational product 
a Sodium will be measured as an assessment of liver failure (hyponatremia). 
b Does not apply in patients on anti-coagulants. 
c  Symptoms of cholestatic hepatitis includes dark urine and jaundice.  Symptoms of hepatic encephalopathy may include lack of 
awareness, shortened attention span, lethargy, gross disorientation, or coma (unresponsive to verbal or noxious stimuli). 
It should be noted that it is difficult to recognize every potential marker of hepatic or renal 
deterioration.  There is no substitute for good medical judgment.  Investigators will be reminded 
to be cautious and mindful in their evaluation of patients’ symptoms, signs, and laboratory 
results.  However, for example, a single abnormal laboratory analyte result may be artefactual; 
accordingly, Investigators will be allowed to implement an alternate follow-up procedure if 
considered appropriate based on their medical judgement, but only after documented agreement 
with the Sponsor’s Medical Monitor. 
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7.4.3. 
Clinical Criteria for Monitoring for Potential Hepatic Decompensation 
Patients will be monitored for potential hepatic decompensation events throughout the study.  
Clinical criteria for monitoring these events and the interruption/discontinuation of 
investigational product is summarized in Table 4. 
Investigational product should be discontinued permanently if the patient received a liver 
transplant or experiences multi-organ failure as defined in Table 4, Part A.  Patients should 
continue to return for scheduled study visits for safety follow-up.  
Patients who experience other potential hepatic decompensation events defined in Table 4, 
Part B should be closely monitored until normalization or stabilization.  Patients may be 
rechallenged after a minimum of 30 days if fully resolved OR stable and approved by the 
Medical Monitor and Investigator.   
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Table 4: 
Clinical Criteria for Monitoring Potential Hepatic Decompensation Events 
and Interruption / Discontinuation of Investigational Product 
Hepatic Decompensation Events Requiring Mandatory Discontinuation of Investigational Product 
Decompensation Event 
Action Taken / 
Rechallenging Criteria 
Liver Transplant 
Multi-organ failure requiring hospitalization 
Discontinue IP permanently and follow patients 
until normalization/stabilization. 
 
Continue to return for scheduled study visits for 
safety follow up. 
Hepatic Decompensation Events Requiring Interruption of Investigational Product 
1. Liver failure defined as worsening synthetic 
function that is persistently worse relative to 
baseline and/or progressive over time (see Table 3, 
Part B)a 
2. Variceal bleeding or recurrent variceal bleedingb 
documented by endoscopy or accompanied by 
anemia or melena with a hemoglobin drop of ≥2 
g/dL 
3. Ascitesc including: 
1. Worsening – requires increase in drug therapy or 
surgical intervention (paracentesis or shunt 
procedure) 
2. Refractory ascites – unresponsive to medication; 
patient not candidate for transjugular intrahepatic 
portosystemic shunt (TIPS) or shunt; requires 
large volume paracentesis 
3. Hyponatremia (≤125 mEq/L) secondary to ascites 
1. Spontaneous Bacterial Peritonitis 
2. Hepatic Encephalopathy, Grade ≥2 
3. Any liver-related event requiring hospitalization and 
treatment (except multi-organ failure) 
4. Hepatorenal syndrome Type 1 or Type 2 and acute 
kidney injury, hepatopulmonary syndrome, or 
portopulmonary syndrome 
Closely monitor until normalization or stabilization. 
 
The patient may be rechallenged after a minimum 
of 30 days if fully resolved OR stable and approved 
by the Medical Monitor and Investigator 
 
IP should be re-initiated at a lower dose (or lower 
dose frequency) and titrated per Investigator 
discretion. 
a Patients experiencing INR ≥2.0 unless due to vitamin K deficiency should be discontinued from IP permanently without 
rechallenge and should to return for scheduled study visits for safety follow up. 
b Endoscopic confirmation of gastric or duodenal varices without evidence of bleeding should be closely monitored; 
investigational product may be interrupted at Investigator discretion 
c New onset ascites requiring treatment should be closely monitored; investigational product may be interrupted at Investigator 
discretion 
7.5. 
Dose Titration Criteria 
Dose titration may follow the scheduled dosing regimens described in Section 7.3 or occur due to 
tolerability concerns. 
Dose titrations may involve increases or decreases in dosing frequency and are dependent on 
tolerability (as assessed by a review of AEs and safety laboratory results).  In general, 
down-titration may be done in response to tolerability concerns and can occur at any time.  
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Up-titration will be done per protocol based on tolerability, as assessed by the Investigator based 
on response, or following resolution of a tolerability concern that previously led to 
down-titration.  Up-titrations may only occur to the maximum dose and frequency indicated as 
defined in Section 7.3. 
Scheduled Dose Titration - After initiation of OCA or matching placebo, titration may be 
considered as early as the Week 12 Visit.  Subsequent titrations in dose for patients may occur no 
earlier than 6 weeks following an up-titration. 
Tolerability Dose Titration - Investigators may decrease the dosing frequency or dose as 
considered clinically appropriate (eg, tolerability). 
7.5.1. 
Pre-Titration Tolerability Assessment Requirements 
Tolerability of investigational product must be assessed prior to titrating a patient to a higher 
dose.  To determine if a patient is eligible for a dose titration refer to Section 7.3. 
7.6. 
Close Observation 
If investigational product is interrupted or discontinued as described in Section 8.4, patients 
should be closely monitored (contacted by the site a minimum of every 2 weeks and scheduled 
visits every 6 weeks; if returning to the site for a scheduled visit is not feasible, use of a local lab 
may be permissible at the Investigator's discretion).  At a minimum, the following assessments 
should be conducted at each study visit:   
 Physical exam and thorough review of patient reported signs and symptoms,  
 Liver biochemistry (including ALP, ALT, AST, GGT, total and conjugated bilirubin, 
creatinine, and albumin), prothrombin time (PT)/INR, serum electrolytes, and 
assessment of Child Pugh (only if the patient is at the study site) and MELD scores.  
In addition, a trough pharmacokinetic sample for assessment of OCA serum drug levels and its 
major metabolites should be obtained in any patient who develops an AE that is indicative of or 
consistent with hepatic injury or decompensation.  
The following additional monitoring procedures should be performed for events of potential 
hepatic injury (per FDA Guidance for Industry on Drug Induced Liver Injury) or suspected 
hepatic decompensation based on criteria described in Section 7.4.1, Section 7.4.2, and 
Section 7.4.3.  These cases need to be discussed with the Sponsor's Medical Monitor: 
 Repeating liver biochemistry and function tests as described in Section 7.4.2.  
Frequency of retesting can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the patient is asymptomatic, as clinically 
indicated.  
 Obtaining a more detailed history of symptoms and prior or concurrent diseases.  
 Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets is important. Concomitant drugs with potential hepatotoxicity should 
be recorded and discontinued unless alternative therapies are not available.  In the 
case of concomitant drugs potentially hepatotoxic, continued use of investigational 
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product should be discussed with the Sponsor's Medical Monitor.  The patient may be 
discontinued from investigational product, if clinically appropriate.  
 Obtaining a history of exposure to environmental chemical agents or herbal 
supplements which may be associated with liver toxicity.  
 Ruling out acute viral hepatitis types A, B, C, D (in those thought to have acute HBV 
infection), and E; autoimmune or alcoholic hepatitis; Wilson's disease, 
hypoxic/ischemic hepatopathy; and biliary tract disease.   
 Investigators should consider testing for Hepatitis E virus when assessing for hepatic 
decompensation as infection with Hepatitis E virus in patients with chronic liver 
diseases such as PBC may rapidly worsen with signs and symptoms similar to drug 
induce liver injury (Kumar 2013) 
 Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin).  
 Seeking hepatology consultation, if the Investigator is not a hepatologist 
7.7. 
Criteria for Study Termination 
The Sponsor (Intercept Pharmaceuticals, Inc.) reserves the right to terminate the study at any 
time.  It is normal procedure to review the emerging clinical and safety data.  As a result of such 
a review or a recommendation by the Data Monitoring Committee (DMC), it may be necessary 
to stop the study before all patients have completed the study.  In addition, the Sponsor may 
terminate the study at an investigational site at any time (eg, Good Clinical Practice [GCP] 
noncompliance or poorly performing sites, as determined by the number of patients enrolled or 
the quality of the study data). 
The Investigator and/or Sponsor (or designee) must notify the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) of discontinuation of a site or the study and the 
reason for doing so. 
Investigators will be informed by the Sponsor as to when the final study visit is to be completed, 
and should then schedule all patients for the end of study (EOS) or end of treatment (EOT) Visit.  
8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Population 
This study will be conducted at approximately 50 international study sites with experience in 
treating patients with PBC with moderate to severe hepatic impairment defined as CP-B and 
CP-C.  Prospective patients will be identified primarily from the hospital and/or physician’s 
database of patients with PBC, or may be referred from other physicians.  Patients may self-refer 
to an Investigator if they become aware of the study through local, national, or international PBC 
patient societies, forums, or networks. 
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8.2. 
Patient Inclusion Criteria 
1. A definite or probable diagnosis of PBC (consistent with American Association for the 
Study of Liver Diseases [AASLD] and European Association for the Study of the Liver 
[EASL] Practice Guidelines [Lindor 2009, EASL 2009]), defined as having ≥2 of the 
following 3 diagnostic factors: 
 History of elevated ALP levels for at least 6 months 
 Positive antimitochondrial antibody (AMA) titer or if AMA negative or low titer 
(≤1:80), PBC-specific antibodies (anti-GP210 and/or anti-SP100) and/or 
antibodies against the major M2 components (PDC-E2, 2-oxo-glutaric acid 
dehydrogenase complex)  
 Liver biopsy consistent with PBC (collected at any time prior to Screening) 
2. Evidence of cirrhosis including at least one of the following: 
 Biopsy results consistent with PBC Stage 4  
 Liver stiffness as assessed by TE Value ≥16.9 kPa 
 Clinical evidence in the absence of acute liver failure consistent with cirrhosis 
including: gastroesophageal varices, ascites, radiological evidence of cirrhosis 
(nodular liver or enlargement of portal vein and splenomegaly) 
 Combined low platelet count (<140 000/mm3) with: 
 persistent decrease in serum albumin, or  
 elevation in prothrombin time /INR (not due to antithrombotic agent use), 
or 
 elevated bilirubin (2× ULN) 
3. Satisfy the criteria of the modified CP classification for hepatic impairment during 
Screening: 
 Moderate:  CP-B (Scores 7 to 9) or 
 Severe:  CP-C (Scores 10 to 12) 
4. MELD score of 6 to 24 at Screening 
5. Age ≥18 years 
6. Taking UDCA for at least 12 months (stable dose for ≥3 months) prior to Day 1, or 
unable to tolerate or unresponsive to UDCA (no UDCA for ≥3 months) 
7. Contraception:  Female patients must be postmenopausal, surgically sterile, or if 
premenopausal (and not surgically sterile), be prepared to use ≥1 effective method of 
contraception during the study and for 30 days after the end of treatment visit.  Effective 
methods of contraception are considered to be those listed below: 
 Barrier method, ie, (a) condom (male or female) with spermicide or 
(b) diaphragm with spermicide; or 
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 Intrauterine device; or 
 Vasectomy (partner); or 
 Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection); or 
 Abstinence, if in line with the preferred and usual lifestyle of the patient (where 
abstinence is defined as refraining from heterosexual intercourse)  
8. Must provide written informed consent and agree to comply with the study protocol. 
8.3. 
Patient Exclusion Criteria 
1. Non-cirrhotic or cirrhotic CP-A (Mild; Score 5 to 6) 
2. History of liver transplant or organ transplant  
3. History of alcohol or drug abuse within 12 months prior to Screening 
4. Current hepatic encephalopathy (as defined by a West Haven score of ≥2 [AASLD, 
EASL 2014]) 
5. History or presence of other concomitant liver diseases including: 
a. Hepatitis C virus infection and RNA positive 
b. Active hepatitis B infection; however, patients who have seroconverted (hepatitis B 
surface antigen and hepatitis B e antigen negative) may be included in this study after 
consultation with the Medical Monitor 
c. Primary sclerosing cholangitis 
d. Alcoholic liver disease 
e. Definite autoimmune liver disease or overlap hepatitis 
f. Gilbert’s Syndrome 
6. In the opinion of the Investigator, fluctuating or rapidly deteriorating hepatic function 
prior to randomization 
7. Patients with history or presence of hepatorenal or hepatopulmonary syndrome 
8. Patients with significant active infection (ie spontaneous bacterial peritonitis) 
9. Patients with known or suspected hepatocellular carcinoma 
10. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
11. Participation in another investigational product, biologic, or medical device study within 
30 days prior to Screening.  Participation in a previous study of OCA is allowed with 
3 months washout prior to enrollment in this study 
12. Mental instability or incompetence, such that the validity of informed consent or ability 
to be compliant with the study is uncertain 
13. UDCA naïve (unless contraindicated) 
14. Known history of human immunodeficiency virus infection 
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15. Treatment with commercially available fibrates or participation in a previous study 
involving fibrates within 3 months before Screening, or plans to use commercially 
available fibrates during the study 
16. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test), or lactating 
8.4. 
Dose Adjustment, Interruption, and Withdrawal from 
Investigational Product or Study 
Investigational product may be temporarily decreased (eg, from 10 mg twice weekly to 5 mg 
twice weekly, or from 5 mg twice weekly to 5 mg once weekly) or temporarily or permanently 
stopped based on tolerability concerns.  Investigational product may be resumed at the 
maintenance dose upon resolution of gastroenteritis or worsening renal function or dehydration if 
there is no evidence of liver injury.  For rechallenge following all other dose interruptions (see 
Table 5), investigational product should be initiated at a lower dose and patients monitored more 
frequently with up-titration considered based on tolerability. 
Adjustments, interruptions, discontinuation, and any rechallenge of investigational product 
should be implemented per the criteria outlined in Table 5.  Patients that discontinue 
investigational product are expected to continue in the study (and follow the regular visit 
schedule, with the exception of PK sampling [trough PK may be required in the event of an AE 
consistent with hepatic injury or decompensation]) until the end of the study, but may withdraw 
consent at any time. 
Table 5: 
Criteria for Dose Adjustment, Interruption, Discontinuation, and 
Rechallenge 
DOSE ADJUSTMENT 
 
 
Criteria 
Action Taken with IP 
Adjustment 
New Onset Severe Pruritus 
Drug holiday or less 
frequent dosing 
Return to original dose regimen if tolerated 
DOSE INTERRUPTION 
 
 
Criteria 
Action Taken with IPa 
Rechallengeb 
If liver biochemistries indicative of 
suspected hepatic injury are identified as 
exceeding upper threshold criteria and 
require immediate interruption (see Part 
A of Table 3)c 
Interrupt immediately 
upon initial observation 
Patient may be rechallenged after a 
minimum of 30 days if fully resolved OR 
stable and approved by the Medical Monitor 
and Investigator. 
 
 
Other liver biochemistries indicative of 
suspected hepatic injury are outside 
upper threshold criteria upon repeat 
testing as defined in Part A of Table 3d 
Interrupt after 
confirmation by repeat 
testing 
Liver biochemistries indicative of 
potential hepatic decompensation in the 
absence of symptoms (see Part B of 
Table 3)e 
Closely monitor until 
normalization or 
stabilization. 
 
If values continue to 
increase relative to the 
baseline value, interrupt 
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Clinical events indicative of hepatic 
decompensation (see Part B of Table 4) 
Closely monitor until 
normalization or 
stabilization 
The patient may be rechallenged after a 
minimum of 30 days if fully resolved OR 
stable and approved by the Medical Monitor 
and Investigator. 
 
IP should be re-initiated at a lower dose (or 
lower dose frequency) and titrated per 
Investigator discretion. 
Gastroenteritis (established severe 
abdominal pain, vomiting, diarrhea for 
more than 4 days) 
Interrupt  
If no evidence of liver injury is detected, IP 
may be restarted at the same dose after 
resolution of intercurrent illness. 
Evidence of worsening of renal function 
or dehydration 
Interrupt  
DOSE DISCONTINUATION 
 
 
Criteria 
Action Taken with IP 
Rechallenge 
If INR increases ≥2.0 in absence of 
clinical symptoms criteria (unless due to 
vitamin K deficiency) f 
Discontinue / 
No Rechallenge 
Discontinue IP permanently and continue to 
return for scheduled study visits for safety 
follow-up.  
 
Continue to return for scheduled study visits 
for safety follow-up. Monitor closely for 
clinical outcomes according to protocol 
assessments. 
If total bilirubin thresholds (Part B of 
Table 3) are observed in the presence of 
clinical symptoms of cholestatic 
hepatitis or hepatic encephalopathyf 
Multi-Organ failure requiring 
hospitalization 
Liver transplantation 
Pregnancy 
Fully resolved = Return to baseline levels or return to within normal limits (WNL). IP = investigational product 
a If patient is unable to be evaluated promptly, study drug must be immediately interrupted. 
b Requires complete documentation of complete resolution or normal/baseline results based on laboratory 
parameters and symptoms.   
c Total bilirubin baseline ≤ULN and ≥3x baseline, baseline >ULN and ≥2x baseline, ALT or AST >3x baseline (and 
>ULN) 
d ALT or AST ≥2x baseline or electrolytes (sodium <130 mEq/L). 
e Total bilirubin baseline ≤ULN and 1.5 mg/dL increase from baseline OR baseline >ULN and 1.0 mg/dL increase 
from baseline; INR >0.3 increase from baseline 
f If INR increases ≥2.0 in the absence of clinical symptoms or if or total bilirubin thresholds OR an INR increase 
from baseline of ≥1.5 are observed in the presence of clinical symptoms of cholestatic hepatitis or hepatic 
encephalopathy. 
8.4.1. 
Other Reasons for Discontinuation of Study or Investigational Product  
The following events are considered appropriate reasons for a patient to discontinue 
investigational product; however, these patients are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
 Patient begins treatment with commercially available OCA. 
 The Investigator or Sponsor considers that it is advisable or in the best interest of the 
patient. 
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 The occurrence of clinical or laboratory AEs considered by the Investigator to be 
clinically important safety concerns and related to study drug. 
 Withdrawal of consent  
 Consent may be fully withdrawn (in which case the patient discontinues both 
investigational product and study visits and procedures). 
 Consent may be modified to discontinue study visits but allow semi-annual 
telephone contact. 
 Consent may be modified to discontinue study visits or semi-annual telephone 
contact but allow continued access to medical records to assess for suspected 
major adverse cardiovascular events (MACE) and liver-related clinical events. 
  Early termination procedures should be conducted if the patient withdraws 
consent (see Section 9.7.13). 
The Investigator is encouraged to contact the Sponsor prior to discontinuing a patient from 
treatment.  The Investigator must notify the Sponsor study monitor by telephone or email as soon 
as possible if any patient prematurely withdraws from the study. 
8.4.1.1. 
Withdrawal of Consent to Continue in the Study  
If the patient decides that it is in his/her best interest to discontinue from the study, he or she may 
withdraw consent.  It is fully understood that all patients volunteer for the study and that they 
may withdraw their consent to continue in the study at any time. 
Early termination procedures should be conducted if the patient withdraws consent (See 
Section 9.7.13). 
A reasonable effort must be made to determine the reason(s) for patient discontinuation.  This 
information and date must be recorded in the appropriate eCRF. 
8.4.1.2. 
Lost to Follow-Up 
Patients will be considered “lost to follow-up” only after documented attempts to reach the 
patient prove unsuccessful.  A reasonable effort (ie, 2 phone calls/messages, no response to 
registered letter) must be made to contact the patient and determine the reason(s) why a patient 
fails to return for a study visit or is lost to follow-up.  This information and date of contact must 
be recorded in the appropriate eCRF. 
8.4.2. 
Patient Discontinuation Notification 
The Investigator must notify the Sponsor as soon as possible if any patient prematurely 
discontinues from the study.  The date when the patient is withdrawn and the primary reason(s) 
for discontinuation must be recorded in the eCRF; additional information may be requested by 
the Sponsor to complete a discontinuation narrative.  This information must be documented in 
the eCRF. 
If a patient is withdrawn from the study early (regardless of the cause), all of the early 
termination (ET)/EOS evaluations are to be performed at the time of withdrawal, to the extent 
possible. 
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9. 
TREATMENT OF PATIENTS 
9.1. 
Investigational Product Treatment Regimen 
The term investigational product refers to either OCA (provided as part of this clinical study) or 
placebo.   
Two treatment groups will be evaluated:  OCA and placebo.  Investigational product will be 
administered orally.  Each dose will be made up of 1 tablet (ie, one OCA 5 mg tablet or one 
OCA 10 mg tablet, or matching placebo).   
Investigational product will be taken orally with water for the duration of the study.  Patients will 
be instructed to begin dosing on Day 1 and are to take investigational product at approximately 
the same time on dosing days.  Patients must be instructed to swallow the tablet whole; they must 
not chew, divide, or crush the tablet. 
At each study visit where the dose of investigational product is administered at the site, all 
assessments, except for the post-dose collection of blood samples for the PK assessment, must be 
completed before administration of investigational product. 
9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.2) 
will be used at the discretion of the usual care provider (or Investigator if also the usual care 
provider).  Relevant information about all concomitant medications (including prescribed, over 
the-counter, or herbal preparations) taken within 30 days of Screening and during the study must 
be recorded in the source documents and eCRF, as well as any dose or dose regimen changes that 
occur during the study.  Concomitant medications should be stable prior to Day 1. 
PBC Specific Therapy 
Investigators will be encouraged to follow guidelines for care based upon local and institutional 
practice patterns and any relevant published practice guidelines.  Throughout the course of the 
study, Investigators are expected to monitor patients’ PBC regimens and, if responsible for usual 
care, may adjust the regimen to achieve locally-appropriate treatment goals.  These goals will be 
individualized, with the understanding that currently applicable PBC guidelines may vary across 
different geographic regions. 
Ideally, patients should generally remain on the baseline PBC therapies throughout the course of 
the study, unless the baseline PBC therapy is no longer considered clinically appropriate by the 
Investigator.  In addition, patients should be reminded to keep taking their blinded 
investigational product. 
9.2.1. 
Drug Interactions 
Bile acid sequestrants (BAS, including cholestyramine and its derivatives, colestipol, 
colesevelam, or other sequestrants) or aluminum hydroxide- or smectite-containing antacids 
should not be taken within 4 hours of taking investigational product (and UDCA if applicable), 
ie, BAS should be administered at minimum 4 hours before or 4 hours after investigational 
product administration. 
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OCA taken concomitantly with warfarin may result in decreased INR levels; therefore, INR 
should be monitored and the dosage of warfarin adjusted, as needed during treatment with OCA 
and after cessation of OCA, to maintain the target INR range.  
The effect of OCA on drug metabolizing enzymes has been evaluated in both in vitro and clinical 
studies.  The PK profile of caffeine, a sensitive CYP1A2 substrate probe, showed weak effect of 
OCA on CYP1A2.  Based on these results, OCA may increase the exposure of narrow 
therapeutic index drugs that are substrates for CYP1A2, such as theophylline and tizanidine. 
Information related to additional drug-drug interaction (DDI) studies is available in the current 
version of the IB.  The aforementioned sections of the IB should be referred to during the course 
of the study, and are accessible to Investigators to help facilitate the assessment of potential 
DDIs with OCA that may be observed in study patients. 
9.2.2. 
Prohibited Medications 
Commercial OCA therapy (if available) is prohibited while on investigational product, and if 
prescribed during the course of the study, the Investigator should be cognizant of the possibility 
of double dosing.  Patients who initiate with commercial OCA therapy must discontinue 
investigational product and are expected to continue through the end of the study (see 
Section 8.4.1).  Fibric acid derivatives (ie, fibrates such as fenofibrate and bezafibrate) are also 
prohibited while on investigational product. 
9.3. 
Treatment Compliance 
The Investigator should assess the patient’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Patients should be instructed to retain all bottles of investigational product, even if empty, and to 
return them to the Investigator at the indicated visits (Table 1).  The Investigator or designee 
should perform investigational product accountability (ie, count of returned tablets) and, if 
applicable, follow-up with the patient to retrieve any investigational product bottles that have not 
been returned.  
If the Investigator has concerns about a patient’s dosing compliance, he or she should discuss 
this with the patient, assess the reasons for noncompliance and the likelihood that the patient will 
remain noncompliant, and notify the Sponsor accordingly.   
9.4. 
Randomization and Blinding 
9.4.1. 
Methods of Assigning Patients to Treatment Groups 
This study will be conducted in a double-blind, placebo-controlled manner.  Enrolled patients 
who meet all eligibility requirements will be randomized in a 1:1 ratio to 1 of 2 treatment groups:  
placebo or OCA based on a predefined randomization code (generated by Sponsor or designee) 
using an interactive web response system (IWRS), which the Sponsor intends will serve as a 
computer-based patient registration system at Screening and Day 1.   
Randomization will be stratified by CP class (CP-B or CP-C).  Baseline MELD scores will be 
monitored on an ongoing basis to ensure adequate distribution of MELD scores.  The IWRS will 
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serve as the investigational product inventory and management system and may be integrated 
with the study database.  
The Investigator or designee will be required to register the patient in the IWRS and may be 
prompted to provide patient data necessary to properly randomize and allocate the patient to 
treatment.  A randomization number will be assigned and investigational product (OCA or 
placebo) dispensing information will be provided (eg, bottle numbers allocated) while 
maintaining the study blind.   
9.4.2. 
Blinding 
The Sponsor, patients, Investigator, and study site staff will be blinded to the patient’s treatment 
allocation during the patient’s participation in the double-blind phase of the study. 
9.4.3. 
Emergency Unblinding Procedures 
Treatment assignment for individual patients will be made available to the Investigator for 
medical emergency use only (such as unblinding which is necessary in order to treat a serious 
adverse event [SAE] through the IWRS system).  When possible, the Medical Monitor should be 
consulted in the event that a medical emergency necessitates unblinding (ie, in situations where 
knowledge of the blinded treatment assignment is necessary for further medical management of 
the patient).  If it is not reasonable to inform the Medical Monitor in advance of the unblinding, 
the Investigator must promptly document in the patient’s record the rationale for unblinding and 
should subsequently contact the Medical Monitor to explain any premature unblinding of 
treatment assignment.  Procedures for unblinding a patient’s treatment will be provided 
separately to the Investigator.  Similarly, if the Medical Monitor breaks the blind for an 
individual patient for the purpose of evaluating an emergent safety issue, the Medical Monitor 
will document within study documentation the rationale, circumstances, and the person or 
persons being informed about the unblinding. 
The DMC will have access to the IWRS and will be able to unblind individual patients.  Refer to 
Section 15.8 for further details regarding DMC access to blinded and unblinded data.  The DMC 
will document details about any unblinded patient data reviews in the closed session DMC 
minutes, which will be made available to the Sponsor only after the database is locked and the 
study is unblinded.  Cases of premature unblinding, as noted above, will also be reviewed by the 
DMC.  
Access to treatment assignments will also be made available to the designated Intercept staff 
responsible for expedited safety reporting of suspected unexpected serious adverse reactions 
(SUSARs) to the Regulatory Authorities. 
9.5. 
Assignment of Site and Patient Numbers 
9.5.1. 
Site Numbers 
Each study site selected to participate in this study will be assigned a site number by the Sponsor.  
The site number will be used to categorize patient data and to identify the site and/or Investigator 
within study documents.  This number will be recorded in the eCRF. 
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9.5.2. 
Patient Numbers 
Patients are assigned using a unique 10-character identifier (AAA-BBBCCC), independent of the 
randomization number. The first 3 digits represent the last 3 digits of the protocol number, 
followed by a hyphen (AAA-). The next 3 digits represent the site number (BBB). The last 
3 digits represent a unique screening number that is assigned in sequential order at each site 
starting with 001 (CCC). 
9.6. 
Restrictions 
Participation in another investigational product, biologic, or medical device study within 30 days 
prior to Screening and during the course of the study is prohibited.  Previous exposure to OCA 
(as a study participant or received commercial OCA therapy) is allowed provided patients 
haven’t taken OCA within 3 months prior to enrollment in this study. 
9.6.1. 
Fasting Requirement at Study Visits 
All patients must have been fasting for at least 8 hours prior to their Screening Visit and all 
subsequent study visits, as all analytes will be assayed in fasting blood or plasma samples.  
Water is permitted during the fasting period. 
9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visit windows are specified in the Schedule of Study Procedures (Table 1).  Visits should be 
based on Day 1 (not on the prior visit) unless stated otherwise.  For example, Week 6 should 
ideally occur 6 calendar weeks (± 7 days) following Day 1.   
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk, and benefit of the 
study to the patient and will provide him/her with a copy of the informed consent form (ICF).  
The patient will be given sufficient time to consider the study before deciding whether or not to 
participate.  The patient will be informed that participation is voluntary and that her/his future 
medical treatment will not be compromised by participation in the study and that he or she can 
withdraw from the study at any time.  The patient must be willing and able to provide written 
informed consent (on hard copies) before entering the study.  The Investigator or a medically 
qualified designee is responsible for administering and documenting the written informed 
consent of the patient.  The patient will be given a copy of the patient information sheet (PIS) 
and his/her signed and dated informed consent form (ICF).   
9.7.3. 
Assessing Cirrhosis 
Acceptable methods of confirming (via medical history) or assessing cirrhosis for purposes of 
the study are defined as a patient who has documented evidence or presence of one or more of 
the following cirrhosis indicators: 
 Biopsy results consistent with PBC Stage 4 (Ludwig 1978)   
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 Liver Stiffness as assessed by TE Value ≥16.9 kPa (Corpechot 2012) 
 The presence of any of the following (unless exclusionary per Section 8.3) in the 
absence of acute liver failure: 
 Gastroesophageal varices 
 Ascites 
 Radiological evidence of cirrhosis (nodular liver or enlargement of portal vein 
and splenomegaly) 
 Combined low platelet count (<140 000/mm3) with: 
 Persistent decrease in serum albumin, or  
 Elevation in prothrombin time /INR (not due to antithrombotic agent use), or 
 Elevated bilirubin (2× ULN) 
9.7.4. 
Screening Procedures (14 days to 28 days prior to Day 1) 
Informed consent must be obtained from the patient before performing any study-related 
procedures, including Screening procedures.  The Screening Visit assessments must be 
performed ≥14 days but less than 28 days prior to Day 1 to determine whether the patient meets 
all the inclusion criteria and none of the exclusion criteria.  Patients who do not fulfill all 
eligibility criteria will not be enrolled in the study.  Patients may be rescreened after 2 months 
have elapsed from the date of their most recent screening visit procedure; however, all Screening 
procedures (including obtaining informed consent) should be repeated and a new three-digit 
Screening number assigned.   
Screening Visit procedures are as follows: 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits. 
 Collect medical history. 
 Collect PBC history.  
 Verify inclusion and exclusion criteria for eligibility. 
 Perform a physical examination, including height, smoking and alcohol consumption 
history, and current habits for both.  
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record any pretreatment-emergent AEs. 
 Record prior (if within 30 days of Screening) and current concomitant medications. 
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 Perform a standard 12-lead electrocardiogram (ECG). 
 Perform assessments for calculation of CP Score (Section 14.1.1) 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Virology Screen (HCV and HBsAg) 
 Obtain urine sample for urinalysis  
 Perform a urine-based beta human chorionic gonadotropin (β-hCG) pregnancy test in 
females of childbearing potential.  
 Instruct the patient to fast overnight (at least 8 hours) before the next visit (water is 
permitted). 
 Record the visit in IWRS.  
 Perform an ultrasound for HCC surveillance and evaluation of gallbladder status 
(if equipment is unavailable, sites should make every attempt to use available 
community referral sites).  If an ultrasound has been done within 12 months of 
Screening, and a report/adequate data are available, a pretreatment ultrasound at 
Screening is not required.  If the ultrasound cannot be performed at Screening 
(eg, device/technician unavailability, scheduling issues, etc), the procedure may be 
completed anytime within the screening visit window or on Day 1.  Results from the 
screening ultrasound should be reviewed to assess possible exclusion criteria prior to 
randomization. 
9.7.5. 
Day 1 Procedures (Randomization) 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits. 
 Review inclusion and exclusion criteria for eligibility. 
 Perform a physical examination.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant heath care professional (HCP) or non-HCP related office 
visits that have occurred since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record any pretreatment-emergent AEs. 
 Review and record prior concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
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 Administer Quality of Life and Patient questionnaires (Section 13.2.7). 
 Randomize the patient only if s/he meets all inclusion criteria and no exclusion 
criteria. 
 Record the visit in IWRS and dispense investigational product 
 Instruct the patient to begin dosing on the day of the Day 1 Visit.   
 Obtain urine sample for urinalysis  
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Markers of fibrosis (ELF [HA, P3NP, and TIMP 1]) 
 Fasting PK assessment 
 Bile Acid/C4/FGF-19  
 Perform TE using the Fibroscan® TE device.  If the TE cannot be performed on Day 1 
(eg, device/technician unavailability, scheduling issues, TE data is needed to inform 
cirrhosis assessment, etc.), the procedure may be completed within the Day 1 Visit 
window, (if data is needed for cirrhosis assessment) or as close as possible to the Day 
1 Visit, preferably, after patient eligibility has been confirmed.  Instruct the patient to 
take Day 1 dose on the day of this visit. 
 If ultrasound for gallbladder assessment was not performed at Screening and the 
historic ultrasound is >12 months from Day 1, perform ultrasound. 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to the visit 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.6. 
Week 3 and Week 42 Safety Visit Procedures 
Preferably, the patient will come in to the clinic for this visit.  Alternatively, the site will 
telephone the patient for assessments and a home health nurse will visit to draw safety labs. 
 Verify that patient is dosing as directed. 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits. 
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 Review and record prior concomitant medications. 
 Assess and record AEs. 
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess investigational product compliance, perform investigational product 
accountability. 
 For Week 42 Only:  Assess for dose titration, if eligible. (Refer to Section 7.3) 
 For Week 42 Only:  Dispense investigational product only if there is dose increase 
or as needed.  No new investigational product bottles will be dispensed if there is only 
change in dosing frequency of the same dose level.  Patients are expected to use up 
each investigational product bottle before a new bottle will be dispensed 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Schedule the next visit (Week 6 or Week 48), reiterate dosing instructions, and advise 
the patient: 
For Week 3 Only:   
 Week 6 Visit should occur 3, 4, or 5 days after taking the Week 6 dose, eg, if 
the Week 6 dose is taken on a Sunday, the patient should come in for the Week 6 
Visit within the following Wednesday and Friday (Figure 3). 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to the visit 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
For Week 42 Only: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.7. 
Week 6 Procedures 
Week 6 Visit should occur 3, 4, or 5 days after taking the Week 6 dose, eg, if the Week 6 dose is 
taken on a Sunday, the patient should come in for the Week 6 Visit within the following 
Wednesday and Friday (Figure 3). 
 Verify that the patient has fasted for at least 8 hours. 
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 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform a physical examination.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.7). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Bile Acids/C4/FGF-19 
 Fasting PK assessment 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s); s/he will dose at the clinic (if this is 
in compliance with the established dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.8. 
Week 9 through Week 48 (Safety Contact) 
Patients should be contacted by telephone/email at Week 9 and every 3 weeks afterward to 
Week 48. 
 Contact patient by phone/email. 
 Review and record prior concomitant medications. 
 Assess and record AEs. 
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 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess investigational product compliance, perform investigational product 
accountability. 
9.7.9. 
Week 12, Week 24, Week 36 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Perform a physical examination.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.7). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible. (Refer to Section 7.3) 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed.   
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation 
 Markers of fibrosis (ELF [HA, P3NP, and TIMP 1])  
 Bile Acid/C4/FGF-19  
 Fasting PK assessment (Week 36 only) 
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 Perform TE using the Fibroscan® TE device.  If the TE cannot be performed on visit 
day (eg, device/technician unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be completed within the visit 
window (if data is needed for cirrhosis assessment) or as close as possible to the visit. 
 Perform an ultrasound for HCC surveillance at Week 24 ONLY (if equipment is 
unavailable, sites should make every attempt to use available community referral 
sites). 
 Serial PK assessment at Week 12 and 24 ONLY (not done at Week 36); the 
following procedures will be conducted in all patients: 
 30 minutes prior to dosing:  collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hour postdose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at:  1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post dose 
Note:  Patients should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until after the 1-hour sample is 
collected.  A meal replacement drink will be provided following collection of the 1-, 4-, 
and 7-hour PK sample.  No other food or drink (water is permitted) will be allowed until 
after the 9-hour sample collection (see Figure 4).  The 24-hour post-dose sample can be 
obtained upon return to the clinic or by a home health care designee. 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to visits; s/he will dose at the clinic 
for Week 18 and Week 30 visits (if this is in compliance with the established 
dosing frequency), and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.10. 
Week 18 and Week 30 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF. 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Perform a physical examination.  
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 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.7). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3). 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed.   
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Bile Acid/C4/FGF-19  
 Serial PK assessment; the following procedures will be conducted in all patients: 
 30 minutes prior to dosing: collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the patient to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hour postdose blood draw, administer meal replacement 
drink (to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours postdose 
Note:  Patients should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until after the 1-hour sample is 
collected.  A meal replacement drink will be provided following collection of the 1-, 4-, 
and 7-hour PK sample.  No other food or drink (water is permitted) will be allowed until 
after the 9-hour sample collection (see Figure 4).  The 24-hour post-dose sample can be 
obtained upon return to the clinic or by a home health care designee. 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
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 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to both visits; s/he will dose at the 
clinic on Week 24 (if this is in compliance with the established dosing frequency), 
and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.11. 
Week 48 Procedures 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
 Perform a physical examination, including smoking and alcohol consumption history, 
and current habits for both.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform ECG. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.7). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3). 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed. 
 Perform urinalysis  
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
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 Markers of fibrosis (ELF [HA, P3NP, and TIMP 1]) 
 Bile Acids/C4/FGF-19 
 Serial PK assessment; the following procedures will be conducted in all patients: 
 30 minutes prior to dosing: collect predose blood sample 
 Dispense/Administer investigational product from the double-blind bottle 
(collected from the patient upon arrival for this visit) with 240 mL (8 oz.) of 
water.   
 Collect blood samples at: 30 min, 45 min, 1 hour postdose 
 Immediately following 1 hour post dose blood draw, administer meal replacement 
(to be consumed within 5 – 10 minutes)  
 Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post dose 
Note:  Patients should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until after the 1-hour sample is 
collected.  A meal replacement drink will be provided following collection of the 1-, 4-, 
and 7-hour PK sample.  No other food or drink (water is permitted) will be allowed until 
after the 9-hour sample collection (see Figure 4).  The 24-hour post-dose sample can be 
obtained upon return to the clinic or by a home health care designee. 
 Perform TE using the Fibroscan® TE device.  If the TE cannot be performed on visit 
day (eg, device/technician unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be completed within the visit 
window (if data are needed for cirrhosis assessment) or as close as possible to the 
visit. 
 Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to the visit, and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.12. 
Every 3 Months after Week 48  
Quarterly 
 Verify that the patient has fasted for at least 8 hours. 
 Record fasting status in the source and eCRF 
 If the patient reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the patient that fasting is required prior to all study 
visits, but water is permitted. 
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 Perform a physical examination, including height, smoking and alcohol consumption 
history, and current habits for both.  
 Review and record any non-study related medical or surgical treatment procedures 
and any medically relevant HCP or non-HCP related office visits that have occurred 
since the previous study visit. 
 Assess and record vital signs and weight (oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform assessments for calculation of CP Score (Section 14.1.1). 
 Administer Quality of Life and Patient questionnaires (see Section 13.2.7). 
 Assess investigational product compliance, perform investigational product 
accountability. 
 Assess for dose titration, if eligible (refer to Section 7.3 ). 
 Dispense investigational product only if there is dose increase or as needed.  No new 
investigational product bottles will be dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed. 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 Schedule the next visit, reiterate dosing instructions, and advise the patient: 
 NOT to take investigational product on the morning of the next visit, and  
 To bring the investigational product bottle(s) to the visit, and 
 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
Patients will complete a TE/ELF (HA, P3NP and TIMP 1) and ultrasound (for HCC 
surveillance) assessment, every 6 months (±2 weeks) after Week 48.  
ECG and urinalysis will be done yearly (±2 weeks) after Week 48.    
9.7.13. 
End of Study/Early Termination/End of Treatment Procedures for Patients That 
Withdraw from Investigational Product or Withdraw Consent 
Patients who discontinue investigational product before Week 48 are expected to continue in the 
study until the end of the study (EOS [when patient terminates the study]) or at the discretion of 
the Sponsor.     
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EOT (when patient discontinues investigational product)/ET procedures will be required 
whenever patients discontinue treatment with investigational product (Table 1, Section 9.7.11).  
The EOT/ET Visit (Table 1) and procedures listed below (Table 6) must be performed as close 
as possible to the patient’s last dose of investigational product.  When a patient discontinues or 
interrupts investigational product and continues with regularly scheduled study visits, the EOS 
Visit will be completed as the patient’s final study visit.  The actual investigational product 
discontinuation scenario (Table 6) will determine the sequence of the EOT/ET and EOS Visits 
and procedures.  In some cases, the EOT/ET Visit and procedures will precede the EOS Visit; in 
others, the EOT/ET and EOS Visits will be combined and performed as close as possible to the 
patient’s last dose of investigational product.  EOT and EOS Visits are encouraged but at no time 
will a missed EOT or EOS visit be considered a protocol deviation. 
When a patient ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (ET) (withdrawal of consent) or discontinuation, an 
EOT/EOS Visit must be performed as near as possible to her/his last dose of investigational 
product and the procedures listed in Table 1 performed.  The purpose of this visit is to conduct 
complete and/or final assessments on or as near as possible to the final day of dosing.  In some 
cases, the patient may discontinue on the day of a scheduled study visit.  In these cases, 
EOT/EOS Visit procedures should be performed in place of the scheduled study visit procedures.  
The data will be recorded as EOT/ET and EOS procedures in the eCRF. 
Table 6: 
Early Discontinuation Scenarios 
 
Investigational 
Product 
Consent 
Study Visit 
Status 
EOT Visita 
EOS 
Visita 
Early 
Termination 
Discontinued 
Withdrawn 
No additional 
visits except 
EOT/EOS 
Combined visit, completed as 
close as possible to last dose of 
investigational product. 
Treatment 
Discontinuationb 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as close as 
possible to last dose 
of investigational 
product. 
Complete 
at final 
study 
visit. 
Discontinued 
Record review 
only 
Record review 
only 
Combined visit, completed as 
close as possible to last dose of 
investigational product. 
Sponsor 
Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit, completed as 
close as possible to last dose of 
investigational product. 
Pregnancy 
Discontinued 
Complete per the above scenarios - Early Termination or Treatment 
Discontinuation 
Lost to 
Follow-Up 
Discontinued 
LTF 
None 
Unable to complete due to LTF 
status 
EOS = end of study; EOT = end of treatment; LTF = lost to follow-up 
a Refer to Section 7.1.2, Schedule of Study Procedures for all procedures and evaluations required at the EOS and 
EOT Visits.  
b Includes initiation of commercially available OCA. 
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9.7.14. 
Unscheduled Safety Visit 
The Investigator may schedule an at-clinic Unscheduled/Safety Visit at any time if clinically 
warranted.  Unscheduled and/or repeat assessments, including additional laboratory tests or 
investigations, may be conducted.   
As appropriate, the Medical Monitor should be contacted. 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
The investigational product is a white, round, film coated tablet containing OCA 5 mg or 10 mg 
or matching placebo.  The tablets contain the following inactive ingredients:  microcrystalline 
cellulose, sodium starch glycolate, and magnesium stearate. 
10.2. 
Investigational Product Packaging and Labeling 
The packaging and labeling of investigational product supplies will be performed according to 
Good Manufacturing Practice standards by a designated qualified vendor.  All investigational 
product will be provided as tablets for oral administration and provided in high density 
polyethylene bottles with heat induction seals and child resistant closures.  The bottle packaging 
will not reveal any information about the treatment dose contained in the bottle.  Multiple bottles 
may be dispensed to the patient at each visit to provide enough tablets for dosing until the next 
visit. 
The designated investigational product packaging/distribution vendor will also be responsible for 
the distribution of the investigational product to the Investigator. 
10.3. 
Investigational Product Storage 
All OCA tablet strengths provided to clinical study sites in support of clinical studies are to be 
shipped and stored at 15°C to 25°C.  Temperature excursions within the range of 2°C and 30°C 
for no more than a 6-month period are acceptable, and the OCA tablet continues to be suitable 
for use in clinical studies.  Additionally, temperature excursions within the range -20°C to 40°C 
for no more than 7 days are acceptable, and the OCA tablet continues to be suitable for use in 
clinical studies.  
10.4. 
Investigational Product Administration 
Refer to Section 9.1. 
10.5. 
Investigational Product Accountability and Disposal 
The Sponsor’s representative will send investigational product to the study site under appropriate 
storage conditions.  All shipments of investigational product should be unpacked and the 
contents reviewed immediately upon receipt.  If it is not possible to verify the contents 
immediately, they must be stored under the appropriate storage conditions until verification of 
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the contents is possible (ideally, within 1 business day from receipt).  The pharmacist or designee 
should verify the investigational product against the shipment documentation.  The pharmacist or 
designee should contact the Sponsor immediately to report any concerns regarding the shipment.  
All investigational product will be provided for use only in this study and is not to be used for 
any other purpose.  The Investigator or designee will maintain a full record of investigational 
product accountability, including records of individual patient dispensing and final return or 
disposition (as directed by the Sponsor).  
The study monitor, also known as the Clinical Research Associate (CRA), will review 
accountability records against investigational product dispensed and that remaining in stock, 
during on site monitoring visits and when the study is completed, or if it is prematurely 
terminated.  The CRA will retrieve documentation detailing and confirming the return or 
destruction of the investigational product.  If the investigational product is to be returned to the 
Sponsor’s vendor for destruction, the CRA will also prepare the investigational product for 
shipment. 
11. 
OVERVIEW OF ASSESSMENTS 
The assessments supporting the objectives for the study are in Table 7: 
Table 7: 
Table of Assessments 
Primary Objectives 
Assessments 
PK parameters 
OCA and its conjugates glyco-OCA and tauro-OCA, and 
metabolite OCA glucuronide 
Safety and tolerability  
SAEs and TEAEs, physical exam, ECG, vital signs, 
clinical laboratory assessments, discontinuations, pruritus, 
and fatigue 
Secondary Objectives 
Assessments 
Changes in risk scores 
Changes in MELD and in CP Scores and components of 
the CP score and MELD score 
Changes in liver biochemistry and hepatobiliary 
damage  
Total and direct bilirubin, ALP, ALT, AST, GGT, INR, 
creatinine, albumin, platelets 
PD parameters 
FGF-19, C4, and plasma bile acids 
Additional Objectives 
Assessments 
Noninvasive measurements of liver fibrosis, liver 
stiffness and cirrhosis 
TE/ELF (HA, P3NP, and TIMP-1) 
PK/PD relationship 
PK parameters compared to PD parameters and safety and 
tolerability assessments (above) 
Patient-reported outcomes 
Pruritus VAS, PBC-40, EQ-5D-5L, CLDQ 
Clinical events 
Death (all-cause and liver-related), liver transplant, MELD 
score ≥15 (for patients with MELD ≤12 at baseline), 
hospitalization for new onset or recurrence of: variceal 
bleed, hepatic encephalopathy, spontaneous bacterial 
peritonitis, uncontrolled ascites, and HCC. 
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ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
C4 = 7α-hydroxy-4-cholesten-3-one; CLDQ = Chronic Liver Disease Questionnaire; CP = Child-Pugh; ECG = 
electrocardiogram; ELF = enhanced liver fibrosis;  
FGF-19 = fibroblast growth factor-19; GGT = gamma-glutamyl transferase; HA = hyaluronic acid;  
INR = international normalized ratio; MELD = Model End Stage Liver Disease; OCA = obeticholic acid; P3NP = 
procollagen 3 N-terminal peptide; PBC = Primary Biliary Cholangitis;  
PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event; TE = Transient Elastography;  
TEAE = treatment emergent adverse events; TIMP-1 = tissue inhibitor of metalloproteinase 1; VAS = visual 
analog scale 
12. 
CLINICAL PHARMACOKINETIC ASSESSMENTS 
Pharmacokinetic analyses will be based on the PK population (Section 15.1).  Patients in the PK 
Population with at least one PD assessment after dosing will be included in the combined PK/PD 
analyses.   
12.1. 
Pharmacokinetic Blood Sampling 
Serial and fasting PK assessments will be performed in all patients participating in the study.   
At Day 1, and Weeks 6, 12, 18, 24, 30, 36, and 48, patients will provide fasted blood samples for 
measurement of OCA and its conjugates, glyco-OCA and tauro-OCA, and metabolite OCA 
glucuronide 30 minutes before administration of investigational product (Table 8).  Patients will 
then receive a dose of investigational product with approximately 240 mL of water.   
Week 6 Visit should occur 3, 4, or 5 days after the Week 6 dose (eg, if the Week 6 dose of 
investigational product is taken on a Sunday, the patient should come in for the Week 6 Visit 
between Wednesday and Friday [Figure 3]).   
During the treatment period: 
 Pharmacokinetic fasting samples will be obtained from all patients at Day 1, and 
Weeks 6, 12, 18, 24, 30, 36, and 48 prior to dose administration in accordance with 
Figure 4. 
 Serial PK assessments will be performed in all patients at Weeks 12, 18, 24, 30, and 48.   
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Figure 3: 
Week 6 Sampling Schedule 
 
IP = investigational product; PK = pharmacokinetic 
At Weeks 12, 18, 24, 30, and 48, serial PK blood samples will be obtained at 0.5, 0.75, 1, 1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours postdose (Figure 4) for all patients.  The patient will be given 
the option to return to the clinic the following morning for the 24-hour postdose sample or 
samples can be obtained by a home health care designee.  The home health care agency must be 
advised one week in advance of the appointment.   
Figure 4: 
Pharmacokinetic Sampling Schedule 
 
h = hour; IP = investigational product; PK = pharmacokinetic  
Patients should not drink additional water for 1 hour after taking the dose of investigational 
product and will remain fasted until after the 1-hour sample is collected.  A meal replacement 
drink will be provided following collection of the 1-, 4-, and 7-hour PK sample.  The nutritional 
information of the meal replacement drink should be submitted to and approved by the Sponsor 
in advance.  No other food or drink (water is permitted) will be allowed until after the 9-hour 
sample collection. 
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Table 8: 
Acceptable Windows for Pharmacokinetic Sample Collection 
Nominal Sampling Time 
Acceptable Sampling Window 
Before administration of investigational product 
(predose or fasting) 
Within 30 minutes before dosing 
0.5 to 1.5 hours after investigational product 
± 10 minutes 
2 to 2.5 hours after investigational product 
± 20 minutes 
3 to 24 hours after investigational product 
± 30 minutes 
12.2. 
Processing and Handling of Pharmacokinetic Samples 
Whole blood will be collected at each scheduled sample timepoint.  Detailed procedures for the 
collection of blood samples including further processing into plasma will be provided in a 
separate laboratory manual.  The storage and shipment procedures for subsequent bioanalysis, 
will be provided to the investigational site and home health care company in a separate document 
before the study is initiated. 
12.3. 
Bioanalysis 
Plasma concentrations of OCA and its conjugates, glyco-OCA and tauro-OCA, and metabolite 
OCA glucuronide will be determined using a validated liquid-chromatography mass 
spectrometry/mass spectrometry (LC/MS/MS) method.  A detailed description of validation 
information and results from the bioanalytical assay will be provided in separate reports.  These 
samples may be used for evaluation of metabolites of OCA or other concomitant medication, for 
further evaluation of the bioanalytical method, and for analyses that provide information on the 
metabolic pathways used or impacted by OCA. 
13. 
ASSESSMENT OF SAFETY 
13.1. 
Adverse Events and Serious Adverse Events 
13.1.1. 
Definitions of Adverse Events 
13.1.1.1. Adverse Event  
AEs are defined as any untoward medical occurrence associated with the use of the 
investigational product in humans, whether or not considered related to investigational product.  
An AE, also referred to as an adverse experience, can be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom, or disease temporally associated with any use of 
the investigational product, without any judgment about causality and irrespective of route of 
administration, formulation, or dose, including an overdose.   
AEs include, but are not limited to: (1) a worsening or change in nature, severity, or frequency of 
condition(s) present at the start of the study; (2) patient deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction.  For reporting purposes, pregnancy is not 
considered an AE.  
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Patients should be questioned about AEs in a general way, without leading the patient or asking 
about the occurrence of any specific symptom.  The Investigator should attempt to establish a 
diagnosis of the event based on signs, symptoms, and/or other clinical information.  The 
diagnosis and not the individual signs/symptoms should be documented as the AE.  For example, 
if the underlying disease process is a stroke, it would not be appropriate to record the AE by 
describing the symptoms “sudden numbness, dizziness, and difficulty speaking.”  The AE 
medical term of “stroke or cerebrovascular accident” should be recorded as it more accurately 
describes the AE. 
Patients should be instructed to contact the site promptly upon awareness if they develop signs 
and symptoms of potential hepatic decompensation such as:  pale-colored stools, urine color 
from pale to deep amber [dark], nausea, vomiting, abdominal pain, diarrhea, weight loss, fever 
and chills, fatigue, weakness, loss of appetite, confusion, swelling of the legs or abdomen, 
yellowing of the skin or the whites of eyes, and bruising easily. 
13.1.1.2. Serious Adverse Event  
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
 Death 
 Is immediately life threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
 Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Events not considered to be SAEs are hospitalizations for: 
 Routine monitoring of the studied indication and not associated with any deterioration 
in condition or AE; 
 Elective treatment for a pre-existing condition that did not worsen; 
 Respite care or observation when there is no AE associated with the hospitalization. 
13.1.1.3. Treatment-Emergent Adverse Event 
A treatment-emergent AE (TEAE) is any event not present before the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
13.1.1.4. Adverse Events of Special Interest  
The following decompensation events are adverse events of special interest; a subset of these are 
also captured as additional efficacy assessments (see Section 14.2.3).   
 Variceal bleeding or recurrent variceal bleeding documented by endoscopy OR 
patient presenting with anemia or melena (hemoglobin drop ≥2 g/dL) and found to 
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have varices documented by endoscopy, irrespective of hospitalization or requirement 
of blood transfusion.  
 Gastrointestinal bleeding as a result of gastric or duodenal varices verified by 
endoscopy 
 Hepatic encephalopathy, Grade ≥2 
 New onset ascites requiring treatment 
 Worsening of ascites (requiring increase in drug therapy or requirement of surgical 
procedure such as paracentesis or shunt placement) 
 Refractory ascites -unresponsive to medications, and patient is not a candidate for 
TIPS or shunt and requires large volume paracentesis 
 Hyponatremia (Na ≤125 mEq/L) secondary to ascites 
 Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis- by cell 
count/chemistry) 
 Hepatorenal syndrome Type 1 and Type 2 and Acute Kidney Injury (AKI) 
 Liver failure defined as worsening of liver synthetic function that is persistently worse 
relative to baseline and/or progressive over time: 
 Hepato-pulmonary syndrome 
 Porto-pulmonary syndrome 
 Liver Transplant 
 Increase in MELD scores by 3 points relative to baseline, persistent over time and 
unrelated to vitamin K deficiency related increase in INR 
 Any liver related event that requires hospitalization and treatment 
13.1.2. 
Relationship to Investigational Product 
The Investigator will document her/his opinion of the relationship of the AE to treatment with 
the investigational product using the criteria outlined in Table 9.  An AE for which there is a 
“reasonable possibility” that the investigational product caused the AE is otherwise referred to as 
suspected adverse reaction (SAR).  “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the investigational product and the AE.   
If the relationship between the AE/SAE and the investigational product is determined to be 
“definite,” “probable,” or “possible” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 
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Table 9: 
Relationship of Adverse Events to Investigational Product 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product or in which the investigational product level has been established in 
body fluids or tissue; that follows a known or expected response pattern to the suspected 
investigational product; and that is confirmed by improvement on stopping or reducing the 
dosage of the investigational product, and reappearance of the reaction on repeated exposure. 
Probable 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product; that follows a known or expected response pattern to the suspected 
investigational product; that is confirmed by stopping or reducing the dosage of the 
investigational product; and that could not be reasonably explained by the known 
characteristics of the patient’s clinical state. 
Possible 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product; that follows a known or expected response pattern to the suspected 
investigational product; but that could readily be produced by a number of other factors. 
Unlikely 
An event that does not follow a reasonable temporal sequence from administration of the 
investigational product; that does not follow a known or suspected response pattern to the 
suspected investigational product; and that could reasonably be explained by known 
characteristics of the patient’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
13.1.3. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 10, must be entered on the AE eCRF.  It should be noted that the term 
“severe” used to grade intensity is not synonymous with the term “serious.”  The assessment of 
severity is made regardless of investigational product relationship or of the seriousness of the 
AE. 
Table 10: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Causing no limitation of usual activities; the patient may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the patient may experience annoying 
discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the patient may experience intolerable 
discomfort or pain. 
13.1.4. 
Reporting of Adverse Events and Serious Adverse Events 
13.1.4.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the patient 
fully completes her/his study participation. 
All AEs, whether believed by the Investigator to be related or unrelated to the investigational 
product, must be documented in the patient’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for 
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duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product.  Redacted medical record source documentation will be requested for all 
SAEs and emergency room visits. 
In addition, the Investigator should contact the study Medical Monitor upon awareness when any 
signs or symptoms of hepatic decompensation are observed in any patient. 
13.1.4.2. Reporting of Serious Adverse Events 
In agreeing to the provisions of this protocol, the Investigator accepts all legal responsibilities for 
immediate reporting of SAEs to the Sponsor.  Immediate reporting implies within 24 hours of 
becoming aware of the occurrence of an SAE. 
All SAEs must be reported to the Sponsor (including suspected liver-related clinical outcome 
events that qualify as serious).  SAEs are reported by entering the SAE data into the study 
specific EDC system.  Entering the SAE data into the EDC system will automatically notify the 
Sponsor of the event.  In the event that the EDC system is inaccessible, an SAE may reported by: 
 E-mail to the SAE email address:  
 
 Fax using a paper SAE report form:  
 
If an SAE is reported by fax, an SAE Report form must also be completed in the EDC system as 
soon as the EDC system is accessible.  At a minimum, the following information should be 
provided at the time of the initial report:   
 Patient number  
 Event term  
 At least 1 criterion classifying the event as serious  
 Name and title of the reporting individual  
 Causal relationship to the investigational product  
The Investigator will assess whether the event is causally related to the investigational product.  
The Sponsor will also assess whether the event is causally related to the investigational product, 
in addition to assessing the overall safety profile of the investigational product.  The Sponsor will 
notify the appropriate regulatory agencies as well as all participating Investigators of Safety 
Reports/Expedited Safety Reports that occur during the study within the time frames required by 
each regulatory agency.  
Following the initial report, any additional information obtained by the Investigator about the 
SAE must be reported promptly to the Sponsor in the same manner as described above for the 
initial SAE report.  Any supporting source documentation should be faxed to 
 or 
emailed to 
 as soon as possible.   
The Investigator is responsible for submitting information on Safety Reports/Expedited Safety 
Reports received from the Sponsor to her/his local IRB/IEC, as directed by the local country 
requirements.  Documentation of the submissions to IRBs/IEC s must be retained in the 
appropriate study file(s).  As instructed by the Sponsor, Safety Reports/Expedited Safety Reports 
should be retained in the appropriate investigative site study files or with the IB.  
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13.1.5. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the EDC represent the official record of all AEs and SAEs reported 
in the study.  The Investigator should comply with requests by the Medical Monitor or other 
Sponsor personnel to record the SAE on the patient’s AE eCRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the Sponsor, the Investigator should 
provide input into the SAE narrative and provide timely information to ensure prompt follow-up 
and closure of the SAE report. 
The Investigator and supporting personnel responsible for patient care should discuss with the 
Medical Monitor any need for supplemental investigations of SAEs.  The results of these 
additional assessments must be reported to the Medical Monitor. 
13.1.6. 
Notification of Post-Treatment SAEs for Patients Who Continue in the Study 
Post-treatment SAEs that occur in patients who remain in the study after investigational product 
has been discontinued must be reported to the Sponsor within 24 hours by following the 
instructions provided in Section 13.1.4.2 . 
SAEs that occur in patients who discontinue investigational product, initiate treatment with 
commercially available Ocaliva, and remain in the study must be reported to the Sponsor within 
24 hours by following the instructions provided in Section 13.1.4.2. 
13.1.7. 
Notification of Post-Study SAEs  
All SAEs that occur within 30 days following discontinuation from the study, whether or not 
they are related to the investigational product, must be reported to the Sponsor within 24 hours 
by following the instructions provided in Section 13.1.4.2. 
If an Investigator becomes aware of an SAE that may be attributable to the investigational 
product at any time after the end of the study, the Sponsor should be notified immediately 
(ie, within 24 hours) by following the instructions provided in Section 13.1.4.2. 
13.1.8. 
Follow-Up of AEs and SAEs 
All AEs must be followed during the course of the study until the AE resolves, is no longer of 
clinical concern, has stabilized or is otherwise explained, or the patient is lost to follow-up. 
AEs ongoing at the final visit that are deemed to be “possibly, probably, or definitely” related or 
of other clinical significance must be followed for as long as necessary to adequately evaluate 
the safety of the patient or until the event stabilizes, resolves, or is no longer of clinical concern.  
The Investigator must ensure that follow-up includes any supplemental investigations indicated 
to elucidate the nature and/or causality of the AE.  This may include additional laboratory tests 
or investigations, or consultation with other healthcare professionals, as considered clinically 
appropriate by the Investigator. 
Drug-Induced Liver Injury or Disease Progression 
All patients showing possible drug-induced liver injury or disease progression should be 
followed until all abnormalities return to normal or to the baseline state.  Drug-induced liver 
injury may develop or progress even after the causative drug has been stopped.  Results should 
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be recorded in the eCRF.  Note that longer follow-up can sometimes reveal an off-drug repetition 
of what had appeared to be drug-induced liver injury, indicating that liver injury was related to 
underlying liver disease. 
Cholecystitis or Pancreatitis 
Patients should be instructed to contact the investigational site if they experience any of the 
following signs and symptoms:  nausea, vomiting, abdominal pain, diarrhea, weight loss, fever 
and chills, worsening or new fatigue, or weakness.  Patients should also be counseled to seek 
immediate medical assistance if they experience persistent severe abdominal pain.   
In the event that cholecystitis and/or pancreatitis is suspected, Investigators should promptly 
bring patients into the clinic to undergo a complete evaluation, including a physical examination, 
and laboratory assessments [ie, amylase and lipase]).  Investigators should refer to standard of 
care guidelines on suspected pancreatitis (Banks 2012, Greenburg 2015).  Diagnosis of acute 
pancreatitis includes 2 of the following:   
 Abdominal pain (acute onset of a persistent, severe, epigastric pain often radiating to 
the back)  
 Serum lipase activity (or amylase) at least 3 times greater than the upper limit of 
normal 
 Characteristic findings of acute pancreatitis on computed tomography or magnetic 
resonance imaging 
To ensure appropriate vigilance, amylase and lipase levels should be monitored monthly for 
3 months after onset of symptoms, irrespective of whether a diagnosis of cholecystitis and or 
pancreatitis is confirmed.  The Investigator should contact the Medical Monitor upon awareness 
of the above (ie, suspected or confirmed diagnosis).  Results should be recorded promptly in the 
eCRF. 
13.1.9. 
Pregnancy and Follow-Up  
Pregnancies are not considered AEs in and of themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical study, she must discontinue treatment with 
investigational product immediately and the Sponsor must be notified within 24 hours of the 
Investigator’s awareness of the pregnancy by completing the Pregnancy CRF in the EDC system 
and downloading and completing the Pregnancy Report Form.  The Pregnancy Report Form 
must be emailed to 
 or faxed to 
  The patient and 
neonate must be followed for outcome information and/or as considered appropriate by the 
Investigator and Sponsor. 
 
Completing the Pregnancy Report Form is not a substitute for reporting an AE/SAE when and 
AE/SAE has occurred.  In the situation when an AE/SAE has occurred, the AE/SAE reporting 
procedures described in Section 13.1.4 must also be followed. 
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13.2. 
Other Safety Parameters 
13.2.1. 
Medical History/Demographics 
A complete medical history will be obtained from the patient at screening.  Demographic 
characteristics (age, gender, race, and ethnicity) will be recorded. 
13.2.2. 
Medical and Surgical Procedures  
Medical and surgical procedures will be recorded at the visits indicated in Table 1. 
13.2.3. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the visits specified in the Schedule of Study Procedures (Table 1).  A basic physical 
examination should be performed, including all body systems pertinent to the patient.  Smoking 
and alcohol consumption history and current habits will be recorded.  Any clinically significant 
abnormality should be reported on the AE eCRF page for findings that appear after consent, and 
on the medical history eCRF for any finding present prior to consent.   
13.2.4. 
Vital Signs and Weight 
Vital signs (oral temperature, sitting heart rate, respiratory rate and sitting blood pressure [BP]) 
and weight will be assessed at indicated visits (Table 1).  When taking heart rate, respiratory rate 
and BP readings, patients should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
13.2.5. 
Electrocardiogram  
Standard ECGs will be collected at indicated visits (Table 1).  The Investigator or designee will 
review the ECG and findings will be recorded in the eCRF as normal, abnormal but not clinically 
significant, or abnormal and clinically significant.  Any clinically significant abnormalities on 
ECGs recorded after Day 1 will also be documented as AEs and entered on the AE page of the 
eCRF.  
Investigative sites must retain a copy of all ECGs evaluated by the Investigator or designee.  
These ECGs must be clearly labeled with the Patient ID number, date, and time.   
13.2.6. 
Laboratory Assessments 
Patients will be instructed to attend each study visit in a fasted state, preferably in the morning, 
and patients should remain fasted until their blood samples have been collected.  At all visits, the 
Investigator or designee will verify that the patient has fasted for at least 8 hours and record 
fasting status in the source and eCRF.  If the patient reports having eaten (water is permitted) 
within 8 hours, the Investigator or designee will document accordingly in the source and eCRF 
and remind the patient that fasting is required before all study visits. 
Blood samples for serum chemistry, coagulation, and hematology; and urine samples will be 
collected at visits as detailed in the Schedule of Study Procedures (see Table 1).  The number and 
volume of samples to be collected at each visit will be detailed in the laboratory manual. 
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Full instructions concerning the number and type of samples to be collected at each visit, the 
required sample volumes, sample collection methods, sample processing, labeling, and shipping 
will be provided in a separate procedural manual.  All necessary collection supplies will be 
provided by the central laboratory and will be appropriately assembled for the specific 
evaluations required at each visit. 
All patients with laboratory tests containing clinically significant abnormal values are to be followed 
regularly until the values return to normal ranges; until a valid reason, other than investigational 
product related AE, is identified; or until further follow-up is deemed medically unnecessary.   
Laboratory samples will be stored for a maximum of up to 1 year after the end of the study 
(depending on stability) in the event that retesting is required, and destroyed after 1 year if not 
analyzed. 
The list of laboratory analytes to be tested is shown in Table 11. 
Table 11: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen, creatinine, aspartate 
aminotransferase [AST, SGOT], alanine aminotransferase 
[ALT, SGPT], ALP, GGT, electrolytes [calcium, chloride, 
potassium, sodium], glucose, total protein, and blood lipids 
(total cholesterol, LDL, HDL and VLDL fractions and 
TG), CPK, magnesium, phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, conjugated (direct) 
bilirubin, total bilirubin, free fatty acids, TFT (TSH, free 
T3 and free T4) 
Hematology 
Hemoglobin, hematocrit, white blood count with 
differential, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, platelets, red blood cell count 
(including MCV, MCH, MCHC) 
Coagulation 
PT, PTT, INR 
Urinalysis; 
Pregnancy 
pH, specific gravity, total protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, 
leucocytes, nitrates; albumin, creatinine, 
albumin/creatinine ratio (if positive); β-hCG 
Markers of Cholecystitis and Pancreatitis 
Amylase and lipase 
Noninvasive measurements of liver fibrosis 
ELF (HA, P3NP, and TIMP-1) 
PK assessments 
OCA (parent and conjugates [glyco and tauro], metabolite 
OCA-glucuronide)  
PD markers 
C4, FGF-19 and plasma bile acids 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hCG = human chorionic 
gonadotropin; C4 = 7α-hydroxy-4-cholesten-3-one; CPK = creatine phosphokinase; ELF = enhanced liver fibrosis; FGF-19 = 
fibroblast growth factor-19; GGT = gamma-glutamyl transferase; HA = hyaluronic acid; HDL = high density lipoprotein; INR 
= international normalized ratio; LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; OCA = obeticholic acid; P3NP = procollagen 
3 N-terminal peptide; PT = Prothrombin time; PTT = partial thromboplastin time; SGOT = Serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase; T3 = triiodothyronine; T4 = thyroxine; TG = triglyceride; TFT = 
thyroid function test; TIMP-1 = tissue inhibitor of metalloproteinase 1; TSH = thyroid stimulating hormone; VLDL = very 
low-density lipoprotein 
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Laboratory reference ranges for the study will be based on the laboratory vendor range. 
Urine based β-hCG pregnancy tests will be performed in female patients of childbearing 
potential per protocol specified visits (see Table 1).  If a urine pregnancy test is positive, a serum 
pregnancy test must be performed to confirm the result.  If positive, the Sponsor must be notified 
and the patient will be followed as outlined in Section 13.1.9 until pregnancy outcome.  
INR will be calculated based on prothrombin time value by the central laboratory.  MELD scores 
will be calculated based on creatinine, bilirubin, and INR values, with modification by United 
Network for Organ Sharing.  Total OCA will be calculated based on the sum of OCA, 
glycol-OCA, and tauro-OCA concentrations.  Laboratory analyte results may be used to calculate 
various cardiovascular risk and fibrosis measurement scores. 
13.2.7. 
Patient-Reported Outcomes and Healthcare Resource Use 
Data will be collected to determine the effects of OCA on health-related quality of life.  
Healthcare resource use as well as a general health status assessment (for the purposes of 
generating health utilities) will be used to support subsequent cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Assessments of patient-reported 
outcomes will take place during the visits indicated in Table 1.   
The following patient-reported outcomes will be used to evaluate the effects of OCA compared 
to placebo on improvements in health-related quality of life: 
 PBC-40:  The PBC-40 is a validated disease-specific 40-question quality of life 
questionnaire, which consists of 6 domains:  General Symptoms, Itch, Fatigue, 
Cognitive Function, Social, and Emotional (Jacoby 2005). 
 EQ-5D-5L:  The EQ-5D-5L consists of 2 sections – the descriptive system and the 
visual analogue scales (VASs).  The descriptive system is organized into 
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  Each dimension has 5 levels:  no problems, slight problems, 
moderate problems, severe problems, and extreme problems.  The VAS records the 
patient’s self-rated health on a 20-cm vertical, line with endpoints labelled “the best 
health you can imagine” and “the worst health you can imagine” (Herdman 2011, 
Oemar 2013). 
 Pruritus VAS:  A VAS will also be used to assess pruritus in individual patients. 
 Chronic Liver Disease Questionnaire:  The CLDQ is a disease-specific health related 
quality of life questionnaire for patients with chronic liver disease.  The questionnaire 
includes 29 items in the following domains: fatigue, activity, emotional function, 
abdominal symptoms, systemic symptoms, and worry).  Each question is answered on 
a scale from 1 (always) to 7 (never) with a higher score corresponding to a better 
quality of life.  The CLDQ produces a summary score and domain scores that 
correlate with the severity of liver disease (Younossi 1999). 
Patients will be asked to complete the questionnaires and initial and date each document.  The 
questionnaires should be filed in the patient’s study records.  These may require transcription to 
the eCRF by study site staff. 
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Healthcare resource use will be collected from eCRFs including number, reason for and duration 
of hospitalizations and emergency room visits, number of outpatient physician visits (patient 
reported), and use of concomitant medications.  The purpose is to evaluate the effects of OCA 
compared to placebo on patient-reported outcomes and healthcare resource. 
14. 
EFFICACY ASSESSMENTS 
14.1. 
Biochemical Measures of Disease Severity 
14.1.1. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is calculated and reported within the EDC system 
based on data entered into the eCRF by adding the scores from the 5 factors outlined in Table 12 
and can range from 5-15.  A total score of 5-6 is considered Grade A (mild, well-compensated 
disease); 7-9 is Grade B (moderate, significant functional compromise); and 10 and above is 
Grade C (severe, decompensated disease).  Calculation of the CP Score includes Investigator 
assessments of ascites and hepatic encephalopathy, which may be assessed during the adverse 
event review at the scheduled visits, as well as total bilirubin, serum albumin, and prothrombin 
time, which will populate from the central laboratory.   
Table 12: 
Child-Pugh Scoring System 
Factor 
Units 
Points 
1 
2 
3 
Serum bilirubin 
μmol/L 
<34 
34-50 
>50 
mg/dL 
<2.0 
2.0-3.0 
>3.0 
Serum albumin 
g/L 
>35 
28-35 
<28 
g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
Seconds prolonged 
0-3 
4-6 
>6 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites 
 
None 
Mild 
Moderate-Severe 
Hepatic encephalopathya 
 
0 
Grade 1 or 2 
Grade 3 or 4 
a Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
 Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves 
 Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
 Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
 Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity  
 (Pugh 1973, Lucey 1997), Vilstrup 2014 
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14.1.2. 
Model of End Stage Liver Disease Score 
The MELD scoring system is used to assess the severity of chronic liver disease.  The MELD 
score is useful in assessing patients with significant decompensation, and the MELD score is 
now used by the United Network for Organ Sharing in the US and Eurotransplants to manage the 
organ allocation for liver transplantation.  The threshold for placement on an organ 
transplantation queue varies between regions across the globe.   
An increasing MELD score is associated with increased severity of hepatic dysfunction and 
increased 3-month mortality risk.  The MELD score is derived from the patient’s serum total 
bilirubin, serum creatinine, and INR, as appropriate, to predict survival (Kamath 2007).  MELD 
score will be calculated and reported for visits where these parameters are measured 
(see Table 1). 
14.1.3. 
Changes in Liver Biochemistry and Hepatobiliary Damage 
ALP, ALT, AST, GGT, total and direct bilirubin, INR, creatinine, albumin, platelets will be 
measured according to the frequency listed in Table 1. 
14.2. 
Additional Assessments 
14.2.1. 
Noninvasive Measurements of Liver Stiffness and Fibrosis 
The ELF test assesses: HA, P3NP, and TIMP-1.  Samples will be assessed in patients according 
to the schedules presented in Table 1. 
The Fibroscan® TE device (Echosens, Paris, France) will be used at all study sites that have the 
equipment to collect hepatic stiffness measurements.  These study sites must have the staff 
trained in the use and data interpretation of the device.  This is a validated and non-invasive 
radiological technique used to assess hepatic fibrosis which will be conducted according to the 
schedule presented in Table 1.   
14.2.2. 
Markers of FXR activation 
Blood samples will be collected in all patients to measure C4, FGF-19, and bile acids.  The 
results of these analyses will be used to assess the PK/PD response of OCA.  Blood samples will 
be assessed in patients according to the schedule presented in Table 1.   
14.2.3. 
Clinical Outcome Events 
Clinical outcome events will be evaluated by an Adjudication Committee (described in 
Section 15.9) to confirm if they meet the criteria to be considered Clinical Outcome Events.  
15. 
STATISTICAL METHODS AND ANALYSES 
Individual patient data obtained from electronic case report forms (eCRFs), central laboratories, 
external sources, and any derived data will be presented in data listings by patient.  All data 
listings that contain an evaluation date will contain a relative study day.  Pre-treatment and on 
treatment study days are numbered relative to the day of the first dose of investigational product 
which is designated as Day 1.   
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All output will be incorporated into Microsoft Word rich text format (.rtf) files, sorted and 
labeled according to the International Conference on Harmonisation (ICH) recommendations, 
and formatted to the appropriate page size(s). 
Tabulations will be produced for appropriate demographic, Baseline, efficacy, and safety 
parameters.   
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) of the parameter will be presented.  Percentage 
calculations will be based on non-missing data, unless otherwise specified.  Percentages are 
rounded to 1 decimal place, unless otherwise specified.   
For continuous variables, the number of patients, mean, standard deviation (SD), standard error 
of the mean (SEM), median, minimum, and maximum values will be presented.  The precision of 
summary statistics, unless otherwise, specified will be as follows:  mean and median to 1 more 
decimal place than the raw data, and SD and SEM to 2 decimal places more than the raw data.  
In general, the decimal places should not exceed 3 decimal places unless appropriate.  
Confidence intervals (CIs) will be provided and will be rounded to 1 decimal place, unless 
otherwise specified. 
Time-to-event data will be summarized using Kaplan-Meier (KM) methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of 
censored observations. 
There will be no formal hypothesis testing in this study.  However, summary statistics for each 
treatment group will be presented, as well as 95% CIs for the difference between the treatment 
groups. 
15.1. 
Analysis Populations 
The following patient populations will be evaluated and used for presentation and analysis of the 
data: 
 The Intent-to-Treat (ITT) Population will include all randomized patients who receive 
any amount of investigational product (OCA or placebo).  The ITT Population will be 
the primary population used for summarizing efficacy assessments.  
 The Safety Population will include all patients who received at least one dose of 
investigational product (placebo or OCA). The Safety Population will be the primary 
population used for safety analyses.  
 The PK population will include all patients receiving OCA who have adequate 
concentration-time profiles to characterize OCA and its conjugates and must not have 
any major protocol deviations that potentially affect exposure levels. 
15.2. 
Determination of Sample Size 
To reasonably characterize the PK of OCA in patients with hepatic impairment, a 
simulation-based approach estimated a requirement of approximately 20 patients in the OCA 
treatment group assuming a 15% discontinuation rate.  A total of 30 patients is adequate with 
10 patients on placebo to be included as a comparator and 20 patients on OCA.  An additional 
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20 patients will be enrolled to support safety and efficacy evaluations.  Therefore, approximately 
50 patients (including at least 20% of patients with CP-C) will be randomized in a 1:1 ratio to 
1 of the 2 treatment groups:  Placebo and OCA.  
15.3. 
Pharmacokinetic Analyses 
The PK Population will be used for analysis of PK parameters, which include plasma OCA 
(parent) and its conjugates (glyco-OCA and tauro-OCA), total OCA, metabolite OCA 
glucuronide, and potentially other conjugates or metabolites not yet identified. 
PK analysis will be based on the PK population.  Values will be calculated using 
non-compartmental methods.  The values will be summarized by active treatment group using 
descriptive statistics.  Full details regarding the planned analyses, methods, and outputs for the 
study will be detailed in the statistical analysis plan (SAP). 
15.4. 
Safety Analyses 
Safety analyses will be conducted using the Safety population.  Safety data, including AEs, AEs 
of special interest including pruritus and hepatic safety, vital signs, ECG, and clinical laboratory 
results will be summarized by treatment group using the Safety Population. 
The incidence of TEAEs and SAEs will be tabulated by system organ class (SOC) and preferred 
term (PT) for each treatment group, and similarly by severity and relationship to treatment.   
Laboratory parameters, physical examinations including vital signs, and ECGs will be 
summarized by treatment group using descriptive statistics at Baseline and at each scheduled 
post-Baseline visit.  The absolute change from baseline will also be summarized. 
No inferential comparison with formal statistical hypothesis testing will be performed for safety 
endpoints.  
15.4.1. 
Adverse Events 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA).  Summary 
tables of TEAEs will be provided.   
Each AE summary will be displayed by treatment group.  Summaries that are displayed by SOC 
and PT will be ordered by descending order of incidence of SOC and PT within each system 
organ class.  Summaries of the following types will be presented: 
 Overall summary of TEAEs. 
 Patient incidence of TEAEs and the total number of entries by MedDRA SOC and 
PT.  This summary will be repeated for all subgroups. 
 Patient incidence of TEAEs by MedDRA SOC, PT, and highest severity.  At each 
level of patient summarization, a patient is classified according to the highest severity 
if the patient reported 1 or more events.  AEs with missing severity will be considered 
severe for this summary. 
 Patient incidence of TEAEs by MedDRA SOC, PT, and closest relationship to 
investigational product (Related/Not Related).  Related AEs are those with 
relationships reported as “Definite,” “Probable,” or “Possible,” and unrelated AEs are 
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those with relationships reported as “Unlikely” or “Not Related.”  At each level of 
patient summarization, a patient is classified according to the closest relationship if 
the patient reported 1 or more events.  AEs with a missing relationship will be 
considered related for this summary. 
 Patient incidence of serious TEAEs and the total number of entries by MedDRA SOC 
and PT. 
 Patient incidence of TEAEs leading to investigational product withdrawal or study 
discontinuation by MedDRA SOC and PT.  This is a subset of the AEs where Action 
Taken with Study Treatment is checked as “Drug Withdrawn” or where “Patient 
Discontinued from Study” is checked. 
The following listings will be presented by treatment group and patient: 
 All adverse events. 
 Serious adverse events (This is a subset of the AEs where serious is marked as 
“Yes”). 
 Severe adverse events (This is a subset of AEs where severity is marked as “Severe”). 
 Related adverse events (This is a subset of the AEs where relationship marked as 
“Definite,” “Probable,” or “Possible”). 
 Adverse events leading to Study Drug Withdrawal or Study Discontinuation (This is a 
subset of the AEs where Action Taken with Study Treatment is checked as “Drug 
Withdrawn” or where “Patient Discontinued from Study” is checked). 
 Adverse events leading to death (This is a subset of the AEs where the corresponding 
AE number is specified on the Death eCRF). 
Adverse events of special interest as defined in Section 13.1.1.4 will be summarized for each 
treatment group.   
15.4.2. 
Clinical Laboratory Evaluations 
Laboratory parameters will be summarized in standard international (SI) system of units by 
treatment group using descriptive statistics at Baseline and at each on-study evaluation.  Re-test 
or unscheduled results will not be summarized but will be included in the data listings.  The 
change from Baseline will also be summarized.  Baseline is defined as the mean of all available 
evaluations prior to treatment.   
In addition, shift tables (ie, low-normal-high at Baseline versus low-normal-high at post Baseline 
visit in a 3-by-3 contingency table) from Baseline to worst value, last value, and at each 
scheduled post-Baseline visit will be provided for hematology and serum chemistry by treatment 
group to assess changes in laboratory values from Baseline to each on-study evaluation.   
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15.4.3. 
Additional Safety Analysis 
Vital Signs and Weight 
The results and change from Baseline to each on-study evaluation visit will be summarized by 
treatment group for weight, oral temperature, sitting heart rate, respiratory rate and sitting blood 
pressure. 
Electrocardiograms 
Electrocardiogram (ECG) results will be summarized at each on-study visit descriptively, 
including the number and percentage of patients with normal, abnormal not clinically significant, 
and abnormal clinically significant results at Baseline and each on-study evaluation. 
15.4.4. 
Adverse Events of Special Interest 
Pruritus: Treatment-emergent pruritus, defined as any PT including “Prur,” will be summarized 
separately by the MedDRA SOC, treatment group, and PT as a subset of all TEAEs.  This 
summary will be repeated for patients with “new or worsened” pruritus events, as defined as 
follows: 
 Mild, moderate, or severe treatment-emergent pruritus events in patients with no 
pruritus at Baseline, or 
 Worsening of the severity of the Baseline condition in patients with pruritus at 
Baseline. 
Baseline pruritus is defined as the Investigator’s rating of severity as collected on the PBC 
Disease History eCRF.  Patients whose Baseline severity is severe will be counted as worsening 
if an AE of pruritus with severe is recorded. 
An analysis of treatment-emergent pruritus event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  Each individual patient year on study will be derived as the last 
known date during the study minus the first dose date plus 1 divided by 365.25 days/year.   
In order to explore the relationship between pruritus and the investigational product, the 
following time-to-event analyses will be performed: 
 Time to first onset of treatment-emergent pruritus  
 The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 
 Patients who never reported an AE of pruritus will be censored at the date of last 
contact. 
 Time to onset of the first moderate or severe treatment-emergent pruritus 
 The time to the start of the first moderate or severe pruritus will be calculated by 
date of onset of the first moderate or severe pruritus – date of first dose of 
investigational product +1. 
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 Patients who never reported a moderate or severe AE of pruritus will be censored 
at the date of completion or discontinuation. 
 Time to onset of the first severe treatment-emergent pruritus 
 The time to the start of the first severe pruritus will be calculated by date of onset 
of the first severe pruritus – date of first dose of investigational product +1. 
 Patients who never reported a severe AE of pruritus will be censored at the date of 
completion or discontinuation. 
The analysis of time to first onset of treatment-emergent pruritus AE, time to onset of the first 
moderate or severe treatment-emergent pruritus, and onset of the first severe treatment-emergent 
pruritus will include the number of patients with pruritus (first onset, first moderate or severe, 
first severe), the number of patients without pruritus (censored), and the minimum and maximum 
times in days.  KM estimates will be calculated by treatment group.  The tabulation will include 
the KM estimate methodology using 25th, 50th (median), and 75th percentiles of the medians and 
corresponding with associated 2-sided 95% confidence intervals (CIs), if the medians can be 
estimated as well as percentage of censored observations. 
Fatigue: Treatment-emergent fatigue is defined as any PT which includes “Fatigue.”  New or 
worsened treatment-emergent fatigue is defined as follows: 
 Any mild, moderate, or severe treatment-emergent fatigue events in patients with no 
fatigue at Baseline, or 
 Worsening of the severity of the Baseline condition in patients with fatigue at 
Baseline. 
Baseline fatigue is defined as the Investigator’s rating of severity as collected on the PBC 
Disease History eCRF.  Patients whose Baseline severity is severe will be counted as worsening 
if an AE of fatigue with severe is recorded. 
An analysis of treatment-emergent fatigue event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  Each individual patient year on study will be derived as the last 
known date during the study minus the first dose date plus 1 divided by 365.25 days/year.   
In order to explore the relationship between fatigue and the investigational product, the following 
time-to-event analyses will be performed: 
 Time to first onset of treatment-emergent fatigue  
 The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 
 Patients who never reported an AE of fatigue will be censored at the date of last 
contact. 
 Time to onset of the first moderate or severe treatment-emergent fatigue 
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 The time to the start of the first moderate or severe fatigue will be calculated by 
date of onset of the first moderate or severe fatigue – date of first dose of 
investigational product +1. 
 Patients who never reported a moderate or severe AE of fatigue will be censored 
at the date of last contact. 
 Time to onset of the first severe treatment-emergent fatigue 
 The time to the start of the first severe fatigue will be calculated by date of onset 
of the first severe fatigue – date of first dose of investigational product +1. 
 Patients who never reported a severe AE of fatigue will be censored at the data of 
last contact. 
The analysis of time to first onset of treatment-emergent fatigue AE, time to onset of the first 
moderate or severe treatment-emergent fatigue, and onset of the first severe treatment-emergent 
fatigue will include the number of patients with pruritus (first onset, first moderate or severe, 
first severe), the number of patients without fatigue (censored), and the minimum and maximum 
times in days.  KM estimates will be calculated by treatment group.  The quartiles, including the 
median time-to-event and their respective 2-sided 95% CIs, will be presented.  KM estimates 
will be plotted as a “survival curve” for each treatment group. 
15.5. 
Efficacy Analyses 
This study does not plan to test a formal hypothesis for any efficacy endpoint.   
The endpoints of efficacy assessments are change in total and direct bilirubin, INR, creatinine, 
albumin, platelets, ALP, ALT, AST, and GGT from baseline to Week 48 (end of the study), 
change from baseline to Week 48 in CP score and components of the CP score, and change from 
baseline to Week 48 in MELD and components of the MELD score.  Analyses of change from 
Baseline to Week 48 (end of study) will be modelled between treatment groups using ANCOVA 
model with change from Baseline as the dependent variable, treatment group and randomization 
stratification factor as fixed effects and the baseline value as a covariate.  The same analysis will 
be carried out using percentage change from Baseline as the dependent variable. 
Analyses of change from Baseline to Week 48 (end of study) will be modelled between 
treatment groups using ANCOVA model with change from Baseline as the dependent variable, 
treatment group and randomization stratification factor as fixed effects and the baseline value as 
a covariate.  The same analysis will be carried out using percentage change from Baseline as the 
dependent variable. 
Summary statistics of the laboratory values will be provided by treatment group.  The results, 
change from Baseline, and percentage change from Baseline values, as well as estimates of 
least-square (LS) means, standard errors (StdErr), and 2-sided 95% CIs, will be presented by 
treatment group.  Estimates of the mean difference between treatment groups, the StdErr of the 
difference, and 2-sided 95% CI of the difference will also be presented.   
Risk Scores: Changes from baseline in the MELD score and in CP score, C4, FGF-19 and 
plasma bile acids will be summarized and analyzed using the Wilcoxon Rank Sum Test.  The 
median differences and 95% CI of the median differences between treatment groups will be 
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constructed using Hodges-Lehmann estimate.  If the median differences between treatments are 
not symmetrical around the median, the Sign Test may be used. 
Shifts in MELD scores from Baseline will be reported by visit using the following categories:  
<10, 10 to <12, 12 to <13, 13 to <14, 14 to <15, and ≥15.   
CP class will be presented in shift tables showing the shift from baseline to each scheduled 
post-baseline visit by the count and percentage of patients within each shift classification. 
Individual factors will be presented in a listing. 
15.6. 
Additional Efficacy Analyses 
Analyses of changes in liver stiffness (TE) and liver fibrosis (ELF [HA, P3NP, and TIMP-1]) 
will be summarized and analyzed using the same methodology specified for the key secondary 
analyses of change in bilirubin. 
The following clinical endpoints will be captured in the study: 
 Time to death (all cause) 
 Time to liver-related death 
 Time to liver transplant 
 MELD score ≥15 (for patients with MELD ≤12 at baseline) 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
 Time to variceal bleed 
 Time to hepatic encephalopathy (as defined by a West Haven score of ≥2) 
 Time to spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 Time to uncontrolled ascites (diuretic resistant ascites requiring therapeutic 
paracentesis at a frequency of at least twice in a month). 
The incidence and time to first occurrence of any above listed clinical events will be summarized 
by treatment group using the log rank test stratified by the randomization stratification factor.  
KM estimates of the distribution of the time-to-event will be tabulated and graphed by treatment 
group.  The tabulation will include the KM methodology using 25th, 50th (median), and 75th 
percentiles with associated 2-sided 95% confidence intervals (CIs), as well as percentage of 
censored observations.  The number and percent of patients censored and with events will be 
presented.  The hazard ratio and 2-sided 95% CI will be estimated based on a Cox regression 
model stratified by randomization strata.  
In addition, the incidence and time to each of the above clinical events, and the incidence and 
time to occurrence of hepatocellular carcinoma (HCC) will be summarized by treatment group 
using the same methods as defined above.  
Full details regarding additional efficacy analyses will be detailed in the SAP. 
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15.7. 
Handling of Missing Data 
Missing data will be assumed to be missing at random.  No data will be imputed. 
15.8. 
Data Monitoring Committee 
An independent DMC includes hepatologists, pharmaceutical physicians, 
epidemiology/cardiology expert(s), and statistician(s) not involved in the study as Investigators, 
adjudication committee members, or consultants.  The DMC will have oversight of the study 
conduct as defined by the DMC charter.  All members will have considerable experience with 
clinical study conduct and DMCs.  Any candidate found to have a conflict of interest or whose 
name is listed on the Food and Drug Administration (FDA) debarment list will not be offered 
membership.  Conflicts of interest will be assessed regularly, and if members are found to have a 
new conflict of interest they will be replaced. 
The DMC will meet approximately quarterly at scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review safety and efficacy data in order to ensure the safe and 
proper treatment of patients.  Based on review of these data, the DMC will advise the Sponsor on 
the validity and scientific merit of continuing the study. 
Written minutes of both the open and closed DMC sessions will be prepared.  The closed 
minutes will be made available to the appointed Sponsor representatives only after the database 
is locked.  
Data listings provided to the DMC do not contain individual patient treatment information; 
however, the DMC will have access to the database and may unblind individual patient data as 
appropriate.  Summary tables reviewed by the DMC during closed sessions will include an 
overall column containing information regarding all patients and separate treatment columns 
with ‘dummy’ labels, ie, the actual treatment groups are used, but are not identified.  Data 
reviewed during the meetings will include, at a minimum, disposition, demographics, exposure, 
clinical laboratory results, MedDRA-coded AEs, and AEs leading to early withdrawal of 
investigational product.  At each meeting, detailed narratives of interval SAEs (including events 
resulting in death) are reviewed by the DMC in addition to a cumulative list of all SAEs. 
The DMC may agree to adjust meeting frequency based upon actual and projected safety and 
efficacy data availability.  Adjustments to or stopping of the protocol defined doses may be 
considered based on DMC evaluation of OCA safety and tolerability. 
All Investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DMC relating to patient safety, which alter the 
conduct of this study.  The Investigators will inform the patients of such actions and the protocol, 
PIS, and ICF will be revised, as appropriate. 
15.9. 
Adjudication Committees 
All suspected liver-related clinical events, major adverse cardiovascular events 
(MACE)/expanded MACE, and drug-related hepatic injury events that occur after administration 
of the first dose of investigational product will be reviewed by the following blinded adjudication 
committees, depending on event type, before inclusion in any analysis.  The 3 committees and 
event types they are responsible for adjudicating are as follows: 
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 Cardiovascular Adjudication Committee (CAC):  Adjudicates all suspected MACE, 
including all deaths 
 Hepatic Outcomes Committee:  Adjudicates all deaths and suspected liver-related 
outcomes 
 Hepatic Safety Committee:  Adjudicates all suspected drug-related hepatic injury 
events 
Each adjudication committee will have a charter that documents the reporting of events by the 
study site, definition of the suspected events to be adjudicated, supply of source documentation 
to the committee, entire data flow and process from committee membership, review of the events 
by the committee, reporting of the final assessment, and the working procedures of the 
committee.   
The adjudication committee members will include experts with relevant adjudication experience; 
they will not be involved in the study as Investigators, DMC members, or consultants.  Any 
candidate found to have a conflict or whose name is listed on the FDA debarment list is not 
offered membership.  Conflicts of interest are assessed regularly, and if members are found to 
have a new conflict of interest they will be replaced. 
The adjudication of suspected events will be based on available source documentation, including 
but not limited to individual clinical study data, hospital records, histology, discharge summaries, 
and/or death certificates.  The adjudication committees will not receive any individual patient 
treatment or site-specific information.  The assessment of events will be conducted in 
compliance with study-specific procedures, manuals, GCP, and all other applicable regulatory 
requirements, including the archiving of essential documents. 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Study Monitoring 
Study records at each site will be monitored at regular intervals by a representative of the 
Sponsor, the CRA.  The role of the CRA is to aid the Investigator in the maintenance and 
documentation of complete, accurate, legible, well organized and easily retrievable data.  In 
addition, the CRA will ensure the Investigator's understanding of all applicable regulations 
concerning the clinical evaluation of the investigational product and will ensure an understanding 
of the protocol, reporting responsibilities and the validity of the data.  This will include ensuring 
that full and appropriate essential documentation is available. 
In order to perform this role, the CRA must perform source data verification and as such must be 
given access to the patient’s primary source documentation (eg, paper or electronic medical 
records such as consent to participate in the study, visit dates, screening and randomization 
numbers, demographic information, medical history, disease history, physical examination, vital 
signs, laboratory assessments [copy of laboratory reports], AEs, concomitant medications, dates 
of dispensing investigational product, ECGs, etc) that support data entries in the eCRF.  The 
eCRF must be completed promptly after each visit to allow the progress and results of the study 
to be closely followed by the Medical Monitor. 
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The Investigator may exercise judgment in allowing the CRA access to particular sections of the 
patient's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
16.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IEC/IRB, and/or 
regulatory agencies to conduct one or more site audits during or after the study and agrees to 
allow access to all study-related documentation and information and be available for discussion 
about the study.   
17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the eCRF or ultimately 
transferred into the database to ensure accuracy and completeness.   
Training sessions, regular monitoring of the study at the study site by the Sponsor or designated 
personnel (eg, CRA), instruction manuals, data verification, cross checking, and data audits will 
be performed to ensure quality of all study data.  Investigators’ meetings and/or onsite study 
initiations will be performed to prepare Investigators and other study site personnel for 
appropriate collection of study data. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit.   
18. 
ETHICS 
18.1. 
Ethics Review 
The final study protocol, including the final version of the PIS-ICF and/or other patient 
information, must be approved or given a favorable opinion in writing by an IRB/IEC as 
appropriate.  The Investigator must submit written IRB/IEC approval to Intercept before he or 
she can enroll any patient into the study.  The Investigator is responsible for providing the IB and 
any other available safety information and information about payments and compensation 
available to study patients to the IRB/IEC for review. 
The Investigator is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements.  A favorable opinion on amendments will be obtained prior 
to implementation, unless the amendment is necessary to reduce immediate risk to study 
participants.  In addition, the IRB/IEC must approve all advertising used to recruit patients for 
the study.  The protocol must be reapproved by the IRB/ IEC upon receipt of amendments and 
annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product, 
according to local regulations and guidelines.  The Sponsor will provide this information to the 
Investigator. 
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Progress reports and notifications of SARs will be provided to the IRB/IEC according to local 
regulations and guidelines.  Investigators or the Sponsor or its designee will provide reports to 
the IRB/IEC as requested, as a minimum annually, and after the study is complete. 
18.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki, “(64th World Medical Association [WMA] General Assembly, 
Fortaleza, Brazil, October 2013),”and are consistent with ICH/GCP, applicable regulatory 
requirements and the Sponsor’s policies. 
18.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the patient is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Patients 
must also be notified that they are free to discontinue from the study at any time.  The patient 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The patient’s signed and dated consent form must be obtained before conducting any study 
procedures. 
The Investigator(s) must maintain the original, signed ICF. A copy of the ICF must be given to 
the patient. 
18.4. 
Patient Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the patient will be 
regarded as confidential and confidentiality of all patients will be maintained.  Monitors 
(eg, CRA, Medical Monitor), auditors and inspectors will require access to a patient’s medical 
notes for the purpose of source document verification but the patient’s confidentiality will be 
maintained at all times.  An agreement for disclosure of any such information will be obtained in 
writing and is included in the statement of informed consent.  The study data shall not be 
disclosed to a third party (with the exception of auditors and/or regulatory authorities) without 
the written consent of the Sponsor.  All data shall be secured against unauthorized access. 
The Investigator will maintain a list of patient’s names and identifying information (eg, patient’s 
hospital number, unique patient number).  This list will not be collected by the Sponsor. 
The PIS-ICF will explain that study data will be stored in a computer database, maintaining 
confidentiality in accordance with national data protection legislation.  All data computer 
processed by the Sponsor or designee will be identified by unique patient number/randomization 
code/site number, only.   
When personal data on patients are stored or processed by computer, the data must be protected 
to prevent disclosure to unauthorized third parties.  The pertinent sections of the data protection 
laws in the country in which the protocol is being conducted will be complied with in full. 
The PIS-ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, regulatory authorities, or IEC/IRBs may require direct access to parts of the hospital or 
study site records relevant to the study, including patient’s medical history. 
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19. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the patients for the duration of the study.  If the Investigator 
is not present in the study site during the assessment, he or she will leave instructions for the 
study site staff and a telephone number where he or she can be reached. 
Named physician(s) will be responsible for the medical follow-up of patients, as applicable. 
19.1. 
Adverse Event Reporting 
The Investigator is responsible for recording AEs reported by the patient or discovered by any 
other means during the study.  In agreeing to the provisions of this protocol, the Investigator 
accepts all legal responsibilities for immediate reporting of SAEs to the Sponsor. 
19.2. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any significant way without 
proper notification to the Sponsor (or designee).  Only the Sponsor may amend the protocol.  
Any change in study conduct considered necessary by the Investigator will be made only after 
consultation with the Sponsor, who will then issue a formal protocol amendment to implement 
the change and obtain regulatory approval.  The only exception is when the Investigator 
considers a patient’s safety to be compromised if immediate action is not taken. 
19.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
 Approved PIS-ICF (all versions) 
 IRB/IEC approvals (of protocol/amendments, patient questionnaires, etc)  
 Form FDA 1572  
 Current medical license of Investigators 
 Curriculum vitae of Investigators 
 Laboratory certification and reference ranges 
 Financial disclosure forms 
19.4. 
Ethics Review (IRB/IEC) 
Please see Section 18.1 for the Investigator’s responsibilities regarding ethics review. 
19.5. 
Archiving and Record Retention 
The Investigator should retain all essential documents and correspondence relating to this study 
in the Investigator Site File (ISF).  Any study documents stored elsewhere should have their 
location referenced in the ISF table of contents or in a note to file. 
All documents relating to the study including the ISF itself, source documents and patient 
medical files (retained per country specific regulations), completed study patient log and 
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confidential patient identification list will be retained by the Investigator until at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the Sponsor.  In the event that storage of records 
becomes a problem at any time during this period, the Sponsor should be consulted for 
assistance.  At the end of the minimum period, the Investigator should obtain written 
authorization from the Sponsor before the destruction of any records.  The Investigator will 
notify the Sponsor if ownership of documents or responsibility for the study site is transferred.  
The Sponsor will inform Investigators should it become aware of any changes in storage 
requirements. 
20. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it Sponsors consistent 
with the Declaration of Helsinki.  Consistent with the recommendations of the editors of several 
leading medical journals, the International Committee of Medical Journal Editors (ICMJE), 
authorship of publications resulting from Intercept sponsored studies should fairly recognize the 
activities of those that have made a significant contribution to the study (http://www.icmje.org).  
Thus, it is anticipated that authorship will reflect the contribution made by the Sponsor 
personnel, the Investigators and others involved, such as statisticians.   
In recent years, issues about conflicts of interest and accuracy of the study data have been raised 
in the medical press.  Accordingly, the Sponsor has developed publication guidelines for clinical 
studies that are appropriate for this study.  Key issues include the following: 
 Clinical Trial Registries (eg, www.clinicaltrials.gov, www.clinicaltrialsregister.eu):  
A description of the study and relevant design elements (eg, basic design, objectives 
and endpoints, sample size, study population, and key inclusion/exclusion criteria) 
and results will be published online in a manner consistent with applicable regulatory 
guidelines. 
 Overview:  Investigators, reviewers and editors will have the right to audit the data to 
verify its accuracy. 
 Responsibility:  Each Investigator is responsible for the accuracy and completeness of 
all data from her/his site.  The Sponsor (or its representatives) is responsible for the 
accuracy of the data entered into the study databases and the analyses conducted. 
 Data Management:  The Sponsor will establish data management and SAP.  The 
Investigators will have the opportunity to provide input into the plans.  The 
Investigators will have the right to review the audit reports and data resolution 
decisions prior to the establishment of a clean file.  The Investigators will have the 
right to appoint appropriately qualified auditors, with GCP experience, to audit the 
Sponsor’s data prior to the establishment of a clean file.  The Investigators must 
provide adequate notice (at least 2 months) to the Sponsor of their intention to audit a 
study.  The audit should be conducted in a timely manner to allow the resolution of 
discrepancies before a clean file is established.  The Investigators will bear all the 
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costs for the conduct of audits that they initiate, except those related to the resolution 
of data queries which the Sponsor will bear.  Such audits must be conducted in such a 
manner as to minimize the time to create the clean file. 
 Authorship:  Intercept, in collaboration with the Investigators, will establish the 
appropriate authorship and responsibility for drafting study documents in accordance 
with the principles of the ICMJE.  All manuscripts will be reviewed and agreed upon 
before submission for publication by all authors.   
 Single Center Publication and Additional Publications:  This is a multicenter study 
and is designed to be published with complete data from all the study sites.  Single 
center publications are therefore not considered appropriate.  Any such publications 
should clearly state that the data are “extracted” from a multicenter study and that the 
study was not intended, or statistically powered, for data presentation by a single 
study site.   
 Intercept Review of External Manuscripts:  Consistent with this, Investigators must 
submit any drafts of any publications or presentations that may arise from this study 
to the Sponsor for review and approval and to ensure consistency with the policy in 
this protocol at least 30 days prior to submission for publication or presentation.  The 
Sponsor will have the right to request appropriate modification to correct facts and to 
represent its, or the Publication Committee’s, opinion if these differ with the proposed 
publication.  
 Confidentiality:  Investigators will conduct all interactions with the company and 
with third parties consistent with the executed confidentiality agreements.  While 
publication, by intention, presents the critical scientific data in a public forum, some 
information (such as future plans, results of preclinical studies or chemical formulae) 
may still need to remain confidential. 
 Medical Journal Review:  Upon request, all pertinent study data and information will 
be made available as supplemental information for journal editors and reviewers to 
evaluate and audit, eg, protocol and amendments, data tabulations, etc.  Arrangements 
will be made to maintain the confidentiality of such supplemental information. 
Arrangements will also be made to maintain the confidentiality of the identity of 
journal reviewers.  Records will be maintained of which documents and datasets were 
reviewed. 
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21. 
LIST OF REFERENCES 
Banks O, Bollen T, Dervenis C, et al.  Classification of acute pancreatitis-2012:  revision of the 
Atlanta classification and definitions by international consensus.  Gut. 2013; 62:102-111. 
Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Digestive and Liver Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin ME, Gish RG, et al. Changing Nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Gastroenterology. 2015b;149(6):1627-9. 
Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: From 'cirrhosis' to 
'cholangitis'. Hepatology. 2015c;62(5):1620-2. 
Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of 
liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 
2012;56(1):198-208. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51(2):237-67. 
Greenburg J., Hsu J., Bawazeer M., et al.  Clinical Practice Guideline:  Management of acute 
pancreatitis.  Can J Surg. 2016; 59 (2):128-140. 
Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European 
Association for the Study of the Liver and the American Association for the Study of Liver 
Diseases. J Hepatol. 2014 Sep;61(3):642-59. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727-36. 
Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the PBC-40, a 
disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 
2005;54(11):1622-9. 
Kamath PS, Kim WR. The model for end-stage liver disease (MELD). Hepatology. 2007 
Mar;45(3):797-805. 
Kim WR, Lindor KD, Locke GR, et al. Epidemiology and natural history of primary biliary 
cirrhosis in a US community. Gastroenterol. 2000;119:1631-36. 
Kumar A, Saraswat VA. Hepatitis E and Acute-on-Chronic Liver Failure. Journal of clinical and 
experimental hepatology. 2013 Sep;3(3):225-30. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis: AASLD Practice 
Guidelines. Hepatology. 2009;50(1):291-308. 
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver 
transplant waiting list: a report of a national conference organized by the American Society of 
Transplant Physicians and the American Association for the Study of Liver Diseases. Liver 
Transpl Surg. 1997;3(6):628-37. 
Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis 
(syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol. 
1978;379(2):103-12. 
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Oemar M, Janssen B. EQ-5D-5L User Guide: Basic Information on how to use the EQ-5D-5L 
instrument. 2013 October;Version 2.0:1-28. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-72. 
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding 
oesophageal varices. Br J Surg. 1973;60(8):646-9. 
Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 
Practice Guideline by the American Association for the Study of Liver Diseases and the 
European Association for the Study of the Liver. Hepatology. 2014 Aug;60(2):715-35. 
Younossi ZM, Guyatt G, Kiwi M, et al. Development of a disease specific questionnaire to 
measure health related quality of life in patients with chronic disease. Gut. 1999;45(2):295-300. 
 
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APPENDIX A. SUMMARY OF CHANGES:  PROTOCOL 747-401 VERSION 2 (DATED 22 MAY 2017) 
Please note that Protocol 747 401 Version 1 was generated to specifically address US FDA post-marketing requirements but 
was not submitted to other Regulatory/Competent Authorities or Ethics Committees due to ongoing negotiations. The changes 
in Version 2 were incorporated based on FDA review of Version 1 of the protocol.  In general: 
 Background information was included to estimate the exposure difference between healthy subjects and patients with 
moderate hepatic impairment to support the rationale for dose selection (Section 5.4.2) 
 Additional PK sampling times were added to adequately characterize the PK of OCA and its active metabolites at 
steady-state in patients with moderate and severe impairment when dosing weekly to biweekly (Section 12) 
 The period between screening and Day 1 was extended to at least 14 days to establish a baseline for serum biomarkers with 
at least two samples two weeks apart (Schedule of Study Procedures, Section 9.7.4) 
 The Week 3 contact Visit by email/telephone was changed to a Safety Visit to assess evidence of early hepatotoxicity 
(Schedule of Study Procedures, Section 9.7.6) 
 Guidelines were added to assess patients for evidence of hepatotoxicity at each visit (Section 8.4.1.2). 
The table below includes substantial revisions made to Protocol 747-401 under Version 2.  Revised text in Version 2 is indicated in 
bold font, and the text deleted from Version 1 is crossed out in the table below.  (Minor/editorial changes and non-substantial changes 
are not listed individually in the summary table below). 
Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
Title Page 
(For FDA Review Only) 
EudraCT Number: 2017-001762-13 
Added  
EudraCT 
Number 
STUDY 
PERSONNEL 
CONTACT 
INFORMATION 
Emergency Contact Information 
Medical Monitor - 24-hour Emergency Reporting 
Contact: 
 MD, Medical Director, 
Drug Safety,  
Intercept Pharmaceuticals, Inc. 
Mobile: 
  
Medical Monitor  
Primary 
Contact: 
 MD, Medical Director, Ph
Intercept Pharmaceuticals, Inc. (Intercept) 
Telephone: 
  
Email: 
 
Updated 
contact list. 
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Section 
Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
Telephon
e: 
  
Email: 
 
Or if Not Available: 
Contact: 
 MD, PhD,  
Intercept Pharmaceuticals, Inc. 
Telephon
e: 
 
SAE Contact Information 
SAE Fax: 
 
SAE email address 
 
Telephone 
 
 
Clinical Operations and Project Management 
Contact: 
 VP, Clinical 
Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 
 
 
 
 
 
SAE Fax: 
 
SAE Email: 
 
 
 
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Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 4: 1 5  Fe b 2 0 1 9  
 
P a ge 9 5  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al  Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d  Te xt ( Versi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
 
T he st u d y is pla n n e d t o ha ve a p pr o xi matel y 2 0  
i n vesti gati o nal sites, gl o ball y 
T he st u d y is pla n ne d t o ha ve a p pr o xi matel y 3 5  
i n vesti gati o nal sites, gl o ball y 
U p date d site 
n u m bers.  
S y n o psis, St u d y 
P eri o d, 7. 1. 3, 
St u d y D urati o n  
St u d ie d P eri o d: T he st u d y  will i ncl u de a 1 4-da y s cree ni n g 
peri o d a n d a 4 8 -wee k d o u ble -bli n d pri mar y  treat me nt 
peri o d.  F oll o wi n g c o m pleti o n of t he W ee k 4 8 visit, 
patie nts will re mai n o n bli n de d i n vesti gati o nal pr o d uct a n d 
be see n at re g ular i nter vals u ntil all patie nts c o m plete t he 
pri mar y treat me nt  peri o d at w hic h p oi nt all  patie nts will 
tra nsiti o n t o a n o pe n -la bel l o n g-ter m safet y e xte nsi o n 
( L T S E). 
St u d y  P eri o d:  P atie nts  will r ecei ve d o u ble -bli n d tre at me nt 
f or at le ast 4 8  wee ks.  P atie nts w h o h a ve c o m plete d t heir 
4 8 -wee k d o u ble bli n d tre at me nt peri o d w ill c o nti n ue 
d o u ble bli n d tre at me nt u ntil all r a n d o mize d p atie nts h a ve 
c o m plete d t heir p artici p ati o n i n t he 4 8 -w ee k  treat me nt 
peri o d a n d t he d at a b ase f or  t hat peri od is l oc ke d 
( a p pr o xi m atel y 3 ye ars).  P atie nts will t he n be gi ve n t he 
o pti o n  t o g o o n  o pe n -la bel tre at me nt. 
U p date d 
descri pti o n of 
st u d y peri o d. 
S y n o psis, 
O bj ecti ves 6. 1 
Pri mar y 
O bj ecti ves; 6. 2 
Sec o n dar y 
O bj ecti ves, 6. 3, 
A d diti o nal 
O bj ecti ves,  
:  I n patie nts wit h M o derate t o Se vere P B C:  
• 
T o e val uate t he p har mac o ki netics ( P K) of O C A a n d its 
c o nj u gates, gl yc o-O C A, ta ur o -O C A, a n d O C A gl uc ur o ni de  
 
Li ver bi oc he mistr y i ncl u di n g t otal bilir u bi n  
 
… as partate a mi n otra nsferase [ A S T], a n d 
ga m ma gl uta m yl tra nsa mi nase  [ G G T 
 
 
 
Bi o mar kers of bile aci d s y nt hesis a n d 
h o me ostasis i ncl u di n g fi br o blast gr o wt h fact or 
1 9 ( F G F 1 9), 7 α h y dr o x y - 4-c h oleste n - 3-o ne 
( C 4), a n d plas ma a n d fecal bile aci ds  
 
T o assess t he P K/ P har mac o d y na mic ( P D) relati o ns hi p 
of O C A o n:  
 
A L P, t otal bilir u bi n, a n d a mi n otra nsferases  
 
Bile aci d h o me ostasis  
 
Safet y a n d t olera bilit y (e g pr urit us) 
 
 
• T o e val uate t he p har mac o ki netics ( P K) of O C A a n d its 
c o nj u gates, gl yc o -O C A, ta ur o -O C A, a n d met a b olite  O C A 
gl uc ur o ni de c o m p are d wit h pl ace b o  
 
Li ver bi oc he mistr y i ncl u di n g t otal a n d direct  
bilir u bi n  
 
… as partate a mi n otra nsferase [ A S T], a n d ga m ma 
gl uta m yl tra nsa mi nase [ G G T],), i nter n ati o n al 
n or m alize d r ati o (I N R), cre ati ni ne, al b u mi n, 
pl atelets    
 
Bi o mar kers of bile aci d s y nt hesis a n d 
h o me ostasis i ncl u di n g fi br o blast gr o wt h fact or 
1 9 ( F G F 1 9), 7 α h y dr o x y - 4-c h oleste n - 3-o ne 
( C 4), a n d plas ma bile aci ds 
 
T o assess t he P K/ P har mac o d y na mic ( P D) relati o ns hi p of 
O C A wit h : 
 
P K p ar a meters c o m p are d t o P D P ar a meters a n d 
S afet y a n d T oler a bilit y assess me nts ( a b o ve)    
 
Clarifie d 
st u d y 
o bj ecti ves.  
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Revised Text (Version 2, 22 May 2017) 
Key Change 
• 
To assess clinical outcomes consistent with end-stage 
liver disease 
• 
To assess patient reported outcomes (Pruritus Visual 
Analogue Scale [VAS], PBC-40, EQ 5D-5L, Chronic 
Liver Disease Questionnaire [CLDQ]) 
• 
To assess clinical events consistent with end-stage liver 
disease 
Synopsis, 
Methodology 
and Section 7.1. 
Overall Study 
Design 
Patients will be screened for up to ≤14 days… 
Patients will be screened ≥14 days but not more than 
28 days… 
Extended to 
14 days to 
satisfy PMR 
for 2 baseline 
measurement
s. 
Synopsis,  
Double-Blind 
Treatment 
Period, 7.1, 
Overall Study 
Design 
Double-Blind Primary Treatment Period 
… (ie, Day 1 through Week 48), clinic visits will occur 
approximately every 6 weeks for the assessment of safety, 
tolerability, PK, and PD (trough).  At each visit, trough PK 
assessments will be performed in all patients participating 
in the study.  Serial PK sampling will be performed at 
Week 12 and only after a patient uptitrates.  Following 
completion of the Week 48 visit, patients will remain on 
blinded investigational product and be seen at regular visits 
every 3 months until all patients complete the 48 week 
primary treatment period. 
…  Double-Blind Treatment Period:  …(ie, Day 1 through 
Week 48), an initial safety visit will occur at Week 3.  
After the Week 6, subsequent clinic visits will occur 
approximately every 6 weeks for the assessment of safety, 
tolerability, PK, and PD.  At each visit (except screening 
and Week 3), fasting PK assessments will be performed in 
all patients participating in the study.  Serial PK sampling 
will be performed at Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week double-blind 
treatment period will continue double blind treatment 
until all randomized patients have completed their 48-
week treatment period and the database for that period is 
locked.  Patients will then be given the option to go on 
open-label treatment.   
Updated 
description of 
study period. 
Synopsis, Long -
term Open Label 
Extension Phase 
Long -term Open Label Extension Phase 
Once all patients have completed the double-blind 48 week 
primary treatment period, patients will have the option to 
continue into an open-label long term safety extension and 
all patients will receive OCA.  Visits in the LTSE will 
occur every 3 months for up to 5 years.  Patients on placebo 
during the primary treatment period will initiate study 
medication at 5-mg OCA once weekly and follow the 
dosing regimen based on their CP score.  Patients on OCA 
Section deleted. 
Updated 
description of 
study. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
during the primary treatment period will continue the dose 
that they are on once unblinded. 
Synopsis and 
Section 7.1.1, 
Study Design 
Diagram 
 
EOS = end of study; EOT = end of treatment, OCA = obeticholic acid 
*Initial dose titration of investigational product may occur at the Week 12 
Visit, or any study visit … 
 
Note: Initial dose titration of investigational product may be considered as 
early as the Week 12 visit, or any study visit thereafter for patients on all 
dosing regimens, based on …. 
Patients who complete Week 48 will continue double-blind treatment 
until all randomized patients have completed their participation in the 
48-week treatment period and the database for that period is locked. 
Updated 
study 
diagram. 
Synopsis, 
Dosing Regimen, 
Section,  7.3 
(Table 2) 
All patients will initiate investigational product once 
weekly with 5 -mg OCA or matching placebo.  Starting at 
Week 12, safety and tolerability of investigational product 
will be evaluated and, if tolerated, the patient can increase 
the dose to the next dose level as described below: 
• At Week 12, if investigational product is tolerated and 
laboratory assessments from the Week 6 visit do not 
indicate a safety concern, the patient will change the 
dosing frequency to 5 mg twice weekly, at least 3 days 
apart.   
 Following an additional 6 weeks of treatment, if 
investigational product is tolerated, patients may be up-
titrated to OCA 10 mg twice weekly at least 3 days 
apart, the maximum dose for patients with CP-C.  
 Following an additional 6 weeks of treatment, if 
tolerated, Patients with CP-B may titrate to a maximum 
dose of OCA 5 mg once daily, the maximum dose for 
patients with CP-B.  
All patients will initiate investigational product once weekly 
with 5 mg OCA or matching placebo.  Titration may be 
considered as early as the Week 12 Visit.  Following visit 
procedures at Week 12, if the investigational product is 
tolerated and laboratory assessments do not indicate a safety 
concern, the patient may up-titrate to OCA 5 mg twice 
weekly and may start the higher dose regimen no earlier 
than 2 days after they took their last dose.  Dosing will 
then occur at least 3 days apart.  Every 6 weeks thereafter, 
based on safety and tolerability assessments, patients can 
be considered for further up titration as described below.  
At each titration visit, the patient may start the higher 
dose regimen no earlier than 2 days after the prior dose. 
Patients with CP-B may titrate to a maximum dose of OCA 
5 mg once daily. 
 
Patients with CP-C may titrate to a maximum dose of 
OCA 10 mg twice weekly at least 3 days apart.  
 
Updated table 
for clarity. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
• 
If, during the course of the study, a patient transitions 
from CP- B to CP-C, or vice versa, the maximal dose 
for the new CP classification would apply. 
 
Planned OCA or Matching Placebo Dosing Regimen by 
Child-Pugh Score 
 
Child-Pugh B 
(Moderate Hepatic 
Impairment) 
Child-Pugh C 
(Severe Hepatic 
Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting Dose 
a (Day 1) 
5 mg 
once 
weekly 
matching 
placebo 
5 mg 
once 
weekly 
matching 
placebo 
Titration 1b 
(≥Week 12) 
5 mg 
twice 
weeklyc 
matching 
placebo 
5 mg 
twice 
weeklyc 
matching 
placebo 
Titration 2b 
(≥6 weeks 
after Titration 
1) 
10 mg 
twice 
weeklyc 
matching 
placebo 
10 mg 
twice 
weeklyc 
matching 
placebo 
Titration 3b 
(≥6 weeks 
after Titration 
2) 
5 mg 
once 
daily 
matching 
placebo 
NA 
matching 
placebo 
 
 
aStarting dose based on patient’s Child-Pugh Score at Screening. 
bPlanned titration regimen is shown; however, the titration of dose and/or 
frequency is dependent on patient tolerability and/or changes in Child-
Pugh Score at any time during the study. 
cDosing per the twice weekly schedule must be at least 3 days apart. 
 
Child-Pugh B 
(Moderate Hepatic 
Impairment) 
Child-Pugh C 
(Severe Hepatic 
Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting Dose 
(Day 1) 
5 mg 
once 
weekly 
matching 
placebo 
5 mg once 
weekly 
matching 
placebo 
Titration 1a  
5 mg 
twice 
weeklyb 
matching 
placebo 
5 mg 
twice 
weeklyc 
matching 
placebo 
Titration 2a  
10 mg 
twice 
weeklyb 
matching 
placebo 
10 mg 
twice 
weeklyc 
matching 
placebo 
Titration 3a  
5 mg 
once 
daily 
matching 
placebo 
NA 
NA 
 
aPlanned titration regimen is shown; however, the titration of dose 
and/or frequency is dependent on patient tolerability and/or changes in 
Child-Pugh Score at any time during the study 
bDosing per the twice weekly schedule must be at least 3 days apart. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
(insertion) 
If, during the course of the study, a patient transitions 
from CP- B to CP-C, or vice versa, the maximal dose for 
the new CP classification would apply.   If a patient 
demonstrates an improvement to CP-A, they should 
follow the dosing regimen for patients with CP-A. 
 
Over the course of the study, a patient’s CP category may 
change.  When a patient demonstrates a change in CP 
category, dosing should be reassessed and modified if 
appropriate.  Changes to the dosing regimen are not 
mandatory and should be based on clinical judgment and 
change in CP score.  The titration steps for CP-B and CP-C 
patients are identical with exception of the maximum allowed 
dose.  Therefore, if a patient changes CP class from B to C, or 
vice versa, the maximal dose for the new regimen will apply.  
If a patient improves to CP-A during the study, the maximal 
CP-B dose will still apply.  If a patient has not yet reached the 
maximal dose, the appropriate titration regimen should be 
followed.  
 
 
 
a Once a patient begins dosing with the new dosing regimen, 
titration should occur as described for the planned dosing 
regimen.  
b 
Dosing per the twice weekly schedule must be at least 3 
days apart. 
Added to 
provide 
more 
information 
on dosing. 
Page 505 of 603


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 4: 1 5  Fe b 2 0 1 9  
 
P a ge 1 0 0  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al  Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d  Te xt ( Versi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
S y n o psis a n d 
Secti o n 8. 2, Ke y 
I ncl usi o n 
Criteria  
2.  E vi de nce of cirr h osis i ncl u di n g at least o ne of t he 
f oll o wi n g: 
 Bi o ps y i n dicati n g cirr h osis or a me dical hist or y wit h 
hist ol o gical e vi de nce of cirr h osis   
 Cli nical e vi de nce c o nsiste nt wit h cirr h osis i ncl u di n g: 
es o p ha geal  varices, ascites, e nce p hal o pat h y,  or p ortal 
h y perte nsi o n  
   Li ver stiff ness as assesse d b y T E of  >1 6. 9 k P a  
 
 
 
 
 
 
 
 
 
 
6.  A ge ≥1 8 years  
7.  T a ki n g U D C A f or at least 1 2 m o nt hs (sta ble d ose f or 
≥3 m o nt hs) pri or t o Da y 1, or u na ble t o t olerate U D C A 
( n o U D C A f or ≥3 m o nt hs)  
8.  C o ntrace pti o n:  Fe male patie nts m ust be 
p ost me n o pa usal, s ur gicall y sterile, or if pre me n o pa usal 
(a n d n ot s ur gicall y sterile), be pre pare d t o use ≥1 
effecti ve met h o d of c o ntrace pti o n d uri n g t he st u d y a n d 
f or 3 0 da ys after t he e n d of treat me nt visit.  Effecti ve 
met h o ds of c o ntrace pti o n are c o nsi dere d t o be t h ose 
liste d bel o w: 
 
B arrier met h o d, ie, (a) c o n d o m ( male or fe male ) 
wit h s per mici de or  ( b) dia p hra g m, wit h 
s per mici de; or  
 
I ntra uteri ne de vice; or  
2.  E vi de nce of cirr h osis i ncl u di n g at least o ne of t he 
f oll o wi n g: 
 Bi o ps y res ults c o nsiste nt wit h P B C St a ge 4   
 Li ver stiff ness as assesse d b y T E M e di a n V al ue 
≥1 6. 9  k P a  
 Cli nical e vi de nce i n t he a bse nce of ac ute li ver f ail ure 
c o nsiste nt wit h cirr h osis i ncl u di n g: g astr oes o p h a ge al  
varices, ascites, r a di ol o gic al e vi de nce of ci rr h osis 
( n o d ul ar li ver or e nl ar ge me nt  of p ortal vei n a n d 
s ple n o me g al y) 
 C o m bi ne d l o w pl atelet c o u nt ( < 1 4 0 0 0 0/ m m 3) wit h 
 persiste nt decre ase i n ser u m al b u mi n, or  
 ele v ati o n i n pr ot hr o m bi n ti me/I N R ( n ot d ue t o 
a ntit hr o m b otic a ge nt use), or  
 ele v ate d bilir u bi n ( 2 × U L N) 
 
6.  T a ki n g U D C A f or at leas t 1 2 m o nt hs (sta ble d ose f or 
≥3  m o nt hs) pri or t o Da y 1, or u na ble t o t olerate or 
u nres p o nsi ve t o  U D C A ( n o U D C A f or ≥3 m o nt hs)  
 
 
Pr o vi de d 
m ore details 
re gar di n g 
i ncl usi o n 
re q uire me nts.  
O nl y liste d 
i ncl usi o ns 
directl y 
relate d t o 
P B C i n 
s y n o psis.   
Ot her cr iteria 
were delete d 
fr o m 
s y n o psis b ut 
re mai n i n t he 
mai n b o d y.  
O nl y criteria 
wit h c ha n ges 
are prese nte d 
i n t his S O C. 
T he f ull 
i ncl usi o n/ 
e xcl usi o n list 
is i n t he b o d y 
of t he 
pr ot oc ol.  
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Revised Text (Version 2, 22 May 2017) 
Key Change 
 
Vasectomy (partner), or  
 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection, or 
 
Abstinence, if in line with the preferred and usual 
lifestyle of the patient (where abstinence is defined 
as refraining from heterosexual intercourse) 
9. Must provide written informed consent and agree to 
comply with the study protocol. 
Synopsis and 
Section 8.3, Key 
Exclusion 
Criteria 
4. History or presence …: 
 
Hepatitis C virus infection RNA positive 
5. 
In the opinion of the Investigator, fluctuating or 
rapidly deteriorating hepatic function during the 
Screening period 
6. Patients with history or presence of hepatorenal or 
hepatopulmonary syndrome 
7. Patients with significant active infection (ie 
spontaneous bacterial peritonitis) 
8. Patients with known or suspected hepatocellular 
carcinoma 
9. History of known or suspected clinically significant 
hypersensitivity to OCA or any of its components 
10. Participation in another investigational product, 
biologic, or medical device study within 30 days prior 
to Screening.  Participation in a previous study of OCA 
is allowed with 3 months washout prior to enrollment 
in this study 
4. Hepatic encephalopathy (as defined by a West Haven 
score of ≥2) 
5. 
History or presence …: 
 
Hepatitis C virus infection and RNA positive 
6. In the opinion of the Investigator, fluctuating or rapidly 
deteriorating hepatic function prior to randomization 
Added 
additional 
key exclusion 
criteria #4.  
Other criteria 
were deleted 
from 
synopsis but 
remain in the 
main body.  
Only criteria 
with changes 
are presented 
in this SOC. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
11. Mental instability or incompetence, such that the 
validity of informed consent or ability to be compliant 
with the study is uncertain 
12. UDCA naïve (unless contraindicated). 
Synopsis, 
Duration of 
Treatment 
The study will include a 14-day screening period and a 48 
week double -blind primary treatment period.   Following 
completion of the Week 48 visit, patients will remain on 
blinded investigational product and be seen at regular visits 
every 3 months until all patients complete the double-blind 
48 week primary treatment period.  Hence, depending on 
the rate of patient enrollment, patients will be exposed to 
investigational product for a minimum of 1 year up to 
approximately 2 years during the blinded period.  
Following completion of the blinded period, Patients will 
have the option to continue into an extension during which 
they will receive open label treatment and be seen at regular 
visits every 3 months for up to 5 years.  
Patients who have completed their 48-week double blind 
treatment period will continue double blind treatment 
until all randomized patients have completed their 
participation in the 48-week treatment period and the 
database for that period is locked (approximately 
3 years).  Patients will then be given the option to go on 
open-label treatment.    
Updated 
description of 
study. 
Synopsis, 
Criteria for 
Evaluation and 
11, Overview of 
Assessments, 
Table 5, 
Additional 
Objectives 
PD Parameters;   
plasma, fecal 
bile acids 
PK 
Plasma 
concentrations 
of OCA and its 
conjugates, 
glyco-OCA, 
tauro-OCA; and 
metabolite OCA 
glucuronide 
Clarified 
study 
parameter for 
evaluation. 
Changes in MELD and in CP score  
 
Changes in MELD and in CP score and 
components of the CP score 
 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
PD parameters 
fecal bile acids 
PK/PD parameters 
bile acids 
Markers of inflammation 
IL-6, hs-CRP, 
TNF-α, IgM, 
IgA, IgG, CK 
18 M30, and 
others as 
determined 
during course 
of study.   
 
IL-6, hs-CRP, 
TNF-α, IgM, IgA, 
IgG, CK 18 M30,  
PK/PD relationship of OCA and liver 
biochemistry 
OCA and its 
conjugates, 
glyco-OCA 
tauro-OCA; 
and OCA 
glucuronide 
PK/PD relationship 
PK parameters 
compared to PD 
Parameters and 
Safety and 
Tolerability 
assessments 
(above) 
PK/PD relationship of OCA and bile acid 
homeostasis 
Bile acids 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
Clinical Outcomes 
Incidence and 
time to first 
occurrence of 
any of the 
following:  all-
cause 
mortality, 
liver-related 
events 
resulting in 
death, hepatic 
failure leading 
to liver 
transplant, 
variceal bleed, 
hepatic 
encephalopath
y, spontaneous 
bacterial 
peritonitis, 
ascites, 
hepatocellular 
carcinoma 
Clinical Events 
Death (all-cause 
and liver-related), 
liver transplant, 
Model of end stage 
liver disease 
(MELD) score ≥15 
(for patients with 
MELD ≤12 at 
baseline), 
Hospitalization for 
new onset or 
recurrence of: 
variceal bleed, 
hepatic 
encephalopathy, 
spontaneous 
bacterial peritonitis, 
Uncontrolled 
ascites, and HCC. 
Synopsis, 
Statistical 
Methods, Safety 
Analyses 
The absolute change from baseline will also be 
summarized.  No inferential comparison of safety endpoints 
will be performed. 
The absolute change from baseline will also be summarized.  
No inferential comparison with formal statistical hypothesis 
testing will be performed for safety endpoints. 
Clarified 
statistical 
methods. 
Synopsis, 
Statistical 
Methods, 
Additional 
Efficacy 
Analyses 
The following clinical outcomes will be captured in the 
study: 
 
All-cause mortality 
 
Liver related death 
 
Liver transplant 
The following endpoints consistent with end-stage liver 
disease will be captured in the study: 
 
Time to death (all cause) 
 
Time to liver-related death 
 
Time to liver transplant 
Clarified 
statistical 
methods. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
 
Variceal bleed 
 
Hepatic encephalopathy 
 
Bacterial peritonitis 
 
Ascites 
 
Hepatocellular carcinoma 
 
 
 
 
 
 
 
 
 
 
The incidence and time to first occurrence of any of the 
above listed clinical outcomes will be summarized ….The 
tabulation will include the KM estimate of the medians and 
corresponding 95% confidence intervals (CIs), if the 
medians can be estimated.  … The hazard ratio and 95% CI 
will be estimated based on a Cox regression model 
stratified by randomization strata. 
In addition, the incidence and time to each of the above 
outcomes  will be summarized by treatment group using the 
same methods as defined above.   
 
Model of end stage liver disease (MELD) 
score ≥15 (for patients with MELD ≤12 at 
baseline) 
 
Hospitalization (as defined by a stay of 
24 hours or greater) for new onset or 
recurrence of: 
 
Time to variceal bleed 
 
Time to hepatic encephalopathy (as 
defined by a West Haven score of ≥2) 
 
Time to spontaneous bacterial peritonitis 
(confirmed by diagnostic paracentesis) 
 
Time to uncontrolled ascites (diuretic 
resistant ascites requiring therapeutic 
paracentesis at a frequency of at least twice 
in a month) 
The incidence and time to first occurrence of the above listed 
clinical outcomes will be summarized ….The tabulation will 
include the KM methodology using 25th, 50th (median), and 
75th percentiles with associated 2-sided 95% confidence 
intervals (CIs), as well as percentage of censored 
observations.  ….  The hazard ratio and 2-sided 95% CI will 
be estimated based on a Cox regression model stratified by 
randomization strata. 
In addition, the incidence and time to each of the above 
clinical events, and the incidence and time to occurrence 
of hepatocellular carcinoma (HCC) will be summarized by 
treatment group using the same methods as defined above. 
 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
Synopsis and 
Section 15.2, 
Sample Size, 
To reasonably characterize the PK of OCA in patients with 
hepatic impairment, a simulation-based approach estimated 
a requirement of approximately 20 patients per OCA 
treatment group assuming a 15% discontinuation rate.  Ten 
patients on placebo will be included as a comparator.  The 
assessment was based on 80% powering for the 90% 
confidence interval of the geometric mean ratio of Total 
OCA (sum of OCA, glyco OCA, and tauro OCA). 
To reasonably characterize the PK of OCA in patients with 
hepatic impairment, a simulation based approach estimated a 
requirement of approximately 20 patients in the OCA 
treatment group assuming a 15% discontinuation rate.  Ten 
patients on placebo will be included as a comparator.  An 
additional 20 patients will be enrolled to support safety 
and efficacy evaluations.  Therefore, approximately 
50 patients (including at least 20% of patients with CP-C) 
will be randomized. 
 
5.2,  Nonclinical 
Experience with 
Obeticholic Acid 
Insertion 
Intercept Pharmaceuticals, Inc. (the Sponsor) has 
completed a standard battery of nonclinical safety 
pharmacology and toxicology studies.  No major 
nonclinical safety effects have been seen other than 
pharmacologic hepatic effects observed at high doses.  
These pharmacologic hepatic effects are consistent with 
the detergent effects of a bile acid at exceedingly high 
hepatocellular exposure. 
Added 
section to 
briefly 
address 
nonclinical 
studies. 
5.3, Clinical 
Development of 
Obeticholic Acid 
As of 31 Jan 2016, approximately 1726 patients have 
received at least 1 dose of OCA.  Of these, 844 were 
healthy volunteers, 458 patients had PBC, 330 patients had 
nonalcoholic steatohepatitis, 41 patients had diabetes 
mellitus/ nonalcoholic fatty liver disease, 33 patients had 
alcoholic cirrhosis/portal hypertension, and 20 patients had 
primary sclerosing cholangitis (PSC). 
As of 31 Jan 2017, approximately 2186 patients have 
received at least 1 dose of OCA.  Of these, 844 were healthy 
volunteers, 525 patients had PBC, 686 patients had 
nonalcoholic steatohepatitis (NASH), 41 patients had 
diabetes mellitus/ nonalcoholic fatty liver disease (NAFLD), 
33 patients had alcoholic cirrhosis/portal hypertension, 
52 patients had primary sclerosing cholangitis (PSC), and 
5 patients had biliary atresia. 
Updated 
numbers of 
patients who 
have received 
OCA. 
5.4, 
 
Rationale 
for Study Design 
and Dose for 
Investigational 
Product 
 
5.4  Rationale for Study Design and Dose for 
Investigational Product 
Inserted new 
header for 
clarity  
5.4.1, Rationale 
for Study Design 
Patients with moderate or severe hepatic impairment (Child 
Pugh B or C) will constitute approximately 20% of the 
patients included in the ongoing clinical outcomes Study 
747 302 which was specifically designed to confirm clinical 
benefit across the spectrum of disease including patients 
The 747-401 study is specifically designed to confirm 
clinical benefit across the spectrum of disease including 
patients with hepatic impairment.  Data collected from Study 
747 401 will serve as a bridge to the 747-302 study. 
Clarified the 
intent of the 
401 study. 
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with hepatic impairment.  Data collected from Study 747 
401 will serve as a bridge between the two studies. 
5.4.2, Rationale 
for Obeticholic 
Acid Dose and 
Duration 
Results from the hepatic impairment study (747-103) 
indicate that plasma exposure increases, in comparison to 
subjects with normal liver function, with increasing severity 
of impairment as classified by Child Pugh A (CP A), CP B 
or Child Pugh C (CP C) scores by 1.4-, 8.0-, and 13 fold, 
respectively.  No apparent impact on the overall safety 
profiles were observed in this study.  Liver exposure, 
however, modestly increased by 1.1-, 1.5, and 1.7-fold, 
respectively, as shown in simulations using a physiologic 
PK model developed to characterize OCA and its 
conjugates.  Together, the results from these analyses 
suggest that the doses of OCA administered to patients with 
moderate or severe hepatic impairment should be modestly 
lower than those for patients with normal hepatic function 
to achieve similar hepatic exposure. 
 
 
 
(insertion) 
 
 
 
 
 
 
 
 
 
 
 
Simulations using a physiologic PK model predicted changes in 
systemic and liver OCA concentrations associated with changes 
in the severity of hepatic impairment (CP Score).  Model 
simulations predicted that for mild (Child-Pugh A [CP-A]), 
moderate (Child-Pugh B [CP-B]), and severe (Child-Pugh C 
[CP-C]) hepatic impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to patients with normal 
hepatic function, whereas total OCA liver concentrations 
increase 1.1-, 1.5-, and 1.7-fold, respectively.  Because the liver is 
the primary site of action for the safety and efficacy of OCA, it is 
important to account for the differences in systemic and liver 
exposure when assessing effective doses.  It is also important to 
note that while hepatically impaired (CP-B and C) patients 
treated with OCA in Phase 1 and 2 studies experienced plasma 
OCA exposures >10-fold higher than those in healthy patients, 
no apparent impact on the overall safety profile was observed, 
consistent with only a modest increase in liver exposure of OCA 
associated with hepatic impairment.  Together, the results from 
these analyses suggest that the doses of OCA administered to 
patients with moderate or severe hepatic impairment should be 
modestly lower than those for patients with normal hepatic 
function to achieve similar hepatic exposure.    
Therefore, the current FDA-approved prescribing information 
for OCA includes a modified dosing regimen in patients with 
moderate and severe hepatic impairment that is designed to 
achieve liver exposures in these patients that would be similar to 
non-hepatically impaired patients through initiation at a lower 
Added 
rationale for 
OCA dosing 
in hepatically 
impaired 
patients. 
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Key Change 
 
Therefore, a modified dosing regimen is recommended for 
OCA in patients with moderate and severe hepatic 
impairment that is designed to initiate doses to achieve 
plasma exposures levels of OCA similar to those without 
hepatic impairment or CP-A.  After which, subjects may 
then titrate their doses upwards to achieve liver exposures 
that would be similar in both patient populations.  This 
modified dosing regimen was selected based on the 
established safety and tolerability of OCA in subjects with 
PBC, along with PK/PD modeling and simulations.  
Patients will initiate dosing at OCA 5 mg once weekly.  
Starting at Week 12, if the prior dose regimen was 
tolerated, the patients will increase the dosing frequency to 
5 mg twice weekly (at least 3 days apart).  After 6 weeks, a 
second titration may occur to OCA 10 mg twice weekly as 
long as tolerated.  Patients classified as CP B may further 
titrate their dose upwards to OCA 5 mg once daily after 
6 weeks on the OCA 10 mg twice weekly regimen. 
dose (5 mg OCA once-weekly) followed by gradual up-titration 
(Section 7.3).   
The dosing regimen in this study follows the FDA-approved 
prescribing information, with the exception of the maximum 
allowed dose in patients with moderate impairment.  While the 
prescribing information allows for a maximum dose of 10 mg 
twice weekly for patients with moderate impairment, the 
protocol allows for a maximum dose of 5 mg once daily.  The 
choice of 5 mg once daily is supported by the estimated steady-
state liver and plasma exposure of total OCA for patients with 
moderate hepatic impairment receiving a 5 mg once daily dose 
relative to healthy patients receiving a 10 mg dose.  A maximum 
allowed dose of 5 mg once daily in patients with moderate 
hepatic impairment is estimated to achieve liver exposure 
similar to non-hepatically impaired patients receiving a 10 mg 
daily dose and maximize efficacy in this patient population. 
 
7.1.2, Schedule 
of Study 
Procedures 
Schedule of Study Procedures (Double-Blind Treatment 
Period) 
Schedule of Study Procedures 
Updated 
procedures to 
match 
updated study 
design. 
7.1.2, Schedule 
of Study 
Procedures, Visit 
Windows 
≤-1 to -14 days 
-28 to -14 days 
Updated 
procedures to 
match 
updated study 
design. 
7.1.2, Schedule 
of Study 
Procedures, Visit 
Weeks Row 
Week 3: Safety Contact 
Week 48 
Under Long-Term Treatment 
Week 3 
Week 48/ET/EOS/EOT 
Every 3 months 
Week 3 
telephone/em
ail contact 
visit now a 
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laboratory 
safety visit. 
7.1.2, Schedule 
of Study 
Procedures 
(Insertion) 
 
Dose Titration 
IL-6, hs-CRP, TNF-α, IgM, IgG, IgA, CK-18-M30, others 
as determined during course of study 
Fecal PK Analysis 
TE Fibroscan® 
ELF 
MELD 
PK trough Collection 
Column: Long-Term Treatment 
Procedures: Medical and Surgical Procedures 
Dose Titration Assessment 
Markers of Inflammation: IL-6, hs CRP, TNF-α, IgM, IgG, 
IgA, CK-18-M30 
 
 
 
TE/ELF (HA, P3NP, and TIMP 1) 
PK Fasting Collection 
Updated 
procedures to 
match 
updated study 
design 
7.1.2, Table 1, 
Schedule of 
Study 
Procedures 
Footnotes 
a 
Patients should be contacted by telephone/email every 
3 weeks (±1 week) between clinic visits starting at Week 3 
and continuing to Week 48 to assess for AEs, concomitant 
medications, and verify that s/he is dosing as directed. 
b 
Visits should be based on Day 1. 
c 
The patient should be instructed to fast overnight (at 
least 8 hours) prior to each visit.  Fasting is required prior to 
all study visits (except Screening Visit 1) but water is 
permitted. 
d 
Medical history performed at Screening only.    
e 
The yearly physical exam will also include an 
assessment of smoking and alcohol consumption history 
and current habits for both.  Height will only be collected at 
Day 1 and Week 48.    
f 
Child-Pugh Score will be calculated based on ascites 
assessment, hepatic encephalopathy grade, and central 
laboratory evaluations per the Child-Pugh scoring system 
noted in the eCRF. 
g 
The EQ-5D-5L Quality of Life questionnaire is 
validated for use in multiple languages. If a validated 
aVisit schedule should be based on Day 1.  Day 1 visit 
must occur at least 2 weeks after screening visit. 
bPatients should be contacted by telephone/email every 
3 weeks (±1 week) between clinic visits starting at Week 9 
and continuing to Week 48 to assess for AEs, concomitant 
medications, medical/surgical procedures, and verify that 
s/he is dosing as directed. 
c Preferably, the patient comes in to the clinic for this 
visit.  Alternatively, site will telephone the patient for 
assessments and home health nurse will visit to draw 
safety labs. 
d Visit should occur 3, 4, or 5 days after taking the Week 6 
dose. 
e 
The patient should be instructed to fast overnight (at least 
8 hours) prior to each visit.  Fasting is required prior to all 
study visits, including screening, but water is permitted. 
f Height and assessment of smoking and alcohol 
consumption history and current habits will be assessed at 
Screening and Week 48.   Assessment of smoking and 
Updated 
procedures to 
match 
updated study 
design 
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translation is not available in the local language required for 
a specific study patient, the data from that questionnaire 
will not be collected.  The CLDQ measures change over 
time in patients with chronic liver disease.  
h 
Patients will be instructed to begin dosing on the Day 1 
visit after completing all study assessments. (ie, on Day 1).  
Patients will be instructed to take investigational product at 
approximately the same time of day.  Patients must be 
instructed to swallow the tablet whole; they must not chew, 
divide, or crush the tablet. 
i 
Initial dose titration of investigational product may 
occur at the Week 12 Visit, or any study visit thereafter for 
patients on all dosing regimens, based on CP score, 
tolerability and safety laboratory tests from the previous 
visit.  Subsequent dose titration(s) may occur no earlier than 
6 weeks after the previous dose titration and will be based 
on tolerability and CP score. 
j 
Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry and at every 
visit.  If positive, a confirmatory blood test must be 
performed at the central laboratory.  If the confirmatory 
blood test is also positive, the patient may not continue in 
the study.  (Additional testing may be conducted where 
required, regionally) 
alcohol consumption history and current habits will be 
assessed quarterly after Week 48. 
g 
Child-Pugh Score will be calculated based on ascites 
assessment, hepatic encephalopathy grade, and central 
laboratory evaluations per the Child-Pugh scoring system 
noted in the eCRF. 
h 
The EQ-5D-5L Quality of Life questionnaire is validated 
for use in multiple languages. If a validated translation is not 
available in the local language required for a specific study 
patient, the questionnaire will not be collected.  The CLDQ 
measures change over time in patients with chronic liver 
disease.  
i 
New investigational product bottles will be dispensed 
if the patient is titrated. Unless up-titrated, patients are 
expected to use up each investigational product bottle 
before a new bottle will be dispensed.  No new bottles will 
be dispensed if dose frequency is changed.  Patients will be 
instructed to begin dosing on Day 1, after completing all 
study assessments.  Patients will be instructed to take 
investigational product at approximately the same time of 
day.  Patients must be instructed to swallow the tablet whole; 
they must not chew, divide, or crush the tablet. 
j 
Dose titration of investigational product may occur 
starting after the Week 12 Visit, or any study visit thereafter 
for patients on all dosing regimens, based on CP score, 
tolerability and safety laboratory tests from the previous visit.  
Subsequent dose titration(s) may occur no earlier than 
6 weeks after the previous dose titration and will be based on 
tolerability and CP score.   
k Urine β-hCG pregnancy tests must be performed in females 
of childbearing potential prior to entry and at every visit 
(except Week 3).  If positive, a confirmatory blood test must 
be performed at the central laboratory.  If the confirmatory 
blood test is also positive, the patient may not continue in the 
study.  (Additional testing may be conducted where required, 
regionally). 
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l The patient will be given the option to return to the 
clinic the following morning for the 24-hour postdose 
sample or samples can be obtained by a home health care 
designee.  Patients who are discontinued from 
investigational product prior to completion of the study 
are encouraged to continue to follow the regular visit 
schedule, with the exception of PK sampling.   
m The noninvasive radiological liver fibrosis 
measurement devices (such as, FibroScan® device 
[Echosens; Paris, France]) will be used at all study sites to 
collect hepatic stiffness measurements. 
n Patients will complete a TE/ELF and ultrasound 
assessment, every 6 months (±2 weeks) after Week 48. 
O ECG and urine dipstick will be done yearly 
(±2 weeks) after Week 48 Visit. 
p 
Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds:  Unless HCC has already been confirmed by 
biopsy, a second confirmatory image (eg, MRI) should be 
obtained to confirm suspected HCC. 
7.1.3, Study 
Duration 
The study will include a 14-day screening period and a 
48 week double-blind primary treatment period.  Following 
completion of the primary treatment period, patients will 
remain on blinded investigational product and be seen at 
regular intervals until all patients complete the primary 
treatment period (Figure 1).  Patients will have the option to 
continue into an open-label LTSE after all patients have 
completed the Week 48 procedures in which they will 
receive open-label treatment and be seen at regular visits 
every 3 months for up to 5 years. 
Patients will receive double-blind treatment for at least 
48 weeks.  Patients who have completed their 48-week 
double blind treatment period will continue double blind 
treatment until all randomized patients have completed 
their 48-week treatment period and the database for that 
period is locked (approximately 3 years).  Patients will 
then be given the option to go on open-label treatment. 
Updated 
description of 
study period. 
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7.3, Planned 
Dosing Regimen 
All patients will initiate investigational product once 
weekly with 5-mg OCA or matching placebo.  Starting at 
Week 12, safety and tolerability of investigational product 
will be evaluated and, if tolerated, the patient can increase 
the dose to the next dose level as described below 
(Table 2): 
• 
At Week 12, if investigational product is tolerated and 
laboratory assessments from the Week 6 visit do not 
indicate a safety concern, the patient will change the dosing 
frequency to 5 mg twice weekly, at least 3 days apart.  
 
Following an additional 6 weeks of treatment, if 
investigational product is tolerated, patients may be up 
titrated to OCA 10 mg twice weekly at least 3 days apart, 
the maximum dose for patients with CP-C 
 
 
Following an additional 6 weeks of treatment, if 
tolerated, patients with CP-B may titrate to a maximum 
dose of OCA 5 mg once daily, the maximum dose for 
patients with CP-B. 
 
All patients will initiate investigational product once weekly 
with 5-mg OCA or matching placebo.   Titration may be 
considered as early as the Week 12 visit.  Following visit 
procedures at Week 12, if the investigational product is 
tolerated and laboratory assessments do not indicate a safety 
concern, the patient will up-titrate to OCA 5 mg twice 
weekly and may start the higher dose regimen no earlier 
than 2 days after they took their last dose.  Dosing will 
then occur at least 3 days apart.  Every 6 weeks thereafter, 
based on safety and tolerability assessments, patients can 
be considered for further up titration as described below 
(Table 3).  At each titration visit, the patient may start the 
higher dose regimen no earlier than 2 days after the prior 
dose. 
 
Patients with CP-C may titrate to a maximum dose of OCA 
10 mg twice weekly at least 3 days apart.  
Patients with CP-B may titrate to a maximum dose of OCA 
5 mg once daily. 
Clarified 
dosing 
regimen. 
7.4, Dose 
Adjustment 
Criteria, 
Scheduled Dose 
Titration 
The first dose titration for any patient may occur no earlier 
than 12 weeks following initiation of OCA or matching 
placebo. 
After initiation of OCA or matching placebo, titration may 
be considered as early as the Week 12 visit.   
Clarified 
dosing 
regimen. 
7.4.1, Pre-
Titration 
Tolerability 
Assessment 
Requirements 
Tolerability of investigational product must be assessed 
prior to titrating a patient to a higher dose.  A review of 
AEs and available safety laboratory results (eg, chemistry, 
hematology, and coagulation) obtained within 
approximately 6 weeks of the up-titration visit must be 
performed as part of the investigational product tolerability 
assessment, prior to any planned up-titration in 
investigational product (eg, Week 6, laboratory results 
should be reviewed prior to titration at Week 12).  If for any 
reason, laboratory results are not available at the time of the 
Tolerability of investigational product must be assessed prior 
to titrating a patient to a higher dose.  To determine if a 
patient is eligible for a dose up-titration refer to 
Section 7.3 
Clarified 
dosing 
regimen. 
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planned up titration visit, additional laboratory samples 
must be obtained and reviewed, prior to up titrating the 
patient to a higher dose. 7.3 
To be eligible for a dose up-titration, patients should not be 
experiencing significant AEs that are suspected to be 
related to investigational product (eg, severe pruritus) or 
displaying other symptoms that may indicate intolerability 
of investigational product. 
7.4.2., Safety 
Criteria for 
Adjustment or 
Stopping Doses 
 
Investigational product may be temporarily decreased (eg, 
by decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability concerns.  The 
dose of investigational product should be resumed to the 
maintenance dose in a blinded manner once the issues 
relating to the lack of tolerability are resolved.   
Subjects who discontinue investigational product are 
expected to continue in the study (and follow the regular 
visit schedule) until the end of the study, and the study will 
only terminate at the time. 
 
This 
information 
has been 
incorporated 
into Section 
8.4, which 
was renamed  
8.4. Dose 
Adjustment, 
Interruption, 
and 
Withdrawal 
from 
Investigation
al Product or 
Study and 
additional 
text was 
added.  
8.4,  Dose 
Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
8.4  Patient Withdrawal Criteria 
 
(Insertion) 
Dose Adjustment, Interruption, and Withdrawal from 
Investigational Product or Study 
Investigational product may be temporarily decreased 
(eg, by decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability concerns.  The 
dose of investigational product should be resumed to the 
maintenance dose in a blinded manner once the issues 
relating to the lack of tolerability are resolved.   
Section 
revised to 
integrate 
withdrawal 
criteria in one 
section of 
protocol.  
Text was 
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Patients who are discontinued from investigational 
product prior to completion of the study are encouraged 
to continue to follow the regular visit schedule, with the 
exception of PK sampling, but may withdraw consent at 
any time. 
previously in 
Section 7.4.2. 
8.4.1. 
Reasons 
for Additional 
Monitoring or 
Mandatory 
Interruption of 
Investigational 
Product 
8.4.1. 
Reasons for Mandatory Discontinuation of 
Investigational Product 
Moved to 8.4.2 
 
 
8.4.1. 
Reasons for Additional Monitoring or Mandatory 
Interruption of Investigational Product 
Heading text 
updated.  
8.4.1.1, Reasons 
for Additional 
Monitoring 
Related to Liver 
Chemistries 
8.4.1.1. Pregnancy 
8.4.1.1. Reasons for Additional Monitoring Related to 
Liver Chemistries 
Patients who develop ALT or AST >2x baseline (and 
>ULN) or total bilirubin >1.5x baseline (and >ULN) 
should have repeat testing within 48 to 72 hours to 
confirm values.  Patients with persistent elevations (eg, 
additional lab testing per Investigator discretion) should 
be closely monitored.  Concomitant elevations in total 
bilirubin or INR with persistent increases in ALT or AST 
should also be closely monitored. 
Pregnancy 
moved to 
Section 
8.4.1.3.  New 
Section with 
text added. 
8.4.1.2. Reasons 
for 
Investigational 
Product 
Interruption 
Related to 
Elevated Liver 
Chemistries 
(Insertion) 
8.4.1.2. Reasons for Investigational Product Interruption 
Related to Elevated Liver Chemistries 
Development of any of the following clinical laboratory 
values, without explanation, during the study mandates 
investigational product interruption: 
• 
AST and/or ALT >3× baseline (and >ULN) 
• 
Total bilirubin >2× baseline (and >ULN) 
Repeat testing within 48 to 72 hours to confirm the 
abnormalities and to determine if they are increasing or 
decreasing should be performed.  Detailed adverse event 
information should also be collected, and the patient 
should be investigated for possible causes of the liver 
chemistry changes, as appropriate.  The Investigator 
New Section 
added to meet 
PMR 
requirements. 
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should obtain a history of concomitant medications 
(including nonprescription medications and herbal and 
dietary supplement preparations) and other possible 
causes of liver enzyme and bilirubin increases.  Any 
potentially hepatotoxic medications should be identified 
and discontinued if advisable.  
If symptoms persist or repeat testing shows AST or ALT 
>3× baseline (and >ULN) or total bilirubin >2× baseline 
(and >ULN), patients should be followed as clinically 
indicated depending on other laboratory and clinical signs 
and symptoms.   
For the purposes of this protocol, if the above referenced 
significant elevation in liver enzyme or bilirubin levels 
resolve following interruption of investigational product 
and no other cause for the elevation is identified, the 
elevations should be assumed to be related to 
investigational product and investigational product 
should be discontinued.  If the liver enzyme or bilirubin 
levels do not resolve following interruption of 
investigational product and no other cause for the 
elevation is identified, it may be assumed that the 
elevations were due to disease progression and the patient 
may be re-challenged following a discussion between the 
Investigator or designee and the Sponsor. 
Elevation of liver enzymes or bilirubin is based on 
comparison to baseline values defined as the mean of all 
available Screening and Day 0 values, which are the mean 
of all available evaluations prior to the first 
administration of investigational product.  At least 2 of 
these samples will be obtained a minimum of 2 weeks 
apart during the Screening period.  Elevations that occur 
gradually over the course of the study may be indicative 
of disease progression and should be assessed as clinically 
appropriate.  Liver enzyme and bilirubin elevations that 
occur over a shorter time, such as within a 6-month 
period, should be evaluated for drug-induced liver injury 
as provided in the guidelines below. 
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If at any time a patient develops signs or symptoms of 
hepatotoxicity such as new onset fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>7%) in combination with 
elevations in liver enzymes, investigational product should 
be interrupted and liver enzymes monitored until signs or 
symptoms resolve.  
Patients who develop evidence of severe drug-induced 
liver injury that is suspected to be causally related to the 
investigational product should be discontinued from 
investigational product and should not be rechallenged.  
Severe drug-induced liver injury includes, but is not 
limited to, functional hepatic impairment, as indicated by 
rising bilirubin or INR that cannot be explained by 
progression of disease.  Natural progression of the 
underlying condition and other causal factors such as a 
common bile duct stone or development of other 
concurrent liver disease should be considered before the 
investigational product is permanently discontinued.  
If after all investigations and actions outlined above have 
been completed, the investigator determines that the 
elevations in liver biochemistries are considered not 
related to investigational product, the Sponsor must be 
contacted before investigational product can be 
reinitiated.  Follow-up procedures for patients resuming 
treatment, including laboratory evaluations and physical 
examinations, must be performed after a maximum of 2 
weeks of retreatment.  Results must be reported to the site 
as soon as possible so the Investigator can determine if it 
appropriate for the patient is to continue treatment.   
The Medical Monitor must be contacted in all cases of 
persistent liver biochemistry elevations. 
All hepatic injury events, regardless of relationship to 
investigational product, will be adjudicated by the 
Hepatic Safety Committee (see Section 15.9) 
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8.4.1.3, 
Pregnancy 
(Insertion) 
Whenever the site is notified of a possible pregnancy, the 
patient should be asked to come in for an unscheduled visit 
to perform a serum pregnancy test.  If a female patient 
becomes pregnant, the patient must stop taking 
investigational product immediately and be withdrawn from 
the study… 
8.4.1.3. Pregnancy 
If a female patient becomes pregnant, she must interrupt 
treatment with investigational product immediately, but 
should continue with the study visit schedule.  As 
described in Section 13.1.10 pregnancy is not considered 
an AE for reporting purposes.  The patient may restart 
investigational product when she is no longer pregnant or 
breastfeeding (if applicable) at the discretion of the 
Investigator and after discussion with the Medical 
Monitor as described in Section 13.1.10).  New baseline 
procedures should include pregnancy testing. 
Was Section 
8.4.1.1 
8.4.2,  Reasons 
for Mandatory 
Discontinuation 
of 
Investigational 
Product 
8.4.2. 
Other Reasons for Discontinuation of 
Investigational Product or Study Termination 
8.4.2. 
Reasons for Mandatory Discontinuation of 
Investigational Product 
Patients who undergo a liver transplant during the course 
of the study must discontinue investigational product and 
discontinue the study visit schedule.  However, these 
patients should be encouraged to consent to the 
semiannual telephone contact and/or continued record 
review only to allow for secondary outcome events data to 
be collected. 
Now Section 
8.4.3 and text 
added. 
 
8.4.2.3. Elevated Liver Enzymes 
Section deleted. 
Information 
in 8.4.1.2 
now covers 
this. 
8.4.3,  Other 
Reasons for 
Discontinuation 
of 
Investigational 
Product or Study 
Termination   
 
Subjects who discontinue investigational product are 
expected to continue in the study until the end of the study 
or at the discretion of the Sponsor.  If a patient experiences 
a suspected clinical outcomes event, he or she should 
continue the regular visit schedule and continue taking 
investigational product as long as the Investigator assesses 
it as safe.   
Early termination procedures should only be conducted if 
the patient withdraws consent (See Section 9.7.14).   
8.4.3. 
Other Reasons for Discontinuation of 
Investigational Product or Study Termination 
The following events are considered appropriate reasons for a 
patient to discontinue investigational product; however, 
these patients are expected to continue in the study until 
study termination (or at the discretion of the Sponsor): 
• 
Patient begins treatment with commercially available 
OCA. 
• 
The Investigator or Sponsor considers that it is 
advisable or in the best interest of the patient. 
Was Section 
8.4.2 and 
additional 
text added. 
Page 523 of 603


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 4: 1 5  Fe b 2 0 1 9  
 
P a ge 1 1 8  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al  Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d  Te xt ( Versi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
It is a gree d t hat, f or reas o na bl e ca use, eit her t he 
I n vesti gat or or t he S p o ns or, ma y ter mi nate t his st u d y. 
T he f oll o wi n g e ve nts are c o nsi dere d a p pr o priate reas o ns f or 
a s u bj ect t o disc o nti n ue fr o m t he s t u d y: 
• 
T he occ urre nce of cli nic al or l a b or at or y A Es 
c o nsi dere d b y t he I n vest i g at or t o be cli nic all y i m p ort a nt 
s afet y c o ncer ns a n d rel ate d t o st u d y dr u g. 
• 
Wit h dr a w al of c o nse nt  
 
C o nse nt m a y be f ull y wit h dr a w n (i n w hic h c ase 
t he p atie nt disc o nti n ues b ot h i n vesti g ati o n al 
pr o d uct a n d st u d y visits a n d pr oce d ures).  
 
C o nse nt m a y be m o dif ie d t o disc o nti n ue st u d y 
visits b ut all o w se mi -a n n u al tele p h o ne c o nt act.  
 
C o nse nt m a y be m o difie d t o disc o nti n ue st u d y 
visits or se mi -a n n u al tele p h o ne c o nt act b ut all o w 
c o nti n ue d access t o me dic al rec or ds t o assess f or 
s us pecte d m aj or a d verse c ar di o v asc ul ar e ve nts 
( M A C E) a n d li ver-rel ate d cli nic al o utc o mes.  
 
E arl y ter mi n ati o n pr oce d ur es s h o ul d be 
c o n d ucte d if t he p atie nt wit h dr a ws c o nse nt ( See 
Secti o n 9. 7. 1 2)  
8. 4. 3. 1.
 
Wit h dra wal 
of C o nse nt t o 
C o nti n ue i n t he 
St u d y  
8. 4. 3. 1.  Wit h dra wal of C o nse nt  
…  t heir c o nse nt t o c o nti n ue i n t he st u dy at a n y ti me  
(I nserti o n) 
A reas o na ble eff ort m ust be ma de t o …  
8. 4. 3. 1.  Wit h dr a w al of C o nse nt t o C o nti n ue i n t he St u d y  
 
E arl y ter mi n ati o n pr oce d ur es s h o ul d be c o n d ucte d if t he 
p atie nt wit h dr a ws c o nse nt ( See Secti o n 9. 7. 1 2 ). 
A d de d m ore 
i nf or mati o n 
re gar di n g 
wit h dra wal 
fro m st u d y.  
8. 4. 3. 2.  L ost t o 
F oll o w -U p  
8. 4. 2. 2.  L ost t o F oll o w -U p  
If a patie nt fails t o ret ur n t o t he cli nic f or a st u d y visit, a n d 
t he I n vesti gat or ceases t o ha ve c o ntact wit h t he patie nt, he 
or s he  will be wit h dra w n fr o m t he st u d y . 
8. 4. 3. 2.  L ost t o F oll o w -U p  
P atie nts will be  c o nsi dere d “l ost t o f oll o w u p ” o nl y after 
d oc u me nte d atte m pts t o re ac h t he p atie nt pr o ve 
u ns uccessf ul.   
U p date d te xt.  
8. 4. 4,  P atie nt 
Disc o nti n uati o n 
N otificati o n  
8. 4. 3. 
P atie nt Disc o nti n uati o n N otifi cati o n  
T he I n vesti g at or m ust n otif y t he S p o ns or as s o o n as 
p ossi ble if a n y patie nt pre mat urel y disc o nti n ues fr o m t he 
st u d y.  T he date w he n t he pati e nt is wit h dra w n a n d t he 
8. 4. 4 . 
P atie nt Disc o nti n uati o n N otifi cati o n  
T he I n vesti gat or m ust n otif y t he S p o ns or as s o o n  as p ossi bl e  
if a n y patie nt pre mat urel y disc o nti n ues fr o m t he st u d y.  T he 
date w he n t he patie nt is wit h dra w n a n d t he pri mar y reas o n(s) 
Clarifie d te xt.  
Pa ge 5 2 4 of 6 0 3


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Key Change 
primary reason(s) for discontinuation must be recorded in 
the eCRF; additional information may be requested by the 
Sponsor to complete a discontinuation narrative.  Patients 
will be considered “lost to follow up” only after reasonable, 
documented attempts to reach the patient prove 
unsuccessful.  In all cases, a reasonable effort must be made 
to determine the reason(s) that a patient fails to return for 
required study visits or discontinues from the study.  This 
information must be documented in the eCRF. 
for discontinuation must be recorded in the eCRF; additional 
information may be requested by the Sponsor to complete a 
discontinuation narrative.  This information must be 
documented in the eCRF. 
9.2, Concomitant 
Medications 
Patients must follow the medication restrictions outlined in 
the inclusion and exclusion criteria (Section ) during the 
study. 
Concomitant medications will be used at the discretion of 
the usual care provider (or Investigator if also the usual care 
provider).  … taken prior to (ie, within 30 days of 
Screening) and …  Concomitant medications should be 
stable prior to Day 1 (ie no change in dosing within 
3 months of screening). 
Concomitant medications (other than prohibited 
concomitant medications listed in Section 9.2.2) will be 
used at the discretion of the usual care provider (or 
Investigator if also the usual care provider).  … taken within 
30 days of Screening and during the study must be recorded 
in the source documents and …  Concomitant medications 
should be stable prior to Day 1. 
Clarified use 
of 
concomitant 
meds. 
9.2.1, Drug 
Interactions 
Patients taking bile acid sequestrants (BAS, including 
cholestyramine and its derivatives, colestipol, colesevelam, 
or other sequestrants) or aluminum hydroxide- or smectite-
containing antacids should be instructed to stagger their 
dosing of investigational product and UDCA, ensuring at 
least 4 hours between doses of the BAS and/or these 
antacids and the investigational product (and UDCA; ie, 
BAS should be administered at minimum 4 hours before or 
4 hours after investigational product administration). 
Bile acid sequestrants (BAS, including cholestyramine and its 
derivatives, colestipol, colesevelam, or other sequestrants) or 
aluminum hydroxide- or smectite-containing antacids should 
not be taken within 4 hours of taking investigational 
product (and UDCA if applicable), ie, BAS should be 
administered at minimum 4 hours before or 4 hours after 
investigational product administration).   
Clarified use 
of 
concomitant 
meds. 
9.2.2, Prohibited 
Medications 
Patients who continue with commercial OCA therapy must 
discontinue investigational product and are expected to 
continue through the end of the study (see Section 8.4.2).  
Fibric acid derivatives (fibrates) and other medication 
intended to lower blood triglyceride levels are also 
prohibited while on investigational product.) 
Patients who continue with commercial OCA therapy must 
discontinue investigational product and are expected to 
continue through the end of the study (see Section 8.4.3).   
Some patient 
may be 
expected to 
be on 
fibrates. 
9.4.2, Blinding 
The patients, Investigator, and study site staff will be 
blinded to… 
The Sponsor, patients, Investigator, and study site staff will 
be blinded to… 
 
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Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
9.6, Restrictions 
Participation in another investigational product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the study is prohibited.   
Participation in another investigational product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the study is prohibited.  Previous 
exposure to OCA (as a study participant or received 
commercial OCA therapy) is allowed within 3 months 
prior to enrollment in this study 
Updated to 
include 
patients who 
may be on 
prescribed 
OCA and 
who received 
investigationa
l OCA as 
study 
participants. 
9.7.1, Visit 
Procedures 
(Insertion) 
Visit windows are specified in the Schedule of Study 
Procedures (Table 1). 
Added text 
pointing to 
visit windows 
for study 
procedures. 
9.7.2, Informed 
Consent 
Procedures 
…The patient must be willing and able to provide written 
informed consent (on hard copies or on electronic devices 
such as iPads) before entering the study.   
The patient must be willing and able to provide written 
informed consent (on hard copies) before entering the study.   
Updated 
language. 
9.7.3, Assessing 
Cirrhosis 
To determine which dosing regimen patients should follow, 
cirrhosis should be assessed by the Investigator at 
Screening Visit 1.  Acceptable methods of confirming (via 
medical history) or assessing cirrhosis for purposes of the 
study are defined as a patient who has documented 
evidence or presence of one or more of the following 
cirrhosis indicators: 
 
varices 
 
Patients will be dosed according to their CP Score 
calculated in the eCRF (see Section 14.1.1 and Table 12). 
Cirrhosis status should be reassessed as clinically indicated 
throughout the study.  Any change in cirrhosis status will 
necessitate re-evaluation of the dosing regimen. 
Acceptable methods of confirming (via medical history) or 
assessing cirrhosis for purposes of the study are defined as a 
patient who has documented evidence or presence of one or 
more of the following cirrhosis indicators: 
 
 
Gastroesophageal varices 
Clarified 
assessment 
instructions. 
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Original Text (Version 1, 20 Dec 2016) 
Revised Text (Version 2, 22 May 2017) 
Key Change 
9.7.4, Screening 
Procedures 
Screening Procedures (-1 day to 14 days prior to Day 1) 
Screening Procedures (14 days to 28 days prior to Day 1) 
Updated 
procedures to 
match 
updated 
protocol 
design. 
The Screening Visit assessments must be performed within 
≤14 days prior to Day 1 to… 
The Screening Visit assessments must be performed ≥14 days 
prior to Day 1 to… 
The patient is to review and sign the ICF 
 
• 
Verify that the patient has fasted for at least 8 hours. 
 
Record fasting status in the source and eCRF 
 
If the patient reports having eaten within 
8 hours, document accordingly in the source and 
eCRF and remind the patient that fasting is 
required prior to all study visits 
• 
Obtain blood samples for serum chemistry, 
hematology, and coagulation tests. 
 
• 
Perform a physical examination. 
Perform a physical examination, including smoking and 
alcohol consumption history, and current habits for both. 
(Insertion) 
• 
Record the visit in IWRS 
 
Perform TE using the Fibroscan® TE device.  If TE has 
been done within 3 months of Day 1 and a 
report/adequate data are available, a pretreatment TE at 
Day 1 is not required.  If the TE cannot be performed on 
Day 1 (eg, device/technician unavailability, scheduling 
issues, TE data is needed to inform cirrhosis assessment, 
etc.), the procedure may be completed within the Day 1 
Visit window, (if data is needed for cirrhosis 
assessment) or as close as possible to the Day 1 Visit, 
preferably, after patient eligibility has been confirmed.  
Instruct the patient to take Day 1 dose on the day of this 
visit. 
 
 
Perform TE using the Fibroscan® TE device.  If the TE 
cannot be performed on Day 1 (eg, device/technician 
unavailability, scheduling issues, TE data is needed to 
inform cirrhosis assessment, etc.), the procedure may be 
completed within the Day 1 Visit window, (if data is 
needed for cirrhosis assessment) or as close as possible to 
the Day 1 Visit, preferably, after patient eligibility has 
been confirmed.  Instruct the patient to take Day 1 dose on 
the day of this visit. 
 
Page 527 of 603


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 4: 1 5  Fe b 2 0 1 9  
 
P a ge 1 2 2  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al  Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d  Te xt ( Versi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
• 
Pr o vi de kits a n d i nstr ucti o ns f or c ollecti o n of st o ol 
s peci me ns at h o me pri or t o t he Da y 1 visit 
 
P erf or m a n ultras o u n d f or H C C s ur veilla nce (if e q ui p me nt 
is u na vaila ble, sites s h o ul d ma ke e ver y atte m pt t o use 
a vaila ble c o m m u nit y referral sites).  If a n ultras o u n d has 
bee n d o ne wit hi n 1 2 m o nt hs of Scree ni n g, a n d a 
re p ort/a de q uate data are a vaila ble, a pretreat me nt 
ultras o u n d at Scree ni n g is n ot re q uire d.  If t he ultras o u n d 
ca n n ot be perf or me d at Scree ni n g (e g, de vice/tec h nicia n 
u na vaila bilit y, sc he d uli n g iss ues, etc), t he pr oce d ure ma y 
be c o m plete d a n yti me wit hi n t he scree ni n g visit wi n d o w 
or o n Da y 0.  Res ults fr o m t he scree ni n g ultras o u n d s h o ul d 
be re vie we d t o assess p ossi ble e xcl usi o n criteria pri or t o 
ra n d o mizati o n. 
 
Clarifie d 
sa m pli n g 
pr oce d ure s. 
9. 7. 5, Da y 1 
Pr oce d ures  
 O btai n bl o o d sa m ples f or  mar kers of i nfla m mati o n  
 E L F (i ncl u di n g H A, P 3 N P, a n d TI M P -1)  
 Tr o u g h  P K assess me nt  
Mar kers of i nfla m mati o n a n d fi br osis (I L -6, hs -C R P, T N F -α, 
I g M, I g G, I g A, C K - 8-M 3 0, H A, P 3 N P, a n d TI M P 1)  
F asti n g  P K assess me nt  
Clarifie d 
sa m pli n g 
pr oce d ures  
…, after patie nt eli gi bilit y has bee n c o nfir me d  
… after patie nt eli gi bilit y has bee n c o nfir me d.  
I nstr uct  t he 
p atie nt t o t a ke D a y 1 d ose o n t he d a y of t his visit.  
Clarifie d 
pr oce d ures  
• 
Rec or d t he visit i n I W R S a n d dis pe nse i n vesti gati o nal 
pr o d uct  
 
I nstr uct t he patie nt t o be gi n d osi n g o n t he da y.  
 
 
 
( Sec o n d t o last b ullet)  …t he pr oce d ure ma y be c o m plete d 
wit hi n t he Da y 1 visit wi n d o w, (if data is nee de d f or 
cirr h osis assess me nt) or as cl ose as p ossi ble t o t he Da y 1 
visit, prefera bl y, after patie n t eli gi bilit y has bee n c o nfir me d.  
 
Rec or d t he visit i n I W R S a n d dis pe nse i n vesti gati o nal 
pr o d uct  
 I nstr uct t he patie nt t o be gi n d osi n g o n t he da y of t he 
D a y 1 visit.  
 
…t he  pr oce d ure  ma y  be  c o m plete d  wit hi n  t he  Da y  1  visit 
wi n d o w, (if data is nee de d f or cirr h osis assess me nt) or as cl ose 
as  p ossi ble  t o  t he  Da y  1  visit,  prefera bl y,  after  patie nt 
eli gi bilit y  has bee n c o nfir me d.  I nstr uct t he p atie nt t o t a ke 
D a y 1 d ose o n t h e d a y of t his visit.  
U p date d 
pr oce d ures t o 
matc h 
u p date d 
pr ot oc ol 
desi g n.  
Pa ge 5 2 8 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 4: 1 5  Fe b 2 0 1 9  
 
P a ge 1 2 3  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al  Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d  Te xt ( Versi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
9. 7. 6, W ee k 3 
Sa fet y Visit 
Pr oce d ures  
W ee k 3 (Safet y  C o ntact)  
W ee k 3  Safet y  Visit Pr oce d u res  
U p date d 
pr oce d ures t o 
matc h 
u p date d 
pr ot oc ol 
desi g n per 
P M R 
re q uire me nts. 
P atie nts s h o ul d be c o ntacte d b y tele p h o ne at W ee k 3 t o 
assess f or A Es a n d verif y t hat s/ he  is d osi n g as directe d.  
• 
C o ntact  patie nt b y p h o ne/e mail . 
Prefer a bl y, t he p atie nt will c o me i n t o t he cli nic f or t his 
visit.  Alter n ati vel y, t he site will tele p h o ne t he p atie nt f or 
assess me nts a n d a h o me he alt h n urse will visit t o dr a w 
s afet y l a bs.  
Verif y t h at p atie nt  is d osi n g as directe d. 
• 
Verif y t h at t he patie nt  h as f aste d f or at le ast 8  h o urs.  
 Rec or d f asti n g st at us i n t he s o urce a n d e C R F  
• If t he p atie nt re p orts h a vi n g e ate n wit hi n 8 h o urs, 
d oc u me nt acc or di n gl y i n t he s o urce a n d e C R F a n d 
re mi n d t he p atie nt t h at f asti n g is re q uire d pri or t o all 
st u d y visits. 
• Re vie w a n d rec or d pri or c o nc o mit a nt me dic ati o ns.  
• Assess a n d rec or d A Es.  
• Re vie w a n d rec or d a n y n o n -st u d y rel ate d me dic al or 
s ur gic al tre at me nt pr oce d ur es a n d a n y me dic all y 
rele v a nt H C P or n o n -H C P rel ate d office visits t h at 
h a ve occ urre d si nce t he pre vi o us st u d y visit.  
• Assess i n vesti g ati o n al pr o d u ct c o m pli a nce, perf or m 
i n vesti g ati o n al pr o d uct acc o unt a bilit y  
 
• O bt ai n bl o o d s a m ples f or  
 Ser u m c he mistr y, he m at ol o g y, a n d c o a g ul ati o n  
 
Sc he d ule t he ne xt visit, reite r ate d osi n g i nstr ucti o ns, a n d 
a d vise t he p atie nt:  
 
Wee k 6 visit s h o ul d occ ur 3, 4, or 5 d a ys after t a ki n g t he 
Wee k 6 d ose, e g if t he Wee k 6 d ose is t a ke n o n a S u n d a y, 
t he p atie nt s h o ul d c o me i n f or t he Wee k 6 visit wit hi n t he 
f oll o wi n g We d nes d a y a n d Fri d a y ( Fi g ure 2). 
 
•   
 
N O T t o t a ke i n vesti g ati o n al pr o d uct o n t he m or ni n g 
of t he ne xt visit, a n d  
Pa ge 5 2 9 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 4: 1 5  Fe b 2 0 1 9  
 
P a ge 1 2 4  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al  Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d  Te xt ( Versi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
 
T o bri n g t he i n vesti g ati o n al pr o d uct b ottle(s); s/ he 
will d ose at t he cli nic (if t his is i n c o m pli a nce wit h 
t he est a blis he d d osi n g fre q u e nc y), a n d 
 
T o f ast o ver ni g ht ( at le ast 8 h o urs) pri or t o t he ne xt 
visit.  F asti n g is re q uire d pri or t o all st u d y visits, b ut 
w ater is per mitte d.  
9. 7. 8, W ee k 9 
t hr o u g h W ee k 4 8 
( Safet y C o ntact) 
(I nserti o n) 
P atie nts s h o ul d be c o nt acte d b y tele p h o ne/e m ail at Wee k 
9 a n d e ver y 3 w ee ks after w ar d t o Wee k 4 8 . 
• 
C o nt act p atie nt b y p h o ne/e m ail.  
• 
Re vie w a n d rec or d pri or c o nc o mit a nt me dic ati o ns.  
• 
Assess a n d rec or d A Es.  
• 
Re vie w a n d rec or d a n y n o n -st u d y rel ate d me dic al or 
s ur gic al tre at me nt pr oce d ur es a n d a n y me dic all y 
rele v a nt H C P or n o n -H C P rel ate d office visits t h at 
h a ve occ urre d si nce t he pre vi o us st u d y visit.  
• 
Assess i n vesti g ati o n al pr o d u ct c o m pli a nc e, perf or m 
i n vesti g ati o n al pr o d uct acc o u nt a bilit y. 
Secti o n 
a d de d t o 
pr o vi de 
g ui da nce f or 
tele p h o ne/e m
ail safet y 
c o ntact.  
9. 7. 9 ,  W ee k 1 2, 
W ee k 2 4, W ee k 
3 6 Pr oce d ures  
W ee k 1 2 Pr oce d ures  
 
 
 
 
 
 
 
 
 
O btai n bl o o d sa m ples f or mar kers of i nfla m mati o n  
 
E L F (i ncl u di n g H A, P 3 N P, a n d TI M P-1)  
 
C 4, a n d  F G F -1 9, bile aci ds  
 
Tr o u g h  P K assess me nt  
 
W ee k 1 2, Wee k 2 4, Wee k 3 6  Pr oce d ures  
• 
Assess i n vesti g ati o n al pr o d u ct c o m pli a nce, perf or m 
i n vesti g ati o n al pr o d uct acc o u nt a bilit y 
• 
Dis pe nse i n vesti g ati o n al pr o d uct o nl y if t here is d ose 
i ncre ase or as nee de d. N o ne w i n vesti g ati o n al pr o d uct 
b ottles will be dis pe nse d if t here is o nl y c h a n ge i n 
d osi n g fre q ue nc y of t he s a me d ose le vel. P atie nts are 
e x pecte d t o use u p e ac h i n vesti g ati o n al pr o d uct b ottle 
bef ore a ne w b ottl e will be dis pe nse d.  
• 
Assess f or d ose titr ati o n,  if eli gi ble. ( Refer t o 
Secti o n  7. 3)  
 O btai n bl o o d sa m ples f or  
 
Ser u m c he mistr y, he m at ol o g y, a n d c o a g ul ati o n   
 
M ar kers of I nfl a m m ati o n (I L -6, hs -C R P, T N F -α, 
I g M, I g G, I g A, C K-1 8 -M 3 0)  
 
Bile Aci d / C 4/ F G F-1 9  
U p date d 
pr oce d ures t o 
matc h 
u p date d 
pr ot oc ol 
desi g n.  
Pa ge 5 3 0 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 4: 1 5  Fe b 2 0 1 9  
 
P a ge 1 2 5  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al  Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d  Te xt ( Versi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
 
F asti n g P K assess me nt  
• 
Perf or m a uri ne -b ase d β -h C G pre g n a nc y test i n 
fe m ales of c hil d be ari n g p ote nti al. 
 
Perf o r m T E usi n g t he Fi br osc a n ® T E de vice.  If t he 
T E c a n n ot be perf or me d o n visit d a y (e g, 
de vice/tec h nici a n u n a v ail a bilit y, sc he d uli n g iss ues, 
T E d at a is nee de d t o i nf or m cirr h osis assess me nt, 
etc.), t he pr oce d ure m a y  be c o m plete d wit hi n t he 
visit wi n d o w (if d at a is nee de d f or cirr h osis 
assess me nt) or as cl ose as p ossi ble t o t he visit.  
• 
Serial P K assess me nt; t he f oll o wi n g pr oce d ures will be 
c o n d ucte d i n all patie n ts 
• 
Serial P K assess me nt at Wee k 1 2 a n d 2 4 O N L Y ( n ot 
d o ne at Wee k 3 6  a n d Wee k 4 2 ); t he f oll o wi n g pr oce d ures 
will be c o n d ucte d i n all patie nts  
U p date d 
pr oce d ures t o 
matc h 
u p date d 
pr ot oc ol 
desi g n.  
9. 7. 9,  W ee k 1 2, 
W ee k 2 4, W ee k 
3 6 Pr oce d ures  
N ote:  P atie nt s s h o ul d n ot  c o ns u me a n y f o o d f or t he 
d ura ti o n of t he 6- h o ur P K assess me nts e xce pt t he meal 
re place me nt dri n k.   
N ote:  P atie nts s h o ul d o nl y c o ns u me me al f oll o wi n g t he 
4- h o ur a n d 7 - h o ur P K assess me nt ti mes (see Fi g ure 3).   
A d de d m ore 
sa m pli n g 
ti mes. 
I nserti o n 
 
P erf or m a n ultras o u n d f or H C C s ur v eilla nce at Wee k 2 4 
O N L Y  (if e q ui p me nt is u na vaila ble, sites s h o ul d ma ke 
e ver y atte m pt t o use a vaila ble c o m m u nit y referral sites).  
 
 
• 
Assess t he patie nt’s s u p pl y of i n vesti gati o nal pr o d uct 
t o e ns ure a n a de q uate a m o u nt.  
delete d  
Delete d f or 
clarit y.  
9. 7. 1 0   W ee k 1 8 
a n d W ee k 3 0 
Pr oce d ures  
 
 
 
 
 
A d de d t he f oll o wi n g pr oce d ure:  
• 
Dis pe n se i n vesti g ati o n al pr o d uct o nl y if t here is d ose 
i ncre ase or as nee de d. N o ne w I P b ottles will be dis pe nse d 
if t here is o nl y c h a n ge i n d osi n g fre q ue nc y of t he s a me 
d ose le vel. P atie nts are e x pecte d t o use u p e ac h  I P b ottle 
bef ore a ne w b ottle will be dis pe nse d.   
Secti o n 
mer ge d i nt o 
9. 7. 8, 
a d diti o nal P K 
assess me nts 
a d de d per 
Pa ge 5 3 1 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 4: 1 5  Fe b 2 0 1 9  
 
P a ge 1 2 6  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al  Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d  Te xt ( Versi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
 O btai n bl o o d sa m ples f or mar kers of i nfla m mati o n 
 
E L F (i ncl u di n g H A, P 3 N P, a n d TI M P -1)  
 
C 4, a n d  F G F -1 9, bile aci ds  
 
Tr o u g h  P K assess me nt  
 
 
 
 
 
 
 
 
 
C ollect bl o o d sa m ples a t: 1. 5, 2, 2. 5, 3, 4, 5, 6 h o urs 
p ost d ose  
 O btai n bl o o d sa m ples f or 
 
Ser u m c he mistr y, he m at ol o g y, a n d c o a g ul ati o n  
 
M ar kers of i nfl a m m ati o n a n d fi br osis (I L 6, 
hs -C R P, T N F α, I g M, I g G, I g A, C K 1 8 M 3 0, 
E L F [ H A, P 3 N P, a n d TI M P 1])  
 
F asti n g P K assess me nt  
 
Bile Aci d/ C 4/ F G F -1 9  
• 
Serial P K assess me nt at Wee k 1 2 a n d 2 4 O N L Y ( n ot 
d o ne at Wee k 3 6) ; t he f oll o wi n g pr oce d ures will be 
c o n d ucte d i n all patie nts:  
 
 
 
C ollect bl o o d s a m ples at: 1. 5, 2, 2. 5, 3, 4, 5, 6 7, 8, 9, 
a n d 2 4  h o urs p ost d ose  
P M R 
re q uire me nts. 
N ote:  P atie nts s h o ul d n ot  c o ns u me a n y f o o d f or t he 
d urati o n of t he 6- h o ur P K assess me nts e xce pt t he meal 
re place me nt dri n k.   
N ote:  P atie nts s h o ul d o nl y c o ns u me a me al f oll o wi n g t he 
4- h o ur a n d 7 - h o ur P K assess me nt ti mes  (see Fi g ure 3).   
A d de d m ore 
sa m pli n g 
ti mes. 
9. 7. 1 0, W ee k 2 4 
Pr oce d ures  
9. 7. 1 0, W ee k 2 4 Pr oce d ures  
delete d  
I nc or p orate d 
i nt o Secti o n 
9. 7. 8  
9. 7. 1 1 , W ee k 4 8 
Pr oce d ures  
9. 7. 1 2 
9. 7. 1 0, Wee k 4 8 Pr oce d ures  
U p date d 
la n g ua ge. 
• 
P erf or m a p h ysical e xa mi nati o n,  
• 
P erf or m a p h ysical e xa mi nati o n, i ncl u di n g s m o ki n g a n d 
alc o h ol c o ns u m pti o n hist or y, a n d c urre nt h a bits f or b ot h  
Clarif y st u d y 
pr oce d ures.  
Pa ge 5 3 2 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 4: 1 5  Fe b 2 0 1 9  
 
P a ge 1 2 7  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al  Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d  Te xt ( Versi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
(I nserti o n) 
• 
Assess i n vesti g ati o n al pr o d u ct c o m pli a nce, perf or m 
i n vesti g ati o n al pr o d uct acc o u nt a bilit y. 
• 
Dis pe nse i n vesti g ati o n al pr o d uct o nl y if t here is d ose 
i ncre ase or as nee de d.  N o ne w i n vesti g ati o n al 
pr o d uct b ottles will be dis pe nse d if t here i s o nl y 
c h a n ge i n d osi n g fre q ue nc y of t he s a me d ose le vel.  
P atie nts are e x pecte d t o use u p e ac h i n vesti g ati o n al 
pr o d uct b ottle bef ore a ne w b ottle will be dis pe nse d . 
• 
Assess f or d ose titr ati o n, i f eli gi ble (refer t o 
Secti o n  7. 3)  
 
Perf or m a n ultr as o u n d f or H C C s ur veill a nce (if 
e q ui p me nt is u n a v ail a ble, sites s h o ul d m a ke e ver y 
atte m pt t o use a v ail a ble c o m m u nit y referr al sites).  
 
Clarif y st u d y 
pr oce d ures.  
O btai n bl o o d sa m ples f or mar kers of i nfla m mati o n 
 
E L F (i ncl u di n g H A, P 3 N P, a n d TI M P -1)  
 
C 4, a n d  F G F -1 9, bile aci ds  
 
Tr o u g h  P K assess me nt  
 
• 
Perf or m uri n al ysis ( di pstic k)  
 
O btai n bl o o d sa m ples f or  
 
Ser u m c he mistr y, he m at ol o g y, a n d c o a g ul ati o n  
 
M ar kers of i nfl a m m ati o n a n d fi br osis (I L 6, hs -
C R P, T N F α, I g M, I g G, I g A, C K 1 8 M 3 0, E L F 
[ H A, P 3 N P, a n d TI M P 1]) 
 
F asti n g P K assess me nt  
 
Bile Aci d/ C 4/ F G F -1 9  
Clarif y st u d y 
pr oce d ures.  
• 
Serial P K assess me nt; will o nl y  be c o n d ucte d i n 
patie nts w h o are u ptitrati n g t o t he ne xt d ose le vel.  
• 
Serial P K assess me nt; t he f oll o wi n g pr oce d ures will be 
c o n d ucte d i n all  patie nts.  
U p date d 
la n g ua ge. 
 
 
I m me diatel y f oll o wi n g 1 hr p ost d ose bl o o d dra w, 
a d mi nister meal re pla ce me nt (t o be c o ns u me d wit hi n 
5 – 1 0  mi n utes)  
A d de d m ore 
sa m pli n g 
ti mes. 
Pa ge 5 3 3 of 6 0 3


Pr ot oc ol 7 4 7 -4 0 1  
Versi o n 4: 1 5  Fe b 2 0 1 9  
 
P a ge 1 2 8  
 
C o nfi de ntial a n d Pr o prietar y    
Secti o n  
Ori gi n al  Te xt ( Versi o n 1, 2 0 Dec 2 0 1 6)  
Re vise d  Te xt ( Versi o n 2, 2 2  M a y  2 0 1 7)  
Ke y C h a n ge  
 C ollect bl o o d sa m ples at: 1. 5, 2, 2. 5, 3, 4, 5, 6, 7, 8, 9, 
a n d 2 4 h o urs p ost d ose.   
N ote:  P atie nts s h o ul d n ot  c o ns u me a n y f o o d f or t he 
d urati o n of t he 6- h o ur P K assess me nts e xc e pt t he meal 
re place me nt dri n k.   
N ote:  P atie n ts s h o ul d o nl y c o ns u me me al f oll o wi n g t he 
4- h o ur a n d 7 - h o ur P K assess me nt ti mes (see Fi g ure 3) .   
A d de d m ore 
sa m pli n g 
ti mes. 
P erf or m T E usi n g t he Fi br osc a n ® T E de vice.   
P erf or m T E usi n g t he Fi br osc a n ® T E de vice.  If t he T E 
c a n n ot be perf or me d o n visit d a y (e g, de vice/tec h nici a n 
u n a v ail a bilit y, sc he d uli n g iss ues, T E  d at a is nee de d t o 
i nf or m cirr h osis assess me nt, etc.), t he pr oce d ure m a y be 
c o m plete d wit hi n t he visit wi n d o w  (if d at a is nee de d f or 
cirr h osis assess me nt) or as cl ose as p ossi ble t o t he visit . 
Clarifie d 
pr oce d ural 
i nstr ucti o ns. 
• 
Assess t he patie nt’s s u p pl y of i n vesti gati o nal pr o d uct 
t o e ns ure a n a de q uate a m o u nt.   
 
Clarifie d 
pr oce d ural 
i nstr ucti o ns 
• 
Sc he d ul e t he f oll o w-u p  visit a n d a d vise t he patie nt:  
• 
Sc he d ule t he ne xt visit , reiter ate d osi n g i nstr ucti o ns , 
a n d a d vise t he patie nt:  
 N O T t o t a ke i n vesti g ati o n al pr o d uct o n t he m or ni n g 
of t he ne xt visit, a n d  
 T o bri n g t he i n vesti g ati o n al pr o d uct b ottle(s); s/ he 
will d ose at t he cli nic (if t his is i n c o m pli a nce wit h t he 
est a blis he d d osi n g fre q ue nc y), a n d  
 T o f ast o ver ni g ht ( at le ast 8 h o urs) pri or t o t he ne xt 
visit.  F asti n g is re q uire d pri or t o all st u d y visits, b ut 
w ater is per mitte d . 
Clarif y st u d y 
pr oce d ures.  
9. 7. 1 2 , E ver y 3 
M o nt hs after 
W ee k 4 8  
9. 7. 1 3 
P atie nts w h o ha ve c o m plete d t heir 4 8 -wee k d o u ble -bli n d 
treat me nt peri o d will c o nti n ue d o u ble bli n d treat me nt u ntil 
all ra n d o mize d patie nts ha ve c o m plete d t heir partici pati o n 
i n t he pri mar y treat me nt peri o d a n d t he data base is 
l oc ke d …. a n d s h o ul d n ot e xce e d t he i n dicate d ma xi mal 
d ose a n d fre q ue nc y i n dicate d f or t heir C P cate g or y .   
9. 7. 1 1.  E ver y 3 M o nt hs after Wee k 4 8  
Q u arterl y  
 
Verif y t h at t he p atie nt h as f aste d f or at le ast 8  h o urs.  
 
Rec or d f asti n g st at us i n t he s o urce a n d e C R F  
 
If t he p atie nt re p orts h a vi n g e ate n  wit hi n 
8 h o urs, d oc u me nt acc or di n gl y i n t he s o urce a n d 
Clarifie d 
dis pe nsi n g 
i nstr ucti o ns. 
Pa ge 5 3 4 of 6 0 3


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Key Change 
Patients will then have the option to continue into an open-
label LTSE. 
 
 
eCRF and remind the patient that fasting is 
required prior to all study visits, but water is 
permitted. 
 
Perform a physical examination, including smoking 
and alcohol consumption history, and current habits 
for both.  
 
Review and record any non-study related medical or 
surgical treatment procedures and any medically 
relevant HCP or non-HCP related office visits that 
have occurred since the previous study visit. 
 
Assess and record vital signs (oral temperature, 
sitting heart rate, respiratory rate, and sitting blood 
pressure). 
 
Assess and record AEs. 
 
Review and record concomitant medications. 
 
Perform assessments for calculation of CP Score 
(Section 14.1.1). 
 
Administer Quality of Life and Patient 
questionnaires (see Section 13.2.6). 
 
Assess investigational product compliance, perform 
investigational product accountability. 
 
Dispense investigational product only if there is dose 
increase or as needed.  No new investigational 
product bottles will be dispensed if there is only 
change in dosing frequency of the same dose level.  
Patients are expected to use up each investigational 
product bottle before a new bottle will be dispensed. 
 
Assess for dose titration, if eligible (refer to 
Section 7.3 ). 
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Key Change 
 
Perform urinalysis (dipstick) 
 
Perform a urine-based β-hCG pregnancy test in 
females of childbearing potential. 
 
Obtain blood samples for 
 Serum chemistry, hematology, and coagulation  
 
Schedule the next visit, reiterate dosing instructions, 
and advise the patient: 
 
NOT to take investigational product on the 
morning of the next visit, and  
 
To bring the investigational product bottle(s); s/he 
will dose at the clinic (if this is in compliance with 
the established dosing frequency), and 
 
To fast overnight (at least 8 hours) prior to the next 
visit.  Fasting is required prior to all study visits, 
but water is permitted. 
Patients will complete a TE/ELF (HA, P3NP and TIMP 1) 
and ultrasound (for HCC surveillance) assessment, every 
6 months (±2 weeks) after Week 48. 
ECG will be done yearly (±2 weeks) after Week 48. 
9.7.13,  End of 
Study/Early 
Termination 
Procedures for 
Patients that 
Withdraw from 
Investigational 
Product or 
9.1.14;   End of Treatment/Early Termination Procedures 
for Patients that Withdraw from Investigational Product or 
Withdraw Consent … 
Patients who discontinue investigational product before are 
expected to continue … 
 
EOT/ET procedures will be required whenever patients 
discontinue treatment with investigational product 
 
9.7.12. . End of Study/Early Termination/End of Treatment 
Procedures for Patients that Withdraw from Investigational 
Product or Withdraw Consent … 
Patients who discontinue investigational product before 
Week 48 are expected to continue ... 
 
EOT (when subject discontinues investigational product)/ET 
procedures will be required whenever patients discontinue 
treatment with investigational product (Table 1, 
Section 9.7.10) 
Clarified 
procedures. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
Withdraw 
Consent 
 
When a patient discontinues investigational product but 
continues with regularly scheduled study visits, the EOS 
Visit will be completed as the patient’s final study visit. 
 
 
(Insertion) 
 
 
When a patient discontinues or interrupts investigational 
product and continues with regularly scheduled study visits, 
the EOS Visit will be completed as the patient’s final study 
visit. 
 
 
EOT and EOS visits are encouraged but at no time will a 
missed EOT or EOS visit be considered a protocol 
deviation. 
9.7.13,  Table 5, 
row 5 
Treatment Interruption  
Interrupted Retained Regular 
Visit Schedule 
Complete as close as possible to last dose 
of investigational product Complete at final study visit 
Deleted  
Removed to 
reduce 
confusion 
10.3, 
Investigational 
Product Storage 
Investigational product should be stored in the containers in 
which they are received from the Sponsor’s supplier, at 
15ºC to 25ºC. 
All OCA tablet strengths provided to clinical trial sites in 
support of clinical studies are to be shipped and stored at 
15°C to 25°C.  Temperature excursions within the range 
of 2°C and 30°C for no more than a 6-month period are 
acceptable, and the OCA tablet continues to be suitable 
for use in clinical studies.   Additionally, temperature 
excursions within the range -20°C to 40°C for no more 
than 7 days are acceptable, and the OCA tablet continues 
to be suitable for use in clinical studies. 
Updated 
storage 
conditions 
per the 
Investigator’s 
Brochure. 
12, 12.1, 
Pharmacokinetic 
Blood Sampling 
 
Subjects with at least one PD assessment after dosing will 
be included in the combined PK/PD analyses 
 
Serial and trough PK assessments will be performed in all 
patients participating in the study. 
 
 
At each visit, patients will provide… 
 
 
Patients in the PK Population with at least one PD 
assessment after dosing will be included in the combined 
PK/PD analyses 
Serial and fasting PK assessments will be performed in all 
patients participating in the study. 
 
At Day 1, and Weeks 6, 12, 18, 24, 30, 36, and 48, patients 
will provide… 
Specific dates 
are required 
to obtain 
optimum PK 
results 
Page 537 of 603


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Revised Text (Version 2, 22 May 2017) 
Key Change 
(Insertion) 
 
Week 6 visit should occur 3, 4, or 5 days after the Week 6 
dose, (eg if the Week 6 dose of drug is taken on a Sunday, 
the patient should come in for the Week 6 visit between 
Wednesday and Friday [Figure 2]). 
(Insertion) 
 
…serial PK blood samples will be obtained at 0.5, 0.75, 1, 
1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose… 
 
Figure 2: 
Week 6 Sampling Schedule 
  
IP = investigational product; PK = pharmacokinetic 
At Weeks 12, 18, 24, 30, and 48, Serial PK blood samples 
will be obtained at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9 
and 24 hours postdose (Figure 3) for all patients.  The 
patient will be given the option to return to the clinic the 
following morning for the 24-hour postdose sample or 
samples can be obtained by a home health care designee.  
The home health care agency must be advised one week in 
advance of the appointment.   
Added 
diagram and 
language to 
clarify PK 
sampling 
procedures. 
(Insertion) 
Figure 3: 
Pharmacokinetic Sampling Schedule 
 
OCA = obeticholic acid; PK = pharmacokinetic 
Added 
diagram and 
language to 
clarify PK 
sampling 
procedures. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
12.1, 
Pharmacokinetic 
Blood Sampling 
 
Table 7: Pharmacokinetic Sampling Schedule 
 
 
Replaced 
with other 
Figures 2 and 
3. 
During the double-blind treatment period and double-blind 
LTSE: 
• 
Pharmacokinetic trough samples will be obtained from 
all patients at all visits prior to dose administration in 
accordance with Table 7. 
• 
Serial PK assessments will be performed in all patients 
at Week 12.  Thereafter, PK assessments will be conducted 
at every titration visit in those patients who were eligible 
and uptitrated their dose.  Sample collection for fecal 
analysis will occur concurrent with serial PK sampling 
visits only.   
During the treatment period: 
• 
Pharmacokinetic fasting samples will be obtained from 
all patients at Weeks 6, 12, 18, 24, 30, 36, and 48 prior to 
dose administration in accordance with Figure 3. 
• 
Serial PK assessments will be performed in all patients 
at Weeks 12, 18, 24, 30, and 48.   
Clarify PK 
sampling and 
collection 
procedures. 
12.2,  Processing 
and Handling of 
Pharmacokinetic 
Samples 
The storage and shipment procedures for subsequent 
bioanalysis will be provided to the investigational site and 
in a separate document before the study is initiated. 
The storage and shipment procedures for subsequent 
bioanalysis will be provided to the investigational site and 
home health care company in a separate document before 
the study is initiated. 
Added option 
of using 
home health 
care service. 
13, Assessment 
of Safety 
Safety will be monitored and assessed by AEs/SAEs, 
medical history, physical examination, vital signs 
measurements, ECG results, and clinical laboratory 
assessments.  
Safety will be assessed in terms of AEs.  All AEs, whether 
observed by the investigator, reported by the patient, noted 
from laboratory findings, or identified by other means, will 
be recorded from the time the patient signs his/her consent 
deleted 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
Page 539 of 603


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Revised Text (Version 2, 22 May 2017) 
Key Change 
form (s)until the patient completes study participation (final 
Follow Up Visit). 
Recording AEs/SAEs in the electronic data capture (EDC) 
system is the method for reporting AEs/SAEs.  It is 
therefore imperative, that AEs/SAEs are recorded into the 
EDC. 
13.1.1.3.
 
Treatment-
Emergent 
Adverse Event 
 
13.1.1.2 
A treatment-emergent AE (TEAE) is any event not present 
before the initiation of the investigational product or any 
event already present that worsens in either intensity or 
frequency following exposure to the investigational 
product. 
Moved to Section 13.1.3. Recording Adverse Event 
Severity 
 
Safety 
information 
updated to 
match 
Protocol 
747-302.   
 
 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
13.1.3.1. Severity 
of Pruritus (as an 
Adverse Event) 
To ensure consistency in reporting, the following guidelines 
for assessing severity of pruritus should be used for AE 
reporting.  As pruritus is a patientive symptom, clinical 
judgment should be used to determine its severity and 
management Table 10 
Table 10 deleted. 
 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
13.1.4.1.
 
Reporting of 
Adverse Events 
(Insertion) 
….  Redacted medical record source documentation will 
be requested for all SAEs and emergency room visits. 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
13.1.4.2.
 
Reporting of 
• 
Telephone:  
 
If an SAE is reported by telephone or fax, … 
If an SAE is reported by fax, … 
Number no 
longer in use. 
Page 540 of 603
PPD


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Revised Text (Version 2, 22 May 2017) 
Key Change 
Serious Adverse 
Events 
 
 
 
 
13.1.5.1.
 
Potential 
Clinical 
Outcome Events 
 
The events listed below will be initially assessed by the 
Investigator to determine if they are Potential Clinical 
Outcome Events.  These events will be evaluated by an 
Adjudication Committee (described in Section 15.9) to 
confirm if they meet the criteria to be considered Clinical 
Outcome Events.  
Potential Clinical Outcome Events: 
Hospitalization for clinical complications of cirrhosis. 
Given that the Potential Clinical Outcome Events could also 
meet the criteria of a SUSAR, which would necessitate 
unblinding for expedited reporting, the Sponsor will not 
expeditiously report suspected Potential Clinical Outcome 
events in order to retain the study blind and preserve the 
integrity of the clinical outcomes endpoint.  These events 
will be selected as a “potential study event” on the Adverse 
Event eCRF and will be submitted for adjudication to the 
Adjudication Committee as described in Section 15.9. 
 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
13.1.7.
 
Notification 
of Post-
Treatment SAEs 
for Patients Who 
Continue in the 
Study 
13.1.7. Notification of Post-Study SAEs  
If an Investigator becomes aware of an SAE that may be 
attributable to the investigational product at any time after 
the end of the study, the Sponsor should be notified 
immediately (ie, within 24 hours) by following the 
instructions provided in Section 13.1.4.2 
13.1.7. Notification of Post-Treatment SAEs for Patients 
Who Continue in the Study 
Post-treatment SAEs that occur in patients who remain in 
the study after investigational product has been 
discontinued must be reported to the Sponsor within 
24 hours by following the instructions provided in 
Section 13.1.4.2. 
SAEs that occur in patients who discontinue 
investigational product, initiate treatment with 
commercially available Ocaliva, and remain in the study 
must be reported to the Sponsor within 24 hours by 
following the instructions provided in Section 13.1.4.2. 
Safety 
information 
updated to 
match 
Protocol 
747-302.  
Deleted text 
is already in 
Section 
13.1.8. 
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Key Change 
13.1.8.
 
Notification 
of Post--Study 
SAEs  
 
(Insertion) 
13.1.8. Notification of Post-Study SAEs  
All SAEs that occur within 30 days following 
discontinuation from the study, whether or not they are 
related to the investigational product, must be reported to 
the Sponsor within 24 hours by following the instructions 
provided in Section 13.1.4.2. 
 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
13.1.8.
 
Notification 
of Post-
Treatment SAEs 
for Subjects Who 
Continue in the 
Study 
13.1.8. Notification of Post-Treatment SAEs for Subjects 
Who Continue in the Study 
Post-treatment SAEs that occur in subjects who remain in 
the study after investigational product has been 
discontinued must be reported to the Sponsor within 24 
hours by following the instructions provided in 
Section 13.1.4.2 
Moved to 13.1.7 
Safety 
information 
updated to 
match 
Protocol 
747-302 9 
(moved to 
13.1.7). 
13.1.10, 
Pregnancy and 
Follow-up 
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant 
while she is enrolled in the clinical study, she must 
discontinue investigational product immediately and the 
Sponsor must be notified within 24 hours of the 
Investigator’s learning of the pregnancy by completing. 
In the situation that the EDC is not functioning, the Medical 
Monitor should be notified by telephone.  The investigator 
remains responsible for entering the pregnancy information 
into the EDC when the EDC becomes functional. 
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant 
while she is enrolled in the clinical study, she must interrupt 
treatment with investigational product immediately (see 
Section) and the Sponsor must be notified within 24 hours of 
the Investigator’s awareness of the pregnancy by completing 
the Pregnancy CRF in the EDC system and downloading 
and completing the Pregnancy Report Form.  The 
Pregnancy Report Form must be emailed to 
 or faxed to 
.   
The patient and neonate must be followed for outcome 
information and/or as considered appropriate by the 
Investigator and Sponsor. 
The patient may restart investigational product when she 
is no longer pregnant or breastfeeding (if applicable) at 
the discretion of the Investigator and after discussion with 
the Medical Monitor.  The patient must have a negative 
pregnancy test before restarting investigational product.  
If a patient’s pregnancy is terminated early (planned or 
unplanned), she must have termination of the pregnancy 
Safety 
information 
updated to 
match 
Protocol 
747-302. 
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Key Change 
confirmed by a serum β-hCG test before restarting 
investigational product. 
13.2.2, Physical 
Examination 
13.2.1 
(Insertion) 
13.2.2 
A basic physical examination… Smoking and alcohol 
consumption history and current habits will be 
recorded…. 
Clarified 
assessments 
13.2.5, 
Laboratory 
Assessments 
For visits that require fasting, the Investigator or designee 
will verify that the patient has fasted for at least 8 hours …   
At all visits (except screening), the Investigator or designee 
will verify that the patient has fasted for at least 8 hours… 
Clarified visit 
procedures 
Blood samples for serum chemistry, coagulation, and 
hematology will be collected at every visit… 
Blood samples for serum chemistry, coagulation, and 
hematology and urine samples will be collected at visits… 
Clarified 
what samples 
will be 
collected. 
13.2.5, 
Laboratory 
Assessments, 
Table 9 
 
Added the following labs: 
 
Serum Chemistry 
 
CPK, TFT (TSH, free T3 and free T4) 
 
Urinalysis (dipstick) 
 
Pregnancy 
 
Noninvasive measurement… 
 
ELF (HA, P3NP, and TIMP-1), TE 
Updated lab 
tests to be 
performed. 
Biomarkers of Hepatic Fibrosis and/or Inflammation;  IL-6, 
hs-CRP, TNF-α, IgM, IgA, IgG, CK 18 M30, and others as 
determined during course of study 
Markers of Inflammation; IL-6, hs-CRP, TNF-α, IgM, IgA, 
IgG, CK-18-M30 
Clarified 
assessments 
Genetics;  DNA including single-nucleotide 
polymorphisms that may be involved in PBC; RNA 
deleted 
No longer 
doing this 
analysis. 
13.2.5, 
Laboratory 
Assessments 
(Insertion) 
PD markers: C4, FGF-19 and plasma bile acids 
Added new 
row  
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Key Change 
13.2.5, 
Laboratory 
Assessments 
(Insertion) 
Laboratory reference ranges for the study will be based 
on the laboratory vendor range. 
Added to 
satisfy PMR 
request. 
14.1.1, Child-
Pugh Score, 
Table 10 
Factor 
Unit
s 
Points 
Deletion 
 
 
 
 
Encephalopathy now 0 
Simplified 
CP scoring 
procedure. 
1 
2 
3 
Serum bilirubin 
μmo
l/L 
<3
5 
35-50 
>50 
Serum albumin 
g/L 
>3
5 
28-35 
<28 
Hepatic encephalopathy 
 
No 
 
 
14.2.1,  Markers 
of Inflammation, 
Apoptosis and 
Necrosis 
Blood samples for analytes including hs-CRP, IgM, TNF-α, 
and cytokeratin-18, neoepitope M30. 
Blood samples for analytes including IL-6, hs-CRP, IgA, 
IgG, IgM, TNF-α, and cytokeratin-18, neoepitope M30. 
Added 
additional 
markers. 
15.4, Safety 
Analyses 
No inferential comparison of safety endpoints will be 
performed.  All safety comparisons will be descriptive. 
No inferential comparison with formal statistical hypothesis 
testing will be performed for safety endpoints. 
Clarified 
statistical 
analyses. 
15.4.3, Adverse 
Events of Special 
Interest 
…  The quartiles, including the median time-to-event and 
their respective 2-sided 95% CIs, will be presented.  KM 
estimates will be plotted as a “survival curve” for each 
treatment group. 
…  The tabulation will include the KM estimate 
methodology using 25th, 50th (median), and 75th percentiles 
of the medians and corresponding with associated 2-sided 
95% confidence intervals (CIs), if the medians can be 
estimated as well as percentage of censored observations. 
Clarified 
statistical 
analyses. 
15.5, Efficacy 
Analyses, 4th 
paragraph 
…  The results, change from Baseline, and percentage 
change from Baseline values, as well as estimates of least-
square (LS) means, standard errors (StdErr), and 95% CIs, 
will be presented by treatment group.  Estimates of the 
mean difference between treatment groups, the StdErr of 
the difference, and 95% CI of the difference will also be 
presented.  No formal hypothesis testing will be performed. 
The results, change from Baseline, and percentage change 
from Baseline values, as well as estimates of least-square 
(LS) means, standard errors (StdErr), and 2-sided 95% CIs, 
will be presented by treatment group.  Estimates of the mean 
difference between treatment groups, the StdErr of the 
difference, and 2-sided 95% CI of the difference will also be 
presented 
Clarified 
statistical 
analyses. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
15.6, Additional 
Efficacy 
Analyses 
The following clinical outcomes will be captured in the 
study: 
• 
All cause mortality 
• 
Liver related death 
• 
Liver transplant 
• 
Variceal bleed 
• 
Hepatic encephalopathy 
• 
Bacterial peritonitis 
• 
Ascites 
• 
Hepatocellular carcinoma 
The following clinical endpoints will be captured in the 
study : 
• 
Time to death (all-cause ) 
• Time to liver-related death 
• Time to hepatic failure leading to liver transplant 
•  Model of end stage liver disease (MELD) score ≥15 
(for patients with MELD ≤12 at baseline) 
• Hospitalization (as defined by a stay of 24 hours or 
greater) for new onset or recurrence of: 
 
Time to variceal bleed 
 
Time to hepatic encephalopathy (as defined by 
a West Haven score of ≥2) 
 
Time to spontaneous bacterial peritonitis 
(confirmed by diagnostic paracentesis) 
• Time to uncontrolled ascites (diuretic resistant ascites 
requiring therapeutic paracentesis at a frequency of at 
least twice in a month). 
 
The incidence and time to first occurrence of any above listed 
clinical events will be summarized by treatment group using 
the log rank test stratified by the randomization stratification 
factor.  KM estimates of the distribution of the time-to-event 
will be tabulated and graphed by treatment group.  The 
tabulation will include the KM methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% 
confidence intervals (CIs), as well as percentage of censored 
observations.  The number and percent of patients censored 
and with events will be presented.  The hazard ratio and 2-
Clarified 
statistical 
endpoints. 
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Key Change 
sided 95% CI will be estimated based on a Cox regression 
model stratified by randomization strata.  
In addition, the incidence and time to each of the above 
clinical events, and the incidence and time to occurrence 
of hepatocellular carcinoma (HCC) will be summarized 
by treatment group using the same methods as defined 
above. 
 
18.3, Written 
Informed 
Consent 
(Insertion) 
The Investigator(s) must maintain the original, signed 
ICF. A copy of the ICF must be given to the patient. 
Updated 
language. 
21, List of 
References 
(Insertion) 
Hepatic encephalopathy in chronic liver disease: 2014 
practice guideline by the European Association for the 
Study of the Liver and the American Association for the 
Study of Liver Diseases. J Hepatol 2014 Sep;61(3):642-59. 
Kamath PS, Kim WR. The model for end-stage liver 
disease (MELD). Hepatology 2007 Mar;45(3):797-805. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl-
chenodeoxycholic acid (6-ECDCA), a potent and selective 
FXR agonist endowed with anticholestatic activity. J Med 
Chem. 2002 Aug 15;45(17):3569-72. 
Added new 
references  
Appendix A, List 
of Study 747-401 
Outcome Events 
Some of the specified clinical endpoints will also by 
definition (see Section 13.1) qualify as Serious Adverse 
Events (SAEs).  The sponsor must be notified of any SAEs 
within 24 hours of the site becoming aware of the event 
(see Section 13.1.4).  The Sponsor is responsible for 
regulatory reporting of SAEs including expeditious 
reporting of SAEs that are considered related to the 
investigational product and considered Unexpected by 
regulatory standards as defined in the Investigational 
Brochure. 
 
This is 
covered in 
the main text. 
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Revised Text (Version 2, 22 May 2017) 
Key Change 
The Sponsor may consider the following lists of events to 
be exempt from expeditious regulatory reporting but will 
continue to report them in a non-expeditious manner: 
Potential Clinical Outcome Events: 
Liver-related events resulting in death 
Hepatic failure leading to liver transplant 
Variceal bleed 
Hepatic encephalopathy 
Spontaneous bacterial peritonitis 
Ascites 
Hepatocellular carcinoma 
 
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APPENDIX B. SUMMARY OF CHANGES:  PROTOCOL 747-401 VERSION 3 (DATED  
04 JAN 2018) 
Protocol 747-401 was revised to include the following information: 
 The Introduction was revised to highlight the need for close monitoring specifically in patients with clinical evidence of 
hepatic decompensation and other complications due to advanced cirrhosis.  Reference is made to sections describing 
specific criteria for investigational product adjustment, interruption, or discontinuation based on adverse events or 
laboratory values. This language also emphasizes the need for careful observation and evaluation of the entire clinical 
picture over and above system-generated alerts and flags for lab values.   
 Dosing regimens were updated to modify dosing to one regimen for patients with moderate and severe hepatic impairment 
(eg, same for CP-B and CP-C), not to exceed 10 mg twice weekly, to align with label dosing guidelines.  Titration is now 
only based on tolerability and not CP score. 
 Reference to an option for open-label treatment was removed.  An open-label extension will be considered only after 
review of blinded safety and PK data from the double-blind treatment period.  For clarity, reference to the Long-Term 
Extension was changed to Double-Blind Extension; visits during this period remain the same. 
 Protocol was updated with discontinuation criteria for decompensation events and biochemical thresholds.  A plan for 
monitoring and drug-induced liver injury algorithm has been included to ensure careful monitoring and drug 
interruption/discontinuation.  Analysis of decompensation events as adverse events of interest has been added.  
Additionally, “Close Observation” per FDA Guidance for Industry on Drug Induced Liver Injury” has been clearly defined 
in the protocol to ensure that patients who experience a potential DILI undergo a full evaluation. 
 Guidance was added that patients should be instructed to contact the site promptly upon awareness if they develop signs 
and symptoms of potential hepatic decompensation such as:  pale-colored stools, urine color from pale to deep amber 
[dark], nausea, vomiting, abdominal pain, diarrhea, weight loss, fever and chills, fatigue, weakness, loss of appetite, 
confusion, swelling of the legs or abdomen, yellowing of the skin or the whites of eyes, and bruising easily. 
 Guidance was added that the Investigator should contact the study Medical Monitor upon awareness when any signs and 
symptoms of hepatic decompensation are observed in any patient. 
 Guidance was added for monitoring amylase and lipase levels in patients with suspected acute pancreatitis.  
 Gallbladder assessments were added at Screening or Day 1. 
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Summary of Changes 
The following revisions were made to the protocol in Protocol Version 3.  Revised and new text in Version 3 is indicated in bold font, 
and the text deleted from Protocol Version 2 is crossed out in the table below.  Minor/editorial changes are not listed individually in 
the summary table below. 
 
 
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Section 
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Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Sponsor’s Approval 
of the Protocol 
 PhD  
 
 
 
 
  
Vice President, Clinical Development 
Intercept Pharmaceuticals, Inc. 
 PhD  
 
 
 
 
  
Sr Vice President, Clinical Development 
Intercept Pharmaceuticals, Inc. 
Signatory’s title changed. 
Study Personnel 
Contact Information 
Medical Monitor  
Primary Contact: 
 MD 
Medical Director, Pharmacovigilance, 
Intercept Pharmaceuticals, Inc. (Intercept) 
Telephone: 
 
Email: 
 
SAE Fax:
 
SAE Email: 
 
Medical Monitor  
Primary Contact: 
 DO, MSPH 
Senior Medical Director, Intercept 
Pharmaceuticals, Inc. (Intercept) 
 
Secondary Contact: 
 MD 
Senior Medical Director, Intercept 
Pharmaceuticals, Inc. (Intercept) 
 
 
24-Hour Telephone: 
 
 
SAE Fax:
 
SAE Email: 
 
Change in personnel. 
Synopsis, Study 
Period; Section 7.1.3, 
Study Duration 
Study Period:  Patients will receive double-blind 
treatment for at least 48 weeks.  Patients who have 
completed their 48-week double blind treatment period 
will continue double-blind treatment until all 
randomized patients have completed their participation 
in the 48-week treatment period and the database for that 
period is locked (approximately 3 years).  Patients will 
then be given the option to go on open-label treatment. 
Study Period:  Patients will receive double-blind 
treatment for at least 48 weeks.  Patients who have 
completed their 48-week double blind treatment period 
will continue double-blind treatment until all 
randomized patients have completed their participation 
in the 48-week treatment period and the database for 
that period is locked (approximately 3 years).  An 
open-label extension study in which all patients 
receive OCA will be considered following review of 
blinded safety and PK data. 
An open-label extension will 
only be considered only after 
review of blinded safety and PK 
data from the double-blind 
treatment period.   
Synopsis, Phase of 
Development 
Phase 4 
Phase 4:  US, Canada, and the EU 
Phase 3b:  All other regions 
Study is only considered a 
Phase 4 in regions where 
Ocaliva has received regulatory 
approval. 
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Synopsis, Additional 
Objectives; Section 
6.3, Additional 
Objectives 
Additional Objectives: 
 
To evaluate the effect of OCA treatment compared 
to placebo on: 
 
Markers of inflammation 
 
Noninvasive markers of liver fibrosis 
(Enhanced Liver Fibrosis [ELF]™ score) 
  
Noninvasive measurement of liver stiffness 
(transient elastography [TE]) 
Additional Objectives: 
 
To evaluate the effect of OCA treatment compared 
to placebo on: 
 
Noninvasive markers of liver fibrosis 
(Enhanced Liver Fibrosis [ELF]™ score) 
 
Noninvasive measurement of liver stiffness 
(transient elastography [TE]) 
Samples were removed to 
simplify the study design. 
Synopsis, Double-
Blind Treatment 
Period; Section 7.1, 
Overall Study Design 
Double-Blind Treatment Period:  During the 48-week 
treatment period (ie, Day 1 through Week 48), an initial 
safety visit will occur at Week 3.  After the Week 6 
Visit, subsequent clinic visits will occur approximately 
every 6 weeks for the assessment of safety, tolerability, 
PK, and PD.  At each visit (except screening and Week 
3), fasting PK assessments will be performed in all 
patients participating in the study.  Serial PK sampling 
will be performed at Week 12, 18, 24, 30, and 48.   
Patients who have completed their 48-week double blind 
treatment period will continue double blind treatment 
until all randomized patients have completed their 48-
week treatment period and the database for that period is 
locked.  Patients will then be given the option to go on 
open-label treatment. 
Double-Blind Treatment Period:  During the 48-week 
treatment period (ie, Day 1 through Week 48), an initial 
safety visit will occur at Week 3.  After the Week 6 
Visit, subsequent clinic visits will occur approximately 
every 6 weeks for the assessment of safety, tolerability, 
PK, and PD.  Titration may be considered as early as 
the Week 12 Visit.  Fasting PK assessments will be 
performed in all patients participating in the study on 
Day 1, Week 6, and Week 36.  Serial PK sampling 
(which also includes a fasted PK assessment) will be 
performed at Week 12, 18, 24, 30, and 48.  
Patients who have completed their 48-week double 
blind treatment period will continue double blind 
treatment until all randomized patients have completed 
their 48-week treatment period and the database for 
that period is locked.  An open-label extension study 
in which all patients receive OCA will be considered 
following review of blinded safety and PK data.   
Clarification for sites needed to 
clarify Fasted and Serial PK 
assessment timepoints. 
 
An open-label extension will 
only be considered only after 
review of blinded safety and PK 
data from the double-blind 
treatment period.   
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Synopsis, Study 
Design Diagram; 
Section 7.1.1 Study 
Design Diagram 
 
OCA = obeticholic acid, PBC = primary biliary 
cholangitis 
Notes: Initial dose titration of investigational product 
may be considered as early as the Week 12 
Visit, or any study visit thereafter for patients on 
all dosing regimens, based on tolerability and 
safety laboratory tests from the previous visit.  
Subsequent dose titration(s) may occur no 
earlier than 6 weeks after the previous dose 
titration and will be based on tolerability and CP 
score.   
Patients who complete Week 48 will continue 
double-blind treatment until all randomized 
patients have completed their participation in the 
48-week treatment period and the database for 
that period is locked. 
 
OCA = obeticholic acid, PBC = primary biliary 
cholangitis 
Notes: Initial dose titration of investigational product 
may be considered as early as the Week 12 
Visit, or any study visit thereafter for patients 
on all dosing regimens, based on tolerability 
and safety laboratory tests from the previous 
visit.  Subsequent dose titration(s) may occur 
no earlier than 6 weeks after the previous dose 
titration and will be based on tolerability.   
Patients who complete Week 48 will continue 
double-blind treatment until all randomized 
patients have completed their participation in 
the 48-week treatment period and the database 
for that period is locked. 
Clarification of extension 
period needed to ensure it is not 
confused with an open-label 
extension. 
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Synopsis, Dosing 
Regimen; Section 7.3 
Planned Dosing 
Regimen 
… 
Dosing will then occur at least 3 days apart.  Every 6 
weeks thereafter, based on safety and tolerability 
assessments, patients can be considered for further up 
titration as described below.  At each titration visit, the 
patient may start the higher dose regimen no earlier than 
2 days after the prior dose. 
Patients with CP-B may titrate to a maximum dose of 
OCA 5 mg once daily. 
Patients with CP-C may titrate to a maximum dose of 
OCA 10 mg twice weekly at least 3 days apart. 
If, during the course of the study, a patient transitions 
from CP- B to CP-C, or vice versa, the maximal dose for 
the new CP classification would apply. 
Planned OCA or Matching Placebo Dosing Regimen by 
Child-Pugh Score 
 
Child-Pugh B 
(Moderate 
Hepatic 
Impairment) 
Child-Pugh C 
(Severe Hepatic 
Impairment) 
 
Treatment Group 
Treatment Group 
 
OCA 
Placebo 
OCA 
Placebo 
Starting 
Dose (Day 
1) 
5 mg 
once 
weekl
y 
matchin
g 
placebo 
5 mg 
once 
weekl
y 
matchin
g 
placebo 
Titration 
1a  
5 mg 
twice 
weekl
yb 
matchin
g 
placebo 
5 mg 
twice 
weekl
yb 
matchin
g 
placebo 
Titration 
2a  
10 mg 
twice 
weekl
yb 
matchin
g 
placebo 
10 mg 
twice 
weekl
yb 
matchin
g 
placebo 
… 
Dosing will then occur at least 3 days apart.  Every 6 
weeks thereafter, based on tolerability assessments, 
patients can be considered for further up titration as 
described below.  At each titration visit, the patient 
may start the higher dose regimen no earlier than 2 
days after the prior dose. 
Patients may titrate to a maximum dose of OCA 10 
mg twice weekly at least 3 days apart.  
Planned OCA or Matching Placebo Dosing Regimen 
 
Child-Pugh B and Child-Pugh C 
(Moderate and Severe Hepatic 
Impairment) 
 
Treatment Group 
 
OCA 
Placebo 
Starting 
Dose (Day 
1) 
5 mg once 
weekly 
matching 
placebo once 
weekly 
Titration 
1a  
5 mg twice 
weeklyb 
matching 
placebo twice 
weeklyb 
Titration 
2a  
10 mg twice 
weeklyb 
matching 
placebo twice 
weeklyb 
a Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
patient tolerability. 
b Dosing per the twice weekly schedule must be at 
least 3 days apart. 
 
Per FDA request to align dosing 
with label dosing guidelines for 
CP-B and CP-C patients. 
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Titration 
3a  
5 mg 
once 
daily 
matchin
g 
placebo 
NA 
NA 
a Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
patient tolerability and/or changes in Child-Pugh Score 
at any time during the study. 
b Dosing per the twice weekly schedule must be at least 
3 days apart. 
Over the course of the study, a patient’s CP category 
may change.  When a patient demonstrates a change in 
CP category, dosing should be reassessed and modified 
if appropriate.  Changes to the dosing regimen are not 
mandatory and should be based on clinical judgment and 
change in CP score.  The titration steps for CP-B and 
CP-C patients are identical with exception of the 
maximum allowed dose.  Therefore, if a patient changes 
CP class from B to C, or vice versa, the maximal dose 
for the new regimen will apply.  If a patient improves to 
CP-A during the study, the maximal CP-B dose will still 
apply.  If a patient has not yet reached the maximal dose, 
the appropriate titration regimen should be followed.  
Maximum Dose for OCA or Matching Placebo for 
Changes in Child-Pugh Category 
 
a Once a patient begins dosing with the new dosing 
regimen, titration should occur as described for the 
planned dosing regimen.  
b Dosing per the twice weekly schedule must be at least 
3 days apart. 
Synopsis, Key 
Inclusion Criteria; 
Section 8.2, Patient 
Inclusion Criteria 
3. 
Satisfy the criteria of the modified CP classification 
for hepatic impairment during Screening (ie, within 14 
days before the first dose of investigational product): 
3. 
Satisfy the criteria of the modified CP 
classification for hepatic impairment during Screening  
Correction 
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Synopsis, Key 
Exclusion Criteria; 
Section 8.3, Patient 
Exclusion Criteria 
4.   Hepatic encephalopathy (as defined by a West 
Haven score of ≥2) 
4.   Current hepatic encephalopathy (as defined by a 
West Haven score of ≥2) 
Correction 
Synopsis, Key 
Exclusion Criteria 
5. 
History or presence of other concomitant liver 
diseases including: 
• 
Hepatitis C virus infection and RNA positive 
• 
Active hepatitis B infection; however, patients who 
have seroconverted (hepatitis B surface antigen and 
hepatitis B antigen negative) may be included in this 
study after consultation with the medical monitor 
5. 
History or presence of other concomitant liver 
diseases including: 
• 
Hepatitis C virus infection and RNA positive 
• 
Active hepatitis B infection; however, patients 
who have seroconverted (hepatitis B surface antigen 
and hepatitis B e antigen negative) may be included in 
this study after consultation with the Medical Monitor 
Correction 
Synopsis, Duration of 
Treatment 
Patients who have completed their 48-week double blind 
treatment period will continue double blind treatment 
until all randomized patients have completed their 
participation in the 48-week treatment period and the 
database for that period is locked (approximately 3 
years).  Patients will then be given the option to go on 
open-label treatment. 
Patients who have completed their 48-week double 
blind treatment period will continue double blind 
treatment until all randomized patients have completed 
their participation in the 48-week treatment period and 
the database for that period is locked (approximately 3 
years).  An open-label extension study in which all 
patients receive OCA will be considered following 
review of blinded safety and PK data. 
An open-label extension will 
only be considered only after 
review of blinded safety and PK 
data from the double-blind 
treatment period.   
Synopsis, Criteria for 
Evaluation; Section 
11, Overview of 
Assessments, Table 7 
Secondary Objectives 
Assessments 
Changes in risk scores 
Changes in MELD and in 
CP score and components 
of the CP score 
Changes in liver 
biochemistry and 
hepatobiliary damage  
Total and direct bilirubin, 
ALP, ALT, AST, GGT, 
INR, creatinine, albumin, 
platelets 
PD parameters 
FGF-19, C4, and plasma 
bile acids 
Additional Objectives 
Assessments 
Markers of 
inflammation 
IL-6, hs-CRP, TNF-α, 
IgM, IgA, IgG, 
CK-18-M30  
Noninvasive 
measurements of liver 
fibrosis, liver stiffness 
and cirrhosis 
TE and ELF (HA, P3NP, 
and TIMP-1) 
Secondary 
Objectives 
Assessments 
Changes in risk scores 
Changes in MELD and in 
CP scores and 
components of the CP 
score and MELD score 
Changes in liver 
biochemistry and 
hepatobiliary damage  
Total and direct bilirubin, 
ALP, ALT, AST, GGT, 
INR, creatinine, albumin, 
platelets 
PD parameters 
FGF-19, C4, and plasma 
bile acids 
Additional 
Objectives 
Assessments 
Noninvasive 
measurements of liver 
fibrosis, liver stiffness 
and cirrhosis 
TE and ELF (HA, P3NP, 
and TIMP-1) 
 
Risk score assessment clarified.  
 
Markers of inflammation were 
removed to simplify the study 
design. 
 
 
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Section 14.1.1, Child-
Pugh Score 
Factor 
Units 
Points 
1 
2 
3 
Serum 
bilirubin 
μmol/L 
<35 
35-50 
>50 
mg/dL 
<2.0 
2.0-
3.0 
>3.0 
 
Factor 
Units 
Points 
1 
2 
3 
Serum 
bilirubin 
μmol/L 
<34 
34-50 
>50 
mg/dL 
<2.0 
2.0-
3.0 
>3.0 
 
Error correction 
Synopsis, Safety 
Analyses; Section 
15.4, Safety Analysis 
Safety analyses will be conducted using the Safety 
population.  Safety data, including AEs, vital signs, 
electrocardiogram, and clinical laboratory results will be 
summarized by treatment group.   
Safety analyses will be conducted using the Safety 
population.  Safety data, including AEs, AEs of special 
interest including pruritus and hepatic safety, vital 
signs, electrocardiogram, and clinical laboratory results 
will be summarized by treatment group.   
Per FDA request 
Synopsis, Additional 
Efficacy Analyses; 
Section 15.6, 
Additional Efficacy 
Analyses 
Analyses of changes in liver stiffness and ELF, 
cytokeratin-and TIMP-1, and markers of inflammation 
will be summarized and analyzed using the same 
methodology specified for the secondary analyses of 
change in bilirubin. 
 
Analyses of changes in liver stiffness (TE) and liver 
fibrosis (ELF [HA, P3NP, and TIMP-1]), will be 
summarized and analyzed using the same methodology 
specified for the secondary analyses of change in 
bilirubin. 
 
Correction 
Synopsis, Sample 
Size Justification; 
Section 15.2, 
Determination of 
Sample Size 
To reasonably characterize the PK of OCA in patients 
with hepatic impairment, a simulation-based approach 
estimated a requirement of approximately 20 patients in 
the OCA treatment group assuming a 15% 
discontinuation rate.  Ten patients on placebo will be 
included as a comparator.  An additional 20 patients will 
be enrolled to support safety and efficacy evaluations.  
Therefore, approximately 50 patients (including at least 
20% of patients with CP-C) will be randomized.  
 
To reasonably characterize the PK of OCA in patients 
with hepatic impairment, a simulation based approach 
estimated a requirement of approximately 20 patients in 
the OCA treatment group assuming a 15% 
discontinuation rate.  A total of 30 patients is 
adequate with 10 patients on placebo to be included as 
a comparator and 20 patients on OCA.  An additional 
20 patients will be enrolled to support safety and 
efficacy evaluations.  Therefore, approximately 50 
patients (including at least 20% of patients with CP-C) 
will be randomized in a 1:1 ratio to 1 of the 2 
treatment groups:  Placebo and OCA. 
Clarification. 
Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
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Section 5.1, 
Overview of Disease 
State and OCA 
In May 2016, the US Food and Drug Administration 
(FDA) granted accelerated approval for OCA (marketed 
as Ocaliva), for the treatment of patients with PBC in 
combination with UDCA in adults with an inadequate 
response to UDCA or as monotherapy in adults unable 
to tolerate UDCA.  In December 2016, the European 
Commission granted conditional approval for Ocaliva 
for the same indication. 
In May 2016, the US Food and Drug Administration 
(FDA) granted accelerated approval for OCA 
(marketed as Ocaliva), for the treatment of patients 
with PBC in combination with UDCA in adults with an 
inadequate response to UDCA or as monotherapy in 
adults unable to tolerate UDCA.  In December 2016, 
the European Commission granted conditional approval 
for Ocaliva for the same indication, and in May 2017 
Ocaliva received approval from Health Canada.  
Study 747-401 is considered a Phase 4 study in 
regions where OCA has received regulatory 
approval for PBC (ie, in the US, Canada, and the 
EU).  In all other regions, this study is considered 
Phase 3b. 
Ocaliva has been approved in 
Canada since last version of 
protocol. 
Study is only considered a 
Phase 4 in regions where 
Ocaliva has received regulatory 
approval. 
Section 5.3, Clinical 
Development of 
Obeticholic Acid 
As of 31 Jan 2017, approximately 2186 patients have 
received at least 1 dose of OCA.  Of these, 844 were 
healthy volunteers, 525 patients had PBC, 686 patients 
had nonalcoholic steatohepatitis (NASH), 41 patients 
had diabetes mellitus/ nonalcoholic fatty liver disease 
(NAFLD), 33 patients had alcoholic cirrhosis/portal 
hypertension, 52 patients had primary sclerosing 
cholangitis (PSC), and 5 patients had biliary atresia. 
As of 13 Oct 2017, approximately 2690 subjects have 
received at least 1 dose of OCA.  Of these, 844 were 
healthy volunteers, 552 patients had PBC, 1141 
patients had nonalcoholic steatohepatitis (NASH), 41 
patients had diabetes mellitus/ nonalcoholic fatty liver 
disease (NAFLD), 33 patients had alcoholic 
cirrhosis/portal hypertension, 73 patients had primary 
sclerosing cholangitis (PSC), and 6 patients had biliary 
atresia. 
Updated exposure numbers 
available 
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5.4.2, Rationale for 
Obeticholic Acid 
Dose and Duration 
Therefore, the current FDA-approved prescribing 
information for OCA includes a modified dosing 
regimen in patients with moderate and severe hepatic 
impairment that is designed to achieve liver exposures in 
these patients that would be similar to non-hepatically 
impaired patients through initiation at a lower dose (5 
mg OCA once-weekly) followed by gradual up-titration 
(Section 7.3).   
The dosing regimen in this study follows the FDA-
approved prescribing information, with the exception of 
the maximum allowed dose in patients with moderate 
impairment.  While the prescribing information allows 
for a maximum dose of 10 mg twice weekly for patients 
with moderate impairment, the protocol allows for a 
maximum dose of 5 mg once daily.  The choice of 5 mg 
once daily is supported by the estimated steady-state 
liver and plasma exposure of total OCA for patients with 
moderate hepatic impairment receiving a 5 mg once 
daily dose relative to healthy patients receiving a 10 mg 
dose.  A maximum allowed dose of 5 mg once daily in 
patients with moderate hepatic impairment is estimated 
to achieve liver exposure similar to non-hepatically 
impaired patients receiving a 10 mg daily dose and 
maximize efficacy in this patient population. 
Therefore, the current FDA-approved prescribing 
information for OCA includes a modified dosing 
regimen in patients with moderate and severe hepatic 
impairment that is designed to achieve liver exposures 
in these patients that would be similar to 
non-hepatically impaired patients through initiation at a 
lower dose (5 mg OCA once-weekly) followed by 
gradual up-titration (Section 7.3).   
 
Text no longer applicable since 
all dosing regimens will follow 
FDA-approved prescribing 
information. 
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Section 5.5, 
Importance of 
Monitoring Disease 
Progression 
New Section 
Given PBC is a chronic, progressive liver disease, it 
is important that patients with PBC are closely 
monitored to ensure early identification of 
decompensation and/or liver injury.  More extensive 
safety monitoring and appropriate dosing 
adjustments, interruptions, and discontinuations 
will be implemented to improve patient oversight 
and safety.  Investigators, together with the 
Sponsor’s Medical Monitor, will consistently and 
frequently assess individual patients to determine 
on an ongoing basis the totality of a patient’s clinical 
profile, which includes careful evaluation of signs 
and symptoms of potential hepatic injury and/or 
decompensation coupled with rules-based 
laboratory monitoring. 
Patients will be monitored for potential hepatic 
injury and/or decompensation.  Criteria for 
implementing dosing adjustments, interruptions, or 
discontinuations, and close monitoring procedures 
postdose-adjustment are described in Section 8.4 
and Section 7.6.  The more extensive monitoring is 
important given the elevated risk of decompensation 
and potential for higher hepatic exposure to OCA in 
this population. 
Language added to generate 
Investigator awareness of the 
disease progression trajectory 
and unpredictable nature of 
progression in patients at high 
risk, as well as incorporation of 
language regarding altered bile 
acid and OCA PK and drug 
exposure in patients with 
hepatic impairment and the 
need for close vigilance to 
identify potential liver toxicity 
or decompensation. 
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Section 5.6, Summary 
of Known Potential 
Risks with 
Investigational 
Product 
The primary AE shown to be related to OCA is pruritus.  
Pruritus has also been observed in clinical studies with 
OCA in other indications, as well as in healthy patients, 
but with a much lower frequency than that observed in 
patients with PBC. 
Consistent with the dose-limiting hepatic toxicities 
observed in the non-clinical studies and the chemical 
characteristics of OCA as a bile acid and detergent, 
dose-related but reversible and asymptomatic increases 
in ALT and AST were observed in healthy volunteers 
treated with multiple doses of OCA starting at the 100 
mg dose (Study 747-102).   
In patients with chronic liver disease such as PBC, 
hepatobiliary findings including increased transaminases 
and bilirubin and signs or symptoms of hepatic 
decompensation such as development of jaundice were 
observed.  These findings were seen more frequently 
with doses of OCA 10 mg once daily to OCA 50 mg 
once daily (up to 5x the highest recommended dose).  In 
addition, cholecystitis, including acute cholecystitis, was 
reported in association with treatment with OCA. 
Lipoprotein changes have also been observed with OCA 
dosing, including a decrease in high density lipoprotein 
(HDLc) and an increase in low density lipoprotein 
(LDLc).  Notably, in patients with PBC, the decrease in 
mean HDLc levels occurred early and stabilized within 3 
months after which time levels generally remained 
constant over the course of treatment.  The average 
levels of HDLc remained within normal limits.  
Commensurate with decreases in HDLc, decreases in 
total cholesterol were observed in patients with PBC, 
while LDLc concentrations remained comparable to 
baseline and placebo in OCA treated patients with the 
exception of a modest transient and early rise after 
initiation of treatment. 
Based on previous PK and short-term studies in patients 
with hepatic impairment, increased systemic exposure 
was not associated with an apparent change in the safety 
profile of OCA as assessed by the incidence and severity 
of AEs or by changes in clinical laboratory tests.  
Hepatotoxicity has been associated with increased liver 
concentrations of OCA.  Hepatic impairment does not 
The rate of progression and risk of decompensation 
is variable and may be rapid in certain patients, 
necessitating closer surveillance of patients at risk.   
Clinical Data 
In two Phase 2 studies and a Phase 3 study 
evaluating OCA in the treatment of subjects with 
PBC, hepatic adverse events were observed in 
subjects receiving doses of OCA ranging from the 
maximum approved dose of 10 mg once daily to 50 
mg (5 times the highest recommended dose).   
Recent safety findings in NASH clinical trials 
include 2 cases of hepatic decompensation reported 
as SUSARs, 1 of which resulted in death.  Both cases 
involved numerous confounding factors that make 
evaluation of association with treatment difficult.  
Details for both events are provided in the 
Investigator’s Brochure Addendum 1 to Version 
Number: 16 (31 March 2017), Effective Date: 02 
October 2017. 
The primary AE shown to be related to OCA is 
pruritus.  Pruritus has also been observed in clinical 
studies with OCA in other indications, as well as in 
healthy subjects, with the highest frequency 
observed in subjects with PBC.  The incidence and 
severity of pruritus have been shown to be dose 
dependent, but there is no evidence of association 
with stage or progression of underlying disease. 
Changes in lipid profiles have also been observed 
with OCA dosing, including an increase in 
low-density lipoprotein (LDL) cholesterol and a 
decrease in high-density lipoprotein (HDL) 
cholesterol.  The clinical significance of these lipid 
findings remains unclear and is being studied 
further. 
Independent data monitoring committees (DMCs) 
have performed detailed reviews of several studies 
including the Phase 3, clinical outcomes study in 
PBC (747-302) and the Phase 3, pivotal study in 
NASH with fibrosis (747-303).  The DMC reviewed 
data (unmasked for PBC and unblinded by 
Updated in relations to other 
revisions made per FDA 
request. 
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affect the ability of OCA to activate FXR in the intestine 
and the liver. 
Refer to the Investigator’s Brochure (IB) for additional 
information regarding the known potential risks with the 
investigational product. 
treatment group for NASH with a total of 
approximately 1000 subjects) in closed sessions, 
which excluded participation of the Sponsor.  Based 
on these reviews, the DMC recommended that both 
studies continue without modification. 
Post-Marketing Cases in PBC 
As of September 2017, greater than 3000 patients 
have received Ocaliva in the post-marketing 
setting.  In patients with moderate to severe hepatic 
impairment (Child-Pugh B and C), liver 
decompensation, liver failure, and death have been 
reported when Ocaliva was dosed up to 7 times the 
recommended once weekly starting dose for such 
patients.  Based on the initial medical assessment of 
these cases, which included patients having 
undergone liver transplant, there was insufficient 
evidence suggesting a causal relationship between 
higher than recommended dosing and the reported 
adverse events. However, Intercept 
Pharmaceuticals, Inc. (the Sponsor) continues to 
assess the potential association between adverse 
events, including deaths, and the higher than 
recommended dosing of Ocaliva observed in PBC 
patients with moderate to severe hepatic 
impairment (Child-Pugh B and C) through ongoing 
post-marketing pharmacovigilance activities. 
Signs and symptoms reported in patients 
experiencing liver-related adverse events who 
received Ocaliva include:  increases in bilirubin and 
other liver enzymes, new or worsening pruritus, 
new or worsening fatigue, vague neuropsychiatric 
symptoms (such as dysphoria), abdominal pain, 
nausea, vomiting, diarrhea, dehydration, jaundice, 
and liver decompensation. 
Refer to the IB for additional information regarding the 
known potential risks with the investigational product. 
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
Treatment Period (Weeks) 
Long-Term 
Safety 
Extension 
Double-Blind Treatment Period 
(Weeks)b 
Double-
Blind 
Extension 
Clarification 
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Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
Insertion 
Week 42 Visit added with assessments to match 
Week 3 Visit plus assesments to assess for dose 
titration and dispense IP. 
Correction 
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1, 
Screening, Day 1 
Insertion 
Gallbladder assessment (ultrasound) 
Gathering additional data at 
Screening may be beneficial in 
identifying at risk populations 
(eg, to assist with the causality 
of potential 
gallbladder/pancreatic 
complications).  
Insertion 
Footnotes added  
r 
If an ultrasound has been done within 12 
months of Screening, and a report/adequate data 
are available, a pretreatment ultrasound at 
Screening is not required. 
s 
If ultrasound for gallbladder assessment was 
not performed at Screening and the historic 
ultrasound is >12 months from Day 1, perform 
ultrasound. 
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
Markers of Inflammation: IL-6, hs-CRP, TNF-α, IgM, 
IgG, IgA, CK-18-M30 
Deletion 
Samples were removed to 
simplify the study design. 
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
Insertion 
Amylase and Lipase:  Sample to be collected if the 
patient experiences acute pancreatitis or 
cholecystitis. 
Per FDA request. 
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
PK Fasting Collection 
Removed for Weeks 12, 18, 24, 30, and 48/ET/EOS/EOT 
Deletion 
Clarification for sites needed to 
clarify Fasted and Serial PK 
assessment timepoints.  Serial 
PK is fasted, so indicating both 
types of assessments for these 
days was redundant.   
Section 7.1.2, 
Schedule of Study 
Procedures, Table 1 
Insertion  
Footnote added to Serum 
Chemistry/Hematology/Coagulation 
l MELD values will be calculated based on serum 
chemistry coagulation values at each visit. 
Clarification. 
Section 7.4, 
Monitoring and 
Management of 
Potential Hepatic 
Injury and/or 
Disease Progression 
New Section 
Given the chronic nature of PBC, it is important to 
monitor for potential hepatic injury, disease 
progression and/or hepatic decompensation.  Child-
Pugh and MELD scores will be reviewed at each 
visit where labs are drawn (Table 1).  In addition, 
adverse events, signs and symptoms of potential 
hepatic injury or decompensation, and laboratory 
values will also be reviewed at regular intervals as 
described in Section 7.1.2.  Based on biochemical 
and clinical assessments, the investigational product 
Extensive safety monitoring 
and dosing adjustments, 
interruptions, or 
discontinuations are required 
given the elevated risk of 
decompensation and higher 
hepatic exposure to OCA in this 
population. It is important that 
Investigators construct an entire 
clinical picture, which includes 
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may be interrupted or discontinued per criteria 
discussed in Section 7.4.2 and Section 7.4.3, and 
close monitoring procedures will be implemented 
(refer to Section 7.6). 
not only rules based monitoring 
but careful evaluation of signs 
and symptoms of potential 
decompensation and diagnostic 
dilemmas. 
Section 7.4.1, Signs 
and Symptoms of 
Potential Hepatic 
Injury or 
Decompensation 
New Section 
Patients should be instructed to contact study 
personnel if they notice any of the following signs 
and symptoms or have healthcare interactions 
outside of the study setting  
Signs and Symptoms of Hepatic Injury or 
Decompensation: 
 
Specific signs and symptoms of liver 
impairment:  yellowing of the skin or 
the whites of eyes, pale-colored stools, 
urine color change from pale to deep 
amber [dark] (reflecting impaired 
bilirubin metabolism) 
 
More general signs and symptoms of 
ascites and encephalopathy:  
confusion, swelling of the legs or 
abdomen 
 
Non-specific signs and symptoms of 
impaired health:  nausea, vomiting, 
abdominal pain, diarrhea, weight loss, 
fever and chills, worsening or new 
fatigue, weakness, loss of appetite 
 
Significant intercurrent illnesses such 
as gastroenteritis may exacerbate 
hepatic injury or decompensation (eg, 
established severe abdominal pain, 
vomiting, and diarrhea for more than 
4 days) and should be an indication 
for prompt investigational product 
interruption and complete patient 
evaluation 
Other Symptoms: 
Per FDA request. 
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 
Worsening of renal function or likely 
dehydration 
Healthcare Provider (HCP) Interactions: 
 
Visits to primary HCP or referral to 
any specialist for any new symptoms 
(other than ongoing care for stable 
comorbidities) 
 
New medications or changes to 
current medications prescribed from 
HCP or any new over the counter 
medications or herbal supplements  
 
Laboratory procedures or 
assessments performed by an HCP  
Signs and symptoms for potential hepatic injury or 
decompensation should be followed by (1) 
evaluation of liver biochemistry for suspected drug-
induced liver injury (DILI) or potential hepatic 
decompensation (Section 7.4.2), (2) assessment of 
clinical events for potential hepatic decompensation 
(Section 7.4.3), (3) triggering of close monitoring or 
investigational product interruption/discontinuation 
per criteria (Section 8.4), (4) documentation in the 
AE eCRF or the SAE eCRFs (Section 13.1), and (5) 
contact with the Medical Monitor. 
Section 7.4.2, Liver 
Biochemistry 
Assessments for 
Potential Hepatic 
Injury or Hepatic 
Decompensation 
New Section 
Liver biochemistry will be assessed to evaluate 
biochemical triggers that will prompt an immediate 
reevaluation of patients for potential hepatic injury 
or hepatic decompensation.  These assessments will 
be performed at: 
 
Each protocol-specified visit (Table 1)  
 
Unscheduled visits as needed in the 
event of signs or symptoms of 
suspected hepatic injury or 
decompensation or if laboratory 
alerts have been triggered 
It is important that the laboratory assessments be 
completed as required and that the central 
Per FDA request. 
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laboratory be used for assessments whenever 
possible.  In the event that a patient cannot return 
to the clinic for a scheduled or unscheduled visit, or 
there is an event that triggers a need for an 
immediate assessment, the use of a local lab is 
permissible at the discretion of the Investigator. In 
these cases, the Investigator will obtain the 
laboratory results and the laboratory normal 
ranges. 
The process for assessing criteria is presented in 
Figure 2, and the specific threshold(s) for each 
laboratory analyte to trigger mandatory repeat 
testing and, potentially, a complete patient 
evaluation (depending on the repeat result) are 
summarized in Table 3. 
Figure 2: 
DILI Management Algorithm 
 
 
DILI = drug-induced liver injury; IP = Investigational Product 
NOTE Other laboratory criteria include:  ALT, AST, total bilirubin, INR, and 
electrolytes (sodium). 
Table 3 
Liver Laboratory Criteria for 
Monitoring of Suspected Hepatic 
Injury or Potential Hepatic 
Decompensation and Criteria for 
Interruption or Discontinuation 
of Investigational Product 
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It should be noted that it is difficult to recognize 
every potential marker of hepatic or renal 
deterioration.  There is no substitute for good 
medical judgment.  Investigators will be reminded 
to be cautious and mindful in their evaluation of 
patients’ symptoms, signs, and laboratory results.  
However, for example, a single abnormal laboratory 
analyte result may be artefactual; accordingly, 
Investigators will be allowed to implement an 
alternate follow-up procedure if considered 
appropriate based on their medical judgement, but 
only after documented agreement with the 
Sponsor’s Medical Monitor. 
7.4.3, Clinical 
Criteria for 
Monitoring for 
Potential Hepatic 
Decompensation 
New Section 
Patients will be monitored for potential hepatic 
decompensation events throughout the study.  
Clinical criteria for monitoring these events and the 
interruption/discontinuation of investigational 
product is summarized in Table 4. 
Investigational product should be discontinued 
permanently if the patient received a liver 
transplant or experiences multi-organ failure as 
defined in Table 4, Part A.  Patients should continue 
to return for scheduled study visits for safety follow 
up.  
Patients who experience other potential hepatic 
decompensation events defined in Table 4, Part B 
should be closely monitored until normalization or 
stabilization.  Patients may be rechallenged after a 
minimum of 30 days if fully resolved OR stable and 
approved by the Medical Monitor and Investigator. 
 
Table 4  Clinical Criteria for Monitoring Potential 
Hepatic Decompensation Events and Interruption / 
Discontinuation of Investigational Product   
Per FDA request. 
7.5, Dose Titration 
Criteria 
Dose Adjustment Criteria 
Dose titration may follow the scheduled dosing regimens 
described in Section 7.3 or occur due to tolerability 
concerns or as a result of changes in a patient’s CP 
Score. 
Dose titrations may involve increases or decreases in 
dosing frequency and are dependent on tolerability (as 
Dose Titration Criteria 
Dose titration may follow the scheduled dosing 
regimens described in Section 7.3 or occur due to 
tolerability concerns. 
Dose titrations may involve increases or decreases in 
dosing frequency and are dependent on tolerability (as 
assessed by a review of AEs and safety laboratory 
Updates made to reflect 
titration for dosing per label 
dosing guidelines. 
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assessed by a review of AEs and safety laboratory 
results).  In general, down-titration may be done in 
response to tolerability concerns and can occur at any 
time.  Up-titration will be done per protocol based on 
tolerability, as assessed by the Investigator based on 
response, or following resolution of a tolerability 
concern that previously led to down-titration.  
Up-titrations may only occur to the maximum dose and 
frequency indicated for each dosing regimen as defined 
in Section 7.3. 
Scheduled Dose Titration - After initiation of OCA or 
matching placebo, titration may be considered as early 
as the Week 12 Visit.  Subsequent titrations in dose or 
dosing frequency for patients may occur no earlier than 
6 weeks following an up-titration. 
Tolerability Dose Titration - Investigators may 
decrease the dosing frequency or dose as considered 
clinically appropriate (eg, tolerability) 
Dose Titration due to Change in CP Score – Over the 
course of the study, a patient’s CP category may change.  
When a patient demonstrates a change in CP category 
(as assessed per Table 12), dosing should be reassessed 
and modified if appropriate (Table 2).  Changes to the 
dosing regimen are not mandatory and should be based 
on clinical judgment and change in CP score.  The 
titration steps for CP-B and CP-C patients are identical 
with exception of the maximum allowed dose.  
Therefore, if a patient changes CP class from B to C, or 
vice versa, the maximal dose for the new regimen will 
apply (Table 2).  If a patient improves to CP-A during 
the study, the maximal CP-B dose will still apply.  If a 
patient has not yet reached the maximal dose, the 
appropriate titration regimen (Table 2) should be 
followed.  
Table 3: 
Maximum Daily dose based on 
change in Child-Pugh Category 
results).  In general, down-titration may be done in 
response to tolerability concerns and can occur at any 
time.  Up-titration will be done per protocol based on 
tolerability, as assessed by the Investigator based on 
response, or following resolution of a tolerability 
concern that previously led to down-titration.  
Up-titrations may only occur to the maximum dose and 
frequency indicated as defined in Section 7.3. 
Scheduled Dose Titration - After initiation of OCA or 
matching placebo, titration may be considered as early 
as the Week 12 Visit.  Subsequent titrations in dose for 
patients may occur no earlier than 6 weeks following 
an up-titration. 
Tolerability Dose Titration - Investigators may 
decrease the dosing frequency or dose as considered 
clinically appropriate (eg, tolerability). 
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a  Once a patient begins dosing with the new dosing 
regimen, titration should occur as described for that 
dosing regimen in Section 7.3 .  
b Dosing per the twice weekly schedule must be at least 
3 days apart. 
CP Scores will be calculated at all study visits (except 
Week 3).  While PBC-specific versions of CP scores are 
available, this study will use the standard calculation 
(Pugh 1973, Lucey 1997).  All associated visit data 
(including central laboratory results) should be entered 
into the electronic case report form (eCRF) in a timely 
fashion to confirm that the patient’s CP Score has not 
changed.  If a change in CP Score is observed 
independent of a study visit, the patient should be 
contacted via phone to discuss the need for a dosing 
modification and should be asked to return to the 
investigative site as soon as possible if a new bottle of 
investigational product is required to be dispensed. 
Section 7.6, Close 
Observation 
New Section 
If investigational product is interrupted or 
discontinued as described in Section 8.4, patients 
should be closely monitored (contacted by the site a 
minimum of every 2 weeks and scheduled visits 
every 6 weeks; if returning to the site for a 
scheduled visit is not feasible, use of a local lab may 
be permissible at the Investigator's discretion).  At a 
minimum, the following assessments should be 
conducted at each study visit:   
 
Physical exam and thorough review of 
patient reported signs and symptoms,  
 
Liver biochemistry (including ALP, 
ALT, AST, GGT, total and 
conjugated bilirubin, creatinine, and 
Per FDA request. 
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albumin), prothrombin time 
(PT)/INR, serum electrolytes, and 
assessment of Child Pugh (only if the 
patient is at the study site) and MELD 
scores.  
In addition, a trough pharmacokinetic sample for 
assessment of OCA serum drug levels and its major 
metabolites should be obtained in any patient who 
develops an AE that is indicative of or consistent 
with hepatic injury or decompensation.  
The following additional monitoring procedures 
should be performed for events of potential hepatic 
injury (per FDA Guidance for Industry on Drug 
Induced Liver Injury) or suspected hepatic 
decompensation based on criteria described in 
Section 7.4.1, Section 7.4.2, Section 7.4.3.  These 
cases need to be discussed with the Sponsor's 
Medical Monitor: 
 
Repeating liver biochemistry and 
function tests as described in Section 
7.4.2.  Frequency of retesting can 
decrease to once a week or less if 
abnormalities stabilize or the study 
drug has been discontinued and the 
patient is asymptomatic, as clinically 
indicated.  
 
Obtaining a more detailed history of 
symptoms and prior or concurrent 
diseases.  
 
Obtaining a history of concomitant 
drug use (including nonprescription 
medications and herbal and dietary 
supplement preparations), alcohol 
use, recreational drug use, and special 
diets is important. Concomitant drugs 
with potential hepatotoxicity should 
be recorded and discontinued unless 
alternative therapies are not 
available.  In the case of concomitant 
drugs potentially hepatotoxic, 
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continued use of investigational 
product should be discussed with the 
Sponsor's Medical Monitor.  The 
patient may be discontinued from 
investigational product, if clinically 
appropriate.  
 
Obtaining a history of exposure to 
environmental chemical agents or 
herbal supplements which may be 
associated with liver toxicity.  
 
Ruling out acute viral hepatitis types 
A, B, C, D (in those thought to have 
acute HBV infection), and E; 
autoimmune or alcoholic hepatitis; 
Wilson's disease, hypoxic/ischemic 
hepatopathy; and biliary tract 
disease.   
 
Investigators should consider testing 
for Hepatitis E virus when assessing 
for hepatic decompensation as 
infection with Hepatitis E virus in 
patients with chronic liver diseases 
such as PBC may rapidly worsen with 
signs and symptoms similar to drug 
induce liver injury (Kumar 2013) 
 
Obtaining additional tests to evaluate 
liver function, as appropriate (e.g., 
INR, direct bilirubin).  
 
Seeking hepatology consultation, if 
the Investigator is not a hepatologist 
Section 8.4, Dose 
Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
Investigational product may be temporarily decreased 
(eg, by decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability concerns.  
The dose of investigational product should be resumed 
to the maintenance dose in a blinded manner once the 
issues relating to the lack of tolerability are resolved.   
Patients who are discontinued from investigational 
product prior to completion of the study are encouraged 
Investigational product may be temporarily decreased 
(eg, from 10 mg twice weekly to 5 mg twice weekly, 
or from 5 mg twice weekly to 5 mg once weekly) or 
temporarily or permanently stopped based on 
tolerability concerns.  Investigational product may be 
resumed at the maintenance dose upon resolution of 
gastroenteritis or worsening renal function or 
dehydration if there is no evidence of liver injury.  
Per FDA request. 
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to continue to follow the regular visit schedule, with the 
exception of PK sampling, but may withdraw consent at 
any time. 
For rechallenge following all other dose 
interruptions (see Table 5), investigational product 
should be initiated at a lower dose and patients 
monitored more frequently with up-titration 
considered based on tolerability. 
Adjustments, interruptions, discontinuation, and 
any rechallenge of investigational product should be 
implemented per the criteria outlined in Table 5.  
Patients that discontinue investigational product are 
expected to continue in the study (and follow the 
regular visit schedule, with the exception of PK 
sampling [trough PK may be required in the event of 
an AE consistent with hepatic injury or 
decompensation]) until the end of the study, but may 
withdraw consent at any time. 
Table 5  Criteria for Dose Adjustment, 
Interruption, Discontinuation, and Rechallenge 
8.4.1, Reasons for 
Additional 
Monitoring of 
Mandatory 
Interruption of 
Investigational 
Product; 8.4.1.1, 
Reasons for 
Additional 
Monitoring Related to 
Liver Chemistries; 
8.4.1.2, Reasons for 
Investigational 
Product Interruption 
Related to Elevated 
Liver Chemistries; 
8.4.1.3, Pregnancy; 
8.4.2., Reasons for 
Mandatory 
Discontinuation of 
Investigational 
Product 
8.4.1. 
Reasons for Additional Monitoring or 
Mandatory Interruption of Investigational Product 
8.4.1.1. Reasons for Additional Monitoring Related to 
Liver Chemistries 
Patients who develop ALT or AST >2× baseline (and 
>ULN) or total bilirubin >1.5× baseline (and >ULN) 
should have repeat testing within 48 to 72 hours to 
confirm values.  Patients with persistent elevations (eg, 
additional lab testing per Investigator discretion) should 
be closely monitored.  Concomitant elevations in total 
bilirubin or INR with persistent increases in ALT or 
AST should also be closely monitored. 
8.4.1.2. Reasons for Investigational Product 
Interruption Related to Elevated Liver Chemistries 
Development of any of the following clinical laboratory 
values, without explanation, during the study mandates 
investigational product interruption: 
• 
AST and/or ALT >3× baseline (and >ULN) 
• 
Total bilirubin >2× baseline (and >ULN) 
Repeat testing within 48 to 72 hours to confirm the 
abnormalities and to determine if they are increasing or 
decreasing should be performed.  Detailed adverse event 
information should also be collected, and the patient 
should be investigated for possible causes of the liver 
Deletion 
Replaced by text in in other 
sections added per FDA 
request. 
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chemistry changes, as appropriate.  The Investigator 
should obtain a history of concomitant medications 
(including nonprescription medications and herbal and 
dietary supplement preparations) and other possible 
causes of liver enzyme and bilirubin increases.  Any 
potentially hepatotoxic medications should be identified 
and discontinued if advisable.  
If symptoms persist or repeat testing shows AST or ALT 
>3× baseline (and >ULN) or total bilirubin >2× baseline 
(and >ULN), patients should be followed as clinically 
indicated depending on other laboratory and clinical 
signs and symptoms.   
For the purposes of this protocol, if the above referenced 
significant elevation in liver enzyme or bilirubin levels 
resolve following interruption of investigational product 
and no other cause for the elevation is identified, the 
elevations should be assumed to be related to 
investigational product and investigational product 
should be discontinued.  If the liver enzyme or bilirubin 
levels do not resolve following interruption of 
investigational product and no other cause for the 
elevation is identified, it may be assumed that the 
elevations were due to disease progression and the 
patient may be re-challenged following a discussion 
between the Investigator or designee and the Sponsor. 
Elevation of liver enzymes or bilirubin is based on 
comparison to baseline values defined as the mean of all 
available Screening and Day 1 values, which are the 
mean of all available evaluations prior to the first 
administration of investigational product.  At least 2 of 
these samples will be obtained a minimum of 2 weeks 
apart during the Screening period.  Elevations that occur 
gradually over the course of the study may be indicative 
of disease progression and should be assessed as 
clinically appropriate.  Liver enzyme and bilirubin 
elevations that occur over a shorter time, such as within 
a 6-month period, should be evaluated for drug-induced 
liver injury as provided in the guidelines below. 
If at any time a patient develops signs or symptoms of 
hepatotoxicity such as new onset fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>7%) in combination with 
elevations in liver enzymes, investigational product 
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should be interrupted and liver enzymes monitored until 
signs or symptoms resolve.  
Patients who develop evidence of severe drug-induced 
liver injury that is suspected to be causally related to the 
investigational product should be discontinued from 
investigational product and should not be rechallenged.  
Severe drug-induced liver injury includes, but is not 
limited to, functional hepatic impairment, as indicated 
by rising bilirubin or INR that cannot be explained by 
progression of disease.  Natural progression of the 
underlying condition and other causal factors such as a 
common bile duct stone or development of other 
concurrent liver disease should be considered before the 
investigational product is permanently discontinued.  
If after all investigations and actions outlined above 
have been completed, the investigator determines that 
the elevations in liver biochemistries are considered not 
related to investigational product, the Sponsor must be 
contacted before investigational product can be 
reinitiated.  Follow-up procedures for patients resuming 
treatment, including laboratory evaluations and physical 
examinations, must be performed after a maximum of 2 
weeks of retreatment.  Results must be reported to the 
site as soon as possible so the Investigator can determine 
if it is appropriate for the patient to continue treatment.   
The Medical Monitor must be contacted in all cases of 
persistent liver biochemistry elevations. 
All hepatic injury events, regardless of relationship to 
investigational product, will be adjudicated by the 
Hepatic Safety Committee (see Section 15.9). 
8.4.1.3. Pregnancy 
If a female patient becomes pregnant, she must interrupt 
treatment with investigational product immediately, but 
should continue with the study visit schedule.  As 
described in Section 13.1.9 pregnancy is not considered 
an AE for reporting purposes.  The patient may restart 
investigational product when she is no longer pregnant 
or breastfeeding (if applicable) at the discretion of the 
Investigator and after discussion with the Medical 
Monitor as described in Section 13.1.9).  New baseline 
procedures should include pregnancy testing. 
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8.4.2. 
Reasons for Mandatory Discontinuation of 
Investigational Product 
Patients who undergo a liver transplant during the course 
of the study must discontinue investigational product 
and discontinue the study visit schedule.  However, 
these patients should be encouraged to consent to the 
semiannual telephone contact and/or continued record 
review only to allow for secondary outcome events data 
to be collected. 
Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 9.5.2., Patient 
Numbers 
Patients will be identified by a unique 6-digit number, 
independent of the randomization number.  The first 3 
digits will represent the site number and the last three 
digits will represent the Screening number. 
Patients are assigned using a unique 10-character 
identifier (AAA-BBBCCC), independent of the 
randomization number. The first 3 digits represent the 
last 3 digits of the protocol number, followed by a 
hyphen (AAA-). The next 3 digits represent the site 
number (BBB). The last 3 digits represent a unique 
screening number that is assigned in sequential 
order at each site starting with 001 (CCC). 
Update per current practice. 
Section 9.7.2, 
Informed Consent 
Procedures 
The Investigator or designee will explain the nature, 
purpose, possible risk, and benefit of the study to the 
patient and will provide him/her with a copy of the 
informed consent form (ICF).  The patient will be given 
sufficient time to consider the study before deciding 
whether or not to participate.  The patient will be 
informed that participation is voluntary and that her/his 
future medical treatment will not be compromised by 
participation in the study and that he or she can 
withdraw from the study at any time.  The patient must 
be willing and able to provide written informed consent 
(on hard copies) before entering the study.  The 
Investigator or a medically qualified designee is 
responsible for administering and documenting the 
written informed consent of the patient.  The patient will 
be given a copy of the patient information sheet (PIS) 
and his/her signed and dated consent form.  Patients will 
also be provided a separate ICF before providing blood 
samples for genetic analysis and must be willing and 
able to provide consent as described above. 
The Investigator or designee will explain the nature, 
purpose, possible risk, and benefit of the study to the 
patient and will provide him/her with a copy of the 
informed consent form (ICF).  The patient will be 
given sufficient time to consider the study before 
deciding whether or not to participate.  The patient will 
be informed that participation is voluntary and that 
her/his future medical treatment will not be 
compromised by participation in the study and that he 
or she can withdraw from the study at any time.  The 
patient must be willing and able to provide written 
informed consent (on hard copies) before entering the 
study.  The Investigator or a medically qualified 
designee is responsible for administering and 
documenting the written informed consent of the 
patient.  The patient will be given a copy of the patient 
information sheet (PIS) and his/her signed and dated 
informed consent form (ICF).   
Correction.  There is no 
separate ICF for this study. 
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Section 9.7.4, 
Screening Procedures 
(14 Days to 28 Days 
prior to Day 1) 
 
Insertion 
 
Perform an ultrasound for HCC surveillance 
and evaluation of gallbladder status (if 
equipment is unavailable, sites should make 
every attempt to use available community 
referral sites).  If… 
Gathering additional data at 
Screening may be beneficial in 
identifying at risk populations 
(eg, to assist with the causality 
of potential 
gallbladder/pancreatic 
complications). 
Section 9.7.5, Day 1 
Procedures 
(Randomization) 
 
Obtain blood samples for 
o 
Serum chemistry, hematology, and 
coagulation  
o 
Markers of inflammation and 
fibrosis (IL-6, hs-CRP, TNF-α, IgM, 
IgG, IgA, CK-18-M30, ELF [HA, 
P3NP, and TIMP 1]) 
o 
Fasting PK assessment 
o 
Bile Acid/C4/FGF-19  
 
Perform TE using the Fibroscan® TE device.  
If the TE cannot be performed on Day 1 (eg, 
device/technician unavailability, scheduling 
issues, TE data is needed to inform cirrhosis 
assessment, etc.), the procedure may be 
completed within the Day 1 Visit window, (if 
data is needed for cirrhosis assessment) or as 
close as possible to the Day 1 Visit, 
preferably, after patient eligibility has been 
confirmed.  Instruct the patient to take Day 1 
dose on the day of this visit. 
 
… 
 
Obtain blood samples for 
o 
Serum chemistry, hematology, and 
coagulation  
o 
Markers of fibrosis (ELF [HA, 
P3NP, and TIMP 1]) 
o 
Fasting PK assessment 
o 
Bile Acid/C4/FGF-19  
 
Perform TE using the Fibroscan® TE device.  
If the TE cannot be performed on Day 1 (eg, 
device/technician unavailability, scheduling 
issues, TE data is needed to inform cirrhosis 
assessment, etc.), the procedure may be 
completed within the Day 1 Visit window, (if 
data is needed for cirrhosis assessment) or as 
close as possible to the Day 1 Visit, 
preferably, after patient eligibility has been 
confirmed.  Instruct the patient to take Day 1 
dose on the day of this visit. 
 
If ultrasound for gallbladder assessment 
was not performed at Screening and the 
historic ultrasound is >12 months from 
Day 1, perform ultrasound. 
Markers of inflammation were 
removed to simplify the study 
design. 
 
Gathering additional data at 
Screening may be beneficial in 
identifying at risk populations 
(eg, to assist with the causality 
of potential 
gallbladder/pancreatic 
complications). 
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Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 9.7.5, Day 1 
Procedures 
(Randomization); 
Section 9.7.11, Week 
48 Procedures; 
9.7.12, Every 3 
Months after Week 
48 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
 
NOT to take investigational product 
on the morning of the next visit, and  
 
To bring the investigational product 
bottle(s); s/he will dose at the clinic 
(if this is in compliance with the 
established dosing frequency), and 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
required prior to all study visits, but 
water is permitted. 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
 
NOT to take investigational 
product on the morning of the next 
visit, and  
 
To bring the investigational 
product bottle(s) to the visit 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
required prior to all study visits, but 
water is permitted. 
Correction.  Patients will only 
be dosed in the clinic on visits 
with Serial PK. 
Section 9.7.6, Week 3 
and Week 42 Safety 
Visit Procedures 
Insertions. 
Week 3 and Week 42 Safety Visit Procedures 
… 
• 
Assess investigational product compliance, 
perform investigational product accountability. 
• 
For Week 42 Only:  Assess for dose titration, if 
eligible. (Refer to Section 7.3) 
• 
For Week 42 Only:  Dispense investigational 
product only if there is dose increase or as needed.  
No new investigational product bottles will be 
dispensed if there is only change in dosing 
frequency of the same dose level.  Patients are 
expected to use up each investigational product 
bottle before a new bottle will be dispensed 
 
• 
Obtain blood samples for 
- 
Serum chemistry, hematology, and 
coagulation  
• 
Schedule the next visit (Week 6 or Week 48), 
reiterate dosing instructions, and advise the patient: 
For Week 3 Only:   
- 
Week 6 Visit should occur 3, 4, or 5 days after 
taking the Week 6 dose, eg, if the Week 6 dose is taken 
Correction to add Week 42 
visit.  Additional clarifications 
needed to distinguish certain 
assessments from Week 3.  
Clarification on which visits 
will have in-clinic dosing. 
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on a Sunday, the patient should come in for the Week 6 
Visit within the following Wednesday and Friday 
(Figure 3). 
- 
NOT to take investigational product on the 
morning of the next visit, and  
- 
To bring the investigational product bottle(s) to 
the visit 
- 
To fast overnight (at least 8 hours) prior to the 
next visit.  Fasting is required prior to all study 
visits, but water is permitted. 
For Week 42 Only: 
- 
NOT to take investigational product on the 
morning of the next visit, and  
- 
To bring the investigational product bottle(s); s/he 
will dose at the clinic (if this is in compliance with the 
established dosing frequency), and 
- 
To fast overnight (at least 8 hours) prior to the 
next visit.  Fasting is required prior to all study visits, 
but water is permitted. 
Section 9.7.7, Week 6 
Procedures 
Insertion 
Week 6 Visit should occur 3, 4, or 5 days after 
taking the Week 6 dose, eg, if the Week 6 dose is 
taken on a Sunday, the patient should come in for 
the Week 6 Visit within the following Wednesday 
and Friday (Figure 3). 
Clarification. 
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Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 9.7.9, Week 
12, Week 24, Week 
36 Procedures 
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation 
 
Markers of inflammation and 
fibrosis (IL-6, hs-CRP, TNF-α, IgM, 
IgG, IgA, CK-18-M30, ELF [HA, 
P3NP, and TIMP 1])  
 
Bile Acid/C4/FGF-19  
 
Fasting PK assessment 
… 
 
Serial PK assessment at Week 12 and 24 
ONLY (not done at Week 36 and 
Week 42); the following procedures will 
be conducted in all patients: 
 
30 minutes prior to dosing: collect 
predose blood sample 
 
Dispense/Administer investigational 
product from the double-blind bottle 
(collected from the patient upon 
arrival for this visit) with 240 mL (8 
oz.) of water.  Instruct the patient to 
swallow the tablet whole; s/he must 
not chew, divide, or crush the tablet.    
 
Collect blood samples at: 30 min, 45 
min, 1 hour postdose 
 
Immediately following 1 hour 
postdose blood draw, administer 
meal replacement drink (to be 
consumed within 5 – 10 minutes)  
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation 
 
Markers of fibrosis (ELF [HA, 
P3NP, and TIMP 1])  
 
Bile Acid/C4/FGF-19  
 
Fasting PK assessment (Week 36 
only) 
… 
 
Serial PK assessment at Week 12 and 24 
ONLY (not done at Week 36); the 
following procedures will be conducted 
in all patients: 
 
30 minutes prior to dosing: collect 
predose blood sample 
 
Dispense/Administer 
investigational product from the 
double-blind bottle (collected from 
the patient upon arrival for this 
visit) with 240 mL (8 oz.) of water.  
Instruct the patient to swallow the 
tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 
Collect blood samples at: 30 min, 
45 min, 1 hour postdose 
 
Immediately following 1 hour 
postdose blood draw, administer 
meal replacement drink (to be 
consumed within 5 – 10 minutes)  
Markers of inflammation were 
removed to simplify the study 
design. 
 
Clarification of serial and 
fasting PK assessments. 
 
Clarification of water and meal 
restrictions on visit day. 
 
Clarification of which visits 
have in-clinic dosing. 
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 
Collect blood samples at: 1.5, 2, 2.5, 
3, 4, 5, 6, 7, 8, 9, and 24 hours 
postdose 
Note:  Patients should only consume a meal 
following the 4-hour and 7-hour PK 
assessment times (see Figure 4).  Patients 
should not drink any water until at least one 
hour postdose. 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
 
NOT to take investigational product 
on the morning of the next visit, and  
 
To bring the investigational product 
bottle(s); s/he will dose at the clinic 
(if this is in compliance with the 
established dosing frequency), and 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
required prior to all study visits, but 
water is permitted. 
 
 
Collect blood samples at: 1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours 
postdose 
Note:  Patients should not drink additional water for 
1 hour after taking the dose of investigational 
product and will remain fasted until after the 
1-hour sample is collected.  A meal replacement 
drink will be provided following collection of the 1-, 
4-, and 7-hour PK sample.  No other food or drink 
(water is permitted) will be allowed until after the 
9-hour sample collection (see Figure 4).  The 24-
hour post-dose sample can be obtained upon return 
to the clinic or by a home health care designee. 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
 
NOT to take investigational 
product on the morning of the next 
visit, and  
 
To bring the investigational 
product bottle(s) to visits; s/he will 
dose at the clinic for Week 18 and 
Week 30 visits (if this is in 
compliance with the established 
dosing frequency), and 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
required prior to all study visits, but 
water is permitted. 
Section 9.7.10, Week 
18 and Week 30 
Procedures 
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation  
 
Bile Acid/C4/FGF-19  
 
Fasting PK assessment 
… 
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation  
 
Bile Acid/C4/FGF-19  
… 
Fasting PK removed; serial PK 
on this visit is fasted. 
 
Clarification of water and meal 
restrictions on visit day 
 
Clarification on which visits 
will have in-clinic dosing. 
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 
Serial PK assessment; the following 
procedures will be conducted in all 
patients: 
 
30 minutes prior to dosing:  collect 
predose blood sample 
 
Dispense/Administer investigational 
product from the double-blind bottle 
(collected from the patient upon 
arrival for this visit) with 240 mL (8 
oz.) of water.  Instruct the patient to 
swallow the tablet whole; s/he must 
not chew, divide, or crush the tablet.    
 
Collect blood samples at: 30 min, 45 
min, 1 hour postdose 
 
Immediately following 1 hour 
postdose blood draw, administer 
meal replacement drink (to be 
consumed within 5 – 10 minutes)  
 
Collect blood samples at:  1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours 
post dose 
Note:  Patients should only consume a meal following 
the 4-hour and 7-hour PK assessment times (see Figure 
4).  Patients should not drink any water until at least one 
hour postdose. 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
 
NOT to take investigational product 
on the morning of the next visit, and  
 
To bring the investigational product 
bottle(s); s/he will dose at the clinic 
(if this is in compliance with the 
established dosing frequency), and 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
 
Serial PK assessment; the following 
procedures will be conducted in all 
patients: 
 
30 minutes prior to dosing: collect 
predose blood sample 
 
Dispense/Administer 
investigational product from the 
double-blind bottle (collected from 
the patient upon arrival for this 
visit) with 240 mL (8 oz.) of water.  
Instruct the patient to swallow the 
tablet whole; s/he must not chew, 
divide, or crush the tablet.    
 
Collect blood samples at: 30 min, 
45 min, 1 hour postdose 
 
Immediately following 1 hour 
postdose blood draw, administer 
meal replacement drink (to be 
consumed within 5 – 10 minutes)  
 
Collect blood samples at: 1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours 
postdose 
Note:  Patients should not drink additional 
water for 1 hour after taking the dose of 
investigational product and will remain 
fasted until after the 1-hour sample is 
collected.  A meal replacement drink will 
be provided following collection of the 1-, 
4-, and 7-hour PK sample.  No other food 
or drink (water is permitted) will be 
allowed until after the 9-hour sample 
collection (see Figure 4).  The 24-hour 
post-dose sample can be obtained upon 
return to the clinic or by a home health 
care designee. 
 
Schedule the next visit, reiterate dosing 
instructions, and advise the patient: 
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required prior to all study visits, but 
water is permitted. 
 
NOT to take investigational 
product on the morning of the next 
visit, and  
 
To bring the investigational 
product bottle(s) to both visits; 
s/he will dose at the clinic on 
Week 24 (if this is in compliance 
with the established dosing 
frequency), and 
 
To fast overnight (at least 8 hours) 
prior to the next visit.  Fasting is 
required prior to all study visits, but 
water is permitted. 
9.7.11, Week 48 
Procedures 
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation  
 
Markers of inflammation and 
fibrosis (IL-6, hs-CRP, TNF-α, IgM, 
IgG, IgA, CK-18-M30, ELF [HA, 
P3NP, and TIMP 1]) 
 
Fasting PK assessment 
 
Bile Acids/C4/FGF-19 
 
Serial PK assessment; the following 
procedures will be conducted in all 
patients: 
 
30 minutes prior to dosing: collect 
predose blood sample 
 
Dispense/Administer investigational 
product from the double-blind bottle 
(collected from the patient upon 
… 
 
Obtain blood samples for 
 
Serum chemistry, hematology, and 
coagulation  
 
Markers of fibrosis (ELF [HA, 
P3NP, and TIMP 1]) 
 
Bile Acids/C4/FGF-19 
 
Serial PK assessment; the following 
procedures will be conducted in all 
patients: 
 
30 minutes prior to dosing: collect 
predose blood sample 
 
Dispense/Administer 
investigational product from the 
double-blind bottle (collected from 
the patient upon arrival for this 
visit) with 240 mL (8 oz.) of water.   
 
Collect blood samples at: 30 min, 
45 min, 1 hour postdose 
Markers of inflammation were 
removed to simplify the study 
design. 
 
Fasting PK removed; serial PK 
on this visit is fasted. 
 
Clarification of water and meal 
restrictions on visit day 
 
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arrival for this visit) with 240 mL (8 
oz.) of water.   
 
Collect blood samples at: 30 min, 45 
min, 1 hour postdose 
 
Immediately following 1 hour post 
dose blood draw, administer meal 
replacement (to be consumed within 
5 – 10 minutes)  
 
Collect blood samples at: 1.5, 2, 2.5, 
3, 4, 5, 6, 7, 8, 9, and 24 hours post 
dose 
Note:  Patients should only consume meal 
following the 4-hour and 7-hour PK 
assessment times (see Figure 4).  Patients 
should not drink any water until at least one 
hour post dose 
 
Immediately following 1 hour post 
dose blood draw, administer meal 
replacement (to be consumed 
within 5 – 10 minutes)  
 
Collect blood samples at: 1.5, 2, 
2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours 
post dose 
Note:  Patients should not drink additional 
water for 1 hour after taking the dose of 
investigational product and will remain 
fasted until after the 1-hour sample is 
collected.  A meal replacement drink will 
be provided following collection of the 1-, 
4-, and 7-hour PK sample.  No other food 
or drink (water is permitted) will be 
allowed until after the 9-hour sample 
collection (see Figure 4).  The 24-hour 
post-dose sample can be obtained upon 
return to the clinic or by a home health 
care designee. 
Section 12.1, 
Pharmacokinetic 
Blood Sampling 
… 
Week 6 Visit should occur 3, 4, or 5 days after the Week 
6 dose (eg, if the Week 6 dose of investigational product 
is taken on a Sunday, the patient should come in for the 
Week 6 Visit between Wednesday and Friday [Figure 
2]).   
… 
Patients should not drink additional water for 1 hour 
after taking the dose of investigational product and will 
remain fasted until after the 1-hour sample is collected.  
A meal will be provided following collection of the 1-, 
4-, and 7-hour PK sample; the meal will be a meal 
… 
Week 6 Visit should occur 3, 4, or 5 days after the 
Week 6 dose (eg, if the Week 6 dose of investigational 
product is taken on a Sunday, the patient should come 
in for the Week 6 Visit between Wednesday and Friday 
[Figure 3]).   
… 
During the treatment period: 
 
Pharmacokinetic fasting samples will 
be obtained from all patients at Day 1, 
and Weeks 6, 12, 18, 24, 30, 36, and 48 
Clarifications. 
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replacement drink with nutrition information that has 
been submitted to and approved by the Sponsor in 
advance.  No other food or drink (water is permitted) 
will be allowed until after the 7-hour sample collection. 
During the treatment period: 
 
Pharmacokinetic fasting samples will be 
obtained from all patients at Weeks 6, 12, 
18, 24, 30, 36, and 48 prior to dose 
administration in accordance with Figure 
3. 
 
Serial PK assessments will be performed 
in all patients at Weeks 12, 18, 24, 30, 
and 48.   
 
prior to dose administration in 
accordance with Figure 4. 
 
Serial PK assessments will be performed
in all patients at Weeks 12, 18, 24, 30, 
and 48.   
Patients should not drink additional water for 1 hour 
after taking the dose of investigational product and will 
remain fasted until after the 1-hour sample is collected.  
A meal replacement drink will be provided following 
collection of the 1-, 4-, and 7-hour PK sample.  The 
nutritional information of the meal replacement 
drink should be submitted to and approved by the 
Sponsor in advance.  No other food or drink (water is 
permitted) will be allowed until after the 9-hour sample 
collection. 
Section 13.1.1.1, 
Adverse Event 
Insertion 
Patients should be instructed to contact the site 
promptly upon awareness if they develop signs and 
symptoms of potential hepatic decompensation such 
as:  pale-colored stools, urine color from pale to 
deep amber [dark], nausea, vomiting, abdominal 
pain, diarrhea, weight loss, fever and chills, fatigue, 
weakness, loss of appetite, confusion, swelling of the 
legs or abdomen, yellowing of the skin or the whites 
of eyes, and bruising easily. 
Given this is an at risk 
population, patients should be 
reminded to contact the 
Investigator or study 
coordinator in case they 
experience side effects or any 
other medical concerns and be 
aware of the signs and 
symptoms of potential hepatic 
decompensation. 
Section 13.1.1.4, 
Adverse Events of 
Special Interest 
Insertion 
The following decompensation events are adverse 
events of special interest; a subset of these are also 
captured as additional efficacy assessments (see 
Section 14.2.3).   
 
Variceal bleeding or recurrent 
variceal bleeding documented by 
endoscopy OR patient presenting with 
anemia or melena (hemoglobin drop 
≥2 gm/dL) and found to have varices 
documented by endoscopy, 
Per FDA request. 
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irrespective of hospitalization or 
requirement of blood transfusion.  
 
Gastrointestinal bleeding as a result 
of gastric or duodenal varices verified 
by endoscopy 
 
Hepatic encephalopathy, Grade ≥2 
 
New onset ascites requiring treatment 
 
Worsening of ascites (requiring 
increase in drug therapy or 
requirement of surgical procedure 
such as paracentesis or shunt 
placement) 
 
Refractory ascites -unresponsive to 
medications, and patient is not a 
candidate for TIPS or shunt and 
requires large volume paracentesis 
 
Hyponatremia (Na ≤125 mEq/L) 
secondary to ascites 
 
Spontaneous bacterial peritonitis 
(confirmed by diagnostic paracentesis- 
by cell count/chemistry) 
 
Hepatorenal syndrome Type 1 and 
Type 2 and Acute Kidney Injury 
(AKI) 
 
Liver failure defined as worsening of 
liver synthetic function that is 
persistently worse relative to baseline 
and/or progressive over time: 
 
Hepato-pulmonary syndrome 
 
Porto-pulmonary syndrome 
 
Liver Transplant 
 
Increase in MELD scores by 3 
points relative to baseline, 
persistent over time and 
unrelated to vitamin K deficiency 
related increase in INR 
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 
Any liver related event that 
requires hospitalization and 
treatment 
Section 13.1.4.1, 
Reporting of Adverse 
Events 
Insertion 
In addition, the Investigator should contact the 
study Medical Monitor upon awareness when any 
signs or symptoms of hepatic decompensation are 
observed in any patient. 
Enhanced communication of 
the Investigator and Medical 
Monitor in the event of signs or 
symptoms of hepatic 
decompensation. 
Section 13.1.8, 
Follow-Up of 
Adverse Events and 
Serious Adverse 
Events 
AEs ongoing at the final visit that are deemed to be 
“possibly, probably, or definitely” related or of other 
clinical significance must be followed for as long as 
necessary to adequately evaluate the safety of the patient 
or until the event stabilizes, resolves, or is no longer of 
clinical concern.  If resolved, a resolution date for the 
AE should be documented on the eCRF.  The 
Investigator must ensure that follow-up includes any 
supplemental investigations indicated to elucidate the 
nature and/or causality of the AE.  This may include 
additional laboratory tests or investigations, or 
consultation with other healthcare professionals, as 
considered clinically appropriate by the Investigator. 
All patients showing possible drug-induced liver injury 
should be followed until all abnormalities return to 
normal or to the baseline state.  Drug-induced liver 
injury may develop or progress even after the causative 
drug has been stopped.  Results should be recorded in 
the eCRF.  Note that longer follow-up can sometimes 
reveal an off-drug repetition of what had appeared to be 
drug-induced liver injury, indicating that liver injury was 
related to underlying liver disease. 
 
AEs ongoing at the final visit that are deemed to be 
“possibly, probably, or definitely” related or of other 
clinical significance must be followed for as long as 
necessary to adequately evaluate the safety of the 
patient or until the event stabilizes, resolves, or is no 
longer of clinical concern.  The Investigator must 
ensure that follow up includes any supplemental 
investigations indicated to elucidate the nature and/or 
causality of the AE.  This may include additional 
laboratory tests or investigations, or consultation with 
other healthcare professionals, as considered clinically 
appropriate by the Investigator. 
 
Drug-Induced Liver Injury or Disease Progression 
All patients showing possible drug-induced liver injury 
or disease progression should be followed until all 
abnormalities return to normal or to the baseline state.  
Drug-induced liver injury may develop or progress 
even after the causative drug has been stopped.  Results 
should be recorded in the eCRF.  Note that longer 
follow-up can sometimes reveal an off-drug repetition 
of what had appeared to be drug-induced liver injury, 
indicating that liver injury was related to underlying 
liver disease. 
Cholecystitis or Pancreatitis 
Patients should be instructed to contact the 
investigational site if they experience any of the 
following signs and symptoms:  nausea, vomiting, 
abdominal pain, diarrhea, weight loss, fever and 
chills, worsening or new fatigue, or weakness.  
Patients should also be counseled to seek immediate 
medical assistance if they experience persistent 
severe abdominal pain.   
In the event that cholecystitis and/or pancreatitis is 
suspected, Investigators should  promptly bring 
patients into the clinic to undergo a complete 
Increased monitoring per 
standard of care if a patient is 
diagnosed or develops 
symptoms consistent with 
pancreatitis. 
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evaluation, including a physical examination, and 
laboratory assessments [ie, amylase and lipase]).  
Investigators should refer to standard of care 
guidelines on suspected pancreatitis (Banks 2012, 
Greenburg 2015).  Diagnosis of acute pancreatitis 
includes 2 of the following:   
• 
Abdominal pain (acute onset of a persistent, 
severe, epigastric pain often radiating to the back)  
• 
Serum lipase activity (or amylase) at least 3 
times greater than the upper limit of normal 
• 
Characteristic findings of acute pancreatitis on 
computed tomography or magnetic resonance 
imaging 
To ensure appropriate vigilance, amylase and lipase 
levels should be monitored monthly for 3 months 
after onset of symptoms, irrespective of whether a 
diagnosis of cholecystitis and or pancreatitis is 
confirmed.  The Investigator should contact the 
Medical Monitor upon awareness of the above (ie, 
suspected or confirmed diagnosis).  Results should be 
recorded promptly in the eCRF. 
Section 13.1.9, 
Pregnancy and 
Follow-Up 
Pregnancies are not considered AEs in and of 
themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical 
study, she must interrupt treatment with investigational 
product immediately (see Section 8.4.1.3) and the 
Sponsor must be notified within 24 hours of the 
Investigator’s awareness of the pregnancy by completing 
the Pregnancy CRF in the EDC system and downloading 
and completing the Pregnancy Report Form.  The 
Pregnancy Report Form must be emailed to 
 or faxed to 
.  
The patient and neonate must be followed for outcome 
information and/or as considered appropriate by the 
Investigator and Sponsor. 
The patient may restart investigational product when she 
is no longer pregnant or breastfeeding (if applicable) at 
the discretion of the Investigator and after discussion 
with the Medical Monitor.  The patient must have a 
negative pregnancy test before restarting investigational 
product.  If a patient’s pregnancy is terminated early 
(planned or unplanned), she must have termination of 
the pregnancy confirmed by a serum β-hCG test before 
restarting investigational product. 
Pregnancies are not considered AEs in and of 
themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical 
study, she must discontinue treatment with 
investigational product immediately and the Sponsor 
must be notified within 24 hours of the Investigator’s 
awareness of the pregnancy by completing the 
Pregnancy CRF in the EDC system and downloading 
and completing the Pregnancy Report Form.  The 
Pregnancy Report Form must be emailed to 
 or faxed to 
.  The patient and neonate must be 
followed for outcome information and/or as considered 
appropriate by the Investigator and Sponsor. 
 
Per new study-specific safety 
updates, pregnancy will require 
discontinuation and no option 
to restart. 
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Section 
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Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 13.2.2., 
Medical and Surgical 
Procedures 
New Section  
Medical and surgical procedures will be recorded 
at the visits indicated in Table 1. 
Section added for consistently 
with Schedule of Events. 
Section 13.2.5, 
Electrocardiogram 
Investigative sites must retain a copy of all ECGs 
evaluated by the Investigator or designee.  These ECGs 
must be clearly labeled with the Patient ID number, date, 
and time.  Full instructions will be provided for 
forwarding the ECGs for central reading. 
Investigative sites must retain a copy of all ECGs 
evaluated by the Investigator or designee.  These 
ECGs must be clearly labeled with the Patient ID 
number, date, and time.   
Correction. 
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Section 13.2.6, 
Laboratory 
Assessments 
Table 9  List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen, 
creatinine, direct bilirubin, total 
bilirubin, aspartate 
aminotransferase [AST, 
SGOT], alanine 
aminotransferase [ALT, 
SGPT], ALP, GGT, 
electrolytes [calcium, chloride, 
potassium, sodium], glucose, 
total protein, and blood lipids 
(total cholesterol, LDL, HDL 
and VLDL fractions and TG), 
CPK, magnesium, phosphorus, 
bicarbonate, unconjugated 
(indirect) bilirubin, conjugated 
(direct) bilirubin, free fatty 
acids, TFT (TSH, free T3 and 
free T4) 
Hematology 
Hemoglobin, hematocrit, white 
blood count with differential, 
neutrophils, lymphocytes, 
monocytes, eosinophils, 
basophils, platelets, red blood 
cell count (including MCV, 
MCH, MCHC) 
Coagulation 
PT, PTT, INR 
Urinalysis (dipstick) 
pH, specific gravity, total 
protein, glucose, ketones, 
bilirubin, blood, microscopic 
exam, urobilinogen, albumin, 
creatine, leucocytes, nitrates, 
albumin/creatine ratio (if 
positive), pregnancy 
Markers of Inflammation  
IL-6, hs-CRP, TNF-α, IgM, 
IgA, IgG, CK-18-M30 
Noninvasive 
measurements of liver 
fibrosis, liver stiffness and 
cirrhosis 
ELF (HA, P3NP, and TIMP-1) 
TE 
PK assessments 
OCA (parent and conjugates 
[glyco and tauro], metabolite 
OCA-glucuronide)  
Table 11  List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea 
nitrogen, creatinine, direct 
bilirubin, total bilirubin, 
aspartate aminotransferase 
[AST, SGOT], alanine 
aminotransferase [ALT, 
SGPT], ALP, GGT, 
electrolytes [calcium, 
chloride, potassium, 
sodium], glucose, total 
protein, and blood lipids 
(total cholesterol, LDL, HDL 
and VLDL fractions and 
TG), CPK, magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) 
bilirubin, conjugated (direct) 
bilirubin, total bilirubin, 
free fatty acids, TFT (TSH, 
free T3 and free T4) 
Hematology 
Hemoglobin, hematocrit, 
white blood count with 
differential, neutrophils, 
lymphocytes, monocytes, 
eosinophils, basophils, 
platelets, red blood cell count 
(including MCV, MCH, 
MCHC) 
Coagulation 
PT, PTT, INR 
Urinalysis (dipstick) 
pH, specific gravity, total 
protein, glucose, ketones, 
bilirubin, blood, microscopic 
exam, urobilinogen, 
leucocytes, nitrates; 
albumin, creatinine, 
albumin/creatinine ratio (if 
positive); β-hCG 
Markers of 
Cholecystitis and 
Pancreatitis 
Amylase and lipase 
Markers of inflammation 
samples were removed to 
simplify the study design. 
Amylase and lipase added per 
FDA request. 
Total OCA calculation update 
is a correction. 
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Key Change 
Reasons / 
Justification for Change 
PD markers 
C4, FGF-19 and plasma bile 
acids 
 
… 
INR will be calculated based on prothrombin time value 
by the central laboratory.  MELD scores will be calculated 
based on creatinine, bilirubin, Na, and INR values, with 
modification by United Network for Organ Sharing.  Total 
OCA will be calculated based on OCA, tauro-OCA, glyco 
OCA, and metabolite OCA glucuronide concentrations.  
Laboratory analyte results may be used to calculate 
various cardiovascular risk and fibrosis measurement 
scores. 
Noninvasive 
measurements of liver 
fibrosis 
ELF (HA, P3NP, and TIMP-
1) 
PK assessments 
OCA (parent and conjugates 
[glyco and tauro], metabolite 
OCA-glucuronide)  
PD markers 
C4, FGF-19 and plasma bile 
acids 
… 
NR will be calculated based on prothrombin time 
value by the central laboratory.  MELD scores will be 
calculated based on creatinine, bilirubin, and INR 
values, with modification by United Network for 
Organ Sharing.  Total OCA will be calculated based 
on the sum of OCA, glyco-OCA, and tauro-OCA 
concentrations.  Laboratory analyte results may be 
used to calculate various cardiovascular risk and 
fibrosis measurement scores. 
Section 14.1.1, 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is calculated 
and reported within the EDC system based on data entered 
into the eCRF by adding the scores from the 5 factors 
outlined in Table 12 and can range from 5-15.  A total 
score of 5-6 is considered Grade A (mild, well-
compensated disease); 7-9 is Grade B (moderate, 
significant functional compromise); and 10 and above is 
Grade C (severe, decompensated disease).  Calculation of 
the CP Score includes Investigator assessments of ascites 
and hepatic encephalopathy, which may be assessed 
during the adverse event review at the scheduled visits, as 
well as total bilirubin, serum albumin, and prothrombin 
time, which will populate from the central laboratory.  
Investigators will be responsible for determining the 
appropriate dosing regimen based on the CP score ( and ).  
Any change in CP Score will necessitate re evaluation of 
the dosing regimen. 
Child-Pugh Score (Pugh 1973, Lucey 1997) is 
calculated and reported within the EDC system based 
on data entered into the eCRF by adding the scores 
from the 5 factors outlined in Table 12 and can range 
from 5-15.  A total score of 5-6 is considered Grade A 
(mild, well-compensated disease); 7-9 is Grade B 
(moderate, significant functional compromise); and 10 
and above is Grade C (severe, decompensated 
disease).  Calculation of the CP Score includes 
Investigator assessments of ascites and hepatic 
encephalopathy, which may be assessed during the 
adverse event review at the scheduled visits, as well as 
total bilirubin, serum albumin, and prothrombin time, 
which will populate from the central laboratory.   
 
Per new dosing guidelines, CP 
score will not determine dosing 
regimen. 
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Section 
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Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 14.1.2, 
Model of End Stage 
Liver Disease Score 
An increasing MELD score is associated with increased 
severity of hepatic dysfunction and increased 3-month 
mortality risk.  The MELD score is derived from the 
patient’s serum total bilirubin, serum creatinine, and INR, 
as appropriate, to predict survival and is calculated 
according to the following formula (Kamath 2007): 
MELD = 3.78×ln[serum bilirubin (mg/dL)] + 
11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43  
MELD score will be calculated and reported in whole 
numbers according to the frequency listed in Table 1. 
An increasing MELD score is associated with 
increased severity of hepatic dysfunction and 
increased 3-month mortality risk.  The MELD score is 
derived from the patient’s serum total bilirubin, serum 
creatinine, and INR, as appropriate, to predict survival 
(Kamath 2007).  MELD score will be calculated and 
reported for visits where these parameters are 
measured (see Table 1). 
Text clarified since calculation 
is not performed by the site. 
Section 14.2.1, 
Markers of 
Inflammation, 
Apoptosis and 
Necrosis 
Markers of Inflammation, Apoptosis and Necrosis 
Blood samples for analytes including IL-6, hs-CRP, IgA, 
IgG, IgM, TNF-α, cytokeratin-18 neoepitope M30.  
Assessments will be performed according to the schedules 
presented in . 
Deletion 
Markers of inflammation were 
removed to simplify the study 
design. 
Section 15.3, 
Pharmacokinetic 
Analyses 
PK analysis will based on the PK population.  Values will 
be calculated using non-compartmental methods.  The 
values will be summarized by active treatment group 
using descriptive statistics. 
 
PK analysis will be based on the PK population.  
Values will be calculated using non-compartmental 
methods.  The values will be summarized by active 
treatment group using descriptive statistics.  Full 
details regarding the planned analyses, methods, 
and outputs for the study will be detailed in the 
SAP. 
Clarification. 
Section 15.4, Safety 
Analyses 
Laboratory parameters, physical examinations including 
vital signs, and ECGs will be summarized by treatment 
group using descriptive statistics at Baseline and at each 
scheduled post-Baseline visit.  The absolute change from 
baseline will also be summarized. 
CP scores will be summarized by treatment group at 
Baseline and at each post-Baseline visit. 
No inferential comparison with formal statistical 
hypothesis testing will be performed for safety endpoints.  
 
Laboratory parameters, physical examinations 
including vital signs, and ECGs will be summarized 
by treatment group using descriptive statistics at 
Baseline and at each scheduled post-Baseline visit.  
The absolute change from baseline will also be 
summarized. 
No inferential comparison with formal statistical 
hypothesis testing will be performed for safety 
endpoints.  
 
Correction. 
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Key Change 
Reasons / 
Justification for Change 
Section 15.4.1, 
Adverse Events 
Insertion 
Adverse events of special interest as defined in 
Section 13.1.1.4 will be summarized for each 
treatment group.   
Per FDA request. 
Section 15.4.2, 
Clinical Laboratory 
Evaluations 
Laboratory parameters will be summarized in standard 
international (SI) system of units by treatment group using 
descriptive statistics at Baseline and at each on-study 
evaluation.  Re-test or unscheduled results will not be 
summarized but will be included in the data listings.  The 
change from Baseline will also be summarized.  Baseline 
is defined as the mean of all available evaluations prior to 
treatment.   
In addition, shift tables (ie, low-normal-high at Baseline 
versus low-normal-high at post Baseline visit in a 3-by-3 
contingency table) from Baseline to worst value, last 
value, and at each scheduled post-Baseline visit will be 
provided for hematology and serum chemistry by 
treatment group to assess changes in laboratory values 
from Baseline to each on-study evaluation.   
Vital Signs and Weight 
The results and change from Baseline to each on-study 
evaluation visit will be summarized by treatment group for 
weight, oral temperature, sitting heart rate, respiratory rate 
and sitting blood pressure. 
Electrocardiograms 
Electrocardiogram (ECG) results will be summarized at 
each on-study visit descriptively, including the number 
and percentage of patients with normal, abnormal not 
clinically significant, and abnormal clinically significant 
results at Baseline and each on-study evaluation. 
Laboratory parameters will be summarized in standard 
international (SI) system of units by treatment group 
using descriptive statistics at Baseline and at each on-
study evaluation.  Re-test or unscheduled results will 
not be summarized but will be included in the data 
listings.  The change from Baseline will also be 
summarized.  Baseline is defined as the mean of all 
available evaluations prior to treatment.   
In addition, shift tables (ie, low-normal-high at 
Baseline versus low-normal-high at post Baseline visit 
in a 3-by-3 contingency table) from Baseline to worst 
value, last value, and at each scheduled post-Baseline 
visit will be provided for hematology and serum 
chemistry by treatment group to assess changes in 
laboratory values from Baseline to each on-study 
evaluation.   
 
Correction.  Moved to separate 
section since not laboratory 
evaluations. 
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Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 15.4.3, 
Additional Safety 
Analysis 
New Section 
Vital Signs and Weight 
The results and change from Baseline to each on-
study evaluation visit will be summarized by 
treatment group for weight, oral temperature, 
sitting heart rate, respiratory rate and sitting blood 
pressure. 
Electrocardiograms 
Electrocardiogram (ECG) results will be 
summarized at each on-study visit descriptively, 
including the number and percentage of patients 
with normal, abnormal not clinically significant, 
and abnormal clinically significant results at 
Baseline and each on-study evaluation. 
Separate section created per 
above deletion. 
Section 15.5, 
Efficacy Analyses 
Risk Scores: Changes from baseline in the MELD score 
and in CP score will be summarized and analyzed using 
the Wilcoxon Rank Sum Test.  The median differences 
and 95% CI of the median differences between treatment 
groups will be constructed using Hodges-Lehmann 
estimate.  If the median differences between treatments 
are not symmetrical around the median, the Sign Test may 
be used. 
Risk Scores: Changes from baseline in the MELD 
score and in CP score, C4, FGF-19 and plasma bile 
acids will be summarized and analyzed using the 
Wilcoxon Rank Sum Test.  The median differences 
and 95% CI of the median differences between 
treatment groups will be constructed using Hodges-
Lehmann estimate.  If the median differences between 
treatments are not symmetrical around the median, the 
Sign Test may be used. 
Clarification. 
Section 15.6, 
Additional Efficacy 
Analyses 
Analyses of changes in liver stiffness and ELF, cytokeratin-and 
TIMP-1, and markers of inflammation will be summarized and 
analyzed using the same methodology specified for the key 
secondary analyses of change in bilirubin. 
… 
Analyses of changes in liver stiffness (TE) and liver fibrosis 
(ELF [HA, P3NP, and TIMP-1]) will be summarized and 
analyzed using the same methodology specified for the key 
secondary analyses of change in bilirubin. 
… 
Full details regarding additional efficacy analyses will be 
detailed in the SAP. 
Clarification 
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Section 
Original Text (Version 2) 
Revised Text (Version 3) 
Key Change 
Reasons / 
Justification for Change 
Section 21, List of 
references 
Insertion 
Banks O, Bollen T, Dervenis C, et al.  Classification 
of acute pancreatitis-2012:  revision of the Atlanta 
classification and definitions by international 
consensus.  Gut. 2013; 62:102-111. 
… 
Greenburg J., Hsu J., Bawazeer M., et al.  Clinical 
Practice Guideline:  Management of acute 
pancreatitis.  Can J Surg. 2016; 59 (2):128-140. 
… 
Kumar A, Saraswat VA. Hepatitis E and Acute-on-
Chronic Liver Failure. Journal of clinical and 
experimental hepatology. 2013 Sep;3(3):225-30. 
… 
Vilstrup H, Amodio P, Bajaj J, et al. Hepatic 
encephalopathy in chronic liver disease: 2014 
Practice Guideline by the American Association for 
the Study of Liver Diseases and the European 
Association for the Study of the Liver. Hepatology. 
2014 Aug;60(2):715-35. 
New references added per 
added cited content. 
 
 
 
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APPENDIX C. SUMMARY OF CHANGES:  PROTOCOL 747-401 VERSION 4 (DATED 15 FEB 2019) 
Protocol 747-401 was revised to include the following information: 
 Updated clinical development data based on IB Version 18 (31 January 2019). 
 Exclusion criteria were updated to mitigate the inclusion of subjects who may be pregnant or breastfeeding as an additional 
safety precaution or who have a known history of human immunodeficiency syndrome infection. 
 Exclusion criteria and prohibited medications sections were updated to prevent the concomitant use of fibrates and OCA.  The 
primary objective of this study is to characterize the pharmacokinetics of OCA in patients with PBC and mild to severe hepatic 
impairment.  The drug-drug interactions of OCA with fibrates have not yet been fully characterized in any population and are 
being restricted in this study as an additional safety precaution until data are available in a less advanced population. 
Summary of Changes 
The following revisions were made to the protocol in Protocol Version 4.  Revised and new text in Version 4 is indicated in bold font, 
and the text deleted from Protocol Version 3 is crossed out in the table below.  Minor/editorial changes are not listed individually in 
the summary table below. 
 
 
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Section 
Original Text (Version 3) 
Revised Text (Version 4) 
Key Change 
Reasons / 
Justification for Change 
Title Page 
Version 3:  04 Jan 2018 
Version 4:  15 Feb 2019 3:  04 Jan 2018 
Date of Update 
Study Personnel 
Contact Information 
 
 MD 
Senior Medical Director, Clinical Division  
INC Research/inVentiv Health 
  
 
 MD 
Senior Medical Director, Clinical Division  
INC Research/inVentiv Health 
Syneos Health 
  
om 
Ray.
 
Personnel Information Update 
Synopsis 
The study is planned to have approximately 35 
investigational sites, globally. 
The study is planned to have approximately 35 50 
investigational sites, globally. 
Number of sites expanded to 
improve study recruitment as 
the patients in this study 
represent a small subset of an 
orphan disease. 
5.1 
Study 747-401 is considered a Phase 4 study in regions 
where OCA has received regulatory approval for PBC 
(ie, in the US, Canada, and the EU).  In all other regions, 
this study is considered Phase 3b. 
Since then, other countries have received approval 
(eg, Australia and Switzerland).  Study 747-401 is 
considered a Phase 4 study in regions where OCA has 
received regulatory approval for PBC (ie, in the US, 
Canada, and the EU).  In; in all other regions, this study 
is considered Phase 3b. 
 
5.3 
As of 13 Oct 2017, approximately 2690 subjects have 
received at least 1 dose of OCA.  Of these, 844 were 
healthy volunteers, 552 patients had PBC, 1141 patients 
had nonalcoholic steatohepatitis (NASH), 41 patients 
had diabetes mellitus/ nonalcoholic fatty liver disease 
(NAFLD), 33 patients had alcoholic cirrhosis/portal 
hypertension, 73 patients had primary sclerosing 
cholangitis (PSC), and 6 patients had biliary atresia. 
As of 28 October 2018, approximately 3470 subjects 
have received ≥ 1 dose of OCA.  This estimation 
includes subjects from blinded ongoing studies.  Of 
these 3470 subjects, 888 were healthy volunteers, 
580 subjects had PBC, 72 subjects had PSC, 
6 subjects had biliary atresia, 41 subjects had 
diabetes mellitus/ nonalcoholic fatty liver disease 
(NAFLD), 1914 subjects had NASH, and 33 subjects 
had portal hypertension due to alcoholic cirrhosis.   
As of 13 Oct 2017, approximately 2690 subjects have 
received at least 1 dose of OCA.  Of these, 844 were 
healthy volunteers, 552 patients had PBC, 1141 
patients had nonalcoholic steatohepatitis (NASH), 41 
patients had diabetes mellitus/ nonalcoholic fatty liver 
disease (NAFLD), 33 patients had alcoholic 
cirrhosis/portal hypertension, 73 patients had primary 
Updated per latest 
Investigational Brochure 
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sclerosing cholangitis (PSC), and 6 patients had biliary 
atresia. 
5.6 
Recent safety findings in NASH clinical trials include 2 
cases of hepatic decompensation reported as SUSARs, 1 
of which resulted in death.  Both cases involved 
numerous confounding factors that make evaluation of 
association with treatment difficult.  Details for both 
events are provided in the Investigator’s Brochure 
Addendum 1 to Version Number: 16 (31 March 2017), 
Effective Date: 02 October 2017. 
The primary AE shown to be related to OCA is pruritus.  
Pruritus has also been observed in clinical studies with 
OCA in other indications, as well as in healthy subjects, 
with the highest frequency observed in subjects with 
PBC.  The incidence and severity of pruritus have been 
shown to be dose dependent, but there is no evidence of 
association with stage or progression of underlying 
disease. 
Changes in lipid profiles have also been observed with 
OCA dosing, including an increase in low-density 
lipoprotein (LDL) cholesterol and a decrease in high-
density lipoprotein (HDL) cholesterol.  The clinical 
significance of these lipid findings remains unclear and 
is being studied further. 
Independent data monitoring committees (DMCs) have 
performed detailed reviews of several studies including 
the Phase 3, clinical outcomes study in PBC (747-302) 
and the Phase 3, pivotal study in NASH with fibrosis 
(747-303).  The DMC reviewed data (unmasked for PBC 
and unblinded by treatment group for NASH with a total 
of approximately 1000 subjects) in closed sessions, 
which excluded participation of the Sponsor.  Based on 
these reviews, the DMC recommended that both studies 
continue without modification. 
Post-Marketing Cases in PBC 
Ongoing NASH clinical trials include reports of 
hepatic decompensation assessed as suspected 
unexpected serious adverse reactions (SUSARs).  
Data remain blinded.  Additional details of these 
SUSARs are provided in the IB Version Number: 18 
(31 January 2019).   
Recent safety findings in NASH clinical trials include 2 
cases of hepatic decompensation reported as SUSARs, 
1 of which resulted in death.  Both cases involved 
numerous confounding factors that make evaluation of 
association with treatment difficult.  Details for both 
events are provided in the Investigator’s Brochure 
Addendum 1 to Version Number: 16 (31 March 2017), 
Effective Date: 02 October 2017. 
The primary AE shown to be related to OCA is 
pruritus.  Pruritus has also been observed in clinical 
studies with OCA in other indications, as well as in 
healthy subjects, with the highest frequency observed 
in subjects with PBC.  The incidence and severity of 
pruritus have been shown to be dose dependent, but 
there is no evidence of association with stage or 
progression of underlying disease. 
Changes in lipid profiles have also been observed with 
OCA dosing, including an increase in low-density 
lipoprotein (LDL) cholesterol and a decrease in high-
density lipoprotein (HDL) cholesterol.  The clinical 
significance of these lipid findings remains unclear and 
is being studied further. 
An independent data monitoring committee (DMC) 
has performed detailed reviews of ongoing studies of 
obeticholic acid, including the Phase 3/4, clinical 
outcomes study in PBC (747-302), this Phase 4 PK 
and safety study in patients with PBC (747-401), the 
Updated per latest 
Investigational Brochure 
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As of September 2017, greater than 3000 patients have 
received Ocaliva in the post-marketing setting.  In 
patients with moderate to severe hepatic impairment 
(Child-Pugh B and C), liver decompensation, liver 
failure, and death have been reported when Ocaliva was 
dosed up to 7 times the recommended once weekly 
starting dose for such patients. 
Phase 3, pivotal study in NASH with fibrosis (747-
303), and the Phase 3 study in NASH with cirrhosis 
(747 304).  The DMC will continue to review data 
quarterly and will provide oversight of the above-
mentioned studies throughout the course of the 
development program.  Additional details are 
provided in IB Version Number: 18 (31 January 
2019). 
Independent data monitoring committees (DMCs) have 
performed detailed reviews of several studies including 
the Phase 3, clinical outcomes study in PBC (747-302) 
and the Phase 3, pivotal study in NASH with fibrosis 
(747-303).  The DMC reviewed data (unmasked for 
PBC and unblinded by treatment group for NASH with 
a total of approximately 1000 subjects) in closed 
sessions, which excluded participation of the Sponsor.  
Based on these reviews, the DMC recommended that 
both studies continue without modification. 
Post-Marketing Cases in PBC 
As of September 2017 October 2018, greater than 
3000 4200 patients have received Ocaliva in the post-
marketing setting.  In patients with moderate to severe 
hepatic impairment (Child-Pugh B and C), liver 
decompensation, liver failure, and death have been 
reported when Ocaliva was dosed up to 7 times the 
recommended once weekly starting dose for such 
patients. 
8.1 
This study will be conducted at approximately 35 
international study sites with experience in treating 
patients with PBC with moderate to severe hepatic 
impairment defined as CP-B and CP-C.   
This study will be conducted at approximately 35 50 
international study sites with experience in treating 
patients with PBC with moderate to severe hepatic 
impairment defined as CP-B and CP-C.   
Number of sites expanded to 
improve study recruitment as 
the patients in this study 
represent a small subset of an 
orphan disease. 
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8.3 
Addition 
14. Known history of human 
immunodeficiency virus infection 
15. Treatment with commercially available 
fibrates or participation in a previous 
study involving fibrates within 3 months 
before Screening, or plans to use 
commercially available fibrates during the 
study 
16. If female:  plans to become pregnant, 
known pregnancy or a positive urine 
pregnancy test (confirmed by a positive 
serum pregnancy test), or lactating 
Addition made to exclusion 
criteria as a safety precaution 
9.2.2 
Addition 
Fibric acid derivatives (ie, fibrates such as 
fenofibrate and bezafibrate) are also prohibited 
while on investigational product. 
Addition made to prohibited 
medication as a safety 
precaution 
 
Page 598 of 603


 
Clinical Study Protocol 747-401 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Pharmacokinetics and Safety of Obeticholic Acid in Patients with Primary 
Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
 
Addendum 1:  19 May 2020 
Country-Specific Protocol Addendum for Multiple Countries 
EudraCT Number: 2017-001762-13 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA  92121 
USA 
 
TEL:  858-652-6800 
FAX:  
 
 
CONFIDENTIAL 
The information contained herein is the property of Intercept Pharmaceuticals, Inc. and may not 
be reproduced, published, or disclosed to others without written authorization of Intercept 
Pharmaceuticals, Inc. 
Page 599 of 603
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INVESTIGATOR’S AGREEMENT 
I have received and read the current version of the Investigator’s Brochure (IB) for obeticholic 
acid (OCA), Protocol 747-401, and this addendum.  Having fully considered all the information 
available, I agree that it is ethically justifiable to give OCA to selected subjects according to this 
protocol. 
I understand that all information concerning OCA supplied to me by the Sponsor, 
Intercept Pharmaceuticals, Inc., and/or its agents in connection with this study and not previously 
published is confidential information.  This includes the IB, clinical study protocol, case report 
forms (CRF), and any other preclinical and clinical data provided by the Sponsor. 
I understand that no data are to be made public or published without prior knowledge and written 
approval by the sponsor. 
By my signature below, I hereby attest that I have read, understood and agreed to abide by all the 
conditions, instructions and restrictions contained in Protocol 747-401 and in accordance with 
Good Clinical Practice (CPMP/ICH/135/95), the Declaration of Helsinki and all regulatory 
requirements for protection of human subjects in clinical studies and privacy requirements for 
the protection of individual and company data. 
I acknowledge that the Sponsor of the study has the right to discontinue the study at any time. 
 
 
 
 
 
 
Investigator’s Name (Printed) 
 
 
 
 
 
 
 
 
Investigator’s Signature 
 
Date 
 
 
 
 
 
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Addendum 1: 19 May 2020
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COUNTRY-SPECIFIC ADDENDUM TO PROTOCOL 747-401 FOR 
MULTIPLE COUNTRIES  
1. 
OVERVIEW AND RATIONALE 
The restrictions that have recently been imposed to contain the global COVID-19 pandemic, 
such as social distancing measures, stay at home orders, and other limitations have impeded the 
ability of subjects and site staff to complete protocol-specified procedures.  Some study sites are 
not able to perform protocol-specified procedures and assessments.  In addition, some subjects 
are unable to return to study sites for evaluations and/or to receive continued supply of 
investigational product (IP).  The purpose of this Country-Specific Protocol Addendum is to 
describe the requirements and processes under which subjects who are unable to return to study 
sites may complete protocol specified assessments and continue to receive investigational 
product until in-person site visits can resume.  In an effort to minimize the potential adverse 
impact of restrictions from the COVID-19 pandemic on achieving the objectives of the study, 
while continuing to ensure the safety of participating subjects, the following approaches will 
apply to the study protocol, effective immediately. 
1.1. 
Alternative Approaches for Subject Assessments and Procedures and 
Continuation of Treatment with Investigational Product During 
COVID-19 Pandemic 
Assessment of subject status must occur prior to the release of additional investigational product. 
For subjects who are unable to attend in-person study visits due to COVID-19 restrictions, the 
following alternative options are deemed acceptable to satisfy the requirements for continued 
supply of investigational product.   
All assessments should adhere as close as possible to the visit windows specified in the protocol 
schedule of visits.  Implementation of alternative means of assessing subjects as well as changes 
in visit windows to assess subjects must be documented by the Investigator.  Subjects who are 
temporarily unable to attend scheduled visits should be encouraged to return to the study site as 
soon as practically feasible for completion of protocol-specified assessments and procedures that 
could not be performed due to restrictions or limitations during the COVID-19 pandemic. 
1.1.1. 
Telemedicine Visits 
In place of in-person visits, assessment of subjects may be performed using a telemedicine 
"virtual visit" as an alternative means of enabling Investigators and site staff to interact with 
study subjects. The provision of telemedicine software is cloud-based and available across 
platforms, compliant with HIPPA/GDPR and 21 CFR Part 11, and intuitive to use.  It allows the 
Investigator and staff to efficiently contact and engage subjects remotely from any location.  
The established telemedicine procedures will be defined at the institution, and at a minimum, 
must consist of a direct telephone or video call discussion with the subject by the Investigator or 
by an appropriate designee from the study team who is currently authorized to undertake 
examinations on the study per Delegation of Authority Log.  Assessment of subjects in this 
manner is to be documented by the Investigator. 
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If an onsite visit or a telemedicine contact is not feasible (eg, no access to the subject) to assess 
subject status, investigational product is not to be released.  
1.1.2. 
Laboratory Tests 
In addition to telemedicine visits, assessment of safety laboratory tests (chemistry panel 
including glucose, hematology panel, coagulation parameters, computed MELD score, and CP 
score), a lipid panel, and liver laboratory tests (eg, ALT, AST, bilirubin), will need to be 
performed at appropriate study visits as specified in the protocol.  If laboratory tests cannot be 
obtained at the study site due to COVID-19 restrictions, they may be performed and analyzed at 
a local laboratory.  The results of all laboratory tests and the reference ranges for each laboratory 
test are to be sent to the Investigator. The results of the laboratory tests will be reviewed by the 
Investigator and with the Medical Monitor, if necessary.  
1.1.3. 
Home Health Care Visits 
If laboratory tests cannot be obtained from local laboratories, home nursing support is an 
accepted option that may be employed to supplement telemedicine interactions to enable the 
collection and processing of blood samples for laboratory tests, and conduct other limited 
assessments (eg, assessment of vital signs).  The home healthcare visits will be performed by 
qualified health care providers including registered and licensed nurses or physicians. 
1.1.4. 
Virtual Study Hub  
To enable continued support of subjects who are enrolled at sites that may not be able to evaluate 
subjects during the COVID-19 pandemic, study sites may temporarily transfer responsibility for 
their subjects to a dedicated study site acting as a virtual study hub to provide support and 
oversight of such subjects.  In this instance, qualified Investigators who are participating in 
Intercept’s PBC studies and are at the dedicated study sites will assume the responsibilities for 
the medical care of the subjects through telemedicine and home-nurse support according to the 
assessments and procedures described in the protocol.  Subjects will be transferred to sites that 
are approved for the specific PBC study that the subject is participating in.  The transfer of 
subjects and all assessments and procedures will be documented.  
1.2. 
Investigational Product 
Based on the individual subject level safety and tolerability assessments, if the Investigator 
considers that the benefit-risk profile remains favorable, investigational product may be 
dispensed to subjects, according to protocol.  Investigational product may be sent directly to the 
subject from either the study site or a study drug depot via a courier service if subjects are not 
able to attend study site visits.  Direct shipment of investigational product from the Investigator 
sites to subjects is to adhere to the site’s institutional and pharmacy procedures.  Approval for 
each shipment of investigational product is to be obtained and documented by the Investigator. 
Unless the Investigator is able to evaluate safety and tolerability and assess the benefit-risk for 
the individual subject, investigational product is not to be provided.  
Page 603 of 603

SAP_001.pdf: 
 
 
OBETICHOLIC ACID (OCA) 
747-401 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Pharmacokinetics and Safety of Obeticholic Acid in Patients with Primary 
Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
 
Statistical Analysis Plan  
 
EudraCT Number: 2017-001762-13  
ClinicalTrials.gov Identifier: NCT03633227 
 
 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
305 Madison Avenue 
Morristown, NJ 07960 
USA 
 
 
 
 
 
CONFIDENTIAL 
The information contained herein is the property of Intercept Pharmaceuticals, Inc. and may not 
be reproduced, published, or disclosed to others without written authorization of Intercept 
Pharmaceuticals, Inc. 


Clinical Study Report 747-401 
16.1.9 Documentation of Statistical Methods 
Page 1
Confidential and Proprietary 
16.1.9 
DOCUMENTATION OF STATISTICAL METHODS 
747-401 Statistical Analysis Plan, Version 1.0, dated 27 Sep 2021.
Page 1 of 46


 
 
 
OBETICHOLIC ACID (OCA) 
 
747-401 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Pharmacokinetics and Safety of Obeticholic Acid in Patients with Primary 
Biliary Cholangitis and Moderate to Severe Hepatic Impairment 
 
 
Statistical Analysis Plan  
 
 
 
 
Author: 
 
Contract Biostatistician, Intercept Pharmaceuticals 
 
 
 
Protocol Version and Date: 
Version 4.0 15 February 2019 
Analysis Plan Version: 
1.0 
Analysis Plan Date: 
27 September 2021 
 
 
 
CONFIDENTIAL 
The information contained herein is the property of Intercept Pharmaceuticals, Inc. and may not be 
reproduced, published, or disclosed to others without written authorization of Intercept Pharmaceuticals, 
Inc. 
Page 2 of 46
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Statistical Analysis Plan Version 1.0 
Protocol 747-401 
SIGNATURE PAGE 
This document has been prepared and/or reviewed by: 
 
Contract Biostatistician 
Intercept Pharmaceuticals, Inc. 
Signature 
This document has been reviewed and accepted by: 
, PhD 
Associate Director, Biostatistics 
Intercept Pharmaceuticals, Inc. 
, PhD 
Director, Clinical Pharmacology 
Intercept Pharmaceuticals, Inc. 
, MD 
Senior Director, Scientific Affairs 
Intercept Pharmaceuticals, Inc. 
Confidential and Proprietary 
Signature 
Si
27 Sep 2021 
Page2 
07Oct2021 
Date 
Date 
II t)t,):: h?'- I 
Date 
{J? tJc t 2.o 2-I 
Date 
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Statistical Analysis Plan Version 1.0 
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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
SCOPE ........................................................................................................................10 
2. 
STUDY OBJECTIVES AND HYPOTHESES ..........................................................10 
2.1. 
Study Objectives .........................................................................................................10 
2.1.1. 
Primary Objective .......................................................................................................10 
2.1.2. 
Secondary Objectives .................................................................................................10 
2.1.3. 
Exploratory Objectives ...............................................................................................10 
2.2. 
Hypotheses ..................................................................................................................11 
3. 
SUMMARY OF STUDY DESIGN ............................................................................11 
3.1. 
Subject Selection ........................................................................................................13 
3.2. 
Randomization and Blinding ......................................................................................13 
3.3. 
Sample Size Determination ........................................................................................14 
4. 
ANALYSIS POPULATIONS AND APPROACHES TO ANALYSIS ....................14 
4.1. 
Randomized Population ..............................................................................................14 
4.2. 
Intent-to-Treat (ITT) Population .................................................................................14 
4.3. 
Safety Population ........................................................................................................14 
4.4. 
Pharmacokinetic Population .......................................................................................14 
4.5. 
Non-COVID-19 Impacted Population ........................................................................14 
5. 
SUBJECT DISPOSITION ..........................................................................................15 
5.1. 
Protocol Deviations ....................................................................................................15 
5.2. 
Inclusion/Exclusion Criteria .......................................................................................16 
6. 
DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS ................16 
7. 
PBC DISEASE HISTORY .........................................................................................17 
8. 
PRIOR THERAPY AND MEDICAL HISTORY ......................................................17 
9. 
EFFICACY ANALYSES ...........................................................................................18 
9.1. 
MELD Score ...............................................................................................................18 
9.2. 
Child-Pugh (CP) Score ...............................................................................................18 
9.3. 
Liver Biochemistry and Hepatobiliary Damage .........................................................20 
9.4. 
Total Bile Acids, Total Endogenous Bile Acids, C4 and FGF-19 
Concentrations ............................................................................................................20 
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9.5. 
Noninvasive Measurements of Liver Stiffness and Fibrosis ......................................21 
9.6. 
Clinical Outcome Events ............................................................................................21 
10. 
SAFETY ANALYSES ...............................................................................................22 
10.1. 
Exposure to Study Treatment .....................................................................................22 
10.2. 
Treatment Compliance ................................................................................................23 
10.3. 
Adverse Events ...........................................................................................................23 
10.3.1. 
Treatment-emergent Adverse Events .........................................................................23 
10.3.2. 
Serious Adverse Events ..............................................................................................24 
10.3.3. 
Adverse Events of Special Interest .............................................................................24 
10.3.4. 
TEAE Analyses ..........................................................................................................25 
10.3.5. 
Pruritus Adverse Events .............................................................................................26 
10.3.6. 
Fatigue Adverse Events ..............................................................................................27 
10.4. 
Clinical Laboratory Evaluations .................................................................................28 
10.4.1. 
Hematology .................................................................................................................28 
10.4.2. 
Chemistry ....................................................................................................................29 
10.4.3. 
Coagulation .................................................................................................................29 
10.5. 
Vital Signs ..................................................................................................................29 
10.6. 
Electrocardiogram (ECG) ...........................................................................................29 
10.7. 
COVID-19 Diagnosis .................................................................................................30 
10.8. 
Concomitant Medications ...........................................................................................30 
10.9. 
Concomitant Medical or Surgical Treatment Procedures ...........................................30 
10.10. 
Subgroup Analyses of Safety ......................................................................................30 
11. 
PHARMACOKINETIC ANALYSES ........................................................................31 
11.1. 
PK Sampling Schedule ...............................................................................................31 
11.2. 
PK Endpoints ..............................................................................................................32 
11.3. 
Handling of Missing Data, BLQ Data, or Data Exclusions ........................................32 
11.4. 
Analysis of Drug Concentration Data .........................................................................33 
11.4.1. 
Listing of Individual Subject Drug Concentration Data .............................................33 
11.4.2. 
Summary of Drug Concentrations ..............................................................................34 
11.5. 
PK Parameters Derivation ..........................................................................................34 
11.5.1. 
Listing of Individual Subject PK Parameters .............................................................34 
11.5.2. 
PK Parameters Summarization ...................................................................................35 
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12. 
PHARMACODYNAMIC ANALYSES .....................................................................35 
12.1. 
PD Sampling Schedule ...............................................................................................35 
12.2. 
PD Endpoints ..............................................................................................................36 
12.3. 
Presentation of PD Results .........................................................................................36 
12.3.1. 
Handling of Missing Data and BLQ Values ...............................................................36 
12.3.2. 
Units Conversion for Bile Acids and their Sub-components ......................................36 
12.3.3. 
Listings and Summary Tables for PD Data ................................................................37 
13. 
EXPLORATORY CORRELATION ANALYSIS BETWEEN PK AND PD ...........37 
14. 
ANALYSES OF PATIENT-REPORTED OUTCOMES AND 
HEALTHCARE RESOURCE USE ...........................................................................38 
14.1. 
EQ-5D-5L ...................................................................................................................38 
14.2. 
PBC-40 .......................................................................................................................38 
14.3. 
Pruritus Visual Analog Scale ......................................................................................38 
14.4. 
Chronic Liver Disease Questionnaire .........................................................................38 
15. 
DEVIATIONS FROM PROTOCOL ..........................................................................39 
16. 
REFERENCES ...........................................................................................................40 
APPENDIX A. DATA PRESENTATION CONVENTIONS: ...................................................41 
General Methods ............................................................................................................................41 
Key Definitions ..............................................................................................................................42 
First Dose Date ..............................................................................................................................42 
Last Dose Date ...............................................................................................................................42 
Study Day  ....................................................................................................................................42 
Time to Event .................................................................................................................................42 
Baseline and Change from Baseline ..............................................................................................42 
Dose Regimen ................................................................................................................................43 
Missing Data ..................................................................................................................................43 
Visit Windows ...............................................................................................................................45 
Pooling of Centers..........................................................................................................................45 
 
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LIST OF TABLES 
Table 1. 
Planned OCA or Matching Placebo Dosing Regimen ................................................12 
Table 2: 
Child-Pugh Scoring System ........................................................................................19 
Table 3: 
Acceptable Windows for Pharmacokinetic Sample Collection ..................................32 
Table 4: 
PK Parameters ............................................................................................................32 
Table 5: 
PK Summary Statistics ...............................................................................................35 
Table 6: 
PK Reporting Precision ..............................................................................................35 
Table 7: 
Bile Acids and Their Sub-Components ......................................................................37 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................12 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
ALP  
Alkaline phosphatase  
ALT  
Alanine aminotransferase  
ANCOVA 
Analysis of covariance 
AR (1) 
Autoregressive (1) 
AST  
Aspartate aminotransferase  
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the concentration 
BMI 
Body mass index 
BLQ 
Below limit of quantification 
BIW 
Twice per week 
C4  
7α-hydroxy-4-cholesten-3-one  
CA 
Cholic acid 
CDCA 
Chenodeoxycholic acid 
CLDQ 
Chronic liver disease questionnaire 
CI 
Confidence interval 
CM 
Concomitant medication 
CP 
Child-Pugh 
CV 
Coefficient of variation 
DB 
Double-blind 
DBext 
Double-blind extension 
DCA 
Deoxycholic acid 
DMC 
Data monitoring committee  
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ELF 
Enhanced liver fibrosis 
EQ-5D-5L 
EuroQol five-dimensional 
ET 
Early termination 
EOT 
End of treatment 
EOS 
End of study 
FGF-19  
Fibroblast growth factor-19  
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Abbreviation or Specialist Term 
Explanation 
FXR  
Farnesoid X receptor  
GGT  
Gamma-glutamyl transferase 
HA 
Hyaluronic acid 
HCC 
Hepatocellular carcinoma  
HCV 
Hepatitis C virus 
INR  
International normalized ratio  
IP 
Investigational product 
ITT  
Intent-to-treat  
IWRS 
Interactive web response system 
KM 
Kaplan-Meier 
LCA 
Lithocholic acid 
LOESS 
Locally estimated scatterplot smoothing 
LLOQ 
Lower limit of quantification 
LLN 
Lower limit of normal 
LS 
Least square 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model of end stage liver disease 
Min 
Minimum 
MMRM 
Mixed model repeated measures 
MR 
Metabolite ratio 
OCA  
Obeticholic acid (also known as INT-747)  
PBC  
Primary biliary cholangitis (also known as primary biliary 
cirrhosis)  
PD 
Pharmacodynamics  
PK 
Pharmacokinetics  
P3NP 
procollagen 3 N-terminal peptide 
PT 
Preferred term 
QW 
Once per week 
REML 
Restricted maximum likelihood  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
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Abbreviation or Specialist Term 
Explanation 
SAS 
Statistical analysis system 
SD 
Standard deviation  
SE 
Standard error 
SI 
Standard international  
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TE 
Transient elastography 
TEAE 
Treatment-emergent adverse event  
TIMP-1 
Tissue inhibitor of metalloproteinase 
TLF 
Table, listing, and figure 
UDCA 
Ursodeoxycholic acid 
ULN 
Upper limit of normal 
VAS  
Visual analogue scale  
WHO 
World Health Organization 
 
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1. 
SCOPE 
This statistical analysis plan (SAP) describes the statistical analyses and data presentations 
planned for protocol 747-401, A Phase 4, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating the Pharmacokinetics and Safety of Obeticholic Acid in Patients with Primary Biliary 
Cholangitis and Moderate to Severe Hepatic Impairment.  It provides a detailed description of 
the strategies, rationales, and statistical techniques to be used to meet the study objectives and 
additional details to the statistical analyses that were described in the protocol.  This SAP will be 
finalized and signed prior to database lock.  Any deviations from the methods specified in this 
SAP will be documented in the clinical study report (CSR).  If additional analyses are required to 
supplement the planned analyses described in this SAP, they will be identified as post-hoc in the 
CSR.  
2. 
STUDY OBJECTIVES AND HYPOTHESES 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
• To evaluate the PK of OCA and its conjugates, glyco-OCA and tauro-OCA, and OCA 
metabolite glucuronide compared with placebo 
• To evaluate the safety and tolerability of OCA treatment compared with placebo 
2.1.2. 
Secondary Objectives 
• To evaluate the effect of OCA treatment compared to placebo on:  
− The MELD score and its components 
− CP score and its components 
− Liver biochemistry including total and direct bilirubin, alkaline phosphatase 
(ALP), and aminotransferases (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], and gamma glutamyl transaminase [GGT]), international 
normalized ratio (INR), creatinine, albumin, platelets 
− Biomarkers of bile acid synthesis and homeostasis including fibroblast growth 
factor 19 (FGF-19), 7α-hydroxy-4-cholesten-3-one (C4), and plasma bile acids 
2.1.3. 
Exploratory Objectives 
• To evaluate the effect of OCA treatment compared to placebo on: 
− Noninvasive markers of liver fibrosis (Enhanced Liver Fibrosis [ELF]™score) 
− Noninvasive measurement of liver stiffness (transient elastography [TE]) 
• To assess the PK/Pharmacodynamic (PD) relationship of OCA with: 
− PK parameters compared to PD parameters and safety and tolerability 
assessments 
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• To assess patient reported outcomes (Pruritus Visual Analogue Scale [VAS], PBC-40, 
EQ 5D-5L, Chronic Liver Disease Questionnaire [CLDQ] 
• To assess clinical events consistent with end-stage liver disease 
− Death (all cause) 
− Liver transplant 
− MELD score ≥15 (for patients with MELD ≤12 at baseline) 
− Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: variceal bleed, hepatic encephalopathy (as defined by a West 
Haven score of ≥2), spontaneous bacterial peritonitis 
− Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis 
at a frequency of at least twice in a month) 
− Hepatocellular carcinoma (HCC) 
2.2. 
Hypotheses 
The primary objective of this study is to evaluate the PK of OCA and its conjugates, safety and 
tolerability of OCA compared with placebo.  Therefore, there is no formal statistical hypothesis 
to be tested. 
3. 
SUMMARY OF STUDY DESIGN 
This is a double-blind, randomized, placebo-controlled study evaluating the PK and safety of 
OCA in patients with PBC and moderate to severe hepatic impairment.  It is a Phase 4 study in 
regions where OCA has received regulatory approval for PBC; in all other regions, this study is 
considered Phase 3b. 
Approximately 50 patients (including at least 20% of patients with CP-C) will be enrolled in the 
study.  Patients will be screened ≥14 days but not more than 28 days prior to entering the study 
(Day 1).  Patients who meet all eligibility requirements will be randomized in a 1:1 ratio to 1 of 2 
treatment groups: placebo or OCA.  Randomization will be stratified by CP class.  Baseline 
MELD scores will be monitored on an ongoing basis to ensure adequate distribution of MELD 
scores.  
Patients will receive double-blind treatment for at least 48 weeks.  During the 48-week treatment 
period (ie, Day 1 through Week 48), an initial safety visit will occur at Week 3.  After the Week 
6 Visit, subsequent clinic visits will occur approximately every 6 weeks for the assessment of 
safety, tolerability, PK, and PD.  Titration may be considered as early as the Week 12 Visit.  
Fasting PK samples (ie, trough only) will be obtained from all patients on Day 1, Week 6, and 
Week 36 prior to dose administration.  Post-dose serial PK assessments (including a trough 
sample) will be performed in all patients at Weeks 12, 18, 24, 30, and 48. 
Patients who have completed their 48-week double-blind treatment period will continue double-
blind treatment until all randomized patients have completed their participation in the 48-week 
treatment period and the database for that period is locked (approximately 3 years).  
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All patients will initiate investigational product (IP) once weekly with 5 mg OCA or matching 
placebo.  Titration may be considered as early as the Week 12 Visit.  Following visit procedures 
at Week 12, if the IP is tolerated and laboratory assessments do not indicate a safety concern, the 
patient may up-titrate to OCA 5 mg twice weekly and may start the higher dose regimen no 
earlier than 2 days after they took their last dose.  Dosing will then occur at least 3 days apart.  
Every 6 weeks thereafter, based on tolerability assessments, patients can be considered for 
further up titration as described below.  At each titration visit, the patient may start the higher 
dose regimen no earlier than 2 days after the prior dose.  Patients may titrate to a maximum dose 
of OCA 10 mg twice weekly at least 3 days apart. 
Figure 1: 
Study Design 
 
OCA = obeticholic acid, PBC = primary biliary cholangitis 
Notes:  Initial dose titration of investigational product may be considered as early as the Week 12 Visit, or any study 
visit thereafter for patients on all dosing regimens, based on tolerability and safety laboratory tests from the 
previous visit.  Subsequent dose titration(s) may occur no earlier than 6 weeks after the previous dose titration 
and will be based on tolerability. 
Patients who complete Week 48 will continue double-blind treatment until all randomized patients have 
completed their participation in the 48-week treatment period and the database for that period is locked. 
 
Table 1. 
Planned OCA or Matching Placebo Dosing Regimen 
 
Child-Pugh B and Child-Pugh C 
(Moderate and Severe Hepatic Impairment) 
Treatment Group 
OCA 
Placebo 
Starting Dose (Day 1) 
5 mg once weekly 
matching placebo once weekly 
Titration 1a  
5 mg twice weeklyb 
matching placebo twice weeklyb 
Titration 2a  
10 mg twice weeklyb 
matching placebo twice weeklyb 
a Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on patient 
tolerability. 
b Dosing per the twice weekly schedule must be at least 3 days apart. 
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3.1. 
Subject Selection 
This study will be conducted at approximately 50 international study sites with experience in 
treating patients with PBC with moderate to severe hepatic impairment defined as CP-B and 
CP-C.  Prospective patients will be identified primarily from the hospital and/or physician’s 
database of patients with PBC, or may be referred from other physicians.  Patients may self-refer 
to an Investigator if they become aware of the study through local, national, or international PBC 
patient societies, forums, or networks.  Subject Inclusion and Exclusion criteria can be found in 
Sections 8.2 and 8.3 of the protocol. 
3.2. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Enrolled patients 
who meet all eligibility requirements will be randomized in a 1:1 ratio to 1 of 2 treatment groups: 
placebo or OCA based on a predefined randomization code (generated by Sponsor or designee) 
using an interactive web response system (IWRS), which the Sponsor intends will serve as a 
computer-based patient registration system at Screening and Day 1.  
Randomization will be stratified by CP class (CP-B or CP-C).  Baseline MELD scores will be 
monitored on an ongoing basis to ensure adequate distribution of MELD scores.  The IWRS will 
serve as the IP inventory and management system and may be integrated with the study database.  
The Investigator or designee will be required to register the patient in the IWRS and may be 
prompted to provide patient data necessary to properly randomize and allocate the patient to 
treatment.  A randomization number will be assigned and IP (placebo or OCA) dispensing 
information will be provided (eg, bottle numbers allocated) while maintaining the study blind. 
The sponsors, patients, investigators, and study site staff will be blinded to the patient’s 
treatment allocation during the patient’s participation in the double-blind phase of the study. 
Treatment assignment for individual patients will be made available to the Investigator for 
medical emergency use only (such as unblinding which is necessary in order to treat a serious 
adverse event through the IWRS system).  When possible, the Medical Monitor should be 
consulted in the event that a medical emergency necessitates unblinding (ie, in situations where 
knowledge of the blinded treatment assignment is necessary for further medical management of 
the patient).  If it is not reasonable to inform the Medical Monitor in advance of the unblinding, 
the Investigator must promptly document in the patient’s record the rationale for unblinding and 
should subsequently contact the Medical Monitor to explain any premature unblinding of 
treatment assignment.  Procedures for unblinding a patient’s treatment will be provided 
separately to the Investigator.  Similarly, if the Medical Monitor breaks the blind for an 
individual patient for the purpose of evaluating an emergent safety issue, the Medical Monitor 
will document within study documentation the rationale, circumstances, and the person or 
persons being informed about the unblinding.  
The data monitoring committee (DMC) will have access to the IWRS and will be able to unblind 
individual patients.  Refer to Section 15.8 of the study protocol for further details regarding 
DMC access to blinded and unblinded data.  The DMC will document details about any 
unblinded patient data reviews in the closed session DMC minutes, which will be made available 
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to the Sponsor only after the database is locked and the study is unblinded.  Cases of premature 
unblinding, as noted above, will also be reviewed by the DMC.  
Access to treatment assignments will also be made available to the designated Intercept staff 
responsible for expedited safety reporting of suspected unexpected serious adverse reactions 
(SUSARs) to the Regulatory Authorities. 
3.3. 
Sample Size Determination 
To reasonably characterize the PK of OCA in patients with hepatic impairment, a simulation-
based approach estimated a requirement of approximately 20 patients in the OCA treatment 
group assuming a 15% discontinuation rate.  A total of 30 patients is adequate with 10 patients 
on placebo to be included as a comparator and 20 patients on OCA.  An additional 20 patients 
will be enrolled to support safety and efficacy evaluations.  Therefore, approximately 50 patients 
(including at least 20% of patients with CP-C) will be randomized in a 1:1 ratio to 1 of 2 
treatment groups: placebo and OCA. 
4. 
ANALYSIS POPULATIONS AND APPROACHES TO ANALYSIS 
4.1. 
Randomized Population 
The Randomized Population will include all randomized patients. 
4.2. 
Intent-to-Treat (ITT) Population 
The Intent-to-Treat (ITT) Population will include all randomized patients who received any 
amount of IP (OCA or placebo).  The ITT Population will be the primary population used for 
summarizing efficacy and pharmacodynamic analyses assessments.  Subjects will be analyzed 
according to randomized treatment. 
4.3. 
Safety Population  
The Safety Population will include all patients who received at least one dose of IP (placebo or 
OCA).  The Safety Population will be the primary population used for safety analyses.  Subjects 
will be analyzed according to treatment actually received.   
4.4. 
Pharmacokinetic Population  
The PK Population will include all patients receiving OCA who have adequate concentration-
time profiles to characterize OCA and its conjugates and must not have any major protocol 
deviations that potentially affect exposure levels. 
4.5. 
Non-COVID-19 Impacted Population 
Non-COVID-19 Impacted Population will include all randomized subjects who do not have any 
COVID-19-related protocol deviations.  The Non-COVID-19 Impacted population will be used 
for sensitivity analyses for the primary and secondary efficacy endpoints.  
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5. 
SUBJECT DISPOSITION 
Subject disposition will be tabulated by treatment group and overall and will include the number 
and proportion of subjects: 
• Enrolled 
• Randomized 
• Randomized but not treated 
• ITT Population 
• Safety Population 
• PK Population 
• Non-COVID-19 Impacted Population  
• Subjects who completed the study, withdrew from the study and the reasons for the 
withdrawal  
• Subjects who completed the study treatment, withdrew from the study treatment and 
reasons for the withdrawal  
• Subjects who completed Week 48 Visit of double-blind (DB) phase  
• Subjects’ study status post study treatment as recorded on the eCRF.  
Proportions will be out of the number of randomized subjects. 
Similar disposition summary will be done also other ITT, Safety, PK and Non-COVID-19 
impacted population.  Proportions will be out of the number of subjects in the given population. 
Subjects’ completion/discontinuation status will be listed including subject identifier, informed 
consent date, treatment completion, date of last treatment, dose regimen at date of last treatment, 
reason for treatment discontinuation, study completion, date of study completion or early 
withdrawal, and reason for study discontinuation. 
5.1. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol without proper notification to the 
Sponsor (or designee).  Only the Sponsor may amend the protocol.  Any change in study conduct 
considered necessary by the Investigator will be made only after consultation with the Sponsor, 
who will then issue a formal protocol amendment to implement the change and obtain regulatory 
approval.  The only exception is when the Investigator considers a patient’s safety to be 
compromised if immediate action is not taken. 
Major protocol deviations that could potentially affect the efficacy or safety conclusions of the 
study will be identified prior to database lock and unblinding of individual subject treatment 
information.  Major protocol deviations will be summarized by deviation category and treatment 
group for the ITT Population. 
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Protocol deviations related to COVID-19 are recorded in the Clinical trial management system as 
outlined within the Protocol Deviation and Non-Compliance Plan and will also be summarized 
by deviation category and treatment group. 
Protocol deviations will be listed by subjects. 
5.2. 
Inclusion/Exclusion Criteria 
Inclusion/exclusion criteria definitions and violations will be listed.  If no inclusion/exclusion 
violations are reported, this will be noted in place of the listing. 
6. 
DEMOGRAPHICS AND BASELINE DISEASE 
CHARACTERISTICS 
Demographics and baseline characteristics will be summarized and presented by treatment group 
and overall for ITT, Safety, and PK Populations. 
Age (years), height (cm), weight (kg), body mass index (BMI) (kg/m2), baseline CP score and 
baseline CP class (Class B/Class C), baseline MELD score, and Rotterdam criteria at baseline 
will be summarized descriptively.  Summary statistics will include the number of subjects and 
the mean, standard deviation (SD), standard error of the mean (SE), median, 25th and 75th 
quartiles, minimum, and maximum values.  Key liver function test results including ALP, total 
bilirubin, INR, platelets, albumin, Total daily dose of UDCA (mg) at baseline, Time from first 
initiated UDCA to first dose (weeks), and Time from last date of highest UDCA use to first dose 
(weeks) will also summarized descriptively.  
Sex, Race, Ethnicity, and Use of UDCA (Yes/No) will be summarized by frequency counts and 
percentages.  A subject can have multiple races and will be summarized as Multiple Races.  A 
subject can also have multiple ethnicities and will be summarized as Multiple Ethnicities. 
BMI is calculated based on weight and height at baseline.   
Demographic data and baseline characteristics (as detailed above) as well as informed consent 
data will be listed. 
• Age (in years) is derived by IWRS as year of screening minus year of birth 
• Height (in cm) = height (in inches) * 2.54 
• Weight (in kg) = weight (in lbs) * 0.4536 
• BMI (kg/m2) = Weight(kg)/[Height(cm)/100]2 
• Total daily dose of UDCA (mg) at baseline is determined as the last dosage reported 
prior to the first dose. 
• Time from first initiated UDCA to first dose (weeks) = (first dose date – date of first 
initiated UDCA)/7 
• Time from last date of highest UDCA use to first dose (weeks) = (first dose date - 
date of highest UDCA)/7 
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• Rotterdam criteria (Kuiper 2009) at baseline is defined as: 
− Low = Total Bilirubin< ULN and Albumin>LLN 
− Moderate = Total Bilirubin<ULN and Albumin<LLN or Total Bilirubin>ULN 
and Albumin>LLN 
− High = Total Bilirubin>ULN and Albumin<LLN 
Demographics and baseline characteristics will be listed by subject. 
7. 
PBC DISEASE HISTORY 
PBC disease history will be summarized and presented by treatment group and overall for ITT, 
Safety, and PK Populations.  The number and percentage of subjects in each of the following 
categories will be presented.  
• Age at PBC diagnosis  
• Duration of PBC in years at time of informed consent  
• Time in years from PBC Diagnosis to first dose of UDCA 
• History of PBC related pruritus (Yes/No) 
• Severity of most recent pruritus event 
• Pruritus ongoing at time of screening (Yes/No) 
8. 
PRIOR THERAPY AND MEDICAL HISTORY 
Prior therapy and medical history are any therapy, procedures, or diseases that occurred, or any 
medication taken prior to the first day of study drug dosing or prior to randomization date if 
subjects were never dosed.  
Medical history will be mapped to preferred terms and system organ classes using MedDRA 
dictionary version 24.0 and summarized by system organ class, preferred term, and treatment 
group and overall using the Safety population.  Summaries will be ordered by descending order 
of incidence of system organ class and preferred term within each system organ class.   
A listing of medical history by subject will be provided.  A listing of cirrhosis status assessment 
by subject will also be provided. 
Historical procedures will be coded with MedDRA version 24.0.  A summary of historical 
procedures will be presented by MedDRA SOC, PT, and by treatment group and overall using 
the Safety Population.  A listing of historical procedures by subject will be provided. 
 
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9. 
EFFICACY ANALYSES 
The efficacy endpoints of the study are defined below.  Additionally, the planned analyses for 
these endpoints are described.  
The efficacy analyses are additional endpoint in this study and will be performed on the 
ITT Population, as defined in Section 4.2.  Summary statistics will be tabulated for baseline, 
change and percent change from baseline to each scheduled visit of DB phase, Week 48 (end of 
DB phase), and each scheduled visit of DB extension (DBext) phase.  An analysis of covariance 
(ANCOVA) model and Wilcoxon Rank Sum Test will be applied to the change and percent 
change from baseline to Week 48 and each scheduled visit of DB phase of efficacy parameters.  
All CIs for point estimates provided will be conducted using the two-sided 95% confidence 
intervals. 
All efficacy data will be provided in listings by subject and visit. 
9.1. 
MELD Score 
MELD score is derived from the patient’s serum total bilirubin, serum creatinine, and INR, as 
appropriate, to predict survival (Kamath 2007).  MELD score will be calculated and reported for 
visits where these parameters are measured as described in the protocol.  An increasing MELD 
score is associated with increased severity of hepatic dysfunction and increased 3-month 
mortality risk. 
• Summary statistics of MELD score including baseline values, change from baseline, 
and Percentage change from baseline values will be presented by treatment group and 
by each scheduled post-baseline visit. 
• Analysis of change from baseline in MELD score will be analyzed using the 
Wilcoxon Rank Sum Test.  The tabulation will include median, interquartile range for 
each treatment group, median differences and 95% CI of the median differences 
between treatment groups using the Hodges-Lehmann estimate.  If the median 
differences between treatments are not symmetrical around the median, the Sign Test 
may be used. 
• MELD score will be presented in shift tables showing the shift from baseline to each 
scheduled post-baseline visit by the count and percentage of patients within each shift 
classification (<10, 10 to <12, 12 to <13, 13 to <14, 14 to <15, and ≥15). 
The MELD Score analyses will be repeated for MELD-Na 
9.2. 
Child-Pugh (CP) Score 
CP Score (Pugh 1973, Lucey 1997) is calculated and reported within the EDC system based on 
data entered into the eCRF by adding the scores from the 5 factors outlined in Table 2 and can 
range from 5-15.  A total score of 5-6 is considered Grade A (mild, well-compensated disease); 
7-9 is Grade B (moderate, significant functional compromise); and 10 and above is Grade C 
(severe, decompensated disease).  Calculation of the CP score includes Investigator assessments 
of ascites and hepatic encephalopathy, which may be assessed during the adverse event review at 
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the scheduled visits, as well as total bilirubin, serum albumin, and prothrombin time, which will 
populate from the central laboratory.  
Table 2: 
Child-Pugh Scoring System 
Factor 
Units 
Points 
1 
2 
3 
Serum bilirubin  
μmol/L 
<34 
34-50 
>50 
mg/dL 
<2.0 
2.0-3.0 
>3.0 
Serum albumin  
g/L 
>35 
28-35 
<28 
 
g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time  
Seconds prolonged 
0-3 
4-6 
>6 
 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites  
 
None 
Mild 
Moderate-Severe 
Hepatic encephalopathya  
 
0 
Grade 1 or 2 
Grade 3 or 4 
a Grade 0: normal consciousness, personality, neurological examination, electroencephalogram  
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves  
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves  
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves  
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity  
(Pugh 1973, Lucey 1997), Vilstrup 2014 
 
• Baseline CP score is calculated based on components measured at Screening visit. 
• Summary statistics of CP score including baseline values, change from baseline, and 
percentage change from baseline values will be presented by treatment group and by 
each scheduled post-baseline visit.  
• Analysis of change from baseline in CP score will be analyzed using the Wilcoxon 
Rank Sum Test.  The median differences and 95% CI of the median differences 
between treatment groups will be constructed using the Hodges-Lehmann estimate.  If 
the median differences between treatments are not symmetrical around the median, 
the Sign Test may be used. 
• CP class (A, B, and C) will be presented in a shift table showing the shift from 
baseline to each scheduled post-baseline visit by the count and percentage of patients 
within each shift classification (A, B, and C). 
• Components of CP score categories as listed in Table 2 will be summarized by the 
count and percentage of patients within each category at baseline and each scheduled 
post-baseline visit. 
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9.3. 
Liver Biochemistry and Hepatobiliary Damage 
Liver biochemistry includes total and direct bilirubin, ALP, ALT, AST, and GGT, INR, 
creatinine, albumin, and platelets. 
• Summary statistics of liver biochemistry including baseline values, change from 
baseline, and percentage change from baseline values will be provided by treatment 
group and by each scheduled post-baseline visit. 
• Change from baseline will be analyzed by using an ANCOVA model with change 
from baseline as the dependent variable, treatment group and randomization 
stratification factor as fixed effects and the baseline value as a covariate.  
• Percent change from baseline will be analyzed by using an ANCOVA model with 
percent change from baseline as the dependent variable, treatment group and 
randomization stratification factor as fixed effects and the baseline value as a 
covariate. 
• As a sensitivity analysis, change from baseline and percent change from baseline of 
liver biochemistry parameters will be analyzed by using a restricted maximum 
likelihood (REML) based MMRM.  Treatment group, time, treatment group by time 
interaction, and randomization stratification factor will be included as fixed effects 
and parameter baseline values will be included as a covariate in the model, where 
time includes all post baseline visits of DB phase.   
• An unstructured covariance structure will be used to model the within-participant 
errors.  If there is a convergence issue with the unstructured covariance model, 
Toeplitz, Autoregressive (1) (AR (1)) covariance structure will be used, following 
this sequence until convergence is achieved.  If the model still does not converge with 
AR (1) structure, no results will be reported.  When the covariance structure is not 
unstructured, the sandwich estimator for the variance-covariance matrix will be 
derived, using the EMPIRICAL option in the PROC MIXED statement in SAS.  The 
p-value will be interpreted at 0.05 level of significance. 
• The tabulation of ANCOVA model and MMRM model will include estimates of 
least-square (LS) means, SEs, and 2-sided 95% CIs for each treatment group. 
Estimates of the mean difference, SE of the difference, 2-sided 95% CI of the 
difference between treatment groups, and p-value will also be presented. 
9.4. 
Total Bile Acids, Total Endogenous Bile Acids, C4 and FGF-19 Concentrations 
Total bile acids, total endogenous bile acids, C4 and FGF-19 concentrations will be analyzed as 
follows: 
• Summary statistics of total bile acids, total endogenous bile acids, C4 and FGF-19 
concentrations including baseline values, change from baseline, and percentage 
change from baseline values will be presented by treatment group and by each 
scheduled post-baseline visit.  
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• Change from baseline in total bile acids, total endogenous bile acids, C4 and FGF-19 
concentrations at each scheduled post-baseline visit will be analyzed using the 
Wilcoxon Rank Sum Test.  
9.5. 
Noninvasive Measurements of Liver Stiffness and Fibrosis 
Noninvasive measurements of liver stiffness (TE) and liver fibrosis (ELF [HA, P3NP, and 
TIMP-1]) will be analyzed as follows: 
• Summary statistics of TE and ELF including baseline values, change from baseline, 
and percentage change from baseline values will be provided by treatment group and 
by each scheduled post-baseline visit. 
• Analyses of change from baseline in liver stiffness and liver fibrosis values will be 
analyzed by using an ANCOVA model with change from baseline as the dependent 
variable, treatment group and randomization stratification factor as fixed effects and 
the baseline value as a covariate. 
• Analyses of percent change from baseline in liver stiffness and liver fibrosis values 
will be analyzed by using an ANCOVA model with percent change from baseline as 
the dependent variable, treatment group and randomization stratification factor as 
fixed effects and the baseline value as a covariate. 
As a sensitivity analysis, change from baseline and percent change from baseline of these 
parameters will be analyzed using the same MMRM model as described in Section 9.3.  
9.6. 
Clinical Outcome Events 
The following clinical outcome events will be captured in the study:  
• Time from first dose to death (all cause)  
• Time from first dose to liver-related death  
• Time from first dose to liver transplant  
• Time from first dose to MELD score ≥15 (for patients with MELD ≤12 at baseline)  
• Time from first dose to earliest hospitalization for new onset or recurrence of: 
− variceal bleed  
− hepatic encephalopathy (as defined by a West Haven score of ≥2) 
− spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)  
• Time from first dose to uncontrolled ascites (diuretic resistant ascites requiring 
therapeutic paracentesis at a frequency of at least twice in a month) 
• Time to first occurrence of any above listed clinical events 
The incidence and time to first occurrence of any above listed clinical events will be summarized 
by treatment group using the log rank test stratified by the randomization stratification factor.  
The minimum and maximum time to clinical event will be presented. KM estimates of the 
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distribution of the time-to-event will be tabulated and graphed by treatment group.  The 
tabulation will include the KM methodology using 25th, 50th (median), and 75th percentiles 
with associated 2-sided 95% CIs, as well as percentage of censored observations.  The number 
and percent of patients censored and with events will be presented.  The hazard ratio and 2-sided 
95% CI will be estimated based on a Cox regression model stratified by randomization strata.  
The proportionality of hazards will be assessed using Schoenfeld residuals.   
In addition, the incidence and time to each of the above clinical events, and the incidence and 
time to occurrence of HCC will be summarized by treatment group using the same methods as 
defined above. 
For the time to event analyses, subjects who do not experience an event will be censored at the 
time of their last contact.  Subjects with no data after randomization will be considered to have 
an event on Day 1 (first day of IP dosing).  All time-to-event endpoints include only adjudicated 
events.   
10. 
SAFETY ANALYSES  
Safety analyses include exposure to study treatment, treatment-emergent adverse events, clinical 
labs, electrocardiograms (ECGs), vital signs, and any abnormal findings observed during 
physical examinations after study enrollment and through discontinuation of study treatment 
+30 days.  Safety analyses will be performed using the Safety population including by treatment 
groups, as defined in Section 4.3 and pooled across all active dose levels.  No inferential 
comparison of safety endpoints will be performed, unless otherwise specified.  
10.1. 
Exposure to Study Treatment 
The duration of exposure (days) will be summarized using descriptive statistics by treatment 
group for DB phase, DBext phase and combined. 
• Duration of exposure to IP (days) = (last treatment date – first treatment date + 1) – 
total duration of temporary IP discontinuation 
The duration of each incidence of temporary IP discontinuation will be calculated as follows: 
• Duration of temporary discontinuation of IP = Date of restart of IP - Date of 
temporary discontinuation of IP + 1.   
The total duration of temporary IP discontinuation is the sum duration of temporary 
discontinuation of IP over each incidence of discontinuation. 
Total subject exposure to IP (mg) will be calculated by adding the doses taken by a subject 
during the DB phase, DBext phase, and combined and will be summarized using descriptive 
statistics.  Duration of exposure to IP (days) will be categorized to following intervals: 1-21, 
22-42, 43-84, 85-126, 127-168, 169-210, 211-252, 253-294, 295-336, 337-420, 421-504, 
505-588, 589-672, 673-756, and >756 days.  Number and percent of subjects in each interval 
will be tabulated by treatment group.  
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At each IP administration, the subject will be asked to record the reason for dose adjustment (if 
any).  If the subject has multiple dose adjustments caused by the same reason, the subject is only 
counted once per reason category.  Reasons for dose adjustment will be summarized by 
treatment group for the DB phase, DBext phase, and combined. 
10.2. 
Treatment Compliance  
Subject’s overall compliance (%) with IP will be calculated as follows: 
• (number of tablets consumed during study / number of tablets expected to be 
consumed during study) *100 
where 
• number of tablets expected to be consumed during study = total number of weeks on 
5 mg once weekly + 2*total number of weeks on 5 mg or 10 mg twice weekly; during 
the period from first treatment date to last, inclusive   
and 
• number of tablets consumed during study = sum of drug taken weekly by a subject 
during the DB phase, DBext phase, and combined 
Treatment compliance with IP will be summarized by treatment group using descriptive statistics 
for DB phase, DBext phase, and combined.  Number and percent of patients with compliance of 
<60%, 60% to <80%, 80% to 120%, and >120% will be tabulated by treatment group for DB 
phase, DBext phase, and combined.   
Subject treatment compliance will be listed based on drug administration data. 
10.3. 
Adverse Events  
Per ICH E6 (R2), an adverse event (AE) is any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.  
AEs will be mapped to preferred terms (PTs) and system organ classes (SOCs) using MedDRA 
dictionary version 24.0.  Subjects experiencing the same event more than once will be counted 
only once at the most severe grade and the closest relationship to study treatment. 
AEs related to COVID-19 will be flagged. 
10.3.1. 
Treatment-emergent Adverse Events 
An AE is defined as a treatment emergent adverse event (TEAE) if it meets one or more of the 
following criteria: 
• An AE starting on or after the first study drug dose and within 30 days after the last 
dose of study drug. 
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• An AE occurring prior to the first study drug dose that worsens (increase in grade) 
after the first study drug dose. 
10.3.2. 
Serious Adverse Events 
A serious adverse event (SAE) is any of the following untoward medical occurrences at any 
dose: 
• Death 
• Is immediately life threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Events not considered to be SAEs are hospitalizations for: 
• Routine monitoring of the studied indication and not associated with any deterioration 
in condition or AE; 
• Elective treatment for a pre-existing condition that did not worsen; 
• Respite care or observation when there is no AE associated with the hospitalization. 
10.3.3. 
Adverse Events of Special Interest 
The following decompensation events are adverse events of special interest:   
• Variceal bleeding or recurrent variceal bleeding documented by endoscopy OR 
patient presenting with anemia or melena (hemoglobin drop ≥2 g/dL) and found to 
have varices documented by endoscopy, irrespective of hospitalization or requirement 
of blood transfusion.  
• Gastrointestinal bleeding as a result of gastric or duodenal varices verified by 
endoscopy 
• Hepatic encephalopathy, Grade ≥2 
• New onset ascites requiring treatment 
• Worsening of ascites (requiring increase in drug therapy or requirement of surgical 
procedure such as paracentesis or shunt placement) 
• Refractory ascites -unresponsive to medications, and patient is not a candidate for 
TIPS or shunt and requires large volume paracentesis 
• Hyponatremia (Na ≤125 mEq/L) secondary to ascites 
• Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis- by cell 
count/chemistry) 
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• Hepatorenal syndrome Type 1 and Type 2 and Acute Kidney Injury (AKI) 
• Liver failure defined as worsening of liver synthetic function that is persistently worse 
relative to baseline and/or progressive over time: 
− Hepato-pulmonary syndrome 
− Porto-pulmonary syndrome 
− Liver Transplant 
− Increase in MELD scores by 3 points relative to baseline, persistent over time and 
unrelated to vitamin K deficiency related increase in INR 
− 
Any liver related event that requires hospitalization and treatment 
10.3.4. 
TEAE Analyses 
The counts and percentages of subjects experiencing a TEAE and TEAEs by PTs and SOCs in 
the following categories will be presented by study treatment arm: 
All AE summaries will be restricted to TEAEs.  Each AE summary will be displayed by 
treatment group for DB phase, DBext phase, and combined.  Summaries that are displayed by 
SOC and PT will be ordered by descending order of incidence of SOC and PT within each 
system organ class. 
Summary tables of the following TEAEs will be presented: 
• Overall summary of TEAEs 
• Patient incidence of TEAEs and the total number of entries by SOC and PT.  This 
summary will be repeated for subgroups specified in Section 10.10. 
• Patient incidence of TEAEs by SOC, PT, and highest severity.  At each level of 
patient summarization, a patient is classified according to the highest severity if the 
patient reported 1 or more events.  AEs with missing severity will be considered 
severe for this summary.  
• Patient incidence of TEAEs by SOC, PT, and closest relationship to IP (Related/Not 
Related). Related AEs are those with relationships reported as “Definite,” “Probable,” 
or “Possible,” and unrelated AEs are those with relationships reported as “Unlikely” 
or “Not Related”.  At each level of patient summarization, a patient is classified 
according to the closest relationship if the patient reported 1 or more events.  AEs 
with a missing relationship will be considered related for this summary.  
• Patient incidence of serious TEAEs and the total number of entries by SOC and PT.  
• Patient incidence of TEAEs leading to IP withdrawal or study discontinuation by 
SOC and PT.  This is a subset of the AEs where Action Taken with Study Treatment 
is checked as “Drug Withdrawn” or where “Patient Discontinued from Study” is 
checked on the eCRF. 
• Patient incidence of COVID-19 related TEAEs. 
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Patient incidence will be summarized as subject counts and percentages unless otherwise 
specified. 
The number of AEs and events per 100 patient years will be summarized by SOC and PT. 
• Individual patient years = (the last recorded study visit date – first dose date 
+1)/365.25 
where: the last recorded study visit date = end of study date recorded on end of 
study CRF page for that patient 
• Total patient years on study = sum of all individual patient years within the Safety 
Population 
• Events per 100 patient years =
Number of Event∗100
Total Patient Years on Study  
The following listings will be presented by treatment group and patient: 
• All AEs  
• Serious AEs 
• Severe AEs 
• Treatment-related AEs 
• AEs leading to Study Drug Withdrawal or Study Discontinuation  
• AEs leading to Death 
• TEAEs related to COVID-19  
• Major adverse cardiovascular events (excluding deaths) 
The original date and time will be shown on all listings of AEs. 
10.3.5. 
Pruritus Adverse Events 
Pruritus: Treatment-emergent pruritus, defined as any PT including “Prur” will be summarized 
separately by the treatment group, SOC, and PT as a subset of all TEAEs.  This summary will be 
repeated for subjects with “new or worsened” pruritus events, as defined as follows: 
• Mild, moderate, or severe treatment-emergent pruritus events in patients with no 
pruritus at baseline, or  
• Worsening of the severity of the baseline condition in patients with pruritus at 
baseline.  
Baseline pruritus is defined as the Investigator’s rating of severity as collected on the PBC 
Disease History eCRF.  Patients whose baseline severity is severe will be counted as worsening 
if an AE of pruritus with severe is recorded. 
An analysis of treatment-emergent pruritus event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  
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In order to explore the relationship between pruritus and the IP, the following time-to-event 
analyses will be performed:  
• Time to first onset of treatment-emergent pruritus 
The time to the start of the first episode = date of onset of first episode – date of first 
dose of IP + 1.  
Patients who never reported an AE of pruritus will be censored at the date of last contact.  
• Time to onset of the first moderate or severe treatment-emergent pruritus  
The time to the start of the first moderate or severe pruritus = date of onset of the first 
moderate or severe pruritus – date of first dose of IP +1.  
Patients who never reported a moderate or severe AE of pruritus will be censored at 
the date of completion or discontinuation.  
• Time to onset of the first severe treatment-emergent pruritus  
The time to the start of the first severe pruritus = date of onset of the first severe 
pruritus – date of first dose of IP +1.  
Patients who never reported a severe AE of pruritus will be censored at the date of 
completion or discontinuation. 
The analysis of time to first onset of treatment-emergent pruritus AE, time to onset of the first 
moderate or severe treatment-emergent pruritus, and onset of the first severe treatment-emergent 
pruritus will include the number of patients with pruritus (first onset, first moderate or severe, 
first severe), the number of patients without pruritus (censored), and the minimum and maximum 
times in days.  KM estimates will be calculated by treatment group.  The tabulation will include 
the KM estimate methodology using 25th, 50th (median), and 75th percentiles of the medians 
and corresponding 2-sided 95% CIs, if the medians can be estimated as well as percentage of 
censored observations.  KM estimates will be plotted as a “survival curve” for each treatment 
group. 
10.3.6. 
Fatigue Adverse Events 
Fatigue: Treatment-emergent fatigue is defined as any PT which includes “Fatigue.” New or 
worsened treatment-emergent fatigue is defined as follows:  
• Any mild, moderate, or severe treatment-emergent fatigue events in patients with no 
fatigue at baseline, or  
• Worsening of the severity of the baseline condition in patients with fatigue at 
baseline. 
Baseline fatigue is defined as the Investigator’s rating of severity as collected on the PBC 
Disease History eCRF.  Patients whose baseline severity is severe will be counted as worsening 
if an AE of fatigue with severe is recorded.  
An analysis of treatment-emergent fatigue event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
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years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  
In order to explore the relationship between fatigue and the IP, the following time-to-event 
analyses will be performed:  
• Time to first onset of treatment-emergent fatigue 
The time to the start of the first episode = date of onset of first episode – date of first 
dose of IP + 1.  
Patients who never reported an AE of fatigue will be censored at the date of last 
contact.  
• Time to onset of the first moderate or severe treatment-emergent fatigue 
The time to the start of the first moderate or severe fatigue = date of onset of the first 
moderate or severe fatigue – date of first dose of IP +1.  
Patients who never reported a moderate or severe AE of fatigue will be censored at 
the date of last contact.  
• Time to onset of the first severe treatment-emergent fatigue 
The time to the start of the first severe fatigue will be calculated by date of onset of 
the first severe fatigue – date of first dose of IP +1.  
Patients who never reported a severe AE of fatigue will be censored at the data of last 
contact.  
The analysis of time to first onset of treatment-emergent fatigue AE, time to onset of the first 
moderate or severe treatment-emergent fatigue, and onset of the first severe treatment-emergent 
fatigue will include the number of patients with fatigue (first onset, first moderate or severe, first 
severe), the number of patients without fatigue (censored), and the minimum and maximum 
times in days.  KM estimates will be calculated by treatment group.  The quartiles, including the 
median time-to-event and their corresponding 2-sided 95% CIs, will be presented. KM estimates 
will be plotted as a “survival curve” for each treatment group. 
10.4. 
Clinical Laboratory Evaluations 
Laboratory parameters will be summarized in standard international (SI) system of units by 
treatment group.  Re-test or unscheduled results will not be summarized but will be included in 
the data listings.  Baseline is defined as the mean of all available evaluations prior to treatment.  
All clinical laboratory data will be listed by subject and visit. 
10.4.1. 
Hematology 
Descriptive statistics will be used to summarize the results and change from Baseline to each on-
study evaluation visit for hemoglobin, hematocrit, white blood count with differential, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets, red blood cell count 
(including MCV, MCH, MCHC). 
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In addition, shift tables (ie, low-normal-high at baseline versus low-normal-high at post baseline 
visit in a 3-by-3 contingency table) from baseline to worst value, last value, and at each 
scheduled post-baseline visit will be provided for hematology and serum chemistry by treatment 
group to assess changes in laboratory values from baseline to each on-study evaluation. 
Quantitative laboratory tests containing less than (<) and greater than (>) symbols are test results 
that are below and above quantifiable limits, respectively.  In order to retain these values for 
analysis purpose, the following imputations will be done within the analysis datasets: 
• For laboratory test results that are below the quantifiable limit: 
− Imputed laboratory results = (numeric portion of the result) x 0.9. 
• For laboratory test results that are above the quantifiable limit: 
− Imputed laboratory results = (numeric portion of the result) x 1.1. 
10.4.2. 
Chemistry 
Descriptive statistics will be used to summarize the results and change from Baseline to each on-
study evaluation visit for albumin, blood urea nitrogen, creatinine, aspartate aminotransferase 
[AST, SGOT], alanine aminotransferase [ALT, SGPT], ALP, GGT, electrolytes [calcium, 
chloride, potassium, sodium], glucose, total protein, and blood lipids (total cholesterol, LDL, 
HDL and VLDL fractions and TG), CPK, magnesium, phosphorus, bicarbonate, unconjugated 
(indirect) bilirubin, conjugated (direct) bilirubin, total bilirubin, free fatty acids, TFT (TSH, free 
T3 and free T4). 
10.4.3. 
Coagulation 
Descriptive statistics will be used to summarize the results and change from Baseline to each on-
study evaluation visit for PT, PTT, INR. 
10.5. 
Vital Signs  
The results and change from baseline to each on-study evaluation visit will be summarized by 
treatment group for weight, oral temperature, sitting heart rate, respiratory rate and sitting blood 
pressure.  
Vital signs and weight data will be listed by subject and visit. 
10.6. 
Electrocardiogram (ECG) 
The central read ECG data will be analyzed based on methodology recommended in the 
International Conference on Harmonisation (ICH) E14 guideline, The Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs.   
Overall interpretation results for ECGs and the investigator interpretation results are collected as 
normal, abnormal not clinically significant (NCS), and abnormal clinically significant (CS).  
Subjects whose interpretations shift from normal to abnormal (CS or NCS) will be listed 
separately, including description of the abnormality and any associated comments. 
ECG data will be listed by subject and visit. 
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10.7. 
COVID-19 Diagnosis 
Results of COVID-19 test and if positive, whether subjects are symptomatic, will be listed by 
subject. 
10.8. 
Concomitant Medications 
Concomitant medications are medications that were started after the initial dose of 
investigational product.  Concomitant medications will be mapped to Anatomic Therapeutic 
Chemical (ATC) class and preferred term using WHO Drug Dictionary Global B3 version, 
March 2021 and summarized by ATC class, preferred term, and treatment in the Safety 
population.  Summaries will be ordered by descending order of incidence of ATC class and 
preferred term within each ATC class. Summary will be tabulated for the DB phase, DBext 
phase, and combined. 
Subject with prior and concomitant medications will be presented in a data listing.  Prohibited 
concomitant medications will be flagged in concomitant medication and presented in a data 
listing.  
10.9. Concomitant Medical or Surgical Treatment Procedures 
Concomitant medical or surgical treatment procedures are defined as all medical or surgical 
treatment procedures occur on or after the first dose of IP.  The number and percentage of 
subjects who have at least one concomitant medical or surgical treatment procedures will be 
displayed together with the number and percentage of subjects using at least 1 concomitant 
medical or surgical treatment procedures within each treatment group by ATC class and 
preferred terms using the Safety Population. 
Concomitant medical or surgical procedures will be summarized by treatment group for DB 
phase, DBext phase and combined.  Subject concomitant or surgical procedures will be presented 
in data listings. 
10.10. 
Subgroup Analyses of Safety 
Adverse events will be summarized for the following subgroups of interest:  
• Age Categories:  <65, ≥65 years 
• Sex:  Male, Female 
In addition, selected safety endpoints may be performed for the following defined subgroups if 
deemed appropriate.    
• CP Class at Baseline: Class B, Class C  
• Age Category:  ≥75 years 
• Race:  White, Non-White (Black or African American, Asian, Native Hawaiian or 
Other Pacific Islander, American Indian or Alaska Native) 
• Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not Reported/Unknown 
• Baseline BMI: <30 kg/m2, ≥30 kg/m2 
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• Baseline Use of UDCA: Yes, No 
• Baseline MELD score: <=12  
• Baseline Rotterdam Status: Low, Moderate, High  
11. 
PHARMACOKINETIC ANALYSES 
PK analyses will be performed using the PK Population (definition in Section 4.4).  PK 
parameters will be derived using Phoenix WinNonlin version 8.0 or higher.  The PK 
concentrations and parameters will be available for: 
• Unconjugated OCA 
• Glyco-OCA 
• Tauro-OCA 
• Total OCA (molar sum of OCA, glyco-OCA, tauro-OCA) 
• Metabolite OCA glucuronide  
11.1. 
PK Sampling Schedule  
Serial and fasting PK assessments will be performed in all patients participating in the study.  
• Pharmacokinetic fasting samples prior to the study medication will be obtained from 
all patients on Day 1, and at Weeks 6, 12, 18, 24, 30, 36, and 48 prior to dose 
administration. 
• Serial PK assessments will be performed in all patients at Weeks 12, 18, 24, 30, and 
48 at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, and 24 hours post-dose. 
The Week 6 Visit should occur 3, 4, or 5 days after the Week 6 dose (eg, if the Week 6 dose of 
IP is taken on a Sunday, the patient should come in for the Week 6 Visit between Wednesday 
and Friday).  This allows for the collection of PK data near the mid-point of the weekly dosing 
interval (ie, 5 mg once weekly). 
Patients will receive a dose of IP with approximately 240 mL of water.  Patients should not drink 
additional water for 1 hour after taking the dose of IP and will remain fasted until after the 
1-hour sample is collected.  A meal replacement drink will be provided following collection of 
the 1-, 4-, and 7-hour PK sample.  The nutritional information of the meal replacement drink 
should be submitted to and approved by the Sponsor in advance.  No other food or drink (water 
is permitted) will be allowed until after the 9-hour sample collection.  
The acceptable windows for the PK blood collection time points are listed in Table 3.  However, 
because the planned non-compartmental PK analyses will use actual collection times (ie, not 
nominal times), data from samples collected outside of these time windows will still be included 
in the non-compartmental analyses.  PK samples that have a collection time outside the 
acceptable time window will be considered as “missing” for the calculation of drug 
concentration summary statistics at that nominal time point. 
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Table 3: 
Acceptable Windows for Pharmacokinetic Sample Collection 
Nominal Sampling Time  
Acceptable Sampling Window  
Before administration of IP (pre-dose or fasting)  
Within 30 minutes before dosing  
0.5 to 1.5 hours after IP  
± 10 minutes  
2 to 2.5 hours after IP  
± 20 minutes  
3 to 24 hours after IP  
± 30 minutes  
11.2. 
PK Endpoints 
Table 4 presents the PK parameters which will be derived for all analytes where possible. 
Table 4: 
PK Parameters 
Calculation 
Period(s) 
 
PK 
Parameter 
 
Units  
 
Definition 
Weeks 12, 18, 
24, 30, 48 with 
serial PK 
sampling  
AUC0-24h 
h*ng/mL 
Area under the concentration versus time curve from zero time 
to 24 hours. 
• 
The linear/linear trapezoidal rule should be used for 
estimation of AUC. 
• 
At least 4 quantifiable concentration-time values must 
be available to compute AUC0-24h 
• 
For last actual sampling times >24 hours, AUC0-24h 
will be interpolated. For last actual sampling times 
from 23 to 24 hours, AUClast will be reported for 
AUC0-24h. For last actual sampling times <23 hours, 
AUC0-24h will not be reported. 
 
Cmax 
ng/mL 
Maximum observed concentration. If all observations are BLQ, 
Cmax will be reported as zero 
 
Ctrough 
ng/mL 
Pre-dose concentration 
 
Tmax 
h 
First time at which Cmax is observed.  If all observations are 
BLQ, Tmax will be reported as not determined (ND) 
 
MRAUC 
unitless 
(ratio) 
The metabolite to parent ratio of AUC0-24h (calculated on molar 
basis) 
 
MRCmax 
unitless 
(ratio) 
The metabolite to parent ratio of Cmax (calculated on molar basis) 
 
11.3. 
Handling of Missing Data, BLQ Data, or Data Exclusions 
Missing concentration data for all patients who are administered scheduled study treatments will 
be considered as non-informative missing and will not be imputed.  No concentration estimates 
will be provided for missing sample values. 
For all analyses (drug concentrations and PK parameters), the following rules will apply: 
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• Concentration values below the assay’s lower limit of quantification (BLQ) will be 
imputed to zero 
• The sampling time of pre-dose samples relative to dosing will also be treated as zero  
Examples of potential reasons for exclusion of data from PK summary analyses include, but are 
not limited to: 
• Subject not fasted for 8 hours prior to PK visit; 
• Subject not adhering to standardized meal timing (or missed meal) during 24-hour PK 
profile collection; 
• Non-standard dosing (eg, drug holiday, altered dose level, altered dose frequency) 
used prior to PK visit. 
Data excluded based on this review will be included in listing outputs but will be excluded from 
summary tables. 
11.4. 
Analysis of Drug Concentration Data 
11.4.1. 
Listing of Individual Subject Drug Concentration Data 
Individual subject plasma concentration data for unconjugated OCA, glyco-OCA, tauro-OCA, 
total OCA, and metabolite OCA glucuronide will be listed by baseline CP category, dosing 
regimen, subject, study visit and time point.  The actual and nominal sampling times of PK blood 
sample collection will be listed for each subject and will include the deviation in time from the 
protocol scheduled time (ie, nominal time), if applicable.  Columns in the listing for 
unconjugated OCA, glyco-OCA, tauro-OCA, total OCA, and OCA glucuronide will be displayed 
on the same page for each subject.  Any individual concentrations excluded from summaries or 
analyses will be flagged and footnoted. 
All measured concentrations will be presented in original units as reported by the Bioanalytical 
lab, ie, ng/mL.  
Total OCA will be calculated as the molar sum of unconjugated OCA, glyco-OCA, and tauro-
OCA in the following manner: 
1. Convert units for each component of total OCA from ng/mL to μM using the molecular 
weight and formula: 
a. Unconjugated OCA (μM) = unconjugated OCA (ng/mL) / 420.6 g/mole 
b. Glyco-OCA (μM) = glyco-OCA (ng/mL) / 477.7 g/mole 
c. Tauro-OCA (μM) = tauro-OCA (ng/mL) / 527.8 g/mole 
2. Sum molar-based components of total OCA: 
a. Total OCA (μM) = Unconjugated OCA (μM) + Glyco-OCA (μM) + Tauro-OCA 
(μM) 
3. Convert total OCA from μM to unconjugated OCA ng/mL-equivalents: 
a. Total OCA (ng/mL) = total OCA (μM) * 420.6 g/mole  
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For the purpose of calculating total OCA, BLQ values for unconjugated OCA, glyco-OCA, and 
tauro-OCA will be imputed to zero prior to calculation of total OCA.  If there is not a valid 
numeric value (BLQ imputations to zero are valid) for one or more of the components of total 
OCA (unconjugated OCA, glyco-OCA, or tauro-OCA) then total OCA will not be calculated and 
will be set to missing.  Total OCA will be calculated in units of “unconjugated OCA ng/mL 
equivalents and will be reported in units of “ng/mL” in analysis outputs. 
11.4.2. 
Summary of Drug Concentrations 
Drug concentration data in ng/mL units will be summarized by analyte (OCA, glyco-OCA, 
tauro-OCA, total OCA, and OCA glucuronide), baseline CP category, dosing regimen, study 
visit and time point using the following descriptive statistics: n, number and % BLQ, arithmetic 
mean, SD, coefficient of variation (CV) %, minimum, median, maximum, Q1 and Q3.   
The Week 6 Visit should occur 3, 4, or 5 days after the Week 6 dose.  Therefore, Week 6 fasting 
trough PK concentrations will be summarized by ‘Week 6 + 3 days’, ‘Week 6 + 4 days’, ‘Week 
6 + 5 days’, and ‘Week 6 Combined’. 
Mean concentrations for OCA, glyco-OCA, tauro-OCA, total OCA, and metabolite OCA 
glucuronide will not be calculated if 50% or more of the actual values at any one time point in 
the terminal phase are BLQ or missing. 
11.5. 
PK Parameters Derivation 
The PK parameters for OCA, glyco-OCA, tauro-OCA, total OCA, and metabolite OCA 
glucuronide will be estimated using concentrations in ng/ml units and actual sample collection 
times as follows: 
• The apparent Cmax and the corresponding Tmax will be read directly from the 
concentration-time plot (observed data). 
• AUC0-24h will be calculated in WinNonlin using a partial area with curve stripping 
disabled (ie, lambda z/terminal slope will not be estimated) and the linear/linear 
trapezoidal rule for extravascular model.  The following rules apply: 
− At least 4 quantifiable concentration-time values must be available to compute 
AUC0-24h 
− For last actual sampling times >24 hours, AUC0-24h will be interpolated.  For last 
actual sampling times from 23 to 24 hours, AUClast value will be reported as 
AUC0-24h.  For last actual sampling times <23 hours, AUC0-24h will not be 
reported. 
▪ AUClast will be calculated using the linear/linear trapezoidal rule  
• MRAUC and MRCmax will be calculated (on a molar basis) as the metabolite to parent 
molar ratios of AUC0-24h and Cmax. 
11.5.1. 
Listing of Individual Subject PK Parameters 
Individual subject PK parameters will be listed for the PK population by subject and include 
information for baseline CP category, dosing regimen, study visit, and time point. 
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11.5.2. 
PK Parameters Summarization 
PK parameters will be summarized by analyte (unconjugated OCA, glyco-OCA, tauro-OCA, 
total OCA, and OCA glucuronide), PK parameter, baseline CP category (CP-B, CP-C, and 
Combined), dosing regimen, and study visit (Week 12, Week 18, Week 24, Week 30, Week 48, 
and All Visits).  For the ‘All Visits’ summary, which summarizes across all visits for each dosing 
regimen, if a subject has data from multiple visits on a particular dosing regimen, the mean of the 
values across those visits will be used so that each subject is only represented once.  The 
summary statistics to be used for each PK parameter are described in Table 5 . 
Table 5: 
PK Summary Statistics 
Variable 
Summarized with: 
AUC0-24h, Ctrough, Cmax, MRAUC and MRCmax 
n, arithmetic mean, SD, CV%, minimum, median, Q1, Q3, 
maximum, geometric mean and geometric CV% 
Tmax 
n, minimum, Q1 (25% percentile), median, Q3 (75% percentile) 
and maximum 
 
The conventions in Table 6 will be used for the presentation of the descriptive statistics of PK 
parameters and of plasma concentrations: 
Table 6: 
PK Reporting Precision 
Statistics 
Degree of Precision 
Minimum, Maximum 
3 significant figures or as needed based on actual measured values (for 
example PK concentrations) except for Tmax which will be reported in the 
same precision as nominal 
Mean (arithmetic and geometric), 
Median, Q1, Q3 
3 significant figures 
Standard deviation 
same precision as mean and median 
CV and Geometric CV 
same precision as mean or geometric mean 
12. 
PHARMACODYNAMIC ANALYSES 
The ITT Population will be used for all PD analyses.  Baseline is defined as the mean of all 
available evaluations before treatment. 
12.1. 
PD Sampling Schedule 
PD blood samples will be collected at pre-dose for Days 1, Week 6, 12, 18, 24, 30, 36 and 48 
Visits.  Plasma concentrations of PD biomarkers for FXR activation including C4, FGF-19, and 
bile acids (15 individual bile acids, 5 bile acid totals, total bile acids, and total endogenous bile 
acids).  
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12.2. 
PD Endpoints 
• concentrations for each PD biomarker at baseline and at each study visit 
• change from baseline for each PD biomarker at each study visit 
• percent change from baseline for each PD biomarker at each study visit 
12.3. 
Presentation of PD Results 
12.3.1. 
Handling of Missing Data and BLQ Values 
Missing PD biomarker data for all subjects who are administered scheduled study treatments will 
be considered as non-informative missing and will not be imputed.  No concentration estimates 
will be provided for missing sample values.  Only samples from subjects that were confirmed 
fasting prior to the study visit will be included in the analyses. 
PD values for C4, FGF-19, and bile acids below the assay’s lower limit of quantification 
(LLOQ) at any point will be set to one-half the lower limit of quantification (LLOQ/2).  It should 
be noted that a high proportion of BLQ values may affect the SD; if more than 30% of values are 
missing, then the SD will not be displayed.  Tables of summary statistics for concentration-time 
data will report N (number of subjects in the analysis population), n (number of actual 
observations), as well as number and percentage of BLQ values.  
12.3.2. 
Units Conversion for Bile Acids and their Sub-components 
Bile acid data will be received from the laboratory in units of ng/mL and will be converted to 
units of μM for analysis and presentation.   
Unit conversion is bile acid concentration (μM) = bile acid concentration (ng/mL) / bile acid 
molecular weight.  
Table 7 below provides molecular weights for the 15 bile acid subcomponents.  The bile acid 
totals will be the sum of each of the three subcomponents presented in Table 7.  
For example, total UDCA (μM) = glyco-UDCA (μM) + tauro-UDCA (μM) + unconjugated 
UDCA (μM) 
Total bile acids will be the sum of all 15 bile acids.  
For example, total bile acids (μM) = total UDCA (μM) + total CDCA (μM) + total DCA (μM) + 
total CA (μM) + total LCA (μM). 
Total endogenous bile acids will be the sum of all bile acids minus the UDCA-related bile acids. 
For example, total endogenous bile acids (μM) = total CDCA (μM) + total DCA (μM) + total CA 
(μM) + total LCA (μM). 
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Table 7: 
Bile Acids and Their Sub-Components 
Derived 
Sub-Components (molecular weight) 
 
Total UDCA 
Glyco-UDCA 
(449.6 g/mol) 
 
Tauro-UDCA 
(499.7 g/mol) 
 
Unconjugated UDCA 
(392.6 g/mol) 
 
Total CDCA 
Glyco-CDCA 
(449.6 g/mol) 
 
Tauro-CDCA 
(499.7 g/mol) 
 
Unconjugated CDCA 
(392.6 g/mol) 
 
Total DCA 
Glyco-DCA 
(449.6 g/mol) 
 
Tauro-DCA 
(499.7 g/mol) 
 
Unconjugated DCA 
(392.6 g/mol) 
 
Total CA 
Glyco-CA 
(465.6 g/mol) 
 
Tauro-CA 
(515.7 g/mol) 
 
Unconjugated CA 
(408.6 g/mol) 
 
Total LCA 
Glyco-LCA 
(433.6 g/mol) 
 
Tauro-LCA 
(483.7 g/mol) 
 
Unconjugated LCA 
(376.6 g/mol) 
 
 
12.3.3. 
Listings and Summary Tables for PD Data 
Plasma concentrations for individual bile acid subcomponent and total concentrations 
(unconjugated, glyco-conjugate, tauro-conjugate, and total) for UDCA, CDCA, DCA, CA, and 
LCA will be listed for each subject, and summarized using descriptive statistics at baseline and at 
each study visit stratified by baseline CP category (CP-B, CP-C, and Combined) and treatment 
(Placebo, 5 mg QW, 5 mg BIW, and 10 mg BIW, Combined OCA).  
Total bile acids (sum of all unconjugated and conjugated bile acids for UDCA, CDCA, DCA, 
CA, and LCA),  total endogenous bile acid (sum of all unconjugated and conjugated bile acids 
for CDCA, DCA, CA, and LCA), as well as concentrations of C4 and FGF-19 will also be listed 
for each subject and summarized using descriptive statistics at baseline and at each study visit 
stratified by baseline CP category (CP-B, CP-C, and Combined) and treatment (Placebo, 
5 mg QW, 5 mg BIW, and 10 mg BIW, Combined OCA). 
All listings and summary tables will include change from baseline and percent change from 
baseline data for each study visit.  Additional PD analyses may be performed, if warranted by the 
data. 
13. 
EXPLORATORY CORRELATION ANALYSIS BETWEEN PK 
AND PD 
Due to the limited data available, exploratory correlation analyses between PK and PD (ie, 
exposure-response) will not be performed. 
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14. 
ANALYSES OF PATIENT-REPORTED OUTCOMES AND 
HEALTHCARE RESOURCE USE 
14.1. 
EQ-5D-5L 
The EQ-5D-5L consists of 2 sections: the descriptive system and the VAS.  The descriptive 
system is organized into 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems.  The VAS records the patient’s self-rated 
health on a 20-cm vertical, line with endpoints labelled “the best health you can imagine” and 
“the worst health you can imagine” (Herdman 2011, Oemar 2013).  
Summary statistics of EQ-5D-5L data including baseline values and change from baseline values 
will be presented by treatment group and by each scheduled post-baseline visit.  
14.2. 
PBC-40 
The PBC-40 is a validated disease-specific 40-question quality of life questionnaire, which 
consists of 6 domains: General Symptoms, Itch, Fatigue, Cognitive Function, Social, and 
Emotional (Jacoby 2005). 
Summary statistics of PBC-40 data including baseline values and change from baseline values 
will be presented by treatment group and by each scheduled post-baseline visit.  
14.3. 
Pruritus Visual Analog Scale 
Pruritus Visual Analog Scale (VAS) will be used to assess pruritus in individual patients.  
Summary statistics of Pruritus VAS data including baseline values and change from baseline 
values will be presented by treatment group and by each scheduled post-baseline visit.  
14.4. 
Chronic Liver Disease Questionnaire 
The CLDQ is a disease-specific health related quality of life questionnaire for patients with 
chronic liver disease.  The questionnaire includes 29 items in the following domains: fatigue, 
activity, emotional function, abdominal symptoms, systemic symptoms, and worry).  Each 
question is answered on a scale from 1 (always) to 7 (never) with a higher score corresponding to 
a better quality of life.  The CLDQ produces a summary score and domain scores that correlate 
with the severity of liver disease (Younossi 1999).  
Summary statistics of CLDQ data including baseline values and change from baseline values 
will be presented by treatment group and by each scheduled post-baseline visit.  
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15. 
DEVIATIONS FROM PROTOCOL 
• As a sensitivity analysis, liver biochemistry parameters will be analyzed by using a 
restricted maximum likelihood (REML) based mixed model repeated measures 
(MMRM), time, the treatment group by time interaction, and the randomization 
stratification factor will be included as fixed effects and the baseline value will be 
included as a covariate in the model, where time includes all post baseline visits of 
DB phase. 
• A sensitivity analysis will be analyzed for liver stiffness and liver fibrosis (ELF [HA, 
P3NP, and TIMP-1]) as described for liver biochemistry parameters. 
• Analysis of Total endogenous bile acids is added. 
• Summary of baseline Rotterdam status is added. 
• Summary of subject disposition and protocol deviations for Non-COVID-19 
Impacted Population are added. 
• COVID-19 Diagnosis is added. 
• COVID-19 AEs are flagged. 
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16. 
REFERENCES 
Guidance for Industry E14: The Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-antiarrhythmic Drugs, U.S. Department of Health and Human 
Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 
October 2005. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L).  Qual Life Res.  2011;20(10):1727-36. 
ICH E9 (R1): Addendum on estimands and sensitivity analysis in clinical trials to the guideline 
on statistical principles for clinical trials, EMA/CHMP/ICH/436221/2017 Committee for 
Medicinal Products for Human Use, 17 February 2020. 
ICH E6 (R2): Good Clinical Practice: Integrated Addendum to ICH E6(R1). U.S. Department of 
Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER), Center for Biologics Evaluation and Research (CBER), March 2018. 
Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the PBC-40, a 
disease specific health related quality of life measure for primary biliary cirrhosis.  Gut. 
2005;54(11):1622-9. 
Kamath PS, Kim WR.  The model for end-stage liver disease (MELD).  Hepatology.  2007 
Mar;45(3):797-805. 
Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary 
cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 
2009;136(4):1281-7. 
Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, Kneteman NM, Lake JR, 
Martin P, McDiarmid SV, Rakela J. Minimal criteria for placement of adults on the liver 
transplant waiting list: a report of a national conference organized by the American Society of 
Transplant Physicians and the American Association for the Study of Liver Diseases. Liver 
Transplantation and Surgery. 1997 Nov;3(6):628-37. 
Oemar M, Janssen B. EQ-5D-5L User Guide: Basic Information on how to use the EQ-5D-5L 
instrument. 2013 October;Version 2.0:1-28. 
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Journal of British Surgery. 1973 Aug;60(8):646-9. 
Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, Weissenborn K, Wong P. 
Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American 
Association for the Study of Liver Diseases and the European Association for the Study of the 
Liver. Hepatology. 2014 Aug;60(2):715-35. 
Younossi ZM, Guyatt G, Kiwi M, et al. Development of a disease specific questionnaire to 
measure health related quality of life in patients with chronic disease.  Gut. 1999;45(2):295-300. 
 
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APPENDIX A. DATA PRESENTATION CONVENTIONS: 
Unless otherwise specified, the baseline value for analyses of all parameters is defined as the last 
non-missing value prior to the first administration of investigational product. 
For categorical variables, the number and percentage of subjects within each category of the 
parameter, including a category for missing data, will be presented.  Percentage calculations will 
be based on the analysis population, unless otherwise specified.   
For continuous variables, summary statistics will include the number of subjects and the mean, 
standard deviation (SD), standard error of the mean (SE), median, 25th and 75th quartiles, 
minimum, and maximum values.   
All statistical analyses will be performed using SAS statistical software Version 9.4 or higher 
unless otherwise noted. 
General Methods 
• Summaries will be presented for each treatment and overall for subjects disposition, 
demographics and baseline characteristics, medical history, disease history, prior 
medications, and historical procedures summary tables.  Summaries will be presented 
for each treatment for other tables. 
• All subjects and relevant data entered into the database will be included in subject 
data listings, including screen failures, where applicable. 
• All data listings that contain an evaluation date will contain a relative study day as 
defined in below.   
• For categorical variables, summary tabulations of the number and percentage of 
patients within each category of the parameter will be presented.  Percentage 
calculations will be based on non-missing data, unless otherwise specified.  
Percentages are rounded to 1 decimal place, unless otherwise specified.  The category 
for missing data will not have percentage. 
• For continuous variables, the number of patients, mean, standard deviation (SD), 
standard error of the mean (SE), median, Q1, Q3, minimum, and maximum values 
will be presented.  The precision of summary statistics, unless otherwise, specified 
will be as follows:  
− minimum, maximum: same decimal place as the raw data, 
− mean, median, Q1, and Q3: 1 more decimal place than the raw data,  
− SD and SE: 2 decimal places more than the raw data.  
• In general, the decimal places should not exceed 3 decimal places unless appropriate.  
95% confidence intervals (CIs) will be provided and will be rounded to 1 decimal 
place. 
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• For results from an analysis of covariance (ANCOVA) model or a mixed model 
repeated measures (MMRM), least square (LS) mean and LS mean difference will be 
presented with one decimal place, and standard error (SE) of LS means and SE of LS 
mean difference will be presented with two decimal places.   
• p-value will be presented with 3 decimal places. 
• Time-to-event data will be summarized using Kaplan-Meier (KM) methodology 
using 25th, 50th (median), and 75th percentiles with associated 2-sided 95% CIs. 
Key Definitions 
First Dose Date 
First dose date is defined as the day of first dose of IP received after randomization. 
Last Dose Date 
Last dose date is defined as day of the last dose of IP.  For subjects ongoing at time of analysis, 
last dose date will be considered the date of the most recent study visit in the database for that 
subject. 
Study Day 
The study day is determined relative to the date of first dose of IP.  The day of the first dose of IP 
will be defined as study day 1.  The day prior to the first dose of IP is study day -1.  There is no 
study day 0. 
For events that occur before the first dose of IP, study day = date of the event – first dose date; 
for events that occur on or after the first dose of IP, study day = date of the event – first dose date 
+ 1. 
Time to Event 
The time to an event will be calculated in days as the date of the first occurrence of the event - 
the date of first IP administration + 1.   
The time to a pre-treatment adverse event will be calculated as the date of first IP administration 
- the date of the first occurrence of the adverse event. 
Baseline and Change from Baseline 
The baseline value for statistical analyses of quantitative parameters is defined as the mean of all 
available evaluations prior to the first administration of IP, unless otherwise specified.  Values 
collected at unscheduled visits prior to the start of the IP administration will be included in the 
calculation of baseline values.  If there is only one evaluation prior to the first administration of 
IP then the available data from this evaluation will be used as the baseline value.  
The baseline value for analyses of lipid parameters is defined as the last fasted evaluation prior to 
the first administration of IP. 
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The baseline value for analyses of qualitative parameters (eg, normal/abnormal) is defined as the 
last evaluation prior to the first administration of IP. 
Baseline values defined above will not change regardless if a subject stops taking IP and begins 
taking commercially marketed OCA.  
Change from baseline = (post-baseline value – baseline value).  
Percent change from baseline = 100*(post-baseline value – baseline value)/ baseline value 
For the purpose of tabulations, the unscheduled post-baseline values generally will be excluded 
from summary tables, but will be included in data listings.  Unscheduled visits will be considered 
for analyses of shift from baseline to worst value (low-normal-high). 
Dose Regimen 
Following the discussion in Section 3, dose regimen for each clinical visit after first dose up to 
Week 12 Visit is OCA 5 mg once weekly; dose regimen after Week 12 Visit could be OCA 5 mg 
once weekly for patient not up-titrated or OCA 5 mg twice weekly for patient up-titrated; and 
dose regimen after Week 18 Visit could be OCA 5 mg once weekly, 5 mg twice weekly, or 
10 mg twice weekly based on patient titration (up-titrated or down-titrated) history prior to the 
visit.  For example, if an up-titration to 5 mg twice weekly is given to a patient at Week 12 Visit, 
this regimen should be the one for this patient at Week 18 visit. 
Missing Data 
All available data of the subjects who withdraw from the study for any reasons will be analyzed.  
Missing data will be assumed to be missing at random.  There will be no imputation of missing 
data for the analysis purpose.  Change from baseline of an endpoint will be missing when either 
baseline value of the endpoint is missing or post-baseline value of the endpoint is missing.   
Incomplete start and end dates for adverse events and concomitant medications are imputed as 
follows: 
Incomplete Start Date: 
Missing day and month 
• If the year is the same as the year of the first dosing date, then the day and month of 
the first dosing date will be assigned to the missing fields. 
• If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields. 
• If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields. 
Missing day only  
• If the month and year are the same as the year and month of first dosing date, then the 
first dosing date will be assigned to the missing day. 
• If the year of the partial date is before the year of the first dosing date or the year of 
the partial date and the first dosing date are the same but the month of partial date is 
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before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day. 
• If either the year of the partial date is after the year of the first dosing date or the year 
of the partial date and the first dose date are the same but the month of partial date is 
after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day. 
• If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date.  
Missing day, month, and year 
• No imputation is needed. 
Incomplete End Date:  
If the imputed stop date is before the start date, then the imputed stop date will be equal to the 
start date. 
Missing day and month 
• If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields.  
• If the year of the incomplete stop date is prior to the year of the last dosing date or 
prior to the year of the first dosing date, then December 31 will be assigned to the 
missing fields.  
• If the year of the incomplete stop date is prior to the year of the last dosing date but is 
the same as the year of the first dosing date, then the first dosing date will be assigned 
to the missing date.  
• If the year of the incomplete stop date is after the year of the last dosing date, then 
January 1 will be assigned to the missing fields. 
Missing day only  
• If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day.  
• If either the year of the partial date is not equal to the year of the last dosing date or 
the year of the partial date and the last dosing date are the same but the month of 
partial date is not equal to the month of the last dosing date, then the last day of the 
month will be assigned to the missing day.  
Missing day, month, and year 
• No imputation is needed. 
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Visit Windows 
Visit windows are specified in the Table 1 of the protocol - Schedule of Study Procedures for the 
2 phases of the study: DB phase and DBext phase.  All data will be tabulated per the evaluation 
visits as recorded on the electronic case report form (eCRF) even if the assessment is outside of 
the visit window.  In data listings, the study day of all dates will be presented.  Data collected at 
unscheduled visits that occurred outside the time windows specified will be included in the data 
listings but will not be included in the analyses unless otherwise stated. 
Pooling of Centers 
Data from all study centers will be combined for analysis. 
 
 
 
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