Conditions: Liver Cirrhosis, Biliary
Keywords: Primary Biliary Cirrhosis PBC Cirrhosis Liver
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 334
Healthy volunteers: no

Brief summary:
Primary Biliary Cholangitis (PBC) is a serious, life-threatening, bile acid related liver disease of unknown cause. Without treatment, it frequently progresses to liver fibrosis and eventual cirrhosis requiring liver transplantation or resulting in death. The investigational drug, Obeticholic Acid (OCA) is a modified bile acid and FXR agonist that is derived from the primary human bile acid chenodeoxycholic acid. The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. The study will assess the effect of OCA compared to placebo, combined with stable standard care, on clinical outcomes in PBC participants.

Detailed description:
This Phase 4, double-blind, randomized, placebo-controlled, multicenter study is being undertaken at up to 170 sites internationally to evaluate the effect of OCA on clinical outcomes in 428 participants with PBC. The study will include a screening period of up to 8 weeks, requiring two clinic visits. Eligible participants will be randomly allocated (1:1) to treatment with either OCA 5 mg or matching placebo tablets, taken orally once daily for the majority of participants; dose and frequency will be modified for participants with cirrhosis and classified as Child-Pugh (CP) B or C. Randomization will be stratified by standard treatment with UDCA (yes/no) and baseline liver function. The treatment period involves clinic visits approximately every 3 months. At the 3 month visit or any study visit thereafter, if study treatment is tolerated, participants' dose should be titrated per protocol in a blinded manner eg for participants who are non-cirrhotic or classified as CP A and randomized to OCA, they should receive the maximum daily dose of 10 mg OCA, those on placebo continue to receive placebo. Subsequently, daily dosage may return to 5 mg if necessary for these participants who are non-cirrhotic or classified as CP A, but should be increased to 10 mg if possible, based on tolerability and clinical judgment. Safety and tolerability will be assessed by monitoring adverse events and vital signs, and blood and urine testing. The study is event driven and total duration will be determined by the time required to accrue approximately 127 primary endpoint events, estimated to be approximately 10 years. Participants are expected to have a minimum follow-up time of approximately 6 years.

Arms:
arm 1: Obeticholic Acid (OCA) 5 mg for a minimum 3 months and then titrating up to a maximum 10 mg for the remainder of the trial (based on tolerability and CP Score). arm 2: None

Interventions: intervention 1: Obeticholic Acid (OCA) intervention 2: Placebo
Intervention descriptions: intervention 1: Non-cirrhotic and classified as CP Class A: 5 mg tablet of OCA once daily titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of participants).

Cirrhotic and classified as CP Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, subsequently titrating up to a maximum dose and frequency of 10 mg OCA twice weekly based on tolerability and biochemical response for the duration of the study. intervention 2: One tablet daily (or a lower frequency depending on CP score) for the remainder of the study

Protocol document:
Prot_000.pdf: 
 
TITLE PAGE 
 
Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cholangitis 
 
THE COBALT STUDY 
Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) 
 
 
EudraCT Number:  2014-005012-42 
ClinicalTrials.gov Identifier: NCT02308111 
 
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 747-302 
16.1.1 Protocol and Protocol Amendments 
Page 1 
Confidential and Proprietary 
16.1.1 
PROTOCOL AND AMENDMENTS 
Protocol 747-302, Version 1, dated 03 Oct 2014 
Protocol 747-302, Amendment 1, dated 29 Apr 2015 
Protocol 747-302, Amendment 1.1, dated 12 Nov 2015 
Protocol 747-302, Version 3, dated 07 Sept 2016 
Protocol 747-302, Version 3.1 (FDA Review Only), dated 21 Dec 2016 
Protocol 747- 302, Version 4, dated 10 May 2017 
Protocol 747- 302, Version 5, dated 04 Jan 2018 
Protocol 747- 302, Version 6, dated 05 Nov 2019 
Protocol Addendums 
Addendum 1 Netherlands to Protocol 747- 302, dated 18 Jan 2017 
Addendum 2 to Protocol 747- 302, dated 27 Apr 2017 
Addendum 1, Country Specific (Turkey) to Protocol 747- 302, dated 02 Jan 2018 
Page 1 of 1682


1. 
TITLE PAGE 
 
 
Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 3b, Double-Blind, Randomized, Placebo-Controlled, Multicenter 
Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in 
Subjects with Primary Biliary Cirrhosis  
 
 
Original:  03 October 2014 
 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA  92121 
USA 
 
TEL: +1 858 652 6800 
FAX: +1 858 558 5961 
 
 
 
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 747-302 
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Page 3
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the current version of the Investigational Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-302.  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 (CRFs) 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 747-302 and in accordance 
with Good Clinical Practice (CPMP/ICH/135/95), 21CFR Part 312 and all applicable regulatory 
requirements. 
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 
Confidential and Proprietary 
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Protocol 747-302 
Original: 03 Oct 2014
Page 4
 
PROCEDURES IN CASE OF EMERGENCY 
 
Emergency Contact Information 
Medical Monitor - 24 hour Emergency Reporting 
Contact: 
 MD, PhD, Executive Director, Clinical Research, 
Intercept Pharmaceuticals, Inc. 
Mobile: 
 (Pacific time zone) 
Telephone: 
  
Email: 
 
SAE Fax: 
+1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
 
Or if Not Available: 
Contact: 
 MD, 
 Development, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Email: 
 (Pacific time zone) 
 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 (Pacific time zone) 
 
 
 
 
 
Confidential and Proprietary 
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Protocol 747-302 
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Page 5
 
2. 
SYNOPSIS 
Name of Sponsor/Company:  Intercept Pharmaceuticals, Inc. 
Name of Investigational Product:  Obeticholic Acid (OCA) 
Name of Active Ingredient:  OCA; 6α-ethyl chenodeoxycholic acid (6-ECDCA); INT-747 
Title of Study:  A Phase 3b, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary 
Cirrhosis 
Study Number:  747-302 
Study Center(s):  Approximately 170 investigational study sites, globally 
Study Period (Years):  The study is event driven and total duration will be determined by the 
time required to accrue approximately 121 primary endpoint events, estimated to be 
approximately 8 years.  Subjects are expected to have a minimum follow-up time of 
approximately 6 years. 
Number of Subjects (planned):  Approximately 350 subjects 
Phase of Study:  Phase 3b 
Objectives:  
Primary 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care, on clinical outcomes in subjects with primary biliary cirrhosis (PBC) as measured by 
time to first occurrence of any of the following adjudicated events, derived as a composite event 
endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
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Protocol 747-302 
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Page 6
 
Secondary 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above and also to include liver-related death. 
To assess the effect of OCA compared to placebo on disease progression via the following: 
• Liver biochemistry  
• Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To assess the pharmacokinetics of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
Methodology: 
This Phase 3b, double-blind, randomized, placebo-controlled, multicenter study will evaluate the 
effect of OCA on clinical outcomes in subjects with PBC.  Subjects will be screened during a ≤1 
to 8 week Screening period prior to entering the study to allow for the collection of repeat serum 
chemistry samples (at least 2 weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
and total bilirubin values (refer to Section 9.7.3).  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be randomized (1:1) to OCA or placebo treatment groups.  The 
randomization will be stratified by ursodeoxycholic acid (UDCA) treatment (yes/no) and 
baseline bilirubin categories (>upper limit of normal [ULN]/ ≤ ULN). 
Investigational product (OCA or matched placebo) will be taken orally, once daily.  
Investigational product will be initiated at 5 mg OCA or matched placebo.  After 6 months of 
treatment with investigational product, the dose may be increased (to the maximum dose of 
10 mg OCA or matched placebo, in a blinded manner) at the 6-month visit or any subsequent 
study visit based on tolerability.  Subjects will be seen at quarterly visits for the duration of the 
study. 
 
 
 
Confidential and Proprietary 
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Protocol 747-302
Original: 03 Oct 2014
Page 7
Schematic Diagram: 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic acid; ULN = upper limit of normal 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with American Association for the 
Study of Liver Diseases [AASLD] and the European Association for the Study of the 
Liver [EASL] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the 
presence of ≥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 in 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 
2. A mean total bilirubin >ULN and ≤3x ULN or an ALP >5x ULN 
3. Age ≥18 years 
4. Either is not taking UDCA (UDCA naïve or no UDCA dose in the past 3 months) or 
has been taking UDCA for at least 12 months with an approved, stable dose for 
≥3 months prior to Day 0 
5. Contraception:  Female subjects must be postmenopausal, surgically sterile, or if 
premenopausal (and not surgically sterile), be prepared to use ≥1 effective (≤1% failure 
rate) method of contraception during the study and for 30 days after the end of treatment 
visit   
6. Must provide written informed consent and agree to comply with the study protocol 
Confidential and Proprietary 
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Protocol 747-302 
Original: 03 Oct 2014
Page 8
 
Exclusion Criteria 
1.  History or presence of other concomitant liver diseases including:  
• Hepatitis C virus infection 
• Active hepatitis B infection; however, subjects 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 
• Nonalcoholic steatohepatitis 
• Gilbert’s Syndrome 
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including: 
• History of liver transplant, current placement on a liver transplant list, or current 
MELD score >12 
• Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
− Variceal bleed 
− Uncontrolled ascites  
− Encephalopathy  
− Spontaneous bacterial peritonitis  
• Known or suspected hepatocellular carcinoma 
• Prior transjugular intrahepatic portosystemic shunt procedure 
• Hepatorenal syndrome (type I or II) or screening serum creatinine >2 mg/dL 
(178 μmol/L) 
3. Subjects who have undergone gastric bypass procedures (gastric lap band is 
acceptable) or ileal resection or plan to undergo either of these procedures 
4. Other medical conditions that may diminish life expectancy to <2 years, including 
known cancers (except carcinomas in situ or other stable, relatively benign conditions 
such as chronic lymphatic leukemia) 
5. History or presence of clinically concerning cardiac arrhythmias likely to affect survival 
during the study, or prolongation of screening (pretreatment) QT 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test), or lactating 
7. Known history of human immunodeficiency virus infection 
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Protocol 747-302 
Original: 03 Oct 2014
Page 9
 
8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months) 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
Investigational Product, Dosage and Mode of Administration:  
OCA (5 mg or 10 mg tablets) 
Placebo (matching tablets) 
Duration of Treatment: 
It is estimated that subjects will be followed up for a minimum of 6 years.  The study is event 
driven and total duration of treatment will be determined by the time to accrue 121 total primary 
endpoint events. 
Duration of Subject Participation: 
It is estimated that subject participation will be a minimum of approximately 6 years. 
Confidential and Proprietary 
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Protocol 747-302 
Original: 03 Oct 2014
Page 10
 
Criteria for Evaluation: 
Primary Objectives 
Assessments 
Clinical outcomes 
• 
Death (all-cause) 
• 
Liver transplant 
• 
MELD score ≥15 
• 
Hospitalization (as defined by a stay of 24 hours or greater) for new 
onset or recurrence of: 
− 
Variceal bleed 
− 
Encephalopathy (as defined by a West Haven score of  ≥2) 
− 
Spontaneous bacterial peritonitis (confirmed by diagnostic 
paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic 
paracentesis at a frequency of at least twice in a month) 
• 
Hepatocellular carcinoma confirmed by 2 complimentary imaging 
modalities 
Secondary Objectives 
 
Individual components of the 
primary endpoint 
As listed above and including liver-related death 
Change in baseline liver 
biochemistry 
Liver biochemistry (see Table 4 for list of analytes to be tested)   
Inflammation and fibrosis 
IgM, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), 
fibroblast growth factor-19 (FGF-19), cytokeratin-18 (CK-18), enhance liver 
fibrosis (ELF), and Fibroscan® 
Clinical outcomes compared to 
historical controls 
Similar endpoints as used for the primary objective where available including 
liver transplant and death 
Pharmacokinetics 
OCA and its conjugates 
Health outcomes and economics 
research 
Including the following: 
Cost-effectiveness and resource utilization 
Quality of life 
Safety and tolerability 
Including the following: 
Treatment-emergent adverse events 
Clinical laboratory values 
 
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Protocol 747-302 
Original: 03 Oct 2014
Page 11
 
Statistical Methods:  
Sample Size Justification 
The following assumptions were used in sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.5 at 8 years with a hazard 
ratio of 0.60, and total study duration of 8 years, allowing for 2 years accrual and 
6 years of follow up 
• 5% of the subjects will have never been treated with UDCA; 95% of the subjects will 
have been on UDCA for at least 1 year 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to clinical outcomes. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: Randomized, Intent-to-Treat (ITT), Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical Control.  Descriptions of subject populations 
are provided in Section 13.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
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Protocol 747-302 
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Page 12
 
Every event for enrolled subjects will be adjudicated by an independent committee. 
Primary Efficacy Analysis 
The primary efficacy analysis will compare randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the ITT population.  The 2 treatment groups will 
be compared 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 determined based on a Cox regression model stratified by randomization strata to 
estimate the magnitude of the effect. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints are as follows: 
• Time to first occurrence of MELD score ≥15 
• Time to liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare randomized OCA to randomized placebo in 
ITT population with respect to the key secondary efficacy endpoints.  Only adjudicated events 
will be included in time-to-event analyses.  The comparison (hypothesis testing) will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of the OCA treatment group.  If the primary comparison is not 
statistically significant then comparison of the secondary endpoints will be considered as 
descriptive and exploratory. 
Other Efficacy Analyses 
The following secondary efficacy analyses will compare OCA to placebo on time to the 
following events: 
• Each component of the primary efficacy endpoint (except MELD score ≥15 which is 
listed above) 
• Liver-related death 
• Liver-related death or liver transplant 
• Liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls. 
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Protocol 747-302 
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Page 13
 
Further details on efficacy, health outcomes, and pharmacokinetic analyses are specified in 
Section 13. 
Safety Analysis 
Safety data, including AEs, vitals, electrocardiogram, and clinical laboratory results will 
compare OCA and placebo using the Safety Population. 
Confidential and Proprietary 
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Protocol 747-302 
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Page 14
 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Overview of Primary Biliary Cirrhosis and Obeticholic Acid ...................................22 
5.2. 
Mechanism of Action of Obeticholic Acid .................................................................22 
5.3. 
Nonclinical Experience with Obeticholic Acid ..........................................................23 
5.4. 
Clinical Experience with Obeticholic Acid ................................................................23 
5.5. 
Rationale for Study Design and Dose for Investigational Product .............................24 
5.5.1. 
Rational for Study Design ..........................................................................................24 
5.5.2. 
Rationale for Dose ......................................................................................................25 
5.5.2.1. 
Rationale for OCA Doses ...........................................................................................25 
5.5.2.2. 
Rationale for Control Groups .....................................................................................25 
5.6. 
Summary of Known Potential Risks with OCA .........................................................25 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................26 
6.1. 
Primary Objective .......................................................................................................26 
6.2. 
Secondary 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 ............................................................................................................31 
7.2. 
Number of Subjects ....................................................................................................31 
7.3. 
Treatment Assignment ................................................................................................31 
7.4. 
Dose Titration Criteria ................................................................................................31 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................31 
7.5. 
Criteria for Study Termination ...................................................................................31 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................32 
8.1. 
Subject Population ......................................................................................................32 
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8.2. 
Subject Inclusion Criteria ...........................................................................................32 
8.3. 
Subject Exclusion Criteria ..........................................................................................33 
8.4. 
Subject Withdrawal from Investigational Product or Study Criteria ..........................34 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product ..........................34 
8.4.2. 
Other Reasons for Discontinuation of Investigational Product ..................................34 
8.4.2.1. 
Withdrawal of Consent ...............................................................................................35 
8.4.2.2. 
Lost to Follow-up .......................................................................................................35 
8.4.3. 
Subject Discontinuation Notification .........................................................................35 
9. 
TREATMENT OF SUBJECTS ..................................................................................35 
9.1. 
Investigational Product Treatment Regimen ..............................................................35 
9.1.1. 
Dose Adjustment Beginning at Month 6 ....................................................................36 
9.2. 
Concomitant Medications ...........................................................................................36 
9.2.1. 
Prohibited Medications ...............................................................................................36 
9.3. 
Treatment Compliance ................................................................................................36 
9.4. 
Randomization and Blinding ......................................................................................37 
9.5. 
Assignment of Site and Subject Numbers ..................................................................37 
9.5.1. 
Site Numbers ..............................................................................................................37 
9.5.2. 
Subject Numbers .........................................................................................................37 
9.6. 
Restrictions .................................................................................................................37 
9.7. 
Visit Procedures ..........................................................................................................37 
9.7.1. 
Visit Windows ............................................................................................................37 
9.7.2. 
Informed Consent Procedures.....................................................................................38 
9.7.3. 
Screening Procedures (≤1 to 8 Weeks prior to Day 0) ...............................................38 
9.7.4. 
Day 0 Procedures (Randomization) ............................................................................39 
9.7.5. 
Safety Contact (Month 1, Month 2, and 2 Weeks Post-Titration [by 
telephone]): .................................................................................................................40 
9.7.6. 
Month 3 Procedures ....................................................................................................41 
9.7.7. 
Month 6 Procedures ....................................................................................................41 
9.7.8. 
Month 9 Procedures ....................................................................................................42 
9.7.9. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment .................................................................................................................43 
9.7.10. 
Month 12 Procedures ..................................................................................................43 
9.7.11. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 weeks]) ......................44 
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9.7.12. 
Month 6 Continued Follow-up Procedures (Semi-annually [±2 weeks]) ...................45 
9.7.13. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) .........................46 
9.7.14. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw Consent ......................................................................................................47 
9.7.15. 
Unscheduled Safety Visit ...........................................................................................48 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............48 
10.1. 
Investigational Product ...............................................................................................48 
10.2. 
Investigational Product Packaging and Labeling .......................................................49 
10.3. 
Investigational Product Storage ..................................................................................49 
10.4. 
Investigational Product Preparation ............................................................................49 
10.5. 
Investigational Product Administration ......................................................................49 
10.6. 
Investigational Product Accountability and Disposal .................................................49 
11. 
ASSESSMENT OF EFFICACY ................................................................................50 
11.1. 
Assessment of Efficacy ...............................................................................................50 
11.1.1. 
Primary Assessments ..................................................................................................50 
11.1.2. 
Secondary Assessments ..............................................................................................50 
11.1.2.1. 
Non-Invasive Assessments of Liver Fibrosis .............................................................50 
11.1.2.2. 
Other ...........................................................................................................................51 
11.1.2.3. 
Other Exploratory Evaluations ...................................................................................51 
11.1.2.4. 
Potential Clinical Outcome Events .............................................................................51 
12. 
ASSESSMENT OF SAFETY .....................................................................................51 
12.1. 
Adverse Events and Serious Adverse Events .............................................................51 
12.1.1. 
Definition of Adverse Events .....................................................................................51 
12.1.1.1. 
Adverse Event .............................................................................................................51 
12.1.1.2. 
Serious Adverse Event ................................................................................................52 
12.1.1.3. 
Treatment-Emergent Adverse Event ..........................................................................52 
12.1.2. 
Relationship to Investigational Product ......................................................................52 
12.1.3. 
Recording Adverse Event Severity .............................................................................53 
12.1.4. 
Reporting of Adverse Events and Serious Adverse Events ........................................53 
12.1.4.1. 
Reporting of Adverse Events ......................................................................................53 
12.1.4.2. 
Reporting of Serious Adverse Events .........................................................................54 
12.1.5. 
Additional Investigator Responsibilities for SAEs .....................................................55 
12.1.6. 
Notification of Post-Study SAEs ................................................................................55 
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12.1.7. 
Follow up of AEs and SAEs .......................................................................................55 
12.1.8. 
Pregnancy and Follow up ...........................................................................................55 
12.2. 
Other Safety Parameters .............................................................................................56 
12.2.1. 
Medical History/Demographics ..................................................................................56 
12.2.2. 
Physical Examination .................................................................................................56 
12.2.3. 
Vital Signs ..................................................................................................................56 
12.2.4. 
Electrocardiogram .......................................................................................................56 
12.2.5. 
Dual Emission X-Ray Absorptiometry .......................................................................56 
12.2.5.1. 
Subject Questionnaires ...............................................................................................56 
12.2.6. 
Laboratory Assessments .............................................................................................57 
13. 
STATISTICAL METHODS .......................................................................................58 
13.1. 
Efficacy Analysis ........................................................................................................58 
13.1.1. 
Analysis Populations ..................................................................................................58 
13.1.1.1. 
Comparability of Historical Controls .........................................................................59 
13.1.2. 
Determination of Sample Size ....................................................................................59 
13.1.2.1. 
Sample Size Re-Estimation Plan ................................................................................60 
13.1.3. 
Primary Efficacy Analysis ..........................................................................................60 
13.1.4. 
Key Secondary Efficacy Analyses ..............................................................................61 
13.1.5. 
Additional Secondary Efficacy Analyses ...................................................................62 
13.1.6. 
Exploratory Efficacy Analyses ...................................................................................62 
13.1.6.1. 
Responder Analyses ....................................................................................................62 
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints ................................................63 
13.1.8. 
Supportive Analysis ....................................................................................................63 
13.1.9. 
Alternative Primary Analysis .....................................................................................65 
13.1.10. 
Handling of Dropouts or Missing Data ......................................................................65 
13.1.10.1. Time to Event Endpoints ............................................................................................65 
13.1.10.2. Quantitative Endpoints ...............................................................................................65 
13.1.10.3. Responder Endpoints ..................................................................................................66 
13.1.11. 
Multiple Comparisons/Multiplicity ............................................................................66 
13.1.12. 
Examination of Subgroups .........................................................................................67 
13.2. 
Safety Analysis ...........................................................................................................67 
13.2.1. 
Adverse Events ...........................................................................................................67 
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13.2.2. 
Clinical Laboratory Evaluations .................................................................................67 
13.2.3. 
Additional Safety Analysis .........................................................................................67 
13.3. 
Data and Safety Monitoring Committee .....................................................................67 
13.4. 
Adjudication Committee .............................................................................................68 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................69 
14.1. 
Study Monitoring ........................................................................................................69 
14.2. 
Audits and Inspections ................................................................................................69 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................69 
16. 
ETHICS ......................................................................................................................70 
16.1. 
Ethics Review .............................................................................................................70 
16.2. 
Ethical Conduct of the Study ......................................................................................70 
16.3. 
Written Informed Consent ..........................................................................................70 
16.4. 
Subject Confidentiality and Data Protection ..............................................................71 
17. 
INVESTIGATOR OBLIGATIONS ...........................................................................71 
17.1. 
AE Reporting ..............................................................................................................71 
17.2. 
Protocol Deviations ....................................................................................................71 
17.3. 
Regulatory Documentation .........................................................................................72 
17.4. 
Ethics Review .............................................................................................................72 
17.5. 
Archiving and Record Retention ................................................................................72 
18. 
PUBLICATION POLICY ..........................................................................................73 
19. 
LIST OF REFERENCES ............................................................................................75 
APPENDIX A. LIST OF STUDY 747-302 OUTCOME EVENTS ...........................................76 
APPENDIX B. LIST OF STUDY 747-302 ANTICIPATED EVENTS ....................................77 
 
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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................29 
Table 2: 
Relationship of Adverse Events to Investigational Product .......................................53 
Table 3: 
Severity of Adverse Events ........................................................................................53 
Table 4: 
List of Laboratory Analytes to be Tested ...................................................................57 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram Study 747-302 ............................................................................28 
  
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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 gonadotrophin 
BAS 
bile acid sequestrants 
CDCA 
chenodeoxycholic acid 
CI 
confidence interval 
CK-18 
cytokeratin-18 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
C-reactive protein 
DEXA 
dual-emission X-ray absorptiometry 
DSMC 
Data Safety Monitoring Committee 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
enhance liver fibrosis 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
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 
HDL 
high density lipoprotein 
IB 
Investigational Brochure 
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Abbreviation or Specialist Term 
Explanation 
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 
LDL 
low density lipoprotein 
LTSE 
Long-term safety extension 
MELD 
model of end stage liver disease  
MRS 
Mayo Risk Score 
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cirrhosis 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
the Sponsor 
Intercept Pharmaceuticals, Inc. 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
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 Primary Biliary Cirrhosis and Obeticholic Acid 
Primary Biliary Cirrhosis (PBC) 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, is currently the only 
treatment approved for PBC (Lindor 2009).  While UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of a poor clinical outcome due to PBC disease 
progression.  There is a clear unmet medical need for better therapies for patients with PBC that 
have an inadequate response to UDCA, or those who cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and effective. 
OCA is a modified bile acid and farnesoid X receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid (CDCA).  OCA is currently being developed in 
the United States (US) and Europe for the treatment of PBC and other chronic liver diseases.  
OCA has been granted Orphan Drug Designation in the US (09 Apr 2008) and Orphan Medicinal 
Product Designation in the European Union (27 Jul 2010) for the treatment of PBC. 
5.2. 
Mechanism of Action of Obeticholic Acid 
OCA is a 6α-ethyl derivative of the naturally occurring primary human bile acid CDCA, which is 
the endogenous ligand for FXR.  FXR is a ligand-dependent transcription factor that is part of 
the nuclear receptor superfamily.  FXR regulates a wide variety of target genes involved in the 
control of bile acid, lipid, and glucose homeostasis and in the regulation of immune responses. 
OCA’s potent FXR agonist effects are believed to account for the predominant efficacy of the 
investigational product.  Some of the pharmacological properties of OCA and other FXR 
agonists that have been elucidated in animal models of chronic liver disease relevant to the 
treatment of PBC include the following: 
• Improvement in hepatic choleresis with reduced inflammation and necrosis  
• Prevention and reversal of hepatic fibrosis 
The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and 
anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury 
and improved liver function in a cholestatic liver disease such as PBC. 
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5.3. 
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. 
5.4. 
Clinical Experience with Obeticholic Acid 
As of 31 March 2014, OCA has been evaluated in the clinic in 18 completed and ongoing 
studies, including subjects with other chronic liver diseases (eg, nonalcoholic steatohepatitis) and 
healthy subjects.  As of 31 March 2014, a total of 1023 subjects have received at least one dose 
of OCA and of these, 414 (40%) were subjects with PBC.  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. 
To date, the efficacy and safety of OCA in PBC has been evaluated in 2 placebo-controlled, 
double-blind, Phase 2 studies (747-201 and 747-202), and 1 placebo-controlled, double-blind 
Phase 3 study (747-301).  Following the double-blind phase, subjects in all 3 studies were 
eligible to continue with treatment in a long-term safety extension (LTSE) phase for up to 
5 years in Study 747-201, up to 1 year in Study 747-202, and up to 5 years in Study 747-301. 
Study 747-201 (59 subjects) 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 subjects) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in subjects 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 subjects) was a Phase 3, double-blind, placebo-controlled, parallel group 
study followed by an LTSE using OCA in subjects with PBC.  The primary endpoint for 
Study 747-301 was a composite endpoint based on the proportion of subjects reaching specific 
criteria for ALP and bilirubin (ALP <1.67x upper limit of normal [ULN] with a ≥15% reduction 
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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 10 mg OCA 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 up to 4 years.  The LSTE phase of studies 
747-201 and 747-301 are ongoing; the LTSE phase of Study 747-202 is complete. 
5.5. 
Rationale for Study Design and Dose for Investigational Product 
5.5.1. 
Rational for Study Design 
OCA is a modified bile acid and FXR agonist that is derived from the primary human bile acid 
chenodeoxycholic acid.  The key mechanisms of action of OCA, including its choleretic, anti-
inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in 
attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. 
PBC is characterized by biochemical increases in ALP and GGT enzymes with or without 
elevations of hepatocellular transaminases and bilirubin (Lindor 2009).  Both the American 
Association for the Study of Liver Diseases (AASLD) (Lindor 2009) and the European 
Association for the Study of the Liver (EASL) (EASL 2009) guidelines base the biochemical 
component of PBC diagnosis on elevations of ALP.  In addition, a growing literature supports 
the use of biochemical endpoints, specifically serum ALP alone or with other parameters such as 
bilirubin, to manage subjects, test the efficacy of novel therapies in clinical studies, and gauge 
the risk of long-term adverse clinical outcomes in subjects with PBC (Beuers 2011, 
Momah 2012).  Data from the Global PBC Study Group (Lammers 2013), which has built a 
database tracking biochemical status and clinical outcomes in several thousand PBC subjects, 
provides evidence for the use of the composite biochemical endpoint of ALP and bilirubin as an 
acceptable surrogate endpoint. 
Study 747-301, a Phase 3 double-blind study, evaluated the safety and efficacy of OCA at doses 
of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability) and 10 mg and used 
a composite biochemical endpoint of ALP and bilirubin as a surrogate endpoint.  In this study, 
both treatment groups exhibited clinically meaningful improvements in liver biochemistry and 
were safe and generally well-tolerated.  Starting subjects on 5 mg OCA and titrating to 10 mg 
based on the clinical response appears to be an appropriate dosing strategy in subjects with PBC. 
Study 747-302 is a clinical outcomes study, supportive of Phase 3 Study 747-301 which was 
based on a surrogate biochemical endpoint, designed to confirm the clinical benefit of OCA 
treatment in patients with PBC.  A retrospective observational database (Global PBC Study 
Group [Lammers 2013]) of patients with PBC allowed for a rigorous patient-level meta-analysis 
and provided an opportunity for a robust assessment of ALP and bilirubin as viable surrogate 
biochemical parameters and a comprehensive understanding of the natural history of the PBC 
disease process.  Data from the Global PBC Study Group was also utilized to inform the design 
of the confirmatory outcomes study. 
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5.5.2. 
Rationale for Dose 
5.5.2.1. 
Rationale for OCA Doses 
The safety and tolerability of multiple doses of OCA have been established in subjects with PBC 
at doses up to 50 mg.  As demonstrated in the Phase 2 PBC studies (Studies 747-201 and 
747-202), OCA significantly reduced serum ALP levels at doses of 10 mg, 25 mg, and 50 mg, 
but with an increase in the incidence and severity of pruritus at higher dose levels.  The Phase 3 
PBC study subsequently evaluated the safety and efficacy of OCA at lower doses of 5 mg 
(titrated to 10 mg after 6 months based on efficacy and tolerability) and 10 mg; both treatment 
groups exhibited clinically meaningful improvements in liver biochemistry and were safe and 
generally well tolerated. 
Based on these data, the intended commercial doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
Study 747-302 will evaluate the effect of OCA on clinical outcomes using the 5 mg OCA dose 
increasing to 10 mg OCA if tolerated. 
5.5.2.2. 
Rationale for Control Groups 
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 a standard of care 
effect.  Notably, accounting for the standard of care effect is critical when designing an 
outcome-based study conducted globally when there are regional differences in the treatment of 
subjects with PBC. 
Historical Control Group 
The available robust historical PBC observational datasets (UK-PBC and Global PBC Study 
Group) will also be leveraged to provide further comparative evaluation of the clinical benefit of 
OCA.  Each database includes >6000 patients with long-term follow-up. 
Comparison of OCA treatment to the historical controls may provide utility in addressing 
potential bias or confounds associated with the placebo arm.  For example, bias associated with 
the potential addition of commercial OCA and/or differences in long-term standard of care 
between the treatment arms including ancillary treatments and diagnostics. 
Therefore, further evaluation of the effect of OCA will compare OCA treatment versus historical 
controls, and will be supportive to placebo comparisons. 
5.6. 
Summary of Known Potential Risks with OCA 
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, but with a much 
lower frequency than that observed in subjects with PBC. 
Additionally, consistent with nonclinical findings and the chemical characteristics of OCA (bile 
acid and detergent), an increase in liver function tests and hepatic AEs, including jaundice, were 
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observed in subjects with liver disease at doses between 10 mg and 50 mg and in healthy 
volunteers who were treated at doses greater than 100 mg in Phase 1 multiple dose studies. 
Lipoprotein changes have also been observed with OCA dosing, including a decrease in high 
density lipoprotein (HDL) and an increase in low density lipoprotein (LDL).  The clinical 
significance of these lipid findings remains unclear and is being studied further.  Notably, despite 
the observed decrease, HDL levels have generally remained within normal limits in subjects 
treated with OCA. 
6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care on clinical outcomes in subjects with PBC as measured by time to first occurrence of any 
of the following adjudicated events, derived as a composite event endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
6.2. 
Secondary Objectives 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above and also to include liver-related death. 
To assess the effect of OCA compared to placebo on disease progression via the following: 
• Liver biochemistry 
• Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To assess the PK of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
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To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3b, double-blind, randomized, placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with bilirubin levels of >ULN and ≤3x ULN or ALP >5x.  
Subjects enrolled will be at higher risk of liver-related clinical complications. 
Approximately 350 subjects meeting all enrollment criteria will be recruited into the study over 
an approximate 2-year period, randomly allocated to treatment with either OCA or matching 
placebo once daily in a 1:1 ratio.  Subjects will be screened during a ≤1 to 8 week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples 
(at least 2 weeks apart) to confirm pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3).  Investigational product will be taken orally, once daily.  The randomization will 
be stratified by UDCA treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN).  In 
addition to the placebo control arm, multiple historical control groups (concurrent and 
retrospective) will be used.  Following 6 months of treatment with investigational product, 
subjects should be titrated in a blinded manner (ie, subjects randomized to OCA will increase 
their dose to 10 mg OCA) based on tolerability.  It is anticipated that subjects will be followed 
for a minimum of approximately 6 years.  The study will continue until approximately 121 
adjudicated primary endpoint events have been accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Safety Monitoring Committee; DSMC) terminates the 
study. 
This study will be conducted at up to approximately 170 international study sites with experience 
in treating subjects with PBC.  Prospective subjects will be identified primarily from the hospital 
and/or physician’s database of subjects with PBC, or may be referred from other physicians.  
Subjects may self-refer to an Investigator if they become aware of the study through local, 
national, or international PBC subject societies, forums, and networks. 
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7.1.1.
Study Design Diagram 
Figure 1: 
Schematic Diagram Study 747-302 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic acid; ULN = upper limit of normal 
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures  
 
Year 1 
Years 2-End of Study 
 
 
Screening 
Visit x 2a 
Day 0 
Safety 
Contactb 
M 3 
M 6 
M 9 
M 12 
M 3 
continued 
follow-up 
M 6 
continued 
follow-up 
M 9 
continued 
follow-up 
M 12 
continued 
follow-up 
EOT/
ETc 
Visit Windows (+/-)d 
≤1 to 8 wks 
prior to 
Day 0 
 
±1 wk 
±2 
wks 
±2 
wks 
±2 
wks 
±2 
wks 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
±2 
wks 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical/PBC Historye  
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Vital Signs (including weight) 
Xf 
X 
 
X 
X 
X 
Xf 
 
X 
 
Xf 
Xf 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
Subject Questionnairesg 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
TE Fibroscan®/DEXAh 
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 
Randomization/Treatment Assigned 
X 
 
 
 
 
 
 
 
 
Dose Titration (if applicable)i 
 
X 
  
 
 
 
 
 
Dispense Investigational Product j 
X 
 
X 
X 
X 
X 
X  
X 
X  
X 
 
IP Accountability/Compliance 
X 
X 
X 
X 
X 
X  
X 
X  
X 
X 
LABORATORY EVALUATIONSk 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
Urine-based β-hCG Pregnancy Testl 
X 
X 
 
 
 
 
 
 
 
 
 
 
Chemistry/Hematology/Coagulation 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Year 1 
Years 2-End of Study 
 
 
Screening 
Visit x 2a 
Day 0 
Safety 
Contactb 
M 3 
M 6 
M 9 
M 12 
M 3 
continued 
follow-up 
M 6 
continued 
follow-up 
M 9 
continued 
follow-up 
M 12 
continued 
follow-up 
EOT/
ETc 
OCA, C4, and FGF-19 (plasma) 
 
X 
 
 
X 
Xm 
X 
 
 
 
X 
X 
Markers of Hepatic Fibrosis and/or 
Inflammationn 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Geneticso 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Blood Sample for Future Analysisp 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
β-hCG = beta human chorionic gonadotrophin; DEXA = dual-emission X-ray absorptiometry; EOT = End of Treatment; ET = Early Termination; 
FGF = fibroblast growth factor-19; IP = Investigational Product; M = month, wk = week 
a All subjects will have two 2 bilirubin assessments at least 2 weeks apart including those subjects who qualify based on ALP criteria.   For subjects that do not 
qualify based on ALP (ALP >5x ULN), the mean of the two 2 bilirubin assessments will be used to determine eligibility (total bilirubin >ULN and ≤3x ULN). 
b The subject should be contacted by telephone on a monthly basis (±1 week) between at-clinic study visits, at Month 1 and Month 2, and also 2 weeks postdose 
titration, to assess for AEs and concomitant medications and to verify that s/he is dosing as directed.   
c As soon as possible upon study discontinuation and as near as possible to last dose taken. 
d Visits should be based on Day 0 (not on the prior visit). 
e Medical history at Screening will include smoking and alcohol consumption history and current habits for both.   
f Height will be collected at this visit. 
g Subject Questionnaires include:  Pruritus VAS, 5-D Pruritus Scale, and Quality of Life questionnaires.  (See Section 11.1.2.2 and Section 12.2.5.1) 
h Transient elastography (TE) will be conducted at selected study sites where the Fibroscan® TE device is available.  If a TE was performed within 3 months of 
Day 0 and a report/adequate data are available, a pretreatment TE at Day 0 is not required.  Similarly, DEXA will be conducted at selected study sites where the 
DEXA device is available.   
i After 6 months of treatment with investigational product, the dose should be increased (in a blinded manner) based on tolerability; this may occur at the Month 
6 visit, or at any study visit thereafter.  Titration above 10 mg OCA is not allowed.   
j Subject to begin dosing on Day 1 
k The subject should be instructed to fast overnight (at least 8 hours) prior to each visit.  Fasting is required prior to all study visits, but water is permitted. 
l Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry.  If positive, a confirmatory blood test must be performed at 
the site.  If the blood test is also positive, the subject may not be enrolled in the study.  (Additional testing may be conducted where required, regionally). 
m Only OCA PK samples will be collected at Month 9 at select study sites in a subset of subjects.  Please refer to Section 9.7.9 for the PK sampling schedule. 
n Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
o A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and 
every other year beginning at Month 12. 
p Please refer to Section 11.1.2.3 for description of the blood sample to be collected for future analysis. 
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7.1.3. 
Study Duration 
The study is event driven and total duration will be determined by the time required to accrue 
approximately 121 primary endpoint events, estimated to be approximately 8 years.  Subjects are 
expected to have a minimum follow-up time of approximately 6 years. 
7.2. 
Number of Subjects 
It is expected that approximately 350 subjects will be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
7.3. 
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate to 10 mg OCA (in a blinded 
manner) at the 6 month study visit or at any study visit thereafter depending on tolerability.   
7.4. 
Dose Titration Criteria 
After 6 months of treatment at the 5 mg dose, the dose of OCA will be increased to the 
maximum dose of 10 mg OCA or matched placebo (in a blinded manner) at the 6-month visit or 
any study visit following the 6-month visit based on tolerability of investigational product.  For 
those subjects that increased their dose to 10 mg, they may decrease his or her dose to 5 mg at 
any time during the study as considered appropriate (eg, tolerability), but should be titrated back 
to 10 mg based on tolerability and clinical judgment by the Investigator as soon as possible with 
the goal that all subjects remain on the 10-mg dose if tolerated. 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
Investigational product may be temporarily decreased (ie, from 10 mg to 5 mg daily, or by 
alternate day dosing) 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 
(5 mg or 10 mg) once the issues relating to the lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated events has accrued.  If a subject reaches an 
event, her or she should continue the regular visit schedule and continue taking investigational 
product as long as the Investigator assesses it as safe.  In general, subjects should be strongly 
encouraged to both stay on investigational product and remain in the study until study 
termination.  Early termination procedures should only be conducted if the subject withdraws 
consent. 
7.5. 
Criteria for Study Termination 
The Sponsor 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 DSMC, it may be necessary to stop the study before all subjects have completed the study.  
In addition, the Sponsor may terminate the study at an investigational site at any time 
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(eg, poorly performing sites, as determined by the number of subjects 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 subjects for the Study/Early Termination Visit.  The window of time 
for scheduling the visit will be based on a final projection of when the requisite 121 adjudicated 
events will have been accrued. 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Population 
This study will be conducted at approximately 170 international study sites with experience in 
treating patients with PBC.  Prospective subjects 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. 
Subject Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with AASLD and EASL practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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 
2. A mean total bilirubin >ULN and ≤3x ULN or an ALP >5x ULN 
3. Age ≥18 years 
4. Either is not taking UDCA (UDCA naïve or no UDCA dose in the past 3 months) or 
has been taking UDCA for at least 12 months with an approved, stable dose for 
≥3 months prior to Day 0 
5. Contraception:  Female subjects must be postmenopausal, surgically sterile, or if 
premenopausal (and not surgically sterile), be prepared to use ≥1 effective (≤1% failure 
rate) method of contraception during the study and for 30 days after the end of treatment 
visit   
6. Must provide written informed consent and agree to comply with the study protocol 
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8.3. 
Subject Exclusion Criteria 
1. History or presence of other concomitant liver diseases including:  
• Hepatitis C virus infection 
• Active hepatitis B infection; however, subjects 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 
• Nonalcoholic steatohepatitis 
• Gilbert’s Syndrome  
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including:  
• History of liver transplant, current placement on a liver transplant list, or current 
MELD score >12 
• Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
− Variceal bleed 
− Uncontrolled ascites 
− Encephalopathy  
− Spontaneous bacterial peritonitis  
• Known or suspected hepatocellular carcinoma 
• Prior transjugular intrahepatic portosystemic shunt procedure 
• Hepatorenal syndrome (type I or II) or Screening serum creatinine >2 mg/dL 
(178 μmol/L) 
3. Subjects who have undergone gastric bypass procedures (gastric lap band is 
acceptable) or ileal resection or plan to undergo either of these procedures 
4. Other medical conditions that may diminish life expectancy to <2 years, including 
known cancers (except carcinomas in situ or other stable, relatively benign conditions 
such as chronic lymphatic leukemia) 
5. History or presence of clinically concerning cardiac arrhythmias likely to affect survival 
during the study, or prolongation of Screening (pretreatment) QT 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test), or lactating 
7. Known history of human immunodeficiency virus infection 
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8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months) 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study   
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
8.4. 
Subject Withdrawal from Investigational Product or Study Criteria 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product 
If a female subject becomes pregnant, she must discontinue taking investigational product, but 
should continue with the study visit schedule.  The subject must be followed as considered 
appropriate by the Investigator and the medical monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an AE.  The subject may reinstate investigational 
product after delivery and cessation of breastfeeding (if applicable) at the discretion of the 
Investigator.  Subjects whose pregnancy is terminated early (planned or unplanned) may be 
permitted to resume participation in the study if termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotrophin (β-hCG) test. 
8.4.2. 
Other Reasons for Discontinuation of Investigational Product  
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.  If a subject reaches an event, 
he or she should continue the regular visit schedule and continue taking investigational product 
as long as the Investigator assesses it as safe.  Subjects who choose to discontinue investigational 
product prior to termination of the study need to also continue to follow the regular visit schedule 
through to study closure.  In general, subjects should be strongly encouraged to both stay on 
investigational product and remain in the study until study termination.  Early termination 
procedures should only be conducted if the subject withdraws consent. 
The following events are considered potential appropriate reasons for a subject to discontinue 
investigational product; however, these subjects are expected to continue in the study until study 
termination and the study will only terminate at the time when the needed number of adjudicated 
events has accrued (or at the discretion of the Sponsor): 
• The Investigator or Sponsor considers that it is advisable or in the best interest of the 
subject 
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• The occurrence of clinical or laboratory AEs considered by the Investigator to be 
clinically important 
• Withdrawal of consent 
The Investigator must notify the Sponsor study monitor by telephone as soon as possible if any 
subject prematurely withdraws from the study.   
8.4.2.1. 
Withdrawal of Consent 
If the subject 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 subjects 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 subject discontinuation.  This 
information and date must be recorded in the appropriate case report form (CRF).   
8.4.2.2. 
Lost to Follow-up 
If a subject fails to return to the clinic for a study visit, and the Investigator ceases to have 
contact with the subject, he or she will be withdrawn from the study. 
A reasonable effort must be made to contact the subject and determine the reason(s) why a 
subject 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 CRF.   
8.4.3. 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by telephone as soon as possible if any 
subject prematurely withdraws from the study.  The date when the subject is withdrawn and the 
reason for discontinuation must be recorded in the CRF.  If a subject is “lost to follow up” (fails 
to return for a visit), a reasonable effort should be made to contact the subject in order to 
determine why the subject failed to return.  This information must be documented in the CRF.  If 
a subject is withdrawn from the study early (regardless of the cause), all of the end of treatment 
(EOT) evaluations should be performed at the time of withdrawal. 
9. 
TREATMENT OF SUBJECTS 
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:  placebo and OCA.  Investigational product will be 
administered orally, once daily for the duration of the study.  Each dose will be made up of 
1 tablet (ie, one 5 mg OCA tablet or one 10 mg OCA tablet, or matching placebo).   
Investigational product will be taken orally, once daily.  Subjects will be instructed to begin 
dosing on the day after the Day 0 visit (ie, on Day 1) and to take investigational product at 
approximately the same time each day.  Subjects must be instructed to swallow the tablet whole; 
they must not chew, divide, or crush the tablet. 
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9.1.1. 
Dose Adjustment Beginning at Month 6 
After 6 months of treatment with investigational product, the dose of investigational product 
should be increased in a blinded manner and based on tolerability; this may occur at the Month 6 
visit, or at any study visit thereafter.  Titration above 10 mg OCA is not permitted.   
9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.1) 
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 Day 0) and during 
the study must be recorded in the source documents and CRF, as well as any dose or dose 
regimen changes that occur during the study.  Concomitant medications should be stable prior to 
Day 0.   
Subjects taking bile acid sequestrants (BAS) 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). 
PBC Specific Therapy 
In general, 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 subjects’ 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, subjects 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, subjects should be reminded to keep taking their blinded 
investigational product. 
9.2.1. 
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 and encourage the discontinuation of open-label OCA therapy.  However, if 
commercial OCA therapy remains, then investigational product should be discontinued to avoid 
potential double dosing.   
9.3. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Subjects should be instructed to retain all bottles of investigational product, even if empty, and to 
return them to the Investigator at the subsequent visit.  The Investigator or designee should 
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perform investigational product accountability and, if applicable, follow up with the subject to 
retrieve any investigational product bottles that have not been returned.  
If the Investigator has concerns about a subject’s dosing compliance s/he should discuss this with 
the subject, assess the reasons for noncompliance and the likelihood that the subject will remain 
noncompliant, and notify the Sponsor accordingly. 
9.4. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Allocation to 1 of 
2 treatment groups (OCA or placebo) will occur on a 1:1 ratio across sites and will be stratified 
by UDCA treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN), as specified by 
the central laboratory.  The randomization will be based on a predefined randomization code 
(generated by the Sponsor or designee) using an interactive web response system (IWRS), which 
the Sponsor intends will serve as a computer-based subject registration system at Screening and 
Day 0.  The IWRS will serve as an investigational product inventory and management system 
and may be integrated with the study database.  
The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide subject data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned (refer to Section 9.5.2, below) and 
investigational product dispensing information (ie, bottle number[s]) will be provided. 
9.5. 
Assignment of Site and Subject 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 subject data and to identify the site and or Investigator 
within study documents.  This number will be recorded in the CRF. 
9.5.2. 
Subject Numbers 
Subjects 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 3 digits will represent the 
Screening number. 
9.6. 
Restrictions 
No additional restrictions. 
9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visits should be based on Day 0 (not on the prior visit), eg, Month 3 should ideally occur 
3 calendar months (± 2 weeks) following Day 0.  The visit windows are as follows: 
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Visit or Procedure 
Visit Window and/or Interval 
Screening 
Interval is ≤1 to 8 weeks prior to Day 0, allowing for 2 Screening 2 
visits to repeat biochemistry tests, and ensuring ample time to receive 
lab results.  The overall Screening interval is up to 56 days.  
Day 0 
This is the day of randomization.  On-treatment visit scheduling 
should be calculated from this point going forward. (The first dose of 
investigational product should be taken the next day, on Day 1.) 
Months 3-12 
±2  week (7 days)  
Quarterly visits (Months 15 – EOT) 
±2 weeks (14 days) 
EOT 
As soon as possible upon study discontinuation and as near as 
possible to last dose taken 
EOT = end of treatment 
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk and benefit of the 
study to the subject and will provide him/her with a copy of the written information and 
informed consent form (ICF).  The subject will be given sufficient time to consider the study 
before deciding whether or not to participate.  The subject 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 s/he can withdraw from the study at any time.  The subject must be willing and 
able to provide written informed consent before entering the study.  The Investigator or a 
medically qualified designee is responsible for administering and documenting the written 
informed consent of the subject.  The subject will be given a copy of the written information and 
his/her signed and dated consent form. 
9.7.3. 
Screening Procedures (≤1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed ≤1 to 8 weeks prior to Day 0 to determine 
whether the subject meets all the inclusion criteria and none of the exclusion criteria.  Subjects 
who do not fulfill all eligibility criteria will not be enrolled in the study.  Subjects may be 
rescreened after 2 months; however, all Screening procedures should be repeated and a new 
3-digit Screening number assigned.  Subjects should be reconsented, as appropriate, at this time. 
Two Screening visits will occur from ≤1 to 8 weeks prior to Day 0 (as outlined below) allowing 
for the collection of repeated serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values): 
• All subjects will have 2 bilirubin assessments at least 2 weeks apart including those 
subjects who qualify based on ALP criteria.  
• For subjects that do not qualify based on ALP alone (ALP >5x ULN), the mean of the 
2 bilirubin assessments will be used to determine eligibility (total bilirubin >ULN and 
≤3x ULN). 
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Screening Visit procedures are as follows: 
• The subject is to review and sign the ICF.  Informed consent must be obtained from 
the subject 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, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure) 
• Perform a standard 12-lead electrocardiogram (ECG) 
• Assess and record any pretreatment-emergent AEs 
• Record prior (if within 30 days of Day 0) and current concomitant medications 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests 
• Obtain urine sample for urinalysis 
• Perform a urine-based β-hCG pregnancy test in females of childbearing potential 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
• In preparation for the dual-emission X-ray absorptiometry (DEXA) bone density scan 
to be done at Day 0 (selected study sites only), subjects who are taking calcium 
supplements should stop taking them for 48 hours before the scan.  If the subject is 
taking any medications for osteoporosis or osteopenia, s/he should not take them on 
the day of the scan. 
It is acceptable to repeat laboratory evaluations or other assessments or procedures within the 
Screening period (Weeks -8 to -1), as appropriate. 
9.7.4. 
Day 0 Procedures (Randomization) 
• Review inclusion and exclusion criteria for eligibility 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure) 
• Subject questionnaires (see Section 12.2.5.1) 
• Perform transient elastography (TE; at selected study sites, where available) using the 
Fibroscan® TE device.  If TE has been done within 3 months of Day 0 and a 
report/adequate data are available, a pretreatment TE at Day 0 is not required   
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• Conduct a DEXA bone density scan (at selected study sites, where available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• Assess and record any pretreatment-emergent AEs 
• Record prior (within 30 days of Day 0) and current concomitant medications 
• Randomize the subject only if s/he meets all inclusion criteria and no exclusion 
criteria 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits 
• 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 tests 
• Obtain blood samples for:  
− OCA, C4, and fibroblast growth factor-19 (FGF-19) 
− Markers of hepatic fibrosis and/or inflammation (including enhance liver fibrosis 
[ELF]) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Access the IWRS and dispense investigational product   
• Instruct the subject to begin dosing on the day after the Day 0 visit (ie, on Day 1).  
Instruct the subject to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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 
9.7.5. 
Safety Contact (Month 1, Month 2, and 2 Weeks Post-Titration [by telephone]): 
• Assess and record AEs 
• Review and record concomitant medications 
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• Assess investigational product compliance  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 3 Procedures 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure) 
• Assess and record AEs 
• Review and record concomitant medications 
• Assess investigational product compliance and perform investigational product 
accountability  
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests 
• Schedule the next visit and assess the subject’s supply of investigational product to 
ensure an adequate amount.  Access the IWRS and dispense investigational product if 
necessary 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 6 Procedures 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure) 
• Subject questionnaires (see Section 12.2.5.1) 
• Assess and record AEs 
• Review and record concomitant medications 
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• Assess investigational product compliance and perform investigational product 
accountability 
• Assess for dose titration, if eligible (refer to Section 7.4) 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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 
• For subjects who will participate in the PK assessment and are taking BAS or 
aluminum hydroxide- or smectite-containing antacids, they should be instructed to 
not take their regular dose on the morning of the study visit.   
9.7.8. 
Month 9 Procedures 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure) 
• Assess and record AEs 
• Review and record concomitant medications 
• Assess investigational product compliance and perform investigational product 
accountability  
• Assess for dose titration, if eligible (refer to Section 7.4) 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary 
• Verify that the subject has fasted for at least 8 hours 
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− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests 
• PK assessment in participating subjects at select study sites (see Section 9.7.9) 
• In preparation for the DEXA bone density scan to be done at the Month 12 visit 
(selected study sites only), subjects who are taking calcium supplements should stop 
taking them for 48 hours before the scan.  If the subject is taking any medications for 
osteoporosis or osteopenia, s/he should not take them on the day of the scan 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic Assessment 
At selected investigational sites, subjects will have the option to consent to participate in an 
additional OCA PK assessment.  PK samples will be used to support further analysis of OCA 
exposure-response in subjects with PBC.  This is optional and subjects may decline to participate 
without affecting their involvement in the rest of the study.  Consent to participate in the 
assessment can be given at any point during study participation prior to the Month 9 visit. 
Following collection of the Month 9 fasted samples (refer to Section 9.7.9), subjects who are 
participating in the PK assessment will each receive a single dose of investigational product 
(10 mg OCA tablet) with approximately 240 mL of water.  Subjects taking BAS or aluminum 
hydroxide- or smectite-containing antacids should be instructed to stagger their dosing of study 
medication and UDCA, ensuring at least 4 hours between doses of the BAS and/or these antacids 
and the study medication (and UDCA).   
Serial blood samples will be obtained for measurement of OCA and its conjugates prior to 
dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose.  Subjects should not drink 
additional water for 1 hour after taking the dose of investigational product and will remain fasted 
until the 4 hour sample is collected.  Lunch will be provided following collection of the 4 hour 
PK sample; the lunch will be a meal replacement drink. 
9.7.10. 
Month 12 Procedures 
• Perform a physical examination (including smoking and alcohol consumption habits) 
• Assess and record vital signs (height ,weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure) 
• Subject questionnaires (see Section 12.2.5.1 ) 
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• Perform TE (at selected study sites, where available) using the Fibroscan® TE device 
• Conduct a DEXA bone density scan (at selected study sites, where available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• Assess and record AEs 
• Review and record concomitant medications 
• Assess investigational product compliance and perform investigational product 
accountability 
• Assess for dose titration, if eligible (refer to Section 7.4) 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits 
• Obtain urine sample for urinalysis 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests 
• Obtain blood samples for: 
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 weeks]) 
Subjects should come to the study center for a quarterly study visit for a clinical laboratory 
evaluation to collect blood samples for calculation of MELD score.  If the subject is not able to 
come to the study center for a visit, home visits may be arranged on a per subject basis.   
• Assess and record AEs 
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• Review and record concomitant medications 
• Assess investigational product compliance and perform investigational product 
accountability  
• Assess for dose titration, if eligible (refer to Section 7.4) 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 6 Continued Follow-up Procedures (Semi-annually [±2 weeks]) 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate and sitting blood pressure) 
• Subject questionnaires (see Section 12.2.5.1) 
• Assess and record AEs 
• Review and record concomitant medications 
• Assess for dose titration, if eligible (refer to Section 7.4) 
• Assess investigational product compliance and perform accountability 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests 
• Obtain blood samples for:  
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− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• At the semi-annual visit, in preparation for the DEXA bone density scan to be done at 
the annual visit (selected study sites only), subjects who are taking calcium 
supplements should stop taking them for 48 hours before the scan.  If the subject is 
taking any medications for osteoporosis or osteopenia, s/he should not take them on 
the day of the scan  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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 
9.7.13. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• Perform a physical examination (including smoking and alcohol consumption habits) 
• Assess and record vital signs (height, weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure) 
• Subject questionnaires (see Section 12.2.5.1) 
• Perform TE (at selected study sites, where available) using the Fibroscan® TE device 
• Conduct a DEXA bone density scan (selected study sites); document whether the 
subject stopped taking her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the scan, if applicable 
• Assess and record AEs 
• Review and record concomitant medications 
• Assess for dose titration, if eligible (refer to Section 7.4) 
• Assess investigational product compliance and perform accountability 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests 
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• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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 
9.7.14. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw Consent 
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.  When a subject ends her/his 
participation in the study (eg, at a point between standard study visits) either due to early 
termination or discontinuation (withdrawal of consent), an EOT 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 final assessments on or as near as possible to 
the final day of dosing.  In some cases, the subject may discontinue on the day of a scheduled 
study visit.  In these cases, the data will be recorded as EOT procedures in the CRF.  
Some assessments noted below may be omitted if they have been completed within the 3 months 
(or the timeframe otherwise specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT Visit: 
If possible to do before the visit, when scheduling the EOT visit, reiterate dosing instructions and 
advise the subject: 
• If applicable, NOT to take investigational product on the morning of the next visit, 
and  
• To bring the investigational product bottle(s); if applicable, s/he will dose at the 
clinic, 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. 
During the EOT Visit: 
• Perform a physical examination (including smoking and alcohol consumption habits) 
• Assess and record vital signs (height, weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure) 
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• Perform a standard 12-lead ECG 
• Subject questionnaires (see Section 12.2.5.1) 
• Perform TE (where available) using the Fibroscan® TE device (not required at EOT if 
done within 6 months) 
• Conduct a DEXA bone density scan (selected study sites); document whether the 
subject stopped taking her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the scan, if applicable 
• Assess and record AEs; all ongoing “related” AEs must be followed until stable or 
resolved 
• Review and record concomitant medications 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles, accordingly, and document returns 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits 
• Obtain urine sample for urinalysis   
• Obtain blood samples for serum chemistry, hematology, and coagulation tests 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
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 5 mg or 10 mg OCA 
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 subject at each visit to provide enough tablets for daily 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 
The investigational product should be stored in the containers in which they are received from 
the Sponsor’s supplier, at controlled room temperature, and protected from excess humidity. 
10.4. 
Investigational Product Preparation 
The investigational product will be provided in bulk bottles and therefore may be repackaged in 
unit dose form for administration to subjects. 
10.5. 
Investigational Product Administration 
Refer to Section 9.1. 
10.6. 
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 subject 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. 
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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Assessment of Efficacy  
11.1.1. 
Primary Assessments 
The following primary efficacy assessments will be measured: 
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of 2 or greater) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
11.1.2. 
Secondary Assessments 
The following secondary efficacy assessments will be measured: 
• Liver-related death 
• Liver biochemistry (see Table 4 for list of analytes to be tested) 
• Biomarkers, including markers of hepatic fibrosis and/or inflammation, to be tested 
will include:  IgM, c-reactive protein (CRP), tumor necrosis factor-α (TNF-α), 
FGF-19, cytokeratin-18 (CK-18) and ELF, Fibroscan (and others as determined 
during the course of the study) 
• Data will be collected to inform quality of life and cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Resource utilization 
information will be collected from CRFs such as number, type and duration of 
hospitalizations, number of outpatient physician visits (subject reported), and use of 
concomitant medications.  
11.1.2.1. Non-Invasive Assessments of Liver Fibrosis 
• Blood samples for measurement of ELF™ test and other analytes will be collected.  
The ELF test assesses: hyaluronic acid (HA), procollagen-3 N-terminal peptide 
(P3NP), and a tissue inhibitor of metalloproteinase 1 (TIMP-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 
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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.   
11.1.2.2. Other 
• OCA (and its conjugates) and C4 will be assayed. 
• Quality of Life questionnaires.  
11.1.2.3. Other Exploratory Evaluations 
• A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved 
in PBC will be conducted for subjects and at study sites willing to provide samples at 
Day 0, Month 12, and every other year at the yearly visits thereafter.  RNA 
expression resulting from treatment with OCA will be assessed at indicated 
timepoints during the study.   Subjects will be permitted to decline to provide a blood 
sample for the genetics study, without affecting their involvement in the study.  
IRB/IEC review and approval will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will be stored for up to 1 year 
after the end of the study and destroyed after 1 year if not analyzed. 
• Blood samples for future analysis of additional analytes, such as PBC autoantibodies 
and other cytokines and interleukins, may be assayed on an exploratory research 
basis.  Blood samples may also be used to assess other disease or investigational 
product characteristics.  Appropriate serum and plasma samples will be collected at 
selected time points during the study.  The samples will be stored for up to 1 year 
after the end of the study and destroyed after 1 year if not analyzed. 
11.1.2.4. Potential Clinical Outcome Events 
The events listed in Appendix A 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 13.4) to confirm if they meet the criteria to be considered 
Clinical Outcome Events.  
12. 
ASSESSMENT OF SAFETY 
12.1. 
Adverse Events and Serious Adverse Events 
12.1.1. 
Definition of Adverse Events  
12.1.1.1. Adverse Event  
An AE is 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. 
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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) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction. 
Subjects should be questioned in a general way, without leading the subject 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. 
12.1.1.2. 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-subject 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 subject or may require medical 
intervention to prevent one of the outcomes listed above 
12.1.1.3. Treatment-Emergent Adverse Event  
A treatment-emergent AE (TEAE) is any event not present prior to the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
12.1.2. 
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 2.  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/serious adverse event (SAE) and the investigational product is 
determined to be “possible” or “probable” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 
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Table 2: 
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 subject’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 
A reaction 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 subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
12.1.3. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 3, must be entered on the AE CRF.  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 3: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Causing no limitation of usual activities; the subject may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the subject may experience annoying discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the subject may experience intolerable 
discomfort or pain. 
12.1.4. 
Reporting of Adverse Events and Serious Adverse Events 
12.1.4.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
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 subject’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE CRF.  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. 
12.1.4.2. 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 medical monitor.  
 MD, PhD 
Telephone:  
 (Pacific time zone) 
Mobile:  
 (Pacific time zone) 
Email: 
 
SAE Fax:  +1 800 497 8521  
SAE Email:  sae@interceptpharma.com 
Alternate Contact: 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
  
All SAEs (including Potential Clinical Outcome Events that qualify as serious) must be reported 
to the medical monitor immediately (ie, within 24 hours) after the Investigator identifies the 
SAE.  SAEs are reported by entering the SAE data into the electronic data capture (EDC) 
system.  Entering the SAE data into the EDC system will automatically notify the medical 
monitor of the event.  In the event that the EDC system is inaccessible, an SAE may be reported 
by telephone or fax using a paper SAE Report form.  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:  subject number and initials, a description of the event, at least one criterion classifying 
the event as serious and the name and title of the reporting individual.  Additionally, judgment of 
causality by the Investigator must be provided as soon as possible to ensure timely reporting to 
regulatory authorities by the Sponsor or designee(s).  Following the initial report, any additional 
information obtained by the Investigator about the SAE must be reported promptly to the 
medical monitor.  Any supporting source documentation should be faxed to +1 800 497 8521 or 
emailed to sae@interceptpharma.com as soon as possible. 
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 
investigational new drug (IND) safety reports that occur during the study within the time frames 
required by each regulatory agency. 
The Investigator is responsible for submitting information on IND safety reports received from 
the Sponsor to her/his local IRB.  Documentation of the submissions to IRBs and health 
authorities must be retained in the appropriate study file(s). 
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Potential Clinical Outcome Events (Appendix A) as well as Anticipated Events (Appendix B) 
will not undergo expeditious reporting to regulatory authorities. 
12.1.5. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the CRF 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 subject’s AE CRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the medical monitor, 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 subject 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. 
12.1.6. 
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 medical monitor should be notified 
immediately (ie, within 24 hours). 
All SAEs that occur within 30 days following the cessation of investigational product, whether 
or not they are related to the study, must be reported to the Sponsor within 24 hours by following 
the instructions provided in Section 12.1.4.2. 
12.1.7. 
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 subject 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 subject 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 CRF.  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. 
12.1.8. 
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 and the Sponsor must be notified within 24 hours of the Investigator’s learning of the 
pregnancy by completing the Pregnancy Notification Form and faxing or emailing to the Sponsor 
at +1 800 497 8521 or sae@interceptpharma.com.  
Safety will be monitored and assessed by AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and clinical laboratory assessments. 
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The subject may reinstate investigational product after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  Subjects whose pregnancy is terminated early 
(planned or unplanned) may be permitted to resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test (see Section 8.4.1). 
12.2. 
Other Safety Parameters 
12.2.1. 
Medical History/Demographics 
A complete medical history and PBC disease-specific history will be obtained from the subject at 
Screening.  Smoking and alcohol consumption history and current habits will be recorded.  
Demographic characteristics (age, gender, race, and ethnicity) will be recorded. 
12.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the timepoints specified in the Schedule of Study Procedures (Section 7.1.2).  A basic physical 
examination should be performed, including all body systems pertinent to the subject.  Any 
clinically significant abnormality should be reported on the AE CRF page.  Information about 
smoking and alcohol consumption habits will be collected at the same (follow-up) timepoints as 
the physical exam. 
12.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits: height, weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure.  When taking heart rate, respiratory rate, and blood 
pressure readings, subjects should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
12.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected at the Screening visit and at EOT.  The Investigator or 
designee will review the 12-lead ECG and findings will be recorded in the CRF as normal, 
abnormal but not clinically significant, or abnormal and clinically significant.  Any clinically 
significant abnormality on ECGs should be reported on the AE CRF page.  
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 subject’s initials, Subject ID number, 
date, and time. 
12.2.5. 
Dual Emission X-Ray Absorptiometry 
A bone density assessment will be done using the DEXA scan. 
12.2.5.1. Subject Questionnaires 
Information about the subject’s PBC disease history (ie, date of diagnosis, treatment history, 
pruritus history, signs and symptoms, and including smoking history) will be collected during 
Screening.  At subsequent study visits (see Section 7.1.2), subjects will be asked to complete the 
following questionnaires; they may be asked to initial and date to document confirmation of their 
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responses, and the questionnaires should be filed in the subject’s study records.  These may 
require transcription to the CRF by study site staff. 
• 5-D Pruritus Questionnaire:  This is a questionnaire that has been validated in several 
different diseases.  It assesses symptoms in terms of 5 domains: degree, duration, 
direction, disability and distribution [Elman 2010] 
• Pruritus VAS:  A Visual Analogue Scale (VAS) will also be used to assess pruritus in 
individual subjects   
12.2.6. 
Laboratory Assessments 
Subjects will be instructed to attend each of their study visits (except Screening) in a fasted state, 
and subjects should remain fasted until their blood samples have been collected.  At each visit, 
the investigator or designee will verify that the subject has fasted for at least 8 hours and record 
fasting status in the source and CRF.  If the subject reports having eaten (water is permitted) 
within 8 hours, the investigator or designee will document accordingly in the source and CRF 
and remind the subject that fasting is required prior to all study visits. 
Blood samples for serum chemistry and hematology will be collected at every visit as detailed in 
the Schedule of Study Procedures (Section 7.1.2).  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 by the central clinical laboratory in a study specific laboratory 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 subjects 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.  Subjects testing positive for urine drug screen will be excluded from the study. 
The list of laboratory analytes to be tested is shown in Table 4. 
Table 4: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry  
Albumin, blood urea nitrogen (BUN), 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 very low density lipoprotein 
[VLDL] fractions and triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, unconjugated (indirect) 
bilirubin, conjugated (direct) bilirubin, free fatty acids, 
thyroid hormones (T3, T4, TSH) 
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Laboratory Assessment 
Analyte 
Hematology 
Hemoglobin, hematocrit, white blood count with 
differential, neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, platelets, red blood cell count 
(including MCV, HBE [MCH], MCHC) 
Coagulation 
Prothrombin time (PT), partial thromboplastin time 
(PTT), international normalized ratio (INR) 
Urinalysis 
pH, specific gravity, total  protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, 
albumin, creatine, leucocytes, nitrates, albumin/creatine 
ratio (if positive) 
Biomarkers of Hepatic Fibrosis and/or Inflammation  
IgM, C-reactive protein (CRP), TNF-α, FGF-19, CK-18, 
ELF, and others as determined during course of study  
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Genetics 
DNA including single-nucleotide polymorphisms 
(SNPs) that may be involved in PBC; RNA 
Blood Sample for Future Analysis 
PBC autoantibodies and other cytokines and interleukins 
TBD 
Other 
OCA (parent and conjugates [glyco and tauro]) and C4 
The Investigator should manage subjects with clinically significant lipoprotein abnormalities 
using local standard of care procedures as appropriate after assessing the individual subject’s 
total cardiovascular risk profile. 
Urine-based β-hCG pregnancy tests will be performed in female subjects of childbearing 
potential per protocol specified visits.  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 
subject will be followed, as outlined in Section 12.1.8 through pregnancy outcome. 
MELD scores, Child-Pugh score and MRS will be calculated at quarterly visits based on serum 
chemistry and coagulation. 
13. 
STATISTICAL METHODS 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
hypothesis tests, will be prepared and approved by the Sponsor and its designees prior to study 
database lock, propensity score determination, and unblinding of the double-blind subject 
treatment assignments.  
13.1. 
Efficacy Analysis 
13.1.1. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
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• The Randomized Population will include all randomized subjects. 
• The Intent-to-Treat (ITT) Population will include all randomized subjects who 
receive any amount of investigational product (OCA or placebo).  The ITT 
Population will be the primary population used for efficacy analyses.  Treatment 
assignment will be based on the randomized treatment. 
• The Safety Population will include all subjects who received any amount of 
investigational product (placebo or OCA).  The Safety Population will be the primary 
population used for safety analyses.  Treatment assignment will be based on the 
treatment actually received. 
• The PK population will include all OCA subjects who have at least one confirmed 
fasted analyzable sample.  Subjects must have been fasting for approximately 8 hours 
prior to the visit and must not have any major protocol deviations that potentially 
affect exposure levels.  The PK population will be used for OCA PK analyses.  
• The Overall Historical Control Population will include subjects from the United 
Kingdom (UK) -PBC Group and Global PBC Study Group databases with 
demonstrated comparability to randomized subjects in this clinical study (747-302) 
with respect to both subject characteristics and disease progression. 
• The UK-PBC Historical Control Population will include subjects from the UK-PBC 
Group databases with demonstrated comparability to randomized subjects in this 
clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
• The Global PBC Historical Control Population will include subjects from the Global 
PBC Study Group database with demonstrated comparability to randomized subjects 
in this clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
13.1.1.1. Comparability of Historical Controls 
Utilization of both historical control/observational databases (UK-PBC and Global PBC Study 
Group), with more than 6000 subjects each, allow for a rigorous subject level meta-analysis.  The 
historical databases include long-term follow up, detailed subject-level information such as 
baseline clinical characteristics, longitudinal liver biochemistry, and long-term outcomes, and 
span a broad range of subject characteristics that may influence disease (disease state, age, 
gender, and regional differences in standard of care).  Historical controls from both databases 
will be chosen based on the same study inclusion/exclusion criteria where possible. 
13.1.2. 
Determination of Sample Size 
The following assumptions were used in sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.5 at 8 years with a hazard 
ratio of 0.60, and total study duration of 8 years, allowing for 2 years accrual and 
6 years of follow up. 
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• 5% of the subjects will have never been treated with UDCA; 95% of the subjects will 
have been on UDCA for at least 1 year. 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance. 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
13.1.2.1. Sample Size Re-Estimation Plan 
Conducting a long-term outcomes study given the low disease prevalence, relatively slow 
disease progression, and ethical considerations, which in combination will impact recruitment 
and event rates, is inherently difficult.  As stated in ICH E9, in long-term trials there is an 
opportunity to check the assumptions that underlay the original design and sample size 
calculations.  The power stated above depends on the total number of events.  Thus, the overall 
survival function can be estimated without unblinding. 
Therefore, starting approximately 2 years after the first subject is randomized, the aggregate 
event rate and sample size based on recruitment and retention will be evaluated in a blinded 
manner quarterly.  This evaluation will determine if any increases in number of subjects are 
required in order to obtain a total of 121 adjudicated events for the final analysis in the combined 
groups.  Specifically, the pooled number of events will be available during the study in a blinded 
manner, without any knowledge of the comparative efficacy in the treatment groups.  This 
method for evaluating the sample size does not inflate the type I error rate.  Additional subjects 
may be enrolled as appropriate. 
If after 4 years of accruing subjects, despite increases in the number of subjects, it is determined 
that at least an additional 2 years (ie, total study duration of at least 10 years) are needed to 
randomize sufficient subjects to achieve a total of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label OCA.  Previously randomized subjects will 
continue to be treated in a blinded manner with either OCA or matching placebo.  If this 
modification is implemented, the alternative primary efficacy analysis is specified is 
Section 13.1.9. 
Any revised sample size or changes to treatment allocation will be justified and documented in a 
protocol amendment and in the CSR. 
13.1.3. 
Primary Efficacy Analysis 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
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• Liver transplant 
• MELD score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
The primary efficacy analysis will compare randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the ITT population.  Only adjudicated events will 
be included in analyses.  The 2 treatment groups will be compared 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 determined based on a 
Cox regression model stratified by randomization strata to estimate the magnitude of the effect. 
13.1.4. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints will compare OCA to placebo on the following: 
• Time to first occurrence of MELD score ≥15 
• Time to liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare randomized OCA to randomized placebo in 
ITT population with respect to the key secondary efficacy endpoints.  Only adjudicated events 
will be included in time-to-event analyses.  The comparison (hypothesis testing) will be 
conducted as specified in Section 13.1.11 in a sequential closed testing gate-keeping procedure, 
provided that the primary efficacy endpoint comparison is statistically significant in favor of the 
OCA treatment group.  If the primary comparison is not statistically significant then comparison 
of the secondary endpoints will be considered as descriptive and exploratory.  This procedure 
controls the study-wise type I error. 
The 2 treatment groups will be compared using the same methodology as specified for the 
primary efficacy analysis (Section 13.1.3). 
Analyses of change from Baseline to end of study in ALP and total bilirubin will be compared 
between treatment groups using analysis of covariance (ANCOVA) with change from Baseline 
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as the dependent variable including treatment group and randomization stratification factor as 
fixed effects and the Baseline values as a covariate.  The same analysis will be carried out using 
percentage change from Baseline as the dependent variable. 
Descriptive statistics of the laboratory values will be summarized by treatment group.  The 
results, change from Baseline, and percentage change from Baseline values as well as estimates 
of least-square means, standard errors, and 95% CIs will be presented by treatment group.  
Estimates of the mean difference between treatment groups, the standard error of the difference, 
and 95% CI of the difference will be presented. 
13.1.5. 
Additional Secondary Efficacy Analyses 
The following time to event secondary efficacy analyses will compare randomized OCA versus 
randomized placebo using the ITT population: 
• Time to each component of the primary efficacy endpoint (except MELD score ≥15 
which is captured above) 
• Time to liver-related death 
• Time to liver-related death or liver transplant 
• Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls as described below in Section 13.1.8. 
Analyses of changes in liver biochemistry (GGT, ALT, AST, conjugated bilirubin, albumin, and 
INR) will be summarized and analyzed using the same methodology as specified in 
Section 13.1.4 for the key secondary analyses of change in ALP and total bilirubin. 
Analyses of changes in MELD score, Child-Pugh score, Mayo Risk Score (MRS), IgM, CRP, 
TNF-α, FGF-19, CK-18, C4, and ELF score will be summarized and analyzed using the 
Wilcoxon Rank Sum Test to compare treatment groups.  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. 
13.1.6. 
Exploratory Efficacy Analyses 
13.1.6.1. Responder Analyses 
The percentage of subjects with a decrease in ALP of ≥15% and ≥40% from Baseline will be 
summarized by treatment group.  In addition, the percentage of subjects with ALP ≤ULN will be 
summarized by treatment group. 
The percentage of subjects that meet the criteria of a responder based on each of the definitions 
below will be summarized by treatment group.  The response classification at baseline will also 
be included in the summary:  
• ALP ≤3x ULN and AST ≤2x ULN and total bilirubin ≤ULN (Corpechot 2008) 
• ALP ≤1.5x ULN and AST ≤1.5x ULN and total bilirubin ≤ULN (Corpechot 2011) 
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• ALP ≤1.67x ULN and total bilirubin ≤ULN (Momah 2012) 
• Normal bilirubin (values ≤ULN) and normal albumin (values ≥lower limit of normal) 
(Kuiper 2009) 
• ALP ≤1.76 x ULN (Kumagi 2010) 
Responder analyses will compare treatment groups using a Cochran–Mantel–Haenszel test 
stratified by the randomization stratification factor.  Missing values will be considered as a 
non-responder.   
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints 
Sufficient data will be collected on resource utilization and quality of life to undertake 
cost-effectiveness analyses that are relevant to the major countries taking part in this study.  
Resource utilization data on hospitalizations, healthcare provider visits, and medications will be 
combined with appropriate national unit costs to calculate a cost per patient per year in the study. 
Quality of life data from patient-reported outcomes measures will be combined with survival 
data to calculate quality adjusted time in the study per patient.  Cost-effectiveness analyses will 
report the incremental cost per major clinical outcome averted, liver-related death averted, 
life-year gained and quality-adjusted life year gained, including OCA as part of usual care versus 
usual care without OCA.  Analyses will be conducted within the study and using a lifetime 
perspective.  A separate economic analysis plan will be prepared and reported separately from 
this protocol. 
13.1.8. 
Supportive Analysis 
Per the International Conference on Harmonisation (ICH) E10 guidance, “where no obvious 
single optimal external control exists, it may be advisable to study multiple external controls”.  
In order to address the risks associated with the inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare clinical outcomes in the OCA treatment arm to 
historical controls.   
In an attempt to avoid the inherent biases with historical controls and to maintain the integrity of 
this comparison, one can invoke matching methods to optimize comparability and find a 
historical control that is “similar” to a participating subject.  The historical database control 
should be as similar as possible to the study population and should have been exposed to a 
similar standard of care (see Section 5.5.2.2). 
A propensity score can be used to reduce bias through matching, stratification, regression 
adjustment, or some combination.  Propensity scores use information from a pool of patients who 
do not participate in the study (historical controls) to identify what would have happened to 
participating subjects in the absence of the treatment.  By comparing how outcomes differ for 
treated subjects relative to historical controls, it is possible to estimate the effects of the 
treatment. 
Although it might be relatively simple to assign a historical control based on a single observable 
characteristic, in practice, if the matching process is to successfully mitigate potential bias, it has 
to be done considering a full range of covariates across which the treatment and historical 
controls might differ.  Although the results of using matching are conditional only on the 
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observed covariates, if one has the ability to measure many of the covariates that are believed to 
be related to the treatment assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained.  Both UK-PBC Group and the 
Global PBC Study Group formally collect numerous covariates that could be used for propensity 
score estimation including standard of care, eg, UDCA. 
Historical controls will be chosen based on the same inclusion/exclusion criteria where possible. 
Propensity scores will be estimated using the available covariates that predict receiving the 
treatment.  Only covariates and not outcome variables will be included in the propensity score 
estimation.  Therefore, there is no chance of biasing results in favor of one treatment. 
The covariates and factors collected in the historical databases will be specified in the SAP. 
Propensity scores will be estimated first through a logistic regression model with treatment group 
as the dependent variable and the above covariates/factors as independent variables.  Then the 
stratum boundaries are determined based on the propensity score values for both groups (OCA 
population and control [historical and randomized placebo]) combined or in the OCA population 
or historical control group alone.  Based on recommendations in the literature, quintiles of the 
estimated propensity score from the combined group will be used to determine the stratum 
boundary cut-offs for the different strata. 
Outcome events collected in the historical database are:  death (liver-related and all-cause), liver 
transplant, hepatocellular carcinoma, and other.  Other is defined as cirrhosis or decompensation 
such as ascites, variceal bleed, and encephalopathy. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare randomized OCA-treated subjects in the ITT population and historical 
controls (Overall Historical Control Population: both the UK-PBC Group and Global PBC Study 
Group databases) on the following outcomes: 
• Time to death (all-cause) 
• Time to liver-related death 
• Time to liver transplant 
• Time to liver transplant or death (all-cause) 
• Time to liver transplant or liver-related death 
• Time to hepatocellular carcinoma 
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 determined based on a Cox regression 
model stratified by randomization strata to estimate the magnitude of the effect. 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
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13.1.9. 
Alternative Primary Analysis 
Based on sample size re-estimations, it may be determined that subjects will be enrolled to 
receive open-label OCA from that point forward, and the new primary efficacy analysis will 
become the comparison of all subjects in OCA population, to all control subjects (randomized 
placebo and historical controls) on time to liver transplant or death (all-cause) (see 
Section 13.1.2.1).  Similar statistical methodology as specified above in Section 13.1.8  for 
supportive analyses will be utilized. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare groups.  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 
determined based on a Cox regression model stratified by randomization strata to estimate the 
magnitude of the effect. 
In addition, the outcome events specified above in Section 13.1.8 will also be evaluated to 
compare all subjects in OCA population to all control subjects (randomized placebo and 
historical controls). 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
13.1.10. 
Handling of Dropouts or Missing Data 
Subjects who discontinue investigational product are expected to continue in the study until 
study termination. 
Missing data will be assumed to be missing at random.  In order to determine the effect of 
missing data on the analysis, efficacy endpoints will be analyzed using different methods of 
imputation as described below. 
13.1.10.1. Time to Event Endpoints 
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 investigational product dosing). 
For analyses of the percentage of subjects with an event, subjects with no data after 
randomization will be considered to have an event. 
All time to event endpoints include only adjudicated events.  Sensitivity analyses may consider 
all events regardless of adjudication.  Events with discrepant adjudication will be analyzed using 
both results. 
13.1.10.2. Quantitative Endpoints 
For efficacy endpoints that utilize an ANCOVA model, observed cases will serve as the primary 
analysis.  Sensitivity analyses to assess the effect of missing data may be conducted where 
missing data is imputed using last observation carried forward. 
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Sensitivity analyses of ANCOVA models will also be evaluated using a restricted maximum 
likelihood based mixed-effect repeated measures model where no imputations will be made for 
missing values.   
13.1.10.3. Responder Endpoints 
In an efficacy analysis in which subjects are classified as either a responder or a non-responder 
(binary outcome) based on dichotomizing a continuous variable, any subject who does not 
provide an assessment at the specified time point for the defining of response will be considered 
to be a non-responder.  That is, for the percentage of responders, the subject will be included in 
the denominator and will not contribute to the numerator. 
For sensitivity analyses using only “observed cases,” subjects who do not provide an assessment 
at the specified timepoint for the defining of response will not be included.  That is, for the 
percentage of responders, the subject will not be included in the numerator or the denominator. 
13.1.11. 
Multiple Comparisons/Multiplicity 
The key secondary efficacy endpoints are as follows: 
• Time to MELD score ≥15 
• Time to first occurrence of liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The hypothesis testing of key secondary analyses will compare placebo and OCA and will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of OCA.  If the primary comparison is not statistically significant 
then comparison of the secondary endpoints will be considered as descriptive and exploratory.  
This procedure controls the study-wise type I error.  
• First (step 1) placebo and OCA will be compared with respect to the primary efficacy 
endpoint.  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• The time to MELD score ≥15 will be compared between placebo and OCA (step 2).  
If the comparison achieves statistical significance at 2-sided 0.05 level in favor of 
OCA group, then 
• The time to liver transplant or death (all-cause) will be compared between placebo 
and OCA (step 3).  If the comparison achieves statistical significance at 2-sided 0.05 
level in favor of OCA group, then 
• Change from Baseline in total bilirubin will be compared between placebo and OCA 
(step 4).  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• Change from Baseline in ALP at the end of study will be compared between placebo 
and OCA (step 5). 
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If at any step defined above the comparison is not statistically significant at the 2-sided 
0.05 level then the remaining comparisons in the stated hierarchy will be considered descriptive 
and exploratory.  The study-wise type I error will be maintained with the above closed 
procedure. 
Additional efficacy endpoints will be analyzed; however hypothesis tests will be applied for 
descriptive and exploratory purposes only.   
13.1.12. 
Examination of Subgroups 
The primary and secondary efficacy endpoints will be analyzed for subject subgroups (eg, age, 
sex, and race) based on the ITT population.  Subgroups will be assessed at baseline and only if 
there are a sufficient number of subjects in each group (eg, >5 subjects per group). 
Baseline subgroups of interest are as follows:  age, age at PBC diagnosis, sex, race, body mass 
index, ALP level, bilirubin level, use of UDCA, years since diagnosis of PBC, and geographic 
region. 
13.2. 
Safety Analysis 
Safety data, including AEs and clinical laboratory observations, will be summarized by treatment 
group using the Safety Population. 
13.2.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary of Regulatory Activities.  Summary tables of 
treatment-emergent AEs will be provided.  The incidence of TEAEs will be tabulated by system 
organ class and preferred term for each treatment group, and by severity and relationship to 
treatment.  Tables of TEAEs leading to investigational product discontinuation and SAEs will be 
provided. 
13.2.2. 
Clinical Laboratory Evaluations 
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will be 
presented for all study visits.  Changes from pretreatment to each study visit will also be 
summarized by treatment group. 
13.2.3. 
Additional Safety Analysis 
Additional safety assessments include vital signs and ECGs.  Descriptive statistics of the vital 
sign and ECG parameters will be presented by treatment group and study visit, as well as the 
change from pretreatment at each visit. 
In addition to potential clinical endpoint events, cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study and will be described separately. 
13.3. 
Data and Safety Monitoring Committee 
An independent DSMC will review safety data at periodic intervals from this study.  The DSMC 
will include internationally recognized hepatologists, pharmaceutical physicians, and a 
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statistician.  All have considerable experience with clinical trial conduct and DSMCs, prior to 
joining the OCA DSMC.  Candidates are screened for conflicts of interest and any candidate 
found to have such a conflict is not offered membership.  Conflicts of interest are assessed 
regularly, and if members are found to have a new conflict of interest they would be replaced. 
The DSMC meets approximately quarterly at scheduled meetings and ad hoc meetings are 
convened, as appropriate.  The DSMC reviews all Intercept sponsored Phase 2 and 3 studies.  
Members of the DSMC will not be allowed to participate as investigators in this study and will 
not otherwise consult for the Sponsor. 
The DSMC will review data on a periodic basis to ensure the safe and proper treatment of 
subjects.  Based on review of these data, the DSMC will advise the Sponsor on the validity and 
scientific merit of continuing the study.  In addition, the DSMC statistician will evaluate the 
sample size as described in Section 13.1.2.1. 
The DSMC operates under an appropriate charter (in compliance with relevant regulatory 
guidance) that defines its organization and operation and includes specific procedures for each 
study.  The DSMC will prepare written minutes of both its open and closed sessions for each 
study.  The closed minutes will be made available to the Sponsor only after the database is 
locked. 
Data listings provided to the DSMC do not contain individual subject treatment information; 
however, the DSMC will have access to the database and may unblind individual subject data as 
appropriate.  Summary tables reviewed by the DSMC during closed sessions will include an 
overall column containing information regarding all subjects 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, Medical Dictionary for Regulatory Activities (MedDRA) coded AE, 
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 DSMC in 
addition to a cumulative list of all SAEs. 
The DSMC may request additional analyses if deemed necessary to fulfill the mission of the 
DSMC.  The DSMC will determine if an unscheduled meeting is necessary based on the 
additional data. 
All investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DSMC relating to subject safety, which alter the 
conduct of this study.  The investigators will inform the subjects of such actions and the protocol, 
PIS, and consent will be revised, as appropriate. 
13.4. 
Adjudication Committee 
All potential endpoint events will be reviewed by an adjudication committee before inclusion in 
the any analysis.  The adjudication of potential clinical endpoint events will include, but is not 
limited to:  available hospital reports, histology, discharge summaries, and death certificates.  
The assessment of events will be conducted in compliance with the protocol, study-specific 
procedures, manuals, Good Clinical Practice (GCP), and all other applicable regulatory 
requirements, including the archiving of essential documents.  A separate adjudication 
committee charter will document the entire data flow and process from committee membership, 
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the reporting of events by the study site, reporting of the final assessment, supply of source 
documentation to the committee, the review of the events by the committee, and the working 
procedures of the committee.  The adjudication committee members will be independent 
hepatologists not involved in the study as investigators, DSMC members, or consultants.  All 
adjudication committee members will remain blinded to treatment group throughout the study. 
In addition to potential clinical endpoint events, cardiovascular events will also be adjudicated.  
The adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study and will be described separately. 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
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 subject’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 CRF.  The CRF 
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 
subject's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
14.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC 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.   
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the CRF or ultimately 
transferred into the database to ensure accuracy and completeness.   
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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 14.2 for more details regarding the audit 
process. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF and/or other subject 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 the Sponsor before he or she can enroll 
any subject 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 subjects to the ethics committee 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 subjects for 
the study.  The protocol must be reapproved by the IRB or 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.  
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, at a minimum annually, and after the study is complete. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (Seoul Revision, 2008) and are consistent with ICH/GCP, applicable 
regulatory requirements and the Sponsor’s policies. 
16.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
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The subject’s signed and dated ICF 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 subject. 
16.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential and confidentiality of all subjects will be maintained.  Monitors (eg, 
CRA, medical monitor), auditors and inspectors will require access to a subject’s medical notes 
for the purpose of source document verification but the subject’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 subject’s names and identifying information (eg, subject’s 
hospital number, unique subject number).  This list will not be collected by the Sponsor. 
The written information sheet 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 subject 
number/randomization code/subject initials/site number, only. 
When personal data on subjects are stored or processed by computer, the data must be protected 
to prevent their disclosure to unauthorized third parties.  The pertinent sections of the data 
protection laws in which the country is being conducted will be complied with in full. 
The written ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IEC/IRB may require direct access to parts of the hospital 
or study site records relevant to the study, including subject’s medical history. 
17. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the subjects 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 subjects, as applicable. 
17.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject 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 medical monitor. 
17.2. 
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.  
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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 subject’s safety to be compromised if immediate action is not taken. 
17.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
• Approved ICF (all versions) 
• IRB/IEC approvals (of protocol/amendments, subject questionnaires, etc) 
• Form FDA 1572  
• Current medical license 
• Curriculum vitae 
• Laboratory certification and reference ranges 
• Financial disclosure forms 
17.4. 
Ethics Review  
Please see Section 16.1 for the Investigator’s responsibilities regarding ethics review. 
17.5. 
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 subject 
medical files (retained per country specific regulations), completed study subject log and 
confidential subject 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 prior to 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. 
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18. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it Sponsors consistent 
with the Declaration of Helsinki (Seoul Revision 2008, 
[http://www.wma.net/en/30publications/10policies/b3/index.html, accessed May 22, 2013]). 
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 Study Registries (eg, clinicaltrials.gov):  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 (when available) 
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:  The Sponsor, 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 
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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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19. 
LIST OF REFERENCES 
Beuers U, Lindor KD. A major step towards effective treatment evaluation in primary biliary 
cirrhosis. J Hepatol. 2011 Dec;55(6):1178-80. 
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and 
long term prognosis in primary biliary cirrhosis. Hepatology. 2008 Sep;48(3):871-877. 
Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: Biochemical response 
to treatment and prediction of long-term outcome. J Hepatol 2011;55:1361–1367. 
Elman S, Hynan L.S., Gabriel V, and Mayo M.J. The 5-D itch scale: a new measure of pruritus, 
British Journal of Dermatology 2010 162, pp587–593. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51:237-267. 
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. 
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 Apr;136(4):1281-7. 
Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict 
long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 
2010 Oct;105(10):2186-94. 
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Alkaline phosphatase values are a 
surrogate marker in prediction of transplant-free-survival in patients with primary biliary 
cirrhosis - an international, collaborative analysis.  J Hepatol. 2013; 58(Suppl):S388. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis: AASLD Practice 
Guidelines. Hepatology. 2009;50(1):291-308. 
Momah N, Silveira MG, Jorgensen R, et al. Optimizing biochemical markers as endpoints for 
clinical trials in primary biliary cirrhosis. Liver Int. 2012;32(5):790-795. 
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APPENDIX A.  LIST OF STUDY 747-302 OUTCOME EVENTS 
Several of the specified clinical endpoints will also by definition (see Section 12.1) 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 12.1.4).  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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APPENDIX B.  LIST OF STUDY 747-302 ANTICIPATED EVENTS 
Jaundice  
Hepatic decompensation/failure 
Hypoalbuminemia 
Hyponatremia 
Splenomegaly 
Hepatorenal syndrome (renal failure in the setting of hepatic failure) 
Hepatopulmonary syndrome (pulmonary failure in the setting of hepatic failure) 
Fractures 
 
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1. 
TITLE PAGE 
 
 
Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 3b, Double-Blind, Randomized, Placebo-Controlled, Multicenter 
Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in 
Subjects with Primary Biliary Cirrhosis  
 
 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA  92121 
USA 
 
TEL: +1 858 652 6800 
FAX: +1 858 558 5961 
 
 
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 Investigational Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-302.  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 (CRFs) 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 747-302 and in accordance 
with Good Clinical Practice (CPMP/ICH/135/95), 21CFR Part 312 and all applicable regulatory 
requirements. 
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, PhD, Executive Director, Clinical Research, 
Intercept Pharmaceuticals, Inc. 
Mobile: 
 (Pacific time zone) 
Telephone: 
  
Email: 
 
SAE Fax: 
+1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
 
Or if Not Available: 
Contact: 
 MD,  Medical Director, Drug Safety,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Email: 
 (Pacific time zone) 
 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 (Pacific time zone) 
 
 
 
 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company:  Intercept Pharmaceuticals, Inc. 
Name of Investigational Product:  Obeticholic Acid (OCA) 
Name of Active Ingredient:  OCA; 6α-ethyl chenodeoxycholic acid (6-ECDCA); INT-747 
Title of Study:  A Phase 3b, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary 
Cirrhosis 
Study Number:  747-302 
Study Center(s):  Approximately 170 investigational study sites, globally 
Study Period (Years):  The study is event driven and total duration will be determined by the 
time required to accrue approximately 121 primary endpoint events, estimated to be 
approximately 8 years.  Subjects are expected to have a minimum follow-up time of 
approximately 6 years. 
Number of Subjects (planned):  Approximately 350 subjects 
Phase of Study:  Phase 3b 
Objectives:  
Primary 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care, on clinical outcomes in subjects with primary biliary cirrhosis (PBC) as measured by 
time to first occurrence of any of the following adjudicated events, derived as a composite event 
endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
Secondary 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above and also to include liver-related death. 
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To assess the effect of OCA compared to placebo on disease progression via the following: 
• Liver biochemistry  
• Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To assess the pharmacokinetics of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
Methodology: 
This Phase 3b, double-blind, randomized, placebo-controlled, multicenter study will evaluate the 
effect of OCA on clinical outcomes in subjects with PBC.  Subjects will be screened during a 1 
to 8 week Screening period prior to entering the study to allow for the collection of repeat serum 
chemistry samples (at least 2 weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
and total bilirubin values (refer to Section 9.7.3).  Mean values for ALP and total bilirubin will 
be calculated using all available screening values.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be randomized (1:1) to OCA or placebo treatment groups.  The 
randomization will be stratified by ursodeoxycholic acid (UDCA) treatment (yes/no) and 
baseline bilirubin categories (>upper limit of normal [ULN]/ ≤ ULN). 
Investigational product (OCA or matched placebo) will be taken orally, once daily.  
Investigational product will be initiated at 5 mg OCA or matched placebo.  After 3 months of 
treatment with investigational product, the dose may be increased (to the maximum dose of 
10 mg OCA or matched placebo, in a blinded manner) at the 3-month visit or any subsequent 
study visit based on tolerability.  Subjects will be seen at quarterly visits for the duration of the 
study. 
 
 
 
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Schematic Diagram:  
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; ULN = upper limit of normal 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with American Association for the 
Study of Liver Diseases [AASLD] and the European Association for the Study of the 
Liver [EASL] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the 
presence of ≥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 in 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 
2. A mean total bilirubin >ULN and ≤3x ULN and/or a mean ALP >5x ULN 
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past ≥3 months) or has been taking 
UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0 
5. Contraception:  Female subjects 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:   
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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• Double barrier method, ie, (a) condom (male or female) or (b) diaphragm, with 
spermicide; or  
• Intrauterine device (IUD); 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 subject)   
6. Must provide written informed consent and agree to comply with the study protocol 
Exclusion Criteria 
1.  History or presence of other concomitant liver diseases including:  
• Hepatitis C virus infection 
• Active hepatitis B infection; however, subjects 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 
• Nonalcoholic steatohepatitis 
• Gilbert’s Syndrome 
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including: 
• 
History of liver transplant, current placement on a liver transplant list, or current MELD 
score >12.  Subjects who are placed on a transplant list despite a relatively early disease 
stage (for example per regional guidelines) may be eligible as long as they do not meet 
any of the other exclusion criteria 
• Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
− Variceal bleed 
− Uncontrolled ascites  
− Encephalopathy  
− Spontaneous bacterial peritonitis  
• Known or suspected hepatocellular carcinoma 
• Prior transjugular intrahepatic portosystemic shunt procedure 
• Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine 
>2 mg/dL (178 μmol/L) 
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3. Mean total bilirubin >3x ULN  
4. Subjects who have undergone gastric bypass procedures (gastric lap band is 
acceptable) or ileal resection or plan to undergo either of these procedures 
5. Other medical conditions that may diminish life expectancy, including known cancers 
(except carcinomas in situ or other stable, relatively benign conditions such as 
chronic lymphatic leukemia) 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test), or lactating 
7. Known history of human immunodeficiency virus infection 
8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months) 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
Investigational Product, Dosage and Mode of Administration:  
OCA (5 mg or 10 mg tablets) 
Placebo (matching tablets) 
Duration of Treatment: 
It is estimated that subjects will be followed up for a minimum of 6 years.  The study is event 
driven and total duration of treatment will be determined by the time to accrue 121 total primary 
endpoint events. 
Duration of Subject Participation: 
It is estimated that subject participation will be a minimum of approximately 6 years. 
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Criteria for Evaluation: 
Primary Objectives 
Assessments 
Clinical outcomes 
• 
Death (all-cause) 
• 
Liver transplant 
• 
MELD score ≥15 
• 
Hospitalization (as defined by a stay of 24 hours or greater) for new 
onset or recurrence of: 
− 
Variceal bleed 
− 
Encephalopathy (as defined by a West Haven score of  ≥2) 
− 
Spontaneous bacterial peritonitis (confirmed by diagnostic 
paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic 
paracentesis at a frequency of at least twice in a month) 
• 
Hepatocellular carcinoma confirmed by 2 complimentary imaging 
modalities 
Secondary Objectives 
 
Individual components of the 
primary endpoint 
As listed above and including liver-related death 
Change in baseline liver 
biochemistry 
Liver biochemistry (see Table 5 for list of analytes to be tested)   
Inflammation and fibrosis 
IgM, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), 
fibroblast growth factor-19 (FGF-19), cytokeratin-18 (CK-18), enhance liver 
fibrosis (ELF), and Fibroscan® 
Clinical outcomes compared to 
historical controls 
Similar endpoints as used for the primary objective where available including 
liver transplant and death 
Pharmacokinetics 
OCA and its conjugates 
Health outcomes and economics 
research 
Including the following: 
Cost-effectiveness and resource utilization 
Quality of life (Fatigue Impact Score and EQ-5D-5L)  
Safety and tolerability 
Including the following: 
Treatment-emergent adverse events 
Clinical laboratory values 
 
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Statistical Methods:  
Sample Size Justification 
The following assumptions were used in sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.5 at 8 years with a hazard 
ratio of 0.60, and total study duration of 8 years, allowing for 2 years accrual and 
6 years of follow up 
• 5% of the subjects will have never been treated with UDCA; 95% of the subjects will 
have been on UDCA for at least 1 year 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to clinical outcomes. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: Randomized, Intent-to-Treat (ITT), Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical Control.  Descriptions of subject populations 
are provided in Section 13.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
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Every event for enrolled subjects will be adjudicated by an independent committee. 
Primary Efficacy Analysis 
The primary efficacy analysis will compare randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the ITT population.  The 2 treatment groups will 
be compared 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 determined based on a Cox regression model stratified by randomization strata to 
estimate the magnitude of the effect. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints are as follows: 
• Time to first occurrence of MELD score ≥15 
• Time to liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare randomized OCA to randomized placebo in 
ITT population with respect to the key secondary efficacy endpoints.  Only adjudicated events 
will be included in time-to-event analyses.  The comparison (hypothesis testing) will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of the OCA treatment group.  If the primary comparison is not 
statistically significant then comparison of the secondary endpoints will be considered as 
descriptive and exploratory. 
Other Efficacy Analyses 
The following secondary efficacy analyses will compare OCA to placebo on time to the 
following events: 
• Each component of the primary efficacy endpoint (except MELD score ≥15 which is 
listed above) 
• Development of varix/varices 
• Liver-related death 
• Liver-related death or liver transplant 
• Liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls. 
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Further details on efficacy, health outcomes, and pharmacokinetic analyses are specified in 
Section 13. 
Safety Analysis 
Safety data, including AEs, vitals, electrocardiogram, and clinical laboratory results will 
compare OCA and placebo using the Safety Population. 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................20 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Overview of Primary Biliary Cirrhosis and Obeticholic Acid ...................................22 
5.2. 
Mechanism of Action of Obeticholic Acid .................................................................22 
5.3. 
Nonclinical Experience with Obeticholic Acid ..........................................................23 
5.4. 
Clinical Experience with Obeticholic Acid ................................................................23 
5.5. 
Rationale for Study Design and Dose for Investigational Product .............................24 
5.5.1. 
Rational for Study Design ..........................................................................................24 
5.5.2. 
Rationale for Dose ......................................................................................................25 
5.5.2.1. 
Rationale for OCA Doses ...........................................................................................25 
5.5.2.2. 
Rationale for Control Groups .....................................................................................25 
5.6. 
Summary of Known Potential Risks with OCA .........................................................26 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................26 
6.1. 
Primary Objective .......................................................................................................26 
6.2. 
Secondary Objectives .................................................................................................27 
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 Subjects ....................................................................................................32 
7.3. 
Treatment Assignment ................................................................................................32 
7.4. 
Dose Titration Criteria ................................................................................................32 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................32 
7.5. 
Criteria for Study Termination ...................................................................................32 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................33 
8.1. 
Subject Population ......................................................................................................33 
8.2. 
Subject Inclusion Criteria ...........................................................................................33 
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8.3. 
Subject Exclusion Criteria ..........................................................................................34 
8.4. 
Subject Withdrawal from Investigational Product or Study Criteria ..........................35 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product ..........................35 
8.4.2. 
Other Reasons for Discontinuation of Investigational Product ..................................35 
8.4.2.1. 
Withdrawal of Consent ...............................................................................................36 
8.4.2.2. 
Lost to Follow-up .......................................................................................................36 
8.4.3. 
Subject Discontinuation Notification .........................................................................36 
9. 
TREATMENT OF SUBJECTS ..................................................................................37 
9.1. 
Investigational Product Treatment Regimen ..............................................................37 
9.1.1. 
Dose Adjustment Beginning at Month 3 ....................................................................37 
9.2. 
Concomitant Medications ...........................................................................................37 
9.2.1. 
Prohibited Medications ...............................................................................................38 
9.3. 
Treatment Compliance ................................................................................................38 
9.4. 
Randomization and Blinding ......................................................................................38 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures ...................................38 
9.5. 
Assignment of Site and Subject Numbers ..................................................................39 
9.5.1. 
Site Numbers ..............................................................................................................39 
9.5.2. 
Subject Numbers .........................................................................................................39 
9.6. 
Restrictions .................................................................................................................39 
9.7. 
Visit Procedures ..........................................................................................................39 
9.7.1. 
Visit Windows ............................................................................................................39 
9.7.2. 
Informed Consent Procedures .....................................................................................40 
9.7.3. 
Screening Procedures (1 to 8 Weeks prior to Day 0) .................................................40 
9.7.4. 
Day 0 Procedures (Randomization) ............................................................................42 
9.7.5. 
Safety Contact (Month 1, Month 2, and 2 Weeks Post-Titration [by 
telephone]): .................................................................................................................44 
9.7.6. 
Month 3 Procedures ....................................................................................................44 
9.7.7. 
Month 6 Procedures ....................................................................................................45 
9.7.8. 
Month 9 Procedures ....................................................................................................46 
9.7.9. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment .................................................................................................................47 
9.7.10. 
Month 12 Procedures ..................................................................................................47 
9.7.11. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 weeks]) ......................49 
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9.7.12. 
Month 6 Continued Follow-up Procedures (Semi-annually [±2 weeks]) ...................49 
9.7.13. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) .........................50 
9.7.14. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent ..................................52 
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 .......................................................55 
10.3. 
Investigational Product Storage ..................................................................................56 
10.4. 
Investigational Product Preparation ............................................................................56 
10.5. 
Investigational Product Administration ......................................................................56 
10.6. 
Investigational Product Accountability and Disposal .................................................56 
11. 
ASSESSMENT OF EFFICACY ................................................................................56 
11.1. 
Assessment of Efficacy ...............................................................................................56 
11.1.1. 
Primary Assessments ..................................................................................................56 
11.1.2. 
Secondary Assessments ..............................................................................................57 
11.1.2.1. 
Non-Invasive Assessments of Liver Fibrosis .............................................................57 
11.1.2.2. 
Other ...........................................................................................................................58 
11.1.2.3. 
Other Exploratory Evaluations ...................................................................................58 
11.1.2.4. 
Potential Clinical Outcome Events .............................................................................59 
12. 
ASSESSMENT OF SAFETY .....................................................................................59 
12.1. 
Adverse Events and Serious Adverse Events .............................................................59 
12.1.1. 
Definition of Adverse Events .....................................................................................59 
12.1.1.1. 
Adverse Event .............................................................................................................59 
12.1.1.2. 
Serious Adverse Event ................................................................................................59 
12.1.1.3. 
Treatment-Emergent Adverse Event ..........................................................................60 
12.1.2. 
Relationship to Investigational Product ......................................................................60 
12.1.3. 
Recording Adverse Event Severity .............................................................................61 
12.1.4. 
Reporting of Adverse Events and Serious Adverse Events ........................................61 
12.1.4.1. 
Reporting of Adverse Events ......................................................................................61 
12.1.4.2. 
Reporting of Serious Adverse Events .........................................................................61 
12.1.5. 
Additional Investigator Responsibilities for SAEs .....................................................62 
12.1.6. 
Notification of Post-Study SAEs ................................................................................63 
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12.1.7. 
Follow up of AEs and SAEs .......................................................................................63 
12.1.8. 
Pregnancy and Follow up ...........................................................................................63 
12.2. 
Other Safety Parameters .............................................................................................64 
12.2.1. 
Medical History/Demographics ..................................................................................64 
12.2.2. 
Physical Examination .................................................................................................64 
12.2.3. 
Vital Signs ..................................................................................................................64 
12.2.4. 
Electrocardiogram .......................................................................................................64 
12.2.5. 
Dual Emission X-Ray Absorptiometry .......................................................................64 
12.2.6. 
Subject Questionnaires ...............................................................................................64 
12.2.7. 
Laboratory Assessments .............................................................................................65 
13. 
STATISTICAL METHODS .......................................................................................67 
13.1. 
Efficacy Analysis ........................................................................................................67 
13.1.1. 
Analysis Populations ..................................................................................................67 
13.1.1.1. 
Comparability of Historical Controls .........................................................................67 
13.1.2. 
Determination of Sample Size ....................................................................................68 
13.1.2.1. 
Sample Size Re-Estimation Plan ................................................................................68 
13.1.3. 
Primary Efficacy Analysis ..........................................................................................69 
13.1.4. 
Key Secondary Efficacy Analyses ..............................................................................69 
13.1.5. 
Additional Secondary Efficacy Analyses ...................................................................70 
13.1.6. 
Exploratory Efficacy Analyses ...................................................................................71 
13.1.6.1. 
Responder Analyses ....................................................................................................71 
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints ................................................71 
13.1.8. 
Supportive Analysis ....................................................................................................71 
13.1.9. 
Alternative Primary Analysis .....................................................................................73 
13.1.10. 
Handling of Dropouts or Missing Data ......................................................................73 
13.1.10.1.  Time to Event Endpoints ............................................................................................74 
13.1.10.2.  Quantitative Endpoints ...............................................................................................74 
13.1.10.3.  Responder Endpoints ..................................................................................................74 
13.1.11. 
Multiple Comparisons/Multiplicity ............................................................................74 
13.1.12. 
Examination of Subgroups .........................................................................................75 
13.2. 
Safety Analysis ...........................................................................................................75 
13.2.1. 
Adverse Events ...........................................................................................................75 
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13.2.2. 
Clinical Laboratory Evaluations .................................................................................76 
13.2.3. 
Additional Safety Analysis .........................................................................................76 
13.3. 
Data and Safety Monitoring Committee .....................................................................76 
13.4. 
Adjudication Committee .............................................................................................77 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................77 
14.1. 
Study Monitoring ........................................................................................................77 
14.2. 
Audits and Inspections ................................................................................................78 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................78 
16. 
ETHICS ......................................................................................................................78 
16.1. 
Ethics Review .............................................................................................................78 
16.2. 
Ethical Conduct of the Study ......................................................................................79 
16.3. 
Written Informed Consent ..........................................................................................79 
16.4. 
Subject Confidentiality and Data Protection ..............................................................79 
17. 
INVESTIGATOR OBLIGATIONS ...........................................................................80 
17.1. 
AE Reporting ..............................................................................................................80 
17.2. 
Protocol Deviations ....................................................................................................80 
17.3. 
Regulatory Documentation .........................................................................................80 
17.4. 
Ethics Review .............................................................................................................80 
17.5. 
Archiving and Record Retention ................................................................................81 
18. 
PUBLICATION POLICY ..........................................................................................81 
19. 
LIST OF REFERENCES ............................................................................................83 
APPENDIX A.  LIST OF STUDY 747-302 OUTCOME EVENTS ...........................................84 
APPENDIX B.  LIST OF STUDY 747-302 ANTICIPATED EVENTS ....................................85 
APPENDIX C. 
ETHICAL CONDUCT ACCORDING TO THE DECLARATION OF 
HELSINKI FOR COUNTRIES PARTICIPATING OUTSIDE THE 
US (DECLARATION OF HELSINKI, FORTELEZA, BRAZIL, 2013) .........86 
APPENDIX D.  SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 
(DATED 29 APR 2015) ....................................................................................91 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................29 
Table 2: 
Early Discontinuation Scenarios .................................................................................53 
Table 3: 
Relationship of Adverse Events to Investigational Product .......................................60 
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Table 4: 
Severity of Adverse Events ........................................................................................61 
Table 5: 
List of Laboratory Analytes to be Tested ...................................................................66 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram Study 747-302 ............................................................................28 
 
 
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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 
CDCA 
chenodeoxycholic acid 
CI 
confidence interval 
CK-18 
cytokeratin-18 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
C-reactive protein 
DEXA 
dual-emission X-ray absorptiometry 
DSMC 
Data Safety Monitoring Committee 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
enhance liver fibrosis 
EOS 
end of study 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
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 
HDL 
high density lipoprotein 
IB 
Investigational Brochure 
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Abbreviation or Specialist Term 
Explanation 
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 
LDL 
low density lipoprotein 
LTSE 
Long-term safety extension 
MELD 
model of end stage liver disease  
MRS 
Mayo Risk Score 
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cirrhosis 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
the Sponsor 
Intercept Pharmaceuticals, Inc. 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
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 Primary Biliary Cirrhosis and Obeticholic Acid 
Primary Biliary Cirrhosis (PBC) 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, is currently the only 
treatment approved for PBC (Lindor 2009).  While UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of a poor clinical outcome due to PBC disease 
progression.  There is a clear unmet medical need for better therapies for patients with PBC that 
have an inadequate response to UDCA, or those who cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and effective. 
OCA is a modified bile acid and farnesoid X receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid (CDCA).  OCA is currently being developed in 
the United States (US) and Europe for the treatment of PBC and other chronic liver diseases.  
OCA has been granted Orphan Drug Designation in the US (09 Apr 2008) and Orphan Medicinal 
Product Designation in the European Union (27 Jul 2010) for the treatment of PBC. 
5.2. 
Mechanism of Action of Obeticholic Acid 
OCA is a 6α-ethyl derivative of the naturally occurring primary human bile acid CDCA, which is 
the endogenous ligand for FXR.  FXR is a ligand-dependent transcription factor that is part of 
the nuclear receptor superfamily.  FXR regulates a wide variety of target genes involved in the 
control of bile acid, lipid, and glucose homeostasis and in the regulation of immune responses. 
OCA’s potent FXR agonist effects are believed to account for the predominant efficacy of the 
investigational product.  Some of the pharmacological properties of OCA and other FXR 
agonists that have been elucidated in animal models of chronic liver disease relevant to the 
treatment of PBC include the following: 
• Improvement in hepatic choleresis with reduced inflammation and necrosis  
• Prevention and reversal of hepatic fibrosis 
The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and 
anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury 
and improved liver function in a cholestatic liver disease such as PBC. 
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5.3. 
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. 
5.4. 
Clinical Experience with Obeticholic Acid 
As of 31 January 2015, OCA has been evaluated in the clinic in 20 completed and ongoing 
studies, including subjects with other chronic liver diseases (eg, nonalcoholic steatohepatitis) and 
healthy subjects.  As of 31 January 2015, approximately 1650 subjects have received at least 
1 dose of OCA and of these, 432 were subjects with PBC with ≤5 years of OCA treatment.  
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. 
To date, the efficacy and safety of OCA in PBC has been evaluated in 2 placebo-controlled, 
double-blind, Phase 2 studies (747-201 and 747-202), and 1 placebo-controlled, double-blind 
Phase 3 study (747-301).  Following the double-blind phase, subjects in all 3 studies were 
eligible to continue with treatment in a long-term safety extension (LTSE) phase for up to 
5 years in Study 747-201, up to 1 year in Study 747-202, and up to 5 years in Study 747-301. 
Study 747-201 (59 subjects) 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 subjects) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in subjects 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 subjects) was a Phase 3, double-blind, placebo-controlled, parallel group 
study followed by an LTSE using OCA in subjects with PBC.  The primary endpoint for 
Study 747-301 was a composite endpoint based on the proportion of subjects reaching specific 
criteria for ALP and bilirubin (ALP <1.67x upper limit of normal [ULN] with a ≥15% reduction 
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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 10 mg OCA 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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is complete. 
5.5. 
Rationale for Study Design and Dose for Investigational Product 
5.5.1. 
Rational for Study Design 
OCA is a modified bile acid and FXR agonist that is derived from the primary human bile acid 
chenodeoxycholic acid.  The key mechanisms of action of OCA, including its choleretic, anti-
inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in 
attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. 
PBC is characterized by biochemical increases in ALP and GGT enzymes with or without 
elevations of hepatocellular transaminases and bilirubin (Lindor 2009).  Both the American 
Association for the Study of Liver Diseases (AASLD) (Lindor 2009) and the European 
Association for the Study of the Liver (EASL) (EASL 2009) guidelines base the biochemical 
component of PBC diagnosis on elevations of ALP.  In addition, a growing literature supports 
the use of biochemical endpoints, specifically serum ALP alone or with other parameters such as 
bilirubin, to manage subjects, test the efficacy of novel therapies in clinical studies, and gauge 
the risk of long-term adverse clinical outcomes in subjects with PBC (Beuers 2011, 
Momah 2012).  Data from the Global PBC Study Group (Lammers 2013), which has built a 
database tracking biochemical status and clinical outcomes in several thousand PBC subjects, 
provides evidence for the use of the composite biochemical endpoint of ALP and bilirubin as an 
acceptable surrogate endpoint. 
Study 747-301, a Phase 3 double-blind study, evaluated the safety and efficacy of OCA at doses 
of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability) and 10 mg and used 
a composite biochemical endpoint of ALP and bilirubin as a surrogate endpoint.  In this study, 
both treatment groups exhibited clinically meaningful improvements in liver biochemistry and 
were safe and generally well-tolerated.  Starting subjects on 5 mg OCA and titrating to 10 mg 
based on the clinical response appears to be an appropriate dosing strategy in subjects with PBC. 
Study 747-302 is a clinical outcomes study, supportive of Phase 3 Study 747-301 which was 
based on a surrogate biochemical endpoint, designed to confirm the clinical benefit of OCA 
treatment in patients with PBC.  A retrospective observational database (Global PBC Study 
Group [Lammers 2013]) of patients with PBC allowed for a rigorous patient-level meta-analysis 
and provided an opportunity for a robust assessment of ALP and bilirubin as viable surrogate 
biochemical parameters and a comprehensive understanding of the natural history of the PBC 
disease process.  Data from the Global PBC Study Group was also utilized to inform the design 
of the confirmatory outcomes study. 
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5.5.2. 
Rationale for Dose 
5.5.2.1. 
Rationale for OCA Doses 
The safety and tolerability of multiple doses of OCA have been established in subjects with PBC 
at doses up to 50 mg.  As demonstrated in the Phase 2 PBC studies (Studies 747-201 and 
747-202), OCA significantly reduced serum ALP levels at doses of 10 mg, 25 mg, and 50 mg, 
but with an increase in the incidence and severity of pruritus at higher dose levels.  The Phase 3 
PBC study subsequently evaluated the safety and efficacy of OCA at lower doses of 5 mg 
(titrated to 10 mg after 6 months based on efficacy and tolerability in the double-blind phase and 
after 3 months in the open-label phase) and 10 mg; both treatment groups exhibited clinically 
meaningful improvements in liver biochemistry and were safe and generally well tolerated.  
Based on these data, the intended commercial doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
The majority of efficacy results with OCA, in terms of change in alkaline phosphatase, was 
observed by 3 months and the time to treatment-emergent pruritus was typically 1 month or less 
in Study 747-301.  As such, Study 747-302 will evaluate the effect of OCA on clinical outcomes 
using the 5 mg OCA dose increasing to 10 mg OCA if tolerated. 
Based on these data, the intended commercial doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
Study 747-302 will evaluate the effect of OCA on clinical outcomes using the 5 mg OCA dose 
increasing to 10 mg OCA if tolerated. 
5.5.2.2. 
Rationale for Control Groups 
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 a standard of care 
effect.  Notably, accounting for the standard of care effect is critical when designing an 
outcome-based study conducted globally when there are regional differences in the treatment of 
subjects with PBC. 
Historical Control Group 
The available robust historical PBC observational datasets (UK-PBC and Global PBC Study 
Group) will also be leveraged to provide further comparative evaluation of the clinical benefit of 
OCA.  Each database includes >6000 patients with long-term follow-up. 
Comparison of OCA treatment to the historical controls may provide utility in addressing 
potential bias or confounds associated with the placebo arm.  For example, bias associated with 
the potential addition of commercial OCA and/or differences in long-term standard of care 
between the treatment arms including ancillary treatments and diagnostics. 
Therefore, further evaluation of the effect of OCA will compare OCA treatment versus historical 
controls, and will be supportive to placebo comparisons (ie, comparisons to historical and 
placebo controls will be evaluated separately). 
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5.6. 
Summary of Known Potential Risks with OCA 
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, but with a much 
lower frequency than that observed in subjects 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 subjects with chronic liver disease such as PBC, hepatic findings including increased 
transaminases and bilirubin and signs or symptoms of hepatic decompensation such as 
development of jaundice were observed mainly at the highest dose of OCA (50mg daily). 
Lipoprotein changes have also been observed with OCA dosing, including a decrease in high 
density lipoprotein (HDL) and an increase in low density lipoprotein (LDL).  Notably, in 
subjects 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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated subjects with the exception of a 
modest transient and early rise after initiation of treatment.   
6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care on clinical outcomes in subjects with PBC as measured by time to first occurrence of any 
of the following adjudicated events, derived as a composite event endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
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6.2. 
Secondary Objectives 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above and also to include liver-related death. 
To assess the effect of OCA compared to placebo on disease progression via the following: 
• Liver biochemistry 
• Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To assess the PK of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3b, double-blind, randomized, placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with bilirubin levels of >ULN and ≤3x ULN or ALP >5x.  
Subjects enrolled will be at higher risk of liver-related clinical complications. 
Approximately 350 subjects meeting all enrollment criteria will be recruited into the study over 
an approximate 2-year period, randomly allocated to treatment with either OCA or matching 
placebo once daily in a 1:1 ratio.  Subjects will be screened during a 1 to 8 week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples 
(at least 2 weeks apart) to confirm pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3).  Investigational product will be taken orally, once daily.  Investigational product 
will be initiated at 5 mg OCA or matched placebo.  The randomization will be stratified by 
UDCA treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN).  In addition to the 
placebo control arm, multiple historical control groups (concurrent and retrospective) will be 
used.  Following 3 months of treatment with investigational product, subjects should be titrated 
in a blinded manner (ie, subjects randomized to OCA will increase their dose to 10 mg OCA) 
based on tolerability.  It is anticipated that subjects will be followed for a minimum of 
approximately 6 years.  The study will continue until approximately 121 adjudicated primary 
endpoint events have been accrued in unique subjects, or until the Sponsor (eg, based on 
advisement by the Data Safety Monitoring Committee; DSMC) terminates the study. 
This study will be conducted at up to approximately 170 international study sites with experience 
in treating subjects with PBC.  Prospective subjects will be identified primarily from the hospital 
and/or physician’s database of subjects with PBC, or may be referred from other physicians.  
Subjects may self-refer to an Investigator if they become aware of the study through local, 
national, or international PBC subject societies, forums, and networks. 
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7.1.1. 
Study Design Diagram 
Figure 1: 
Schematic Diagram Study 747-302 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; ULN = upper limit of normal 
 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures  
 
Year 1 
Years 2 through End of Study 
 
Screening 
Visit 1a 
Screening 
Visit 2a 
Day 0 
Safety 
Contactb 
M 3 
M 6 
M 9 
M 12 
M 3 
continued 
follow-up 
M 6 
continued 
follow-up 
M 9 
continued 
follow-up 
M 12 
continued 
follow-up 
EOT/
EOSc 
Visit Windows (+/-)d 
3 to 8 wks 
prior to 
Day 0 
1 to 6 wks 
prior to 
Day 0 
 
±1 wk 
±2 
wks 
±2 
wks 
±2 
wks 
±2 
wks 
±2 
wks 
±2 wks 
±2 wks 
±2 wks 
±2 
wks 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/PBC Historye  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
Xe 
 
 
 
Xe 
X 
Vital Signs (including weight) 
Xf 
 
X 
 
X 
X 
X 
Xf 
 
X 
 
Xf 
Xf 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Subject Questionnaires 
(5-D Pruritus Scale and Pruritus 
VAS) 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Quality of Life Questionnaires  
(PBC-40, EQ-5D-5L, and FIS) g 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
TE Fibroscan®/DEXAh 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Endoscopyi 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Hepatic Ultrasoundj 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Physical Exam and Assessments for 
Mayo Risk and Child-Pugh Scoresk 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Adverse Events  
X 
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 
X 
Health Outcome Assessments l 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization/Treatment Assigned 
 
 
X 
 
 
 
 
 
 
 
 
 
 
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Table 1: 
Schedule of Study Procedures (Continued) 
Year 1 
Years 2 through End of Study 
Screening 
Visit 1a 
Screening 
Visit 2a 
Day 0 
Safety
Contactb 
M 3 
M 6 
M 9 
M 12
M 3 
continued 
follow-up 
M 6 
continued 
follow-up 
M 9 
continued 
follow-up 
M 12 
continued 
follow-up 
EOT/
EOSc 
Visit Windows (+/-)d 
3 to 8 wks 
prior to 
Day 0 
1 to 6 wks 
prior to 
Day 0 
 
±1 wk 
±2 
wks 
±2 
wks 
±2 
wks 
±2 
wks 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
±2 
wks 
Dose Titration (if applicable)m 
 
X
Dispense Investigational Productn 
X
 
X 
X 
X 
X 
X 
X 
X 
X
IP Accountability/Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSo 
Urinalysis  
X 
X 
X 
X 
X 
Urine-based β-hCG Pregnancy Testp 
X
X
Chemistry/Hematology/Coagulation
X
Xa
X
 
X 
X 
X 
X 
X
X
X
X 
X
OCA, C4, and FGF-19 (plasma) 
X
 
X 
X 
Xq 
X
X 
X
Markers of Hepatic Fibrosis and/or 
Inflammationr 
X
 
X
 
X
X
X 
X
Geneticss 
X
 
X
X 
Blood Sample for Future Analysist 
X
 
X
 
X
X
X 
X
β-hCG = beta human chorionic gonadotropin; DEXA = dual-emission X-ray absorptiometry; EOS= End of Study; EOT = End of Treatment; FGF = fibroblast growth factor-19; 
FIS= Fatigue Impact Score; IP = Investigational Product; M = month, wk = week 
a All subjects will have the chemistry panel retested to ensure subjects have 2 ALP and bilirubin assessments at least 2 weeks apart to calculate the mean result for both analytes. 
The mean of all screening ALP and bilirubin assessments will be used to determine eligibility.  Samples for hematology and coagulation will not be collected at Screening 
Visit 2. 
b The subject should be contacted by telephone on a monthly basis in between at-clinic study visits at Month 1 and Month 2 (± 1 week), and also 2 weeks post dose titration (up or 
down), to assess for AEs and concomitant medications and to verify that s/he is dosing as directed. 
c As soon as possible upon study discontinuation and as near as possible to last dose taken. 
d Visits should be based on Day 0 (not on the prior visit). 
e Medical history at Screening and the yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both.   
f Height will be collected at this visit. 
g The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2  and Section 12.2.6). 
h Transient elastography (TE) will be conducted at selected study sites where the Fibroscan® TE device is available.  Similarly, DEXA will be conducted at selected study sites 
where the DEXA device is available.   Please refer to Section 9.7.4 for additional information related to the allowed windows at Day 0 for these specific procedures. 
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i Endoscopy will be conducted at selected study sites where the device is available to assess for the presence of oesophageal varix/varices.  Please refer to Section 9.7.4 for 
additional information related to the allowed window at Day 0 for this specific procedure.  
j Ultrasound will be conducted to enhance  HCC surveillance. If a lesion is found, a second confirmatory image (eg, MRI) should be obtained.   Please refer to Section 9.7.4 for 
additional information related to the allowed windows at Day 0 for this specific procedure 
k 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 case report form.  Mayo Risk Score will be calculated based on central laboratory evaluations, diuretic use data, and peripheral edema assessment data captured in the CRF. 
l Health Outcome Assessments: Data related to non-study related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
m After 3 months of treatment with investigational product, the dose should be increased (in a blinded manner) based on tolerability; this may occur at the Month 3 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed.   
n Subject to begin dosing on Day 1 
o The subject should be instructed to fast overnight (at least 8 hours) prior to each visit (except Screening Visit 1).  Fasting is required prior to all study visits, but water is 
permitted. 
p Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry.  If positive, a confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not be enrolled in the study.  (Additional testing may be conducted where required, regionally). 
q Only OCA PK samples will be collected at Month 9 at select study sites in a subset of subjects.  Please refer to Section 9.7.9 for the PK sampling schedule. 
r Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
s A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12 
t Please refer to Section 11.1.2.3 for description of the blood sample to be collected for future analysis. 
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7.1.3. 
Study Duration 
The study is event driven and total duration will be determined by the time required to accrue 
approximately 121 primary endpoint events, estimated to be approximately 8 years.  Subjects are 
expected to have a minimum follow-up time of approximately 6 years. 
7.2. 
Number of Subjects 
It is expected that approximately 350 subjects will be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
7.3. 
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate to 10 mg OCA (in a blinded 
manner) at the 3-month study visit or at any study visit thereafter depending on tolerability.   
7.4. 
Dose Titration Criteria 
After 3 months of treatment at the 5 mg dose, the dose of OCA will be increased to the 
maximum dose of 10 mg OCA or matched placebo (in a blinded manner) at the 3-month visit or 
any study visit following the 3-month visit based on tolerability of investigational product.  For 
those subjects that increased their dose to 10 mg, they may decrease his or her dose to 5 mg at 
any time during the study as considered appropriate (eg, tolerability), but should be titrated back 
to 10 mg based on tolerability and clinical judgment by the Investigator as soon as possible with 
the goal that all subjects remain on the 10-mg dose if tolerated. 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
Investigational product may be temporarily decreased (ie, from 10 mg to 5 mg daily, or by 
alternate day dosing) 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 
(5 mg or 10 mg) once the issues relating to the lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated events has accrued.  If a subject reaches an 
event, he or she should continue the regular visit schedule and continue taking investigational 
product as long as the Investigator assesses it as safe.  In general, subjects should be strongly 
encouraged to both stay on investigational product and remain in the study until study 
termination.   
7.5. 
Criteria for Study Termination 
The Sponsor 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 DSMC, it may be necessary to stop the study before all events have been accrued, and 
when subjects are still active on the study.  In addition, the Sponsor may terminate the study at 
an investigational site at any time (eg, poorly performing sites, as determined by the number of 
subjects enrolled or the quality of the study data). 
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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 subjects for the End of Study Visit.  The window of time for 
scheduling the visit will be based on a final projection of when the requisite 121 adjudicated 
events will have been accrued. 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Population 
This study will be conducted at approximately 170 international study sites with experience in 
treating patients with PBC.  Prospective subjects 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. 
Subject Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with AASLD and EASL practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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. 
2. A mean total bilirubin >ULN and ≤3x ULN and/or a mean ALP >5x ULN  
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking 
UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0. 
5. Contraception:  Female subjects 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:   
• Double barrier method, ie, (a) condom (male or female) or (b) diaphragm, with 
spermicide; or  
• Intrauterine device (IUD); or  
• Vasectomy (partner), or  
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• Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection, or 
• Abstinence, if in line with the preferred and usual lifestyle of the subject)   
6. Must provide written informed consent and agree to comply with the study protocol 
8.3. 
Subject Exclusion Criteria 
1. History or presence of other concomitant liver diseases including:  
• Hepatitis C virus infection 
• Active hepatitis B infection; however, subjects 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 
• Nonalcoholic steatohepatitis 
• Gilbert’s Syndrome  
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including:  
• History of liver transplant, current placement on a liver transplant list, or current 
MELD score >12.  Subjects who are placed on a transplant list despite a relatively 
early disease stage (for example per regional guidelines) may be eligible as long 
as they do not meet any of the other exclusion criteria. 
• Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
− Variceal bleed 
− Uncontrolled ascites 
− Encephalopathy  
− Spontaneous bacterial peritonitis  
• Known or suspected hepatocellular carcinoma 
• Prior transjugular intrahepatic portosystemic shunt procedure 
• Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine 
>2 mg/dL (178 μmol/L)  
3. Mean total bilirubin >3x ULN  
4. Subjects who have undergone gastric bypass procedures (gastric lap band is 
acceptable) or ileal resection or plan to undergo either of these procedures. 
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5. Other medical conditions that may diminish life expectancy, including known cancers 
(except carcinomas in situ or other stable, relatively benign conditions such as 
chronic lymphatic leukemia). 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test by the central laboratory), or lactating. 
7. Known history of human immunodeficiency virus infection. 
8. Medical conditions that may cause non-hepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months). 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study. 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0. 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components. 
8.4. 
Subject Withdrawal from Investigational Product or Study Criteria 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product 
If a female subject becomes pregnant, she must discontinue taking investigational product, but 
should continue with the study visit schedule.  The subject must be followed as considered 
appropriate by the Investigator and the medical monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an AE.  The subject may reinstate investigational 
product after delivery and cessation of breastfeeding (if applicable) at the discretion of the 
Investigator.  Subjects whose pregnancy is terminated early (planned or unplanned) may be 
permitted to resume participation in the study if termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotropin (β-hCG) test performed at the central laboratory. 
8.4.2. 
Other Reasons for Discontinuation of Investigational Product  
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.  If a subject reaches an event, 
he or she should continue the regular visit schedule and continue taking investigational product 
as long as the Investigator assesses it as safe.  Subjects who choose to discontinue investigational 
product prior to termination of the study need to also continue to follow the regular visit schedule 
through to study closure.  In general, subjects should be strongly encouraged to both stay on 
investigational product and remain in the study until study termination.  Early termination 
procedures should only be conducted if the subject withdraws consent (See Section 9.7.14  Early 
Discontinuation and/or Early Termination Procedures). 
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The following events are considered appropriate reasons for a subject to discontinue 
investigational product; however, these subjects are expected to continue in the study until study 
termination and the study will only terminate at the time when the needed number of adjudicated 
events has accrued (or at the discretion of the Sponsor): 
• The Investigator or Sponsor considers that it is advisable or in the best interest of the 
subject. 
• The occurrence of clinical or laboratory AEs considered by the Investigator to be 
clinically important. 
• Withdrawal of consent 
− Consent may be fully withdrawn 
− 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 potential 
adjudicated hepatic and/or cardiovascular events. 
The Investigator must notify the Sponsor study monitor by telephone or email as soon as 
possible if any subject prematurely withdraws from the study.   
8.4.2.1. 
Withdrawal of Consent 
If the subject 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 subjects 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 subject discontinuation.  This 
information and date must be recorded in the appropriate case report form (CRF).   
8.4.2.2. 
Lost to Follow-up 
If a subject fails to return to the clinic for a study visit, and the Investigator ceases to have 
contact with the subject, he or she will be withdrawn from the study. 
A reasonable effort must be made to contact the subject and determine the reason(s) why a 
subject 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 CRF.   
8.4.3. 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by telephone or email as soon as 
possible if any subject prematurely withdraws from the study.  The date when the subject is 
withdrawn and the reason for discontinuation must be recorded in the CRF.  If a subject is “lost 
to follow up” (fails to return for a visit), a reasonable effort should be made to contact the subject 
in order to determine why the subject failed to return.  This information must be documented in 
the CRF.  If a subject is withdrawn from the study early (regardless of the cause), all of the 
EOT/EOS evaluations should be performed at the time of withdrawal, as appropriate (See 
Section 9.7.14  Early Discontinuation and/or Early Termination Procedures). 
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9. 
TREATMENT OF SUBJECTS 
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:  placebo and OCA.  Investigational product will be 
administered orally, once daily for the duration of the study.  Each dose will be made up of 
1 tablet (ie, one 5 mg OCA tablet or one 10 mg OCA tablet, or matching placebo).   
Investigational product will be taken orally, once daily.  Subjects will be instructed to begin 
dosing on the day after the Day 0 visit (ie, on Day 1) and to take investigational product at 
approximately the same time each day.  Subjects must be instructed to swallow the tablet whole; 
they must not chew, divide, or crush the tablet. 
9.1.1. 
Dose Adjustment Beginning at Month 3 
After 3 months of treatment with investigational product, the dose of investigational product 
should be increased in a blinded manner and based on tolerability; this may occur at the Month 3 
visit, or at any study visit thereafter.  Titration above 10 mg OCA is not permitted.   
9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.1) 
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 CRF, as well as any dose or dose 
regimen changes that occur during the study.  Concomitant medications should be stable prior to 
Day 0.   
Subjects taking bile acid sequestrants (BAS) 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). 
PBC Specific Therapy 
In general, 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 subjects’ 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, subjects 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, subjects should be reminded to keep taking their blinded 
investigational product. 
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9.2.1. 
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 and encourage the discontinuation of open-label OCA therapy.  However, if 
commercial OCA therapy remains, then investigational product should be discontinued to avoid 
potential double dosing.  Subjects that discontinue investigational product but continue 
commercial OCA therapy are expected to continue through the end of the study, and the study 
will only terminate at the time when the needed number of adjudicated events has accrued or at 
the discretion of the Sponsor.  Subjects will need to complete EOT procedures but continue with 
regularly scheduled visits until the study is terminated (See Section 9.7.14 Early Discontinuation 
and/or Early Termination Procedures). 
9.3. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Subjects should be instructed to retain all bottles of investigational product, even if empty, and to 
return them to the Investigator at the subsequent visit.  The Investigator or designee should 
perform investigational product accountability and, if applicable, follow up with the subject to 
retrieve any investigational product bottles that have not been returned.  
If the Investigator has concerns about a subject’s dosing compliance s/he should discuss this with 
the subject, assess the reasons for noncompliance and the likelihood that the subject will remain 
noncompliant, and notify the Sponsor accordingly. 
9.4. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Allocation to 1 of 
2 treatment groups (OCA or placebo) will occur on a 1:1 ratio across sites and will be stratified 
by UDCA treatment (yes/no) and mean baseline bilirubin categories (>ULN/≤ULN), as specified 
by the central laboratory.  The randomization will be based on a predefined randomization code 
(generated by the Sponsor or designee) using an interactive web response system (IWRS), which 
the Sponsor intends will serve as a computer-based subject registration system at Screening and 
Day 0.  The IWRS will serve as an investigational product inventory and management system 
and may be integrated with the study database.  
The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide subject data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned (refer to Section 9.5.2, below) and 
investigational product dispensing information (ie, bottle number[s]) will be provided. 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects will be made available to the Investigator for 
emergency use only 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 is necessary for further medical management of the 
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subject).  If it is not reasonable to inform the Medical Monitor in advance of unblinding the 
Investigator must promptly document in the subject’s source record and should subsequently 
contact the Medical Monitor to explain any premature unblinding of treatment assignment (such 
as unblinding which is necessary in order to treat an SAE). Procedures for unblinding a subject’s 
treatment will be provided separately to the Investigator.  Similarly, if the Medical Monitor 
breaks the blind for an individual subject for the purpose of evaluating an emergent safety issue, 
the Medical Monitor will document within trial documentation the rationale, circumstances, and 
the person or persons being informed about the unblinding. 
The Data and Safety Monitoring Committee (DSMC) will have access to the IWRS and will be 
able to unblind individual subjects.  Refer to Section 13.3 for further details regarding DSMC 
access to blinded and unblinded data.  The DSMC will document details about any unblinded 
subject data reviews in the closed session DSMC minutes, which will be made available to the 
Sponsor only after the database is locked and the trial is unblinded.   Cases of premature 
unblinding, as noted above, will also be reviewed by the DSMC.  
Access to treatment assignments will also be made available through the IWRS system to the 
appropriate named individual(s) responsible for reporting SAEs and suspected unexpected 
serious adverse reactions (SUSARs) to the Regulatory Authorities. 
9.5. 
Assignment of Site and Subject 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 subject data and to identify the site and or Investigator 
within study documents.  This number will be recorded in the CRF. 
9.5.2. 
Subject Numbers 
Subjects 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 3 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 trial is prohibited.   
9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visits should be based on Day 0 (not on the prior visit), eg, Month 3 should ideally occur 
3 calendar months (± 2 weeks) following Day 0.  The visit windows are as follows: 
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Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening visit 1 interval is 3 to 8 weeks prior to Day 0.  Screening 
visit 2 interval is 1 to 6 weeks prior to Day 0 for screening visit 1.  
Screening visit 2 interval is 1 to 6 weeks prior to Day 0.  The visit 
window for Screening 2 visits allows for the repeat biochemistry 
tests to be collected at least two weeks after the initial biochemistry 
sample was collected, and will ensure ample time to receive lab 
results.  The overall Screening interval is up to 56 days, but 
screening procedures should not be performed during the last 
7 days of the window.  
Day 0 
This is the day of randomization.  On-treatment visit scheduling 
should be calculated from this point going forward. (The first dose 
of investigational product should be taken the next day, on Day 1.) 
Months 3-12 
±2  week (14 days)  
Quarterly visits (Months 15 – EOS) 
±2 weeks (14 days) 
EOT 
(When subject discontinues investigational 
product) 
As soon as possible upon study discontinuation and as near as 
possible to last dose taken 
EOS 
(When subject terminates the study) 
The final study visit; EOS will occur concurrent with EOT if a 
subject discontinues study medication at the time the subject’s 
participation in the study ends (eg, withdrawal of consent or study 
termination by the Sponsor); EOS will occur after the EOT if the 
subject discontinues study medication  but continues in the study. 
EOT = end of treatment 
EOS = end of study 
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk and benefit of the 
study to the subject and will provide him/her with a copy of the written information and 
informed consent form (ICF).  The subject will be given sufficient time to consider the study 
before deciding whether or not to participate.  The subject 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 s/he can withdraw from the study at any time.  The subject must be willing and 
able to provide written informed consent before entering the study.  The Investigator or a 
medically qualified designee is responsible for administering and documenting the written 
informed consent of the subject.  The subject will be given a copy of the written information and 
his/her signed and dated consent form. 
Any change in a subject’s consent status (eg, semi-annual telephone contact or medical record 
review) must be documented in a signed informed consent form or addendum.  The subject will 
be given a signed and dated copy of the consent document. 
9.7.3. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 to 8 weeks prior to Day 0 to determine 
whether the subject meets all the inclusion criteria and none of the exclusion criteria.  Screening 
Visit 1 will occur 2 to 8 weeks prior to Day 0; Screening Visit 2 will occur 1 to 6 weeks prior to 
Day 0, depending on the date that the first serum chemistry sample was collected. Subjects who 
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do not fulfill all eligibility criteria will not be enrolled in the study.  Subjects 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 3-digit Screening number assigned.   
Two Screening visits will occur from 1 to 8 weeks prior to Day 0 (as outlined below) allowing 
for the collection of repeated serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values: 
• All subjects will have 2 bilirubin and  ALP assessments at least 2 weeks apart. 
• The mean of all available (at least 2; including both scheduled and 
unscheduled) bilirubin and ALP assessments will be used to determine eligibility 
(total bilirubin >ULN and ≤3x ULN and/or an ALP >5x ULN).   
Screening Visit 1 procedures are as follows: 
• The subject is to review and sign the ICF.  Informed consent must be obtained from 
the subject 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, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Assess and record any pretreatment-emergent AEs. 
• Record prior (if within 30 days of Screening) and current concomitant medications. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
Screening Visit 2 procedures are as follows: 
• Verify inclusion and exclusion criteria for eligibility. 
• Assess and record any pretreatment-emergent AEs. 
• Record current concomitant medications. 
• Verify that the subject has fasted for at least 8 hours. 
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− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
•
Obtain blood samples for serum chemistry tests.
•
The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.
Fasting is required prior to all study visits, but water is permitted.
•
In preparation for the dual-emission X-ray absorptiometry (DEXA) bone density scan
to be done at Day 0 (selected study sites only), subjects who are taking calcium
supplements should stop taking them for 48 hours before the scan.  If the subject is
taking any medications for osteoporosis or osteopenia, s/he should not take them on
the day of the scan.
It is acceptable to repeat laboratory evaluations or other assessments or procedures within the 
Screening period (Weeks -8 to -1), as appropriate. 
9.7.4. 
Day 0 Procedures (Randomization) 
•
Review inclusion and exclusion criteria for eligibility.
•
Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory
rate, and sitting blood pressure).
•
Subject and Quality of Life questionnaires (see Section 11.1.2.2 and Section 12.2.6).
•
Perform transient elastography (TE; at selected study sites, where available) using the
Fibroscan® TE device.  If TE has been done within 6 months of Day 0 and a
report/adequate data are available, a pretreatment TE at Day 0 is not required.  If the
TE cannot be performed on Day 0 (e.g., device/technician unavailability, scheduling
issues, etc), the procedure may be completed within the screening visit window, as
close as possible to the Day 0 visit, after subject eligibility has been confirmed.
•
Conduct a DEXA bone density scan (at selected study sites, where available);
document whether the subject stopped taking her/his calcium supplements for
48 hours before the scan and medications for osteoporosis or osteopenia on the day of
the scan, if applicable.  If DEXA has been done within 12 months of Day 0 and a
report/adequate data are available, a pretreatment DEXA at Day 0 is not required. If
the DEXA cannot be performed on Day 0 (e.g., device/technician unavailability,
scheduling issues, etc), the procedure may be completed within the screening visit
window, as close as possible to the Day 0 visit, after subject eligibility has been
confirmed.
•
Perform an esophagogastroduodenoscopy (endoscopy; at selected study sites, where
available) to assess the presence or absence of oesophageal varix/varices.  If an
endoscopy has been done within 12 months of Day 0 and a report/adequate data are
available, a pretreatment endoscopy at Day 0 is not required. If the endoscopy cannot
be performed on Day 0 (e.g., device/technician unavailability, scheduling issues, etc),
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the procedure may be completed within the screening visit window, as close as 
possible to the Day 0 visit, after subject eligibility has been confirmed. 
− Subsequent endoscopies should be performed annually or per standard of care and 
the Investigator’s clinical judgment throughout the course of the study.  
Endoscopies should also be performed when platelet counts are <150 x 109 /L. 
• 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 Day 0 and a report/adequate data are available, a 
pretreatment ultrasound at Day 0 is not required. If the ultrasound cannot be 
performed on Day 0 (e.g., device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening visit window, as close as 
possible to the Day 0 visit, after subject eligibility has been confirmed. 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Assess and record any pretreatment-emergent AEs. 
• Review and record prior concomitant medications. 
• 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. 
• Randomize the subject only if s/he meets all inclusion criteria and no exclusion 
criteria. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• 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 tests. 
• Obtain blood samples for:  
− OCA, C4, and fibroblast growth factor-19 (FGF-19) 
− Markers of hepatic fibrosis and/or inflammation (including enhance liver fibrosis 
[ELF]) 
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− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Access the IWRS and dispense investigational product. 
• Instruct the subject to begin dosing on the day after the Day 0 visit (ie, on Day 1).  
Instruct the subject to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
9.7.5. 
Safety Contact (Month 1, Month 2, and 2 Weeks Post-Titration [by telephone]): 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Assess investigational product compliance. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 3 Procedures 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 and perform investigational product 
accountability. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
•  Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
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− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests.  
• Obtain blood samples for: 
− OCA, C4, and FGF-19 
• Schedule the next visit and assess the subject’s supply of investigational product to 
ensure an adequate amount.  Access the IWRS and dispense investigational product if 
necessary. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 6 Procedures 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.6) 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 and perform investigational product 
accountability. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Verify that the subject has fasted for at least 8 hours. 
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− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
• For subjects who will participate in the PK assessment and are taking BAS or 
aluminum hydroxide- or smectite-containing antacids, they should be instructed to 
not take their regular dose on the morning of the study visit.   
9.7.8. 
Month 9 Procedures 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 and perform investigational product 
accountability. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
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• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• PK assessment in participating subjects at select study sites (see Section 9.7.9). 
• In preparation for the DEXA bone density scan to be done at the Month 12 visit 
(selected study sites only), subjects who are taking calcium supplements should stop 
taking them for 48 hours before the scan.  If the subject is taking any medications for 
osteoporosis or osteopenia, s/he should not take them on the day of the scan. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic Assessment 
At selected investigational sites, subjects will have the option to consent to participate in an 
additional OCA PK assessment.  PK samples will be used to support further analysis of OCA 
exposure-response in subjects with PBC.  This is optional and subjects may decline to participate 
without affecting their involvement in the rest of the study.  Consent to participate in the 
assessment can be given at any point during study participation prior to the Month 9 visit. 
Following collection of the Month 9 fasted samples (refer to Section 9.7.8 , subjects who are 
participating in the PK assessment will each receive a single dose of investigational product 
(blinded OCA or placebo tablet) with approximately 240 mL of water.  Subjects taking BAS or 
aluminum hydroxide- or smectite-containing antacids should be instructed to stagger their dosing 
of study medication and UDCA, ensuring at least 4 hours between doses of the BAS and/or these 
antacids and the study medication (and UDCA).   
Serial blood samples will be obtained for measurement of OCA and its conjugates prior to 
dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours post dose.  Samples should be collected 
within a window of ±5 minutes of the scheduled sample time.  Subjects should not drink 
additional water for 1 hour after taking the dose of investigational product and will remain fasted 
until the 4 hour sample is collected.  Lunch will be provided following collection of the 4 hour 
PK sample; the lunch will be a meal replacement drink.  Samples will be stored for up to 5 years 
after the end of the study and will be destroyed after 5 years if not analyzed. 
9.7.10. 
Month 12 Procedures 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Assess and record vital signs (height ,weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Subject and Quality of Life questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform TE (at selected study sites, where available) using the Fibroscan® TE device. 
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• Conduct a DEXA bone density scan (at selected study sites, where available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable. 
• Perform an endoscopy (at selected study sites, where available) to assess the presence 
or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 and perform investigational product 
accountability. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for: 
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
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• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 weeks]) 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 and perform investigational product 
accountability. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 6 Continued Follow-up Procedures (Semi-annually [±2 weeks]) 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.6) 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
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− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 (refer to Section 7.4). 
• Assess investigational product compliance and perform accountability. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− Markers of hepatic fibrosis and/or inflammation (including ELF). 
− Blood sample for future analysis (refer to Section 11.1.2.3). 
• At the semi-annual visit, in preparation for the DEXA bone density scan to be done at 
the annual visit (selected study sites only), subjects who are taking calcium 
supplements should stop taking them for 48 hours before the scan.  If the subject is 
taking any medications for osteoporosis or osteopenia, s/he should not take them on 
the day of the scan. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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 
9.7.13. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Assess and record vital signs (height, weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
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• Subject and Quality of Life questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform TE (at selected study sites, where available) using the Fibroscan® TE device. 
• Conduct a DEXA bone density scan (selected study sites); document whether the 
subject stopped taking her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the scan, if applicable. 
• Perform an endoscopy (at selected study sites, where available) to assess the presence 
or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 (refer to Section 7.4). 
• Assess investigational product compliance and perform accountability. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
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− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
9.7.14. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent 
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects discontinue treatment with investigational 
product.  The EOT visit and procedures listed below must be performed as close as possible to 
the subject’s last dose of investigational product.  When a subject discontinues investigational 
product but continues with regularly scheduled study visits, the EOS visit will be completed later 
in the study as the subject’s final study visit.  The actual investigational product discontinuation 
scenario (Table 2) will determine the sequence of the EOT and EOS visits and procedures.  In 
some cases, the EOT visit and procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible to the subject’s last dose of 
investigational product.   
When a subject ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (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 subject 
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 and EOS procedures in the CRF.  
 
 
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Table 2: 
Early Discontinuation Scenarios 
 
EOS = end of study; EOT = end of treatment; IP = investigational product 
a Refer to Section 7.1.2 Schedule of Study Procedures for all procedures and evaluations required at the End of 
Treatment and End of Study Visits. 
b Outcomes data to be discussed or collected include data related to adjudicated hepatic and cardiovascular event-
related data.  No additional data (e.g. AE, concomitant medication, etc) data will be collected, except as indicated 
in Section 12.1.6. 
Some assessments noted below may be omitted if they have been completed within the 6 months 
(or the timeframe otherwise specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT/EOS Visit: 
If possible to do before the visit, when scheduling the EOT/EOS visit, reiterate dosing 
instructions and advise the subject: 
• If applicable, NOT to take investigational product on the morning of the next visit, 
and  
• To bring the investigational product bottle(s); if applicable, s/he will dose at the 
clinic, and 
 
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 IP 
Treatment 
Discontinuation 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
Discontinued 
Semiannual 
contactb 
Telephone 
contact every 6 
months (±2 
weeks) 
Combined Visit, Completed as 
close as possible to last dose IP 
Discontinued 
Record 
review 
onlyb 
Record review 
only 
Combined visit 
Completed as close as possible 
to last dose IP 
Sponsor Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit 
Completed as close as possible 
to last dose IP 
Pregnancy 
Interrupted 
Retained 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
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 
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• To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior to 
all study visits, but water is permitted. 
During the EOT/EOS Visit: 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Assess and record vital signs (height, weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead ECG. 
• Subject and Quality of Life  questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform TE (where available) using the Fibroscan® TE device (not required at 
EOT/EOS if done within 6 months). 
• Conduct a DEXA bone density scan (selected study sites; not required at EOT/EOS if 
done within 6 months); document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites); not required at 
EOT/EOS if done within 6 months. 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Assess and record AEs; all ongoing “related” AEs must be followed until stable or 
resolved. 
• Review and record concomitant medications. 
• 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 and perform accountability; retrieve used 
bottles, accordingly, and document returns. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
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• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
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.   
In the event of an inexplicable and acute (for example not explained by natural progression of the 
chronic disease) increase in alanine aminotransferase (ALT) to >3× baseline (and >upper limit of 
normal [ULN]) or total bilirubin >2× baseline (and >ULN), the subject should be followed by 
repeat testing within 48 to 72 hours of the serum chemistry to confirm the abnormalities and to 
determine if they are increasing or decreasing. AE information should also be collected.  If 
symptoms persist or repeat testing shows ALT >3× baseline (and >ULN) or total bilirubin 
>2× baseline (and >ULN), subjects should be followed until resolution of the abnormality and as 
clinically indicated depending on other laboratory and clinical signs and symptoms. 
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 5 mg or 10 mg OCA 
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 subject at each visit to provide enough tablets for daily 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. 
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10.3. 
Investigational Product Storage 
The investigational product should be stored in the containers in which they are received from 
the Sponsor’s supplier, at controlled room temperature, and protected from excess humidity. 
10.4. 
Investigational Product Preparation 
The investigational product will be provided to the distribution center in bulk bottles and 
therefore may be repackaged in unit dose form for administration to subjects before shipping to 
the sites. 
10.5. 
Investigational Product Administration 
Refer to Section 9.1. 
10.6. 
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 subject 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. 
11. 
ASSESSMENT OF EFFICACY 
11.1. 
Assessment of Efficacy  
11.1.1. 
Primary Assessments 
The following primary efficacy assessments will be measured: 
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
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• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of 2 or greater) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities. 
11.1.2. 
Secondary Assessments 
The following secondary efficacy assessments will be measured: 
• Liver-related death 
• Liver biochemistry (see Table 5 for list of analytes to be tested) 
• Biomarkers, including markers of hepatic fibrosis and/or inflammation, to be tested 
will include:  IgM, c-reactive protein (CRP), tumor necrosis factor-α (TNF-α), 
FGF-19, cytokeratin-18 (CK-18) and ELF, Fibroscan (and others as determined 
during the course of the study). 
• Data will be collected to inform quality of life and cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Quality of life will be 
assessed by questionnaires (PBC-40, EQ-5D-5L, and FIS) administered annually.  
Resource utilization information will be collected from the Medical and Surgical 
Treatment Procedures and Office Visit Log or other CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician visits (subject reported), 
and use of concomitant medications.  
• Endoscopy will be conducted at selected study sites where the device is available to 
assess for the presence of oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual study assessments or standard 
of care will be collected in the case report form to assess for the development of 
varix/varices. 
11.1.2.1. Non-Invasive Assessments of Liver Fibrosis 
• Blood samples for measurement of ELF™ test and other analytes will be collected.  
The ELF test assesses: hyaluronic acid (HA), procollagen-3 N-terminal peptide 
(P3NP), and a tissue inhibitor of metalloproteinase 1 (TIMP-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.   
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11.1.2.2. Other 
• OCA (and its conjugates) and C4 will be assayed. 
• Quality of Life questionnaires. 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 (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 respondent’s self-rate 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). 
− Fatigue Impact Scale (FIS):  The FIS is a validated 40 question questionnaire 
organized into 3 dimensions:  cognitive, physical, and social.  Each dimension has 
5 levels:  no problem, small problem, moderate problem, big problem, and 
extreme problem (Fisk 1994). 
11.1.2.3. Other Exploratory Evaluations 
• A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved 
in PBC will be conducted for subjects and at study sites willing to provide samples at 
Day 0, Month 12, and every other year at the yearly visits thereafter.  RNA 
expression resulting from treatment with OCA will be assessed at indicated 
timepoints during the study.   Subjects will be permitted to decline to provide a blood 
sample for the genetics study, without affecting their involvement in the study.  
IRB/IEC review and approval will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will be stored for up to 1 year 
after the end of the study and destroyed after 1 year if not analyzed. 
• Blood samples for future analysis of additional analytes, such as PBC autoantibodies 
and other cytokines and interleukins, may be assayed on an exploratory research 
basis.  Blood samples may also be used to assess other disease or investigational 
product characteristics.  Appropriate serum and plasma samples will be collected at 
selected time points during the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their involvement in the study.  IRB/IEC 
review and approval will be required and willing subjects must specifically consent to 
participate in this evaluation.  The samples will be stored for up to 1 year after the end 
of the study and destroyed after 1 year if not analyzed. 
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11.1.2.4. Potential Clinical Outcome Events 
The events listed in Appendix A 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 13.4) to confirm if they meet the criteria to be considered 
Clinical Outcome Events.  
12. 
ASSESSMENT OF SAFETY 
12.1. 
Adverse Events and Serious Adverse Events 
12.1.1. 
Definition of Adverse Events  
12.1.1.1. Adverse Event  
An AE is 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) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction. 
Subjects should be questioned in a general way, without leading the subject 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. 
12.1.1.2. 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-subject 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 subject 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. 
12.1.1.3. Treatment-Emergent Adverse Event  
A treatment-emergent AE (TEAE) is any event not present prior to the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
12.1.2. 
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 3.  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/serious adverse event (SAE) and the investigational product is 
determined to be “possible” or “probable” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 
Table 3: 
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 subject’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 
A reaction 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 subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
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12.1.3. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 4, must be entered on the AE CRF.  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 4: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Causing no limitation of usual activities; the subject may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the subject may experience annoying 
discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the subject may experience intolerable 
discomfort or pain. 
12.1.4. 
Reporting of Adverse Events and Serious Adverse Events 
12.1.4.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
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 subject’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE CRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product. 
12.1.4.2. 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 medical monitor.  
 MD, PhD 
Telephone:  
 (Pacific time zone) 
Mobile:  
 (Pacific time zone) 
Email: 
 
SAE Fax:  +1 800 497 8521  
SAE Email:  sae@interceptpharma.com 
Alternate Contact: 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
 
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All SAEs occurring while subjects are receiving investigational product or are on an 
investigational product holiday (including Potential Clinical Outcome Events that qualify as 
serious) must be reported to the medical monitor immediately (ie, within 24 hours) after the 
Investigator identifies the SAE.  SAEs are reported by entering the SAE data into the electronic 
data capture (EDC) system.  Entering the SAE data into the EDC system will automatically 
notify the medical monitor of the event.  In the event that the EDC system is inaccessible, an 
SAE may be reported by telephone or fax using a paper SAE Report form.  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:  subject number and initials, a description of the event, at least one 
criterion classifying the event as serious and the name and title of the reporting individual.  
Additionally, judgment of causality by the Investigator must be provided as soon as possible to 
ensure timely reporting to regulatory authorities by the Sponsor or designee(s).  Following the 
initial report, any additional information obtained by the Investigator about the SAE must be 
reported promptly to the medical monitor.  Any supporting source documentation should be 
faxed to +1 800 497 8521 or emailed to sae@interceptpharma.com as soon as possible. 
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.  A SAE assessed 
with a possible, probable, or definite causal relationship to the investigational product and 
unexpected according to IB Reference Safety Information (RSI), is known as a suspected 
unexpected serious adverse reaction (SUSAR).  The Sponsor will notify the appropriate 
regulatory agencies as well as all participating Investigators of investigational new drug (IND) 
safety reports (SUSARs) that occur during the study within the time frames required by each 
regulatory agency.  The Investigator is responsible for submitting information on IND safety 
reports/SUSARs received from the Sponsor or Sponsor designee to her/his local EC/IRB.  
Documentation of the submissions to IRBs and health authorities must be retained in the 
appropriate study file(s). 
Potential Clinical Outcome Events (Appendix A) as well as Anticipated Events (Appendix B) 
will not undergo expeditious reporting to regulatory authorities. 
12.1.5. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the CRF 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 subject’s AE CRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the medical monitor, 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 subject 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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12.1.6. 
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 medical monitor should be notified 
immediately (ie, within 24 hours). 
All SAEs that occur within 30 days following the cessation of investigational product, whether 
or not they are related to the study, must be reported to the Sponsor within 24 hours by following 
the instructions provided in Section 12.1.4.2. 
SAEs that occur more than 30 days after a subject has discontinued study medication, and are not 
considered related to investigational product, must still be reported in the EDC system; however, 
these events are not required to be reported within 24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to investigational product, action taken with study 
medication, treatment, outcome, and potential endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event summary, SAE details) may also be required to be 
entered, when requested by the sponsor. 
12.1.7. 
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 subject 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 subject 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 CRF.  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. 
12.1.8. 
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 and the Sponsor must be notified within 24 hours of the Investigator’s learning of the 
pregnancy by completing the Pregnancy Notification Form and faxing or emailing to the Sponsor 
at +1 800 497 8521 or sae@interceptpharma.com.  
Safety will be monitored and assessed by AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and clinical laboratory assessments. The Sponsor may 
also follow the health of an infant born subsequent to use of investigational product. 
The subject may reinstate investigational product after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  Subjects whose pregnancy is terminated early 
(planned or unplanned) may be permitted to resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test (see Section 8.4.1). 
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12.2. 
Other Safety Parameters 
12.2.1. 
Medical History/Demographics 
A complete medical history and PBC disease-specific history will be obtained from the subject at 
Screening.  Smoking and alcohol consumption history and current habits will be recorded.  
Demographic characteristics (age, gender, race, and ethnicity) will be recorded. 
12.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the timepoints specified in the Schedule of Study Procedures (Section 7.1.2).  A basic physical 
examination should be performed, including all body systems pertinent to the subject.  Any 
clinically significant abnormality should be reported on the AE CRF page for findings that 
appear after consent, and on the medical history CRF for any finding present prior to consent.  
Information about smoking and alcohol consumption habits will be collected at the same 
(follow-up) timepoints as the physical exam. 
12.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits: height, weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure.  When taking heart rate, respiratory rate, and blood 
pressure readings, subjects should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
12.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected at the Screening visit 1 and at EOT/EOS.  The 
Investigator or designee will review the 12-lead ECG and findings will be recorded in the CRF 
as normal, abnormal but not clinically significant, or abnormal and clinically significant.  Any 
clinically significant abnormality on ECGs should be reported on the AE CRF page.  
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 subject’s initials, Subject ID number, 
date, and time. 
12.2.5. 
Dual Emission X-Ray Absorptiometry 
A bone density assessment will be done using the DEXA scan. 
12.2.6. 
Subject Questionnaires 
Information about the subject’s PBC disease history (ie, date of diagnosis, treatment history, 
pruritus history, signs and symptoms, and including smoking history) will be collected during 
Screening.  At subsequent study visits (see Section 7.1.2), subjects will be asked to complete the 
following questionnaires; they may be asked to initial and date to document confirmation of their 
responses, and the questionnaires should be filed in the subject’s study records.  These may 
require transcription to the CRF by study site staff. 
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• 5-D Pruritus Questionnaire:  This is a questionnaire that has been validated in several 
different diseases.  It assesses symptoms in terms of 5 domains: degree, duration, 
direction, disability and distribution (Elman 2010). 
• Pruritus VAS:  A Visual Analogue Scale (VAS) will also be used to assess pruritus in 
individual subjects. 
12.2.7. 
Laboratory Assessments 
Subjects will be instructed to attend each of their study visits (except Screening) in a fasted state, 
and subjects should remain fasted until their blood samples have been collected.  At each visit, 
the Investigator or designee will verify that the subject has fasted for at least 8 hours and record 
fasting status in the source and CRF.  If the subject reports having eaten (water is permitted) 
within 8 hours, the Investigator or designee will document accordingly in the source and CRF 
and remind the subject that fasting is required prior to all study visits. 
Blood samples for serum chemistry and hematology will be collected at every visit as detailed in 
the Schedule of Study Procedures (Section 7.1.2).  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 by the central clinical laboratory in a study specific laboratory 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 subjects 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 5. 
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Table 5: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry  
Albumin, blood urea nitrogen (BUN), 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 very low density 
lipoprotein [VLDL] fractions and triglycerides[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, HBE [MCH], MCHC) 
Coagulation 
Prothrombin time (PT), partial thromboplastin time 
(PTT), international normalized ratio (INR) 
Urinalysis 
pH, specific gravity, total  protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, 
albumin, creatine, leucocytes, nitrates, 
albumin/creatine ratio (if positive) 
Biomarkers of Hepatic Fibrosis and/or Inflammation  
IgM, C-reactive protein (CRP), TNF-α, FGF-19, CK-
18, ELF, and others as determined during course of 
study  
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Genetics 
DNA including single-nucleotide polymorphisms 
(SNPs) that may be involved in PBC; RNA 
Blood Sample for Future Analysis 
PBC autoantibodies and other cytokines and 
interleukins TBD 
Other 
OCA (parent and conjugates [glyco and tauro]) and C4 
The Investigator should manage subjects with clinically significant lipoprotein abnormalities 
using local standard of care procedures as appropriate after assessing the individual subject’s 
total cardiovascular risk profile. 
Urine-based β-hCG pregnancy tests will be performed in female subjects of childbearing 
potential per protocol specified visits.  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 
subject will be followed, as outlined in Section 12.1.8 through pregnancy outcome. 
MELD scores, Child-Pugh score and MRS will be calculated at quarterly (MELD scores only) 
and semi-annual visits based on serum chemistry and coagulation. 
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13. 
STATISTICAL METHODS 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
hypothesis tests, will be prepared and approved by the Sponsor and its designees prior to study 
database lock, propensity score determination, and unblinding of the double-blind subject 
treatment assignments.  
13.1. 
Efficacy Analysis 
13.1.1. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
• The Randomized Population will include all randomized subjects. 
• The Intent-to-Treat (ITT) Population will include all randomized subjects who 
receive any amount of investigational product (OCA or placebo).  The ITT 
Population will be the primary population used for efficacy analyses.  Treatment 
assignment will be based on the randomized treatment. 
• The Safety Population will include all subjects who received any amount of 
investigational product (placebo or OCA).  The Safety Population will be the primary 
population used for safety analyses.  Treatment assignment will be based on the 
treatment actually received. 
• The PK population will include all OCA subjects who have at least one confirmed 
fasted analyzable sample.  Subjects must have been fasting for approximately 8 hours 
prior to the visit and must not have any major protocol deviations that potentially 
affect exposure levels.  The PK population will be used for OCA PK analyses.  
• The Overall Historical Control Population will include subjects from the United 
Kingdom (UK) -PBC Group and Global PBC Study Group databases with 
demonstrated comparability to randomized subjects in this clinical study (747-302) 
with respect to both subject characteristics and disease progression. 
• The UK-PBC Historical Control Population will include subjects from the UK-PBC 
Group databases with demonstrated comparability to randomized subjects in this 
clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
• The Global PBC Historical Control Population will include subjects from the Global 
PBC Study Group database with demonstrated comparability to randomized subjects 
in this clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
13.1.1.1. Comparability of Historical Controls 
Utilization of both historical control/observational databases (UK-PBC and Global PBC Study 
Group), with more than 6000 subjects each, allow for a rigorous subject level meta-analysis.  The 
historical databases include long-term follow up, detailed subject-level information such as 
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baseline clinical characteristics, longitudinal liver biochemistry, and long-term outcomes, and 
span a broad range of subject characteristics that may influence disease (disease state, age, 
gender, and regional differences in standard of care).  Historical controls from both databases 
will be chosen based on the same study inclusion/exclusion criteria where possible. 
13.1.2. 
Determination of Sample Size 
The following assumptions were used in sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.5 at 8 years with a hazard 
ratio of 0.60, and total study duration of 8 years, allowing for 2 years accrual and 
6 years of follow up. 
• 5% of the subjects will have never been treated with UDCA; 95% of the subjects will 
have been on UDCA for at least 1 year. 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance. 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
13.1.2.1. Sample Size Re-Estimation Plan 
Conducting a long-term outcomes study given the low disease prevalence, relatively slow 
disease progression, and ethical considerations, which in combination will impact recruitment 
and event rates, is inherently difficult.  As stated in ICH E9, in long-term trials there is an 
opportunity to check the assumptions that underlay the original design and sample size 
calculations.  The power stated above depends on the total number of events.  Thus, the overall 
survival function can be estimated without unblinding. 
Therefore, starting approximately 2 years after the first subject is randomized, the aggregate 
event rate and sample size based on recruitment and retention will be evaluated in a blinded 
manner quarterly.  This evaluation will determine if any increases in number of subjects are 
required in order to obtain a total of 121 adjudicated events for the final analysis in the combined 
groups.  Specifically, the pooled number of events will be available during the study in a blinded 
manner, without any knowledge of the comparative efficacy in the treatment groups.  This 
method for evaluating the sample size does not inflate the type I error rate.  Additional subjects 
may be enrolled as appropriate. 
If after 4 years of accruing subjects, despite increases in the number of subjects, it is determined 
that at least an additional 2 years (ie, total study duration of at least 10 years) are needed to 
randomize sufficient subjects to achieve a total of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label OCA.  Previously randomized subjects will 
continue to be treated in a blinded manner with either OCA or matching placebo.  If this 
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modification is implemented, the alternative primary efficacy analysis is specified is 
Section 13.1.9. 
Any revised sample size or changes to treatment allocation will be justified and documented in a 
protocol amendment and in the CSR. 
13.1.3. 
Primary Efficacy Analysis 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
• Liver transplant 
• MELD score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities. 
The primary efficacy analysis will compare randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the ITT population.  Only adjudicated events will 
be included in analyses.  The 2 treatment groups will be compared 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 determined based on a 
Cox regression model stratified by randomization strata to estimate the magnitude of the effect. 
13.1.4. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints will compare OCA to placebo on the following: 
• Time to first occurrence of MELD score ≥15 
• Time to liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare randomized OCA to randomized placebo in 
ITT population with respect to the key secondary efficacy endpoints.  Only adjudicated events 
will be included in time-to-event analyses.  The comparison (hypothesis testing) will be 
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conducted as specified in Section 13.1.11 in a sequential closed testing gate-keeping procedure, 
provided that the primary efficacy endpoint comparison is statistically significant in favor of the 
OCA treatment group.  If the primary comparison is not statistically significant then comparison 
of the secondary endpoints will be considered as descriptive and exploratory.  This procedure 
controls the study-wise type I error. 
The 2 treatment groups will be compared using the same methodology as specified for the 
primary efficacy analysis (Section 13.1.3). 
Analyses of change from Baseline to end of study in ALP and total bilirubin will be compared 
between treatment groups using analysis of covariance (ANCOVA) with change from Baseline 
as the dependent variable including treatment group and randomization stratification factor as 
fixed effects and the Baseline values as a covariate.  The same analysis will be carried out using 
percentage change from Baseline as the dependent variable. 
Descriptive statistics of the laboratory values will be summarized by treatment group.  The 
results, change from Baseline, and percentage change from Baseline values as well as estimates 
of least-square means, standard errors, and 95% CIs will be presented by treatment group.  
Estimates of the mean difference between treatment groups, the standard error of the difference, 
and 95% CI of the difference will be presented. 
13.1.5. 
Additional Secondary Efficacy Analyses 
The following time to event secondary efficacy analyses will compare randomized OCA versus 
randomized placebo using the ITT population: 
• Time to each component of the primary efficacy endpoint (except MELD score ≥15 
which is captured above) 
• Time to development of varix/varices 
• Time to liver-related death 
• Time to liver-related death or liver transplant 
• Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls as described below in Section 13.1.8. 
Analyses of changes in liver biochemistry (GGT, ALT, AST, conjugated bilirubin, albumin, and 
INR) will be summarized and analyzed using the same methodology as specified in 
Section 13.1.4 for the key secondary analyses of change in ALP and total bilirubin. 
Analyses of changes in MELD score, Child-Pugh score, Mayo Risk Score (MRS), IgM, CRP, 
TNF-α, FGF-19, CK-18, C4, and ELF score will be summarized and analyzed using the 
Wilcoxon Rank Sum Test to compare treatment groups.  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. 
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13.1.6. 
Exploratory Efficacy Analyses 
13.1.6.1. Responder Analyses 
The percentage of subjects with a decrease in ALP of ≥15% and ≥40% from Baseline will be 
summarized by treatment group.  In addition, the percentage of subjects with ALP ≤ULN will be 
summarized by treatment group. 
The percentage of subjects that meet the criteria of a responder based on each of the definitions 
below will be summarized by treatment group.  The response classification at baseline will also 
be included in the summary:  
• ALP ≤3x ULN and AST ≤2x ULN and total bilirubin ≤ULN (Corpechot 2008) 
• ALP ≤1.5x ULN and AST ≤1.5x ULN and total bilirubin ≤ULN (Corpechot 2011) 
• ALP ≤1.67x ULN and total bilirubin ≤ULN (Momah 2012) 
• Normal bilirubin (values ≤ULN) and normal albumin (values ≥lower limit of normal) 
(Kuiper 2009) 
• ALP ≤1.76 x ULN (Kumagi 2010) 
Responder analyses will compare treatment groups using a Cochran–Mantel–Haenszel test 
stratified by the randomization stratification factor.  Missing values will be considered as a 
non-responder.   
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints 
Sufficient data will be collected on resource utilization and quality of life to undertake 
cost-effectiveness analyses that are relevant to the major countries taking part in this study.  
Resource utilization data on hospitalizations, healthcare provider visits, and medications will be 
combined with appropriate national unit costs to calculate a cost per patient per year in the study. 
Quality of life data from patient-reported outcomes measures will be combined with survival 
data to calculate quality adjusted time in the study per patient.  Cost-effectiveness analyses will 
report the incremental cost per major clinical outcome averted, liver-related death averted, 
life-year gained and quality-adjusted life year gained, including OCA as part of usual care versus 
usual care without OCA.  Analyses will be conducted within the study and using a lifetime 
perspective.  A separate economic analysis plan will be prepared and reported separately from 
this protocol. 
13.1.8. 
Supportive Analysis 
Per the International Conference on Harmonisation (ICH) E10 guidance, “where no obvious 
single optimal external control exists, it may be advisable to study multiple external controls”.  
In order to address the risks associated with the inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare clinical outcomes in the OCA treatment arm to 
historical controls.   
In an attempt to avoid the inherent biases with historical controls and to maintain the integrity of 
this comparison, one can invoke matching methods to optimize comparability and find a 
historical control that is “similar” to a participating subject.  The historical database control 
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should be as similar as possible to the study population and should have been exposed to a 
similar standard of care (see Section 5.5.2.2). 
A propensity score can be used to reduce bias through matching, stratification, regression 
adjustment, or some combination.  Propensity scores use information from a pool of patients who 
do not participate in the study (historical controls) to identify what would have happened to 
participating subjects in the absence of the treatment.  By comparing how outcomes differ for 
treated subjects relative to historical controls, it is possible to estimate the effects of the 
treatment. 
Although it might be relatively simple to assign a historical control based on a single observable 
characteristic, in practice, if the matching process is to successfully mitigate potential bias, it has 
to be done considering a full range of covariates across which the treatment and historical 
controls might differ.  Although the results of using matching controls are conditional only on 
the observed covariates, if one has the ability to measure many of the covariates that are believed 
to be related to the treatment assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained.  Both UK-PBC Group and the 
Global PBC Study Group formally collect numerous covariates that could be used for propensity 
score estimation including standard of care, eg, UDCA. 
Historical controls will be chosen based on the same inclusion/exclusion criteria where possible. 
Propensity scores will be estimated using the available covariates that predict receiving the 
treatment.  Only covariates and not outcome variables will be included in the propensity score 
estimation.  Therefore, there is no chance of biasing results in favor of one treatment. 
The covariates and factors collected in the historical databases will be specified in the SAP. 
Propensity scores will be estimated first through a logistic regression model with treatment group 
as the dependent variable and the above covariates/factors as independent variables.  Then the 
stratum boundaries are determined based on the propensity score values for both groups (OCA 
population and control [historical and randomized placebo]) combined or in the OCA population 
or historical control group alone.  Based on recommendations in the literature, quintiles of the 
estimated propensity score from the combined group will be used to determine the stratum 
boundary cut-offs for the different strata. 
Outcome events collected in the historical database are:  death (liver-related and all-cause), liver 
transplant, hepatocellular carcinoma, and other.  Other is defined as cirrhosis or decompensation 
such as ascites, variceal bleed, and encephalopathy. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare randomized OCA-treated subjects in the ITT population and historical 
controls (Overall Historical Control Population: both the UK-PBC Group and Global PBC Study 
Group databases) on the following outcomes: 
• Time to death (all-cause) 
• Time to liver-related death 
• Time to liver transplant 
• Time to liver transplant or death (all-cause) 
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• Time to liver transplant or liver-related death 
• Time to hepatocellular carcinoma 
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 determined based on a Cox regression 
model stratified by randomization strata to estimate the magnitude of the effect. 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
13.1.9. 
Alternative Primary Analysis 
Based on sample size re-estimations, it may be determined that subjects will be enrolled to 
receive open-label OCA from that point forward, and the new primary efficacy analysis will 
become the comparison of all subjects in OCA population, to all control subjects (randomized 
placebo and historical controls) on time to liver transplant or death (all-cause) (see 
Section 13.1.2.1).  Similar statistical methodology as specified above in Section 13.1.8 for 
supportive analyses will be utilized. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare groups.  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 
determined based on a Cox regression model stratified by randomization strata to estimate the 
magnitude of the effect. 
In addition, the outcome events specified above in Section 13.1.8 will also be evaluated to 
compare all subjects in OCA population to all control subjects (randomized placebo and 
historical controls). 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
13.1.10. 
Handling of Dropouts or Missing Data 
Subjects who discontinue investigational product are expected to continue in the study until 
study termination. 
Missing data will be assumed to be missing at random.  In order to determine the effect of 
missing data on the analysis, efficacy endpoints will be analyzed using different methods of 
imputation as described below. 
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13.1.10.1. Time to Event Endpoints 
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 investigational product dosing). 
For analyses of the percentage of subjects with an event, subjects with no data after 
randomization will be considered to have an event. 
All time to event endpoints include only adjudicated events.  Sensitivity analyses may consider 
all events regardless of adjudication.  Events with discrepant adjudication will be analyzed using 
both results. 
13.1.10.2. Quantitative Endpoints 
For efficacy endpoints that utilize an ANCOVA model, observed cases will serve as the primary 
analysis.  Sensitivity analyses to assess the effect of missing data may be conducted where 
missing data is imputed using last observation carried forward. 
Sensitivity analyses of ANCOVA models will also be evaluated using a restricted maximum 
likelihood based mixed-effect repeated measures model where no imputations will be made for 
missing values.   
13.1.10.3. Responder Endpoints 
In an efficacy analysis in which subjects are classified as either a responder or a non-responder 
(binary outcome) based on dichotomizing a continuous variable, any subject who does not 
provide an assessment at the specified time point for the defining of response will be considered 
to be a non-responder.  That is, for the percentage of responders, the subject will be included in 
the denominator and will not contribute to the numerator. 
For sensitivity analyses using only “observed cases,” subjects who do not provide an assessment 
at the specified timepoint for the defining of response will not be included.  That is, for the 
percentage of responders, the subject will not be included in the numerator or the denominator. 
13.1.11. 
Multiple Comparisons/Multiplicity 
The key secondary efficacy endpoints are as follows: 
• Time to MELD score ≥15 
• Time to first occurrence of liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The hypothesis testing of key secondary analyses will compare placebo and OCA and will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of OCA.  If the primary comparison is not statistically significant 
then comparison of the secondary endpoints will be considered as descriptive and exploratory.  
This procedure controls the study-wise type I error.  
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• First (step 1) placebo and OCA will be compared with respect to the primary efficacy 
endpoint.  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• The time to MELD score ≥15 will be compared between placebo and OCA (step 2).  
If the comparison achieves statistical significance at 2-sided 0.05 level in favor of 
OCA group, then 
• The time to liver transplant or death (all-cause) will be compared between placebo 
and OCA (step 3).  If the comparison achieves statistical significance at 2-sided 
0.05 level in favor of OCA group, then 
• Change from Baseline in total bilirubin will be compared between placebo and OCA 
(step 4).  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• Change from Baseline in ALP at the end of study will be compared between placebo 
and OCA (step 5). 
If at any step defined above the comparison is not statistically significant at the 2-sided 
0.05 level then the remaining comparisons in the stated hierarchy will be considered descriptive 
and exploratory.  The study-wise type I error will be maintained with the above closed 
procedure. 
Additional efficacy endpoints will be analyzed; however hypothesis tests will be applied for 
descriptive and exploratory purposes only.   
13.1.12. 
Examination of Subgroups 
The primary and secondary efficacy endpoints will be analyzed for subject subgroups (eg, age, 
sex, and race) based on the ITT population.  Subgroups will be assessed at baseline and only if 
there are a sufficient number of subjects in each group (eg, >5 subjects per group). 
Baseline subgroups of interest are as follows:  age, age at PBC diagnosis, sex, race, body mass 
index, ALP level, bilirubin level, use of UDCA, years since diagnosis of PBC, and geographic 
region. 
13.2. 
Safety Analysis 
Safety data, including AEs and clinical laboratory observations, will be summarized by treatment 
group using the Safety Population. 
13.2.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary of Regulatory Activities.  Summary tables of 
treatment-emergent AEs will be provided.  The incidence of TEAEs will be tabulated by system 
organ class and preferred term for each treatment group, and by severity and relationship to 
treatment.  Tables of TEAEs leading to investigational product discontinuation and SAEs will be 
provided. 
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13.2.2. 
Clinical Laboratory Evaluations 
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will be 
presented for all study visits.  Changes from pretreatment to each study visit will also be 
summarized by treatment group. 
13.2.3. 
Additional Safety Analysis 
Additional safety assessments include vital signs and ECGs.  Descriptive statistics of the vital 
sign and ECG parameters will be presented by treatment group and study visit, as well as the 
change from pretreatment at each visit. 
In addition to potential clinical endpoint events, cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study and will be described separately. 
13.3. 
Data and Safety Monitoring Committee 
An independent DSMC will review safety data at periodic intervals from this study.  The DSMC 
will include internationally recognized hepatologists, pharmaceutical physicians, and a 
statistician.  All have considerable experience with clinical trial conduct and DSMCs, prior to 
joining the OCA DSMC.  Candidates are screened for conflicts of interest and any candidate 
found to have such a conflict is not offered membership.  Conflicts of interest are assessed 
regularly, and if members are found to have a new conflict of interest they would be replaced. 
The DSMC meets approximately quarterly at scheduled meetings and ad hoc meetings are 
convened, as appropriate.  The DSMC reviews all Intercept sponsored Phase 2 and 3 studies.  
Members of the DSMC will not be allowed to participate as investigators in this study and will 
not otherwise consult for the Sponsor. 
The DSMC will review data on a periodic basis to ensure the safe and proper treatment of 
subjects.  Based on review of these data, the DSMC will advise the Sponsor on the validity and 
scientific merit of continuing the study. 
The DSMC operates under an appropriate charter (in compliance with relevant regulatory 
guidance) that defines its organization and operation and includes specific procedures for each 
study.  The DSMC will prepare written minutes of both its open and closed sessions for each 
study.  The DSMC will document details about any unblinded subject data reviews in the closed 
session DSMC minutes, which will be made available to the Sponsor only after the database is 
locked and the trial is unblinded.   Cases of premature unblinding, as noted above, will also be 
reviewed by the DSMC.  
Data listings provided to the DSMC do not contain individual subject treatment information; 
however, the DSMC will have access to the database and may unblind individual subject data as 
appropriate.  Summary tables reviewed by the DSMC during closed sessions will include an 
overall column containing information regarding all subjects 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, Medical Dictionary for Regulatory Activities (MedDRA) coded AE, 
and AEs leading to early withdrawal of investigational product.  At each meeting, detailed 
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narratives of interval SAEs (including events resulting in death) are reviewed by the DSMC in 
addition to a cumulative list of all SAEs. 
The DSMC may request additional analyses if deemed necessary to fulfill the mission of the 
DSMC.  The DSMC will determine if an unscheduled meeting is necessary based on the 
additional data. 
All Investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DSMC relating to subject safety, which alter the 
conduct of this study.  The Investigators will inform the subjects of such actions and the 
protocol, PIS, and consent will be revised, as appropriate. 
13.4. 
Adjudication Committee 
All potential endpoint events will be reviewed by an adjudication committee before inclusion in 
the any analysis.  The adjudication of potential clinical endpoint events will include, but is not 
limited to:  available hospital reports, histology, discharge summaries, and death certificates.  
The assessment of events will be conducted in compliance with the protocol, study-specific 
procedures, manuals, Good Clinical Practice (GCP), and all other applicable regulatory 
requirements, including the archiving of essential documents.  A separate adjudication 
committee charter will document the entire data flow and process from committee membership, 
the reporting of events by the study site, reporting of the final assessment, supply of source 
documentation to the committee, the review of the events by the committee, and the working 
procedures of the committee.  The adjudication committee members will be independent 
hepatologists not involved in the study as investigators, DSMC members, or consultants.  All 
adjudication committee members will remain blinded to treatment group throughout the study. 
In addition to potential clinical endpoint events, cardiovascular events will also be adjudicated.  
The adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study and will be described separately. 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
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 subject’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 
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of dispensing investigational product, ECGs, etc) that support data entries in the CRF.  The CRF 
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 
subject's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
14.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC 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.   
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the CRF 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 14.2 for more details regarding the audit 
process. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF and/or other subject 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 the Sponsor before he or she can enroll 
any subject 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 subjects to the ethics committee 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 subjects for 
the study.  The protocol must be reapproved by the IRB or IEC upon receipt of amendments and 
annually, as local regulations require. 
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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.  
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, at a minimum annually, and after the study is complete. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles and are consistent with 
ICH/GCP, local applicable regulatory requirements (in addition to Appendix C), and the 
Sponsor’s policies. 
16.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated ICF 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 subject. 
16.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential and confidentiality of all subjects will be maintained.  Monitors (eg, 
CRA, medical monitor), auditors and inspectors will require access to a subject’s medical notes 
for the purpose of source document verification but the subject’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 subject’s names and identifying information (eg, subject’s 
hospital number, unique subject number).  This list will not be collected by the Sponsor. 
The written information sheet 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 subject 
number/randomization code/subject initials/site number, only. 
When personal data on subjects are stored or processed by computer, the data must be protected 
to prevent their disclosure to unauthorized third parties.  The pertinent sections of the data 
protection laws in which the country is being conducted will be complied with in full. 
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The written ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IEC/IRB may require direct access to parts of the hospital 
or study site records relevant to the study, including subject’s medical history. 
17. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the subjects 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 subjects, as applicable. 
17.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject 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 medical monitor. 
17.2. 
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 subject’s safety to be compromised if immediate action is not taken. 
17.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
• Approved ICF (all versions) 
• IRB/EC approvals (of protocol/amendments, subject questionnaires, etc) 
• Form FDA 1572  
• Current medical license 
• Curriculum vitae 
• Laboratory certification and reference ranges 
• Financial disclosure forms 
17.4. 
Ethics Review  
Please see Section 16.1 for the Investigator’s responsibilities regarding ethics review. 
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17.5. 
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 subject 
medical files (retained per country specific regulations), completed study subject log and 
confidential subject 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 prior to 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. 
18. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it Sponsors consistent 
with the Declaration of Helsinki (Seoul Revision 2008, 
[http://www.wma.net/en/30publications/10policies/b3/index.html, accessed May 22, 2013]).  
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 Study Registries (eg, clinicaltrials.gov):  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 (when available) 
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. 
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• 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:  The Sponsor, 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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19. 
LIST OF REFERENCES 
Beuers U, Lindor KD. A major step towards effective treatment evaluation in primary biliary 
cirrhosis. J Hepatol. 2011 Dec;55(6):1178-80. 
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and 
long term prognosis in primary biliary cirrhosis. Hepatology. 2008 Sep;48(3):871-877. 
Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: Biochemical response 
to treatment and prediction of long-term outcome. J Hepatol 2011;55:1361–1367. 
Elman S, Hynan L.S., Gabriel V, and Mayo M.J. The 5-D itch scale: a new measure of pruritus, 
British Journal of Dermatology 2010 162, pp587–593. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51:237-267. 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact of fatigue: initial validation of 
the fatigue impact scale. Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
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 Dec;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 
Nov;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. 
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 Apr;136(4):1281-7. 
Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict 
long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 
2010 Oct;105(10):2186-94. 
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Alkaline phosphatase values are a 
surrogate marker in prediction of transplant-free-survival in patients with primary biliary 
cirrhosis - an international, collaborative analysis.  J Hepatol. 2013; 58(Suppl):S388. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis: AASLD Practice 
Guidelines. Hepatology. 2009;50(1):291-308. 
Momah N, Silveira MG, Jorgensen R, et al. Optimizing biochemical markers as endpoints for 
clinical trials in primary biliary cirrhosis. Liver Int. 2012;32(5):790-795. 
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. 
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APPENDIX A. LIST OF STUDY 747-302 OUTCOME EVENTS 
Several of the specified clinical endpoints will also by definition (see Section 12.1) 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 12.1.4).  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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APPENDIX B.   LIST OF STUDY 747-302 ANTICIPATED EVENTS 
Jaundice  
Hepatic decompensation/failure 
Hypoalbuminemia 
Hyponatremia 
Splenomegaly 
Hepatorenal syndrome (renal failure in the setting of hepatic failure) 
Hepatopulmonary syndrome (pulmonary failure in the setting of hepatic failure) 
Fractures 
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APPENDIX C. ETHICAL CONDUCT ACCORDING TO THE 
DECLARATION OF HELSINKI FOR COUNTRIES 
PARTICIPATING OUTSIDE THE US (DECLARATION 
OF HELSINKI, FORTELEZA, BRAZIL, 2013) 
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Copyright 2013 American Medical Association. All rights reserved.
World Medical Association Declaration of Helsinki
Ethical Principles for Medical Research
Involving Human Subjects
World Medical Association
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1. The World Medical Association (WMA) has developed the Dec-
larationofHelsinkiasastatementofethicalprinciplesformedi-
cal research involving human subjects, including research on
identifiable human material and data.
The Declaration is intended to be read as a whole and each of
its constituent paragraphs should be applied with consider-
ation of all other relevant paragraphs.
2. ConsistentwiththemandateoftheWMA,theDeclarationisad-
dressed primarily to physicians. The WMA encourages others
who are involved in medical research involving human subjects
to adopt these principles.
General Principles
3. TheDeclarationofGenevaoftheWMAbindsthephysicianwith
the words, “The health of my patient will be my first consider-
ation,”andtheInternationalCodeofMedicalEthicsdeclaresthat,
“A physician shall act in the patient's best interest when provid-
ing medical care.”
4. It is the duty of the physician to promote and safeguard the
health,well-beingandrightsofpatients,includingthosewhoare
involvedinmedicalresearch.Thephysician'sknowledgeandcon-
science are dedicated to the fulfilment of this duty.
5. Medical progress is based on research that ultimately must in-
clude studies involving human subjects.
6. Theprimarypurposeofmedicalresearchinvolvinghumansub-
jects is to understand the causes, development and effects of
diseasesandimprovepreventive,diagnosticandtherapeuticin-
terventions (methods, procedures and treatments). Even the
bestproveninterventionsmustbeevaluatedcontinuallythrough
research for their safety, effectiveness, efficiency, accessibility
and quality.
7. Medicalresearchissubjecttoethicalstandardsthatpromoteand
ensure respect for all human subjects and protect their health
and rights.
8. Whiletheprimarypurposeofmedicalresearchistogeneratenew
knowledge, this goal can never take precedence over the rights
and interests of individual research subjects.
9. Itisthedutyofphysicianswhoareinvolvedinmedicalresearch
to protect the life, health, dignity, integrity, right to self-
determination,privacy,andconfidentialityofpersonalinforma-
tion of research subjects. The responsibility for the protection
ofresearchsubjectsmustalwaysrestwiththephysicianorother
health care professionals and never with the research subjects,
even though they have given consent.
10. Physiciansmustconsidertheethical,legalandregulatorynorms
andstandardsforresearchinvolvinghumansubjectsintheirown
countries as well as applicable international norms and stan-
dards.Nonationalorinternationalethical,legalorregulatoryre-
quirementshouldreduceoreliminateanyoftheprotectionsfor
research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that mini-
mises possible harm to the environment.
12. Medicalresearchinvolvinghumansubjectsmustbeconducted
onlybyindividualswiththeappropriateethicsandscientificedu-
cation, training and qualifications. Research on patients or
healthyvolunteersrequiresthesupervisionofacompetentand
appropriately qualified physician or other health care profes-
sional.
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13. Groups that are underrepresented in medical research should
be provided appropriate access to participation in research.
14. Physicians who combine medical research with medical care
should involve their patients in research only to the extent that
this is justified by its potential preventive, diagnostic or thera-
peuticvalueandifthephysicianhasgoodreasontobelievethat
participation in the research study will not adversely affect the
health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be en-
sured.
Risks, Burdens and Benefits
16. Inmedicalpracticeandinmedicalresearch,mostinterventions
involve risks and burdens.
Medical research involving human subjects may only be con-
ductediftheimportanceoftheobjectiveoutweighstherisksand
burdens to the research subjects.
17. All medical research involving human subjects must be pre-
ceded by careful assessment of predictable risks and burdens
to the individuals and groups involved in the research in com-
parisonwithforeseeablebenefitstothemandtootherindividu-
als or groups affected by the condition under investigation.
Measurestominimisetherisksmustbeimplemented.Therisks
mustbecontinuouslymonitored,assessedanddocumentedby
the researcher.
18. Physiciansmaynotbeinvolvedinaresearchstudyinvolvinghu-
mansubjectsunlesstheyareconfidentthattheriskshavebeen
adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive proof of definitive outcomes, physi-
cians must assess whether to continue, modify or immediately
stop the study.
Vulnerable Groups and Individuals
19. Somegroupsandindividualsareparticularlyvulnerableandmay
haveanincreasedlikelihoodofbeingwrongedorofincurringad-
ditional harm.
All vulnerable groups and individuals should receive specifi-
cally considered protection.
20. Medical research with a vulnerable group is only justified if the
research is responsive to the health needs or priorities of this
group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to ben-
efit from the knowledge, practices or interventions that result
from the research.
Scientific Requirements and Research Protocols
21. Medicalresearchinvolvinghumansubjectsmustconformtogen-
erally accepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as appropriate, ani-
mal experimentation. The welfare of animals used for research
must be respected.
22. The design and performance of each research study involving
human subjects must be clearly described and justified in a re-
search protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include
information regarding funding, sponsors, institutional affilia-
tions, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compen-
sating subjects who are harmed as a consequence of participa-
tion in the research study.
In clinical trials, the protocol must also describe appropriate ar-
rangements for post-trial provisions.
Research Ethics Committees
23. Theresearchprotocolmustbesubmittedforconsideration,com-
ment, guidance and approval to the concerned research ethics
committee before the study begins. This committee must be
transparent in its functioning, must be independent of the re-
searcher, the sponsor and any other undue influence and must
be duly qualified. It must take into consideration the laws and
regulations of the country or countries in which the research is
to be performed as well as applicable international norms and
standardsbutthesemustnotbeallowedtoreduceoreliminate
anyoftheprotectionsforresearchsubjectssetforthinthisDec-
laration.
The committee must have the right to monitor ongoing stud-
ies.Theresearchermustprovidemonitoringinformationtothe
committee, especially information about any serious adverse
events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of
thestudy,theresearchersmustsubmitafinalreporttothecom-
mittee containing a summary of the study’s findings and con-
clusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of re-
search subjects and the confidentiality of their personal infor-
mation.
Informed Consent
25. Participation by individuals capable of giving informed consent
as subjects in medical research must be voluntary. Although it
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may be appropriate to consult family members or community
leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving
informed consent, each potential subject must be adequately
informed of the aims, methods, sources of funding, any pos-
sible conflicts of interest, institutional affiliations of the re-
searcher,theanticipatedbenefitsandpotentialrisksofthestudy
and the discomfort it may entail, post-study provisions and any
other relevant aspects of the study. The potential subject must
be informed of the right to refuse to participate in the study or
to withdraw consent to participate at any time without repri-
sal. Special attention should be given to the specific informa-
tionneedsofindividualpotentialsubjectsaswellastothemeth-
ods used to deliver the information.
Afterensuringthatthepotentialsubjecthasunderstoodthein-
formation, the physician or another appropriately qualified in-
dividual must then seek the potential subject’s freely-given in-
formed consent, preferably in writing. If the consent cannot be
expressedinwriting,thenon-writtenconsentmustbeformally
documented and witnessed.
Allmedicalresearchsubjectsshouldbegiventheoptionofbeing
informed about the general outcome and results of the study.
27. When seeking informed consent for participation in a research
study the physician must be particularly cautious if the poten-
tial subject is in a dependent relationship with the physician or
mayconsentunderduress.Insuchsituationstheinformedcon-
sentmustbesoughtbyanappropriatelyqualifiedindividualwho
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving in-
formedconsent,thephysicianmustseekinformedconsentfrom
thelegallyauthorisedrepresentative.Theseindividualsmustnot
be included in a research study that has no likelihood of benefit
forthemunlessitisintendedtopromotethehealthofthegroup
represented by the potential subject, the research cannot in-
stead be performed with persons capable of providing in-
formed consent, and the research entails only minimal risk and
minimal burden.
29. When a potential research subject who is deemed incapable of
givinginformedconsentisabletogiveassenttodecisionsabout
participationinresearch,thephysicianmustseekthatassentin
addition to the consent of the legally authorised representa-
tive. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally in-
capable of giving consent, for example, unconscious patients,
may be done only if the physical or mental condition that pre-
ventsgivinginformedconsentisanecessarycharacteristicofthe
research group. In such circumstances the physician must seek
informedconsentfromthelegallyauthorisedrepresentative.If
nosuchrepresentativeisavailableandiftheresearchcannotbe
delayed,thestudymayproceedwithoutinformedconsentpro-
videdthatthespecificreasonsforinvolvingsubjectswithacon-
dition that renders them unable to give informed consent have
beenstatedintheresearchprotocolandthestudyhasbeenap-
provedbyaresearchethicscommittee.Consenttoremaininthe
researchmustbeobtainedassoonaspossiblefromthesubject
or a legally authorised representative.
31. Thephysicianmustfullyinformthepatientwhichaspectsoftheir
care are related to the research. The refusal of a patient to par-
ticipateinastudyorthepatient’sdecisiontowithdrawfromthe
study must never adversely affect the patient-physician rela-
tionship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or
similarrepositories,physiciansmustseekinformedconsentfor
its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracti-
cable to obtain for such research. In such situations the re-
search may be done only after consideration and approval of a
research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new inter-
vention must be tested against those of the best proven inter-
vention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary
to determine the efficacy or safety of an intervention
andthepatientswhoreceiveanyinterventionlesseffectivethan
thebestprovenone,placebo,ornointerventionwillnotbesub-
ject to additional risks of serious or irreversible harm as a result
of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. Inadvanceofaclinicaltrial,sponsors,researchersandhostcoun-
trygovernmentsshouldmakeprovisionsforpost-trialaccessfor
all participants who still need an intervention identified as ben-
eficialinthetrial.Thisinformationmustalsobedisclosedtopar-
ticipants during the informed consent process.
Research Registration and Publication and Dissemination
of Results
35. Every research study involving human subjects must be regis-
teredinapubliclyaccessibledatabasebeforerecruitmentofthe
first subject.
World Medical Association Declaration of Helsinki
Special Communication Clinical Review & Education
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November 27, 2013
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36. Researchers, authors, sponsors, editors and publishers all have
ethical obligations with regard to the publication and dissemi-
nationoftheresultsofresearch.Researchershaveadutytomake
publicly available the results of their research on human sub-
jectsandareaccountableforthecompletenessandaccuracyof
their reports. All parties should adhere to accepted guidelines
for ethical reporting. Negative and inconclusive as well as posi-
tiveresultsmustbepublishedorotherwisemadepubliclyavail-
able. Sources of funding, institutional affiliations and conflicts
of interest must be declared in the publication. Reports of re-
search not in accordance with the principles of this Declaration
should not be accepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven inter-
ventions do not exist or other known interventions have been
ineffective, the physician, after seeking expert advice, with in-
formed consent from the patient or a legally authorised repre-
sentative, may use an unproven intervention if in the physi-
cian's judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should subse-
quently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be re-
corded and, where appropriate, made publicly available.
ARTICLE INFORMATION
Corresponding Author: World Medical
Association, 13, ch. du Levant, CIB - Bâtiment A,
01210 Ferney-Voltaire, France; wma@wma.net.
Published Online: October 19, 2013.
doi:10.1001/jama.2013.281053.
Disclaimer: ©2013 World Medical Association, Inc.
All Rights Reserved. All intellectual property rights
in the Declaration of Helsinki are vested in the
World Medical Association. The WMA has granted
JAMA exclusive rights to publish the
English-language version of the Declaration
through December 31, 2013.
Online-Only Content: Audio podcast is available at
www.jama.com.
Clinical Review & Education Special Communication
World Medical Association Declaration of Helsinki
2194
JAMA
November 27, 2013
Volume 310, Number 20
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APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 (DATED 29 APR 2015) 
Rationale 
The changes to the Original Version of the protocol, detailed below, modify the dose titration schedule based on observed efficacy and 
tolerability of OCA, address advice provided by regulatory agencies, and clarify questions raised by study site personnel currently 
using Original protocol version 1 dated 03 October 2014. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.  (Note:  Differences are denoted in bold font; Minor 
formatting changes are not listed) 
Section 
Original Text 
Revised Text 
Title Page 
Original:  03 October 2014 
Original:  03 October 2014 
Amendment 1:  xx April 2015 
Procedures in 
Case of 
Emergency 
 
Procedures in Case of Emergency 
 
Study Personnel Contact Information 
 
Or if Not 
Available 
Contact:
 MD, 
 & 
 Development, Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
 
Contact:
 MD, Medical Director, Drug Safety, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
Synopsis 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
≤1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 2 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 2 
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Section 
Original Text 
Revised Text 
weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
and total bilirubin values (refer to Section 9.7.3).   Subjects who 
meet all inclusion criteria and none of the exclusion criteria will be 
randomized (1:1) to OCA or placebo treatment groups.  The 
randomization will be stratified by ursodeoxycholic acid (UDCA) 
treatment (yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 6 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 6-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
 
 
 
weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
and total bilirubin values (refer to Section 9.7.3).  Mean values for 
ALP and total bilirubin will be calculated using all available 
screening values.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment (yes/no) and baseline 
bilirubin categories (>upper limit of normal [ULN]/ ≤ ULN). 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 3 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 3-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
 
 
 
 
 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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Section 
Original Text 
Revised Text 
 
Synopsis 
Inclusion Criteria 
2.  A mean total  bilirubin >ULN and ≤3x ULN or an ALP >5x 
ULN  
4.  Either is not taking UDCA (UDCA naïve or no UDCA dose in 
the past 3 months) or has been taking UDCA for at least 12 months 
with an approved, stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
contraception during the study and for 30 days after the end of 
treatment visit. 
 
Inclusion Criteria 
2. A mean total bilirubin >ULN and ≤3x ULN and/or a mean 
ALP >5x ULN 
4.  Either is not taking UDCA (no UDCA dose in the past 
3 months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
 
Synopsis 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
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Original Text 
Revised Text 
 
 
 
3. Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
4.  Other medical conditions that may diminish life expectancy to 
<2 years, including known cancers (except carcinomas in situ or 
other stable, relatively benign conditions such as chronic lymphatic 
leukemia) 
5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of screening (pretreatment) QT 
 
stage (for example per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
3.  Mean total bilirubin >3x ULN 
 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
5.  Deleted text 
Synopsis 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life 
 
 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life (Fatigue 
Impact Score and EQ-5D-
5L) 
 
Synopsis 
Statistical Methods: Other Efficacy Analyses 
• 
Added text 
Statistical Methods: Other Efficacy Analyses 
• 
Development of varix/varices 
4 
List of Abbreviations 
Added text 
 
List of Abbreviations 
EOS 
 end of study 
 
5.4 
As of 31 March 2014, OCA has been evaluated in the clinic in 18 
completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
As of 31 January 2015, OCA has been evaluated in the clinic in 20 
completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
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subjects.  As of 31 March 2014, a total of 1023 subjects have 
received at least one dose of OCA and of these, 414 (40%) were 
subjects with PBC.   
 
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 up to 4 years.  The LSTE phase of studies 
747-201 and 747-301 are ongoing; the LTSE phase of Study 747-
202 is complete 
subjects.  As of 31 January 2015, approximately 1650 subjects 
have received at least 1 dose of OCA and of these, 432 were 
subjects with PBC with ≤5 years of OCA treatment.   
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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is 
complete 
5.5.2.1 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg and 10 mg; both treatment 
groups exhibited clinically meaningful improvements in liver 
biochemistry and were safe and generally well tolerated. 
 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg (titrated to 10 mg after 6 
months based on efficacy and tolerability in the double-blind 
phase and after 3 months in the open-label phase) and 10 mg; 
both treatment groups exhibited clinically meaningful 
improvements in liver biochemistry and were safe and generally 
well tolerated.  Based on these data, the intended commercial 
doses of OCA for the treatment of patients with PBC are 5 mg 
and 10 mg. 
The majority of efficacy results with OCA, in terms of change 
in alkaline phosphatase, was observed by 3 months and the 
time to treatment-emergent pruritus was typically 1 month or 
less in Study 747-301.  As such, Study 747-302 will evaluate the 
effect of OCA on clinical outcomes using the 5 mg OCA dose 
increasing to 10 mg OCA if tolerated. 
 
5.5.2.2. 
Rationale for Control Groups; Historical Control Group 
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
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Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons.   
placebo comparisons (ie, comparisons to historical and placebo 
controls will be evaluated separately). 
 
5.6 
Additionally, consistent with nonclinical findings and the 
chemical characteristics of OCA (bile acid and detergent), an 
increase in liver function tests and hepatic AEs, including 
jaundice, were observed in subjects with liver disease at doses 
between 10 mg and 50 mg and in healthy volunteers who were 
treated at doses greater than 100 mg in Phase 1 multiple dose 
studies. 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  The clinical 
significance of these lipid findings remains unclear and is being 
studied further.  Notably, despite the observed decrease, HDL 
levels have generally remained within normal limits in subjects 
treated with OCA. 
• 
Deleted text 
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 subjects with chronic liver disease such as PBC, hepatic 
findings including increased transaminases and bilirubin and 
signs or symptoms of hepatic decompensation such as 
development of jaundice were observed mainly at the highest 
dose of OCA (50mg daily). 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  Notably, in subjects 
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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated 
subjects with the exception of a modest transient and early rise 
after initiation of treatment.
7.1 
Overall Study Design 
…Subjects will be screened during a ≤1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3)….Following 6 months of treatment with 
investigational product, subjects should be titrated in a blinded 
Overall Study Design 
…Subjects will be screened during a 1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to Section 9.7.3). 
….Following 3 months of treatment with investigational product, 
subjects should be titrated in a blinded manner (ie, subjects 
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manner (ie, subjects randomized to OCA will increase their dose to 
10 mg OCA) based on tolerability…. 
randomized to OCA will increase their dose to 10 mg OCA) based 
on tolerability…. 
7.1.1 
Study Design Diagram 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
Study Design Diagram 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
7.1.2 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
1st column heading was “Screening Visit  x2) 
 
Visit Window ≤1 to 8 wks … 
Visit window in 2nd column added new text 
Added text 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
Now 2 columns: 1st column now “Screening Visit 1” 
2nd column now Screening Visit 2 
3 to 8 wks… 
1 to 6 wks prior to Day 0 
 
Added Procedures: 
Quality of Life Questionnaires (PBC-40, EQ-5D-5L, and 
FIS) g  (Day 0, Annually, EOT/EOS) 
Endoscopy I (Day 0, annually, per standard of care) 
Hepatic Ultrasound (Day 0, Annually, EOT/EOS) 
Physical Exam and Assessments for Mayo Risk Score and Child-
Pugh (every 6 months) 
Health Outcome Assessments (All visits) 
Added Dose Titration at M3 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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Footnote a:   All subjects will have two 2 bilirubin assessments at 
least 2 weeks apart including those subjects who qualify based 
on ALP criteria.  For subjects that do not qualify based on 
ALP (ALP >5x ULN), the mean of the two 2 bilirubin 
assessments will be used to determine eligibility (total bilirubin 
>ULN and ≤3x ULN). 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2, and also 2 weeks post dose titration, to assess for AEs 
and concomitant medications and to verify that s/he is dosing as 
directed 
 
Footnote e:  Medical history at Screening will smoking and alcohol 
consumption history and current habits for both.   
Footnote g:  Subject Questionnaires include: Pruritus VAS, 5-D 
Pruritus Scale and Quality of Life questionnaires (See 
Section 11.1.2.2 and Section 12.2.5.1) 
 
 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.   
 
Footnote i: Added text 
 
 
 
 
Footnote j:  Added text 
 
 
Footnote a All subjects will have the chemistry panel retested 
to ensure subjects have 2 ALP and bilirubin assessments at 
least 2 weeks apart to calculate the mean result for both 
analytes.   The mean of the all screening ALP and bilirubin 
assessments will be used to determine eligibility).  Samples for 
hematology and coagulation will not be collected at Screening 
visit 2. 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2 (± 1 week), and also 2 weeks post dose titration (up or 
down), to assess for AEs and concomitant medications and to 
verify that s/he is dosing as directed.   
Footnote e:  Medical history at Screening and the yearly physical 
exam will include an assessment of smoking and alcohol 
consumption history and current habits for both.   
Footnote g:  The EQ-5D-5L and FIS Quality of Life 
questionnaires are validated for use in multiple languages. If 
a validated translation is not available in the local language 
required for a specific study subject, the data from that 
questionnaire will not be collected.    (See Section 11.1.2.2 and 
Section 12.2.6) 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.  Please refer to Section 9.7.4 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote i: Endoscopy will be conducted at selected study sites 
where the device is available to assess for the presence of 
oesophageal varix/varices.  Please refer to Section 9.7.4 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote j:  Ultrasound will be conducted to enhance HCC 
surveillance.  If a lesion is found, a second confirmatory 
image (eg, MRI) should be obtained.  Please refer to 
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Footnote k:  Added text 
 
 
 
Footnote l:  Added text 
 
 
Footnote m:  After 6 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 6 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit.  Fasting is required prior to all 
study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at site.  If the blood 
test is also positive, the subject may not be enrolled in the study.  
(Additional testing may be conducted where required, 
regionally). 
 
 
 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
Section 9.7.4 for additional information related to the allowed 
windows at Day 0 for these specific procedures. 
Footnote k:  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 case report form.  Mayo Risk Score will be 
calculated based on central laboratory evaluations, diuretic 
use data, and peripheral edema assessment data captured in 
the CRF.  
Footnote l:  Health Outcome Assessments: Data related to non-
study related medical or surgical treatment procedures that 
the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the 
subject attended should be collected throughout the study. 
Footnote m:  After 3 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 3 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit (except Screening visit 1).  
Fasting is required prior to all study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not 
be enrolled in the study.  (Additional testing may be conducted 
where required, regionally). 
 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not 
change 
7.3 
Treatment Assignment 
Treatment Assignment 
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Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 6 month study visit or at 
any study visit thereafter depending on tolerability.   
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 3 month study visit or 
at any study visit thereafter depending on tolerability.   
7.4 
Dose Titration Criteria 
After 6 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
placebo (in a blinded manner) at the 6-month visit or any study visit 
following the 6-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
Dose Titration Criteria 
After 3 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
placebo (in a blinded manner) at the 3-month visit or any study visit 
following the 3-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
7.4.1 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, her or she should continue the regular 
visit schedule and continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination.  Early termination 
procedures should only be conducted if the subject withdraws 
consent. 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, he or she should continue the regular 
visit schedule and continue taking investigational product as long 
as the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination. 
7.5 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all subjects have 
completed the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the Study/Early Termination Visit. 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all events have been 
accrued, and when subjects are still active on the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the End of Study Visit. 
8.2 
Subject Inclusion Criteria  
2.  A mean total bilirubin >ULN and ≤3x ULN or an ALP >5x 
ULN 
Subject Inclusion Criteria 
2.  A mean total bilirubin >ULN and ≤3x ULN and/or a mean ALP 
>5x ULN  
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4.  Either is not taking UDCA (UDCA naïve or no UDCA 
dose in the past 3 months) or has been taking UDCA for at 
least 12 months with an approved, stable dose for ≥3 months 
prior to Day 0 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
contraception during the study and for 30 days after the end of 
treatment visit. 
4.  Either is not taking UDCA (no UDCA dose in the past 3 
months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
 
 
8.3 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
3.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example, per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
3.  Mean total bilirubin >3x ULN 
 
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4.  Other medical conditions that may diminish life expectancy 
to <2 years, including known cancers (except carcinomas in 
situ or other stable, relatively benign conditions such as chronic 
lymphatic leukemia) 
5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of Screening (pretreatment) QT 
 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test), or lactating 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
 
5. Deleted text 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test by the central laboratory), or lactating 
 
8.4.1 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test. 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test performed at the central 
laboratory. 
8.4.2 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent. 
 
 
The following events are considered potential appropriate reasons 
for a subject to discontinue investigational product;…  
• 
Withdrawal of Consent 
- 
Added text 
 
 
 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent (See Section 9.7.14 Early 
Discontinuation and/or Early Termination Procedures). 
 
The following events are considered appropriate reasons for a 
subject to discontinue investigational product; … 
• 
Withdrawal of Consent 
- 
Consent may be fully withdrawn 
- 
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 
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The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study.   
allow continued access to medical records to 
assess for potential adjudicated hepatic and/or 
cardiovascular events 
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study.   
8.4.3 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study….This information must be documented in the CRF.  
If a subject is withdrawn from the study early (regardless of the 
cause), all of the end of treatment (EOT) evaluations should be 
performed at the time of withdrawal, as appropriate.  
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study….This information must be documented 
in the CRF.  If a subject is withdrawn from the study early 
(regardless of the cause), all of the (EOT/EOS) evaluations should 
be performed at the time of withdrawal, as appropriate (See 
Section 9.7.14 Early Discontinuation and/or Early Termination 
Procedures). 
9.1.1 
Dose Adjustment Beginning at Month 6 
After 6 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 6 visit, or at 
any study visit thereafter.   
Dose Adjustment Beginning at Month 3 
After 3 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 3 visit, or at 
any study visit thereafter.   
9.2 
Concomitant Medications 
Relevant information about all concomitant medications (including 
prescribed, over-the-counter, or herbal preparations) taken prior to 
(ie, within 30 days of Day 0) and during the study must be recorded 
in the source documents and CRF, as well as any dose or dose 
regimen changes that occur during the study.   
Concomitant Medications 
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 CRF, as well as any dose or 
dose regimen changes that occur during the study. 
9.2.1 
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
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investigational product should be discontinued to avoid potential 
double dosing.   
 
investigational product should be discontinued to avoid potential 
double dosing.  Subjects that discontinue investigational product 
but continue commercial OCA therapy are expected to 
continue through the end of the study, and the study will only 
terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.  Subjects 
will need to complete EOT procedures but continue with 
regularly scheduled visits until the study is terminated (See 
Section 9.7.14 Early Discontinuation and/or Early Termination 
Procedures). 
 
9.4 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN), 
as specified by the central laboratory.   
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and mean baseline bilirubin categories 
(>ULN/≤ULN), as specified by the central laboratory.   
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9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
• 
Added text - New section inserted. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects will be made 
available to the Investigator for emergency use only 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 is necessary for further medical management of the 
subject).  If it is not reasonable to inform the Medical Monitor 
in advance of unblinding the Investigator must promptly 
document in the subject’s source record and should 
subsequently contact the Medical Monitor to explain any 
premature unblinding of treatment assignment (such as 
unblinding which is necessary in order to treat an SAE). 
Procedures for unblinding a subject’s treatment will be 
provided separately to the Investigator.  Similarly, if the 
Medical Monitor breaks the blind for an individual subject for 
the purpose of evaluating an emergent safety issue, the Medical 
Monitor will document within trial documentation the 
rationale, circumstances, and the person or persons being 
informed about the unblinding. 
The Data and Safety Monitoring Committee (DSMC) will have 
access to the IWRS and will be able to unblind individual 
subjects.  Refer to Section 13.3 for further details regarding 
DSMC access to blinded and unblinded data.  The DSMC will 
document details about any unblinded subject data reviews in 
the closed session DSMC minutes, which will be made available 
to the Sponsor only after the database is locked and the trial is 
unblinded.   Cases of premature unblinding, as noted above, 
will also be reviewed by the DSMC.  
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Access to treatment assignments will also be made available 
through the IWRS system to the appropriate named 
individual(s) responsible for reporting SAEs and suspected 
unexpected serious adverse reactions (SUSARs) to the 
Regulatory Authorities. 
9.6 
Restrictions 
No additional restrictions. 
Restrictions 
Participation in another investigation product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the trial is prohibited. 
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9.7.1 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Interval is ≤1 to 8 weeks prior to Day 
0, allowing for 2 Screening 2 visits to 
repeat biochemistry tests, and 
ensuring ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days. 
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (7 days)  
Quarterly visits (Months 
15 – EOT) 
±2 weeks (14 days) 
EOT 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOT = end of treatment 
 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening visit 1 interval is 3 to 8 
weeks prior to Day 0 for screening 
visit 1.  Screening visit 2 interval is 
1 to 6 weeks prior to Day 0.   The 
visit window for Screening 2 visits 
allows for the repeat biochemistry 
tests to be collected at least two 
weeks after the initial biochemistry 
sample was collected, and will 
ensure ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days, but 
screening procedures should not be 
performed during the last 7 days of 
the window.  
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (14 days)  
Quarterly visits 
(Months 15 – EOS) 
±2 weeks (14 days) 
EOT 
(When subject 
discontinues 
investigational 
product) 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOS 
(When subject 
terminates the study) 
The final study visit; EOS will 
occur concurrent with EOT if a 
subject discontinues study 
medication at the time the subject’s 
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participation in the study ends (eg, 
withdrawal of consent or study 
termination by the Sponsor); EOS 
will occur after the EOT if the 
subject discontinues study 
medication  but continues in the 
study. 
EOT = end of treatment 
EOS = end of study 
 
9.7.2 
Informed Consent Procedures 
• 
Added text 
Informed Consent Procedures 
Any change in a subject’s consent status (eg, semi-annual 
telephone contact or medical record review) must be 
documented in a signed informed consent form or addendum.  
The subjects will be given a signed and dated copy of the 
consent document. 
9.7.3 
Screening Procedures (≤1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed ≤1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Subjects who 
do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects may be rescreened after 2 months; however, all Screening 
procedures should be repeated and a new 3-digit Screening number 
assigned.  
 
 
 
 
 
• 
All subjects will have 2 bilirubin and ALP 
assessments at least 2 weeks apart including those 
subjects who qualify based on ALP criteria. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Screening 
Visit 1 will occur 3 to 8 weeks prior to Day 0; Screening Visit 2 
will occur 1 to 6 weeks prior to Day 0, depending on the date 
that the first serum chemistry sample was collected. Subjects 
who do not fulfill all eligibility criteria will not be enrolled in the 
study.  Subjects 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 3-digit Screening number 
assigned. 
 
• 
All subjects will have 2 bilirubin and  ALP assessments at 
least 2 weeks apart 
 
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• 
For subjects that do not qualify based on ALP alone 
(ALP >5x  
ULN), the mean of the 2 bilirubin assessments will be 
used to determine eligibility (total bilirubin >ULN 
and ≤3x ULN). 
  
 
 
• 
Screening Visit procedures are as follows: 
• 
Record prior (if within 30 days of Day 0) and current 
concomitant medications 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual emission X ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
 
 
• 
Added text 
 
• 
For subjects that do not qualify based on ALP alone (ALP 
>5x ULN), the mean of all available (at least 2; 
including both scheduled and unscheduled) bilirubin 
assessments will be used to determine eligibility (total 
bilirubin >ULN and ≤3x ULN).   
 
 
 
• 
Screening Visit 1 procedures are as follows: 
• 
Record prior (if within 30 days of Screening) and current 
concomitant medications 
• 
Deleted text  
 
• 
Deleted text 
 
 
 
 
 
 
Screening Visit 2 procedures are as follows: 
• 
Verify inclusion and exclusion criteria for eligibility 
• 
Assess and record any pretreatment-emergent AEs 
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• 
Record current concomitant medications 
• 
Verify that the subject has fasted for at least 8 hours 
- 
Record fasting status in the source and CRF 
- 
If the subject reports having eaten within 8 hours, 
document accordingly in the source and CRF and 
remind the subject that fasting is required prior to all 
study visits 
• 
Obtain blood samples for serum chemistry tests 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual-emission X-ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
9.7.4 
Day 0 Procedures (Randomization) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE has 
been done within 3 months of Day 0 and a report/adequate data 
are available, a pretreatment TE at Day 0 is not required.   
 
 
• 
Day 0 Procedures (Randomization) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6.) 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE 
has been done within 6 months of Day 0 and a 
report/adequate data are available, a pretreatment TE at 
Day 0 is not required.  If the TE cannot be performed on 
Day 0 (e.g., device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the 
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• 
 Conduct a DEXA bone density scan (at selected study sites, 
where available); document whether the subject stopped taking 
her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the 
scan, if applicable.  
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
 
 
 
 
 
screening visit window, as close as possible to the Day 0 
visit, after subject eligibility has been confirmed.   
• 
 Conduct a DEXA bone density scan (at selected study 
sites, where available); document whether the subject 
stopped taking her/his calcium supplements for 48 hours 
before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable.  If DEXA 
has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment 
DEXA at Day 0 is not required.  If DEXA cannot be 
performed on Day 0 (e.g., device/technician 
unavailability, scheduling issues, etc), the procedure 
may be completed within the screening visit window, as 
close as possible to the Day 0 visit, after subject 
eligibility has been confirmed. 
• 
Perform an esophagogastroduodenoscopy (endoscopy; 
at selected study sites, where available) to assess the 
presence or absence of oesophageal varix/varices. If an 
endoscopy has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment endoscopy at Day 0 is not required. If the 
endoscopy cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
- 
Subsequent endoscopies should be performed 
annually or per standard of care and the 
Investigator’s clinical judgment throughout 
the course of the study.  Endoscopies should 
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• 
Added text 
 
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
• 
Added text 
 
• 
Record prior (within 30 days of Day 0) and current  
concomitant medications 
also be performed when platelet counts are 
<150 x 109 /L. 
• 
Perform an ultrasound (if equipment is unavailable, 
sites should make every attempt to use available 
community referral sites) for HCC surveillance.  If an 
ultrasound has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment ultrasound at Day 0 is not required. If 
the ultrasound cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
 Review and record prior concomitant medications 
• 
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. 
9.7.6 
Month 3 Procedures 
Month 3 Procedures 
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• 
Added text 
• 
Added text 
• 
Assess for dose titration, if eligible (refer to Section 7.4) 
• 
Obtain blood samples for: 
- 
OCA, C4, and FGF-19 
9.7.7 
 
Month 6 Procedures 
• 
Added text 
 
Month 6 Procedures 
• 
 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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.8 
Month 9 Procedures 
• 
Added text 
Month 9 Procedures 
• 
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 
 
9.7.9 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.9), subjects who are participating in the PK assessment 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.8), subjects who are participating in the PK assessment 
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will each receive a single dose of investigational product (10 mg 
OCA tablet) with approximately 240 mL of water. 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours postdose.  Subjects should not drink additional water 
for 1 hour after taking the dose of investigational product and will 
remain fasted until the 4 hour sample is collected.  Lunch will be 
provided following collection of the 4 hour PK sample; the lunch 
will be a meal replacement drink. 
 
 
will each receive a single dose of investigational product (blinded 
OCA or placebo tablet) with approximately 240 mL of water. 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours post dose.  Samples should be collected within a 
window of ±5 minutes of the scheduled sample time.  Subjects 
should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until the 4 hour 
sample is collected.  Lunch will be provided following collection of 
the 4 hour PK sample; the lunch will be a meal replacement drink.  
Samples will be stored for up to 5 years after the end of the 
study and will be destroyed after 5 years if not analyzed. 
9.7.10 
 
Month 12 Procedures 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Added text 
Month 12 Procedures 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
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o 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.11 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
Subjects should come to the study center for a quarterly study 
visit for a clinical laboratory evaluation to collect blood samples 
for calculation of MELD score.  If the subject is not able to 
come to the study center for a visit, home visits may be 
arranged on a per subject basis. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
• 
Deleted text 
• 
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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
9.7.12 
Month 6 Continue Follow-up Procedures (Semi-annually [±2 
weeks]) 
• 
Added text 
Month 6 Continue Follow-up Procedures (Semi-annually [±2 
weeks]) 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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 
9.7.13 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject questionnaires (see Section 12.2.5.1) 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
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• 
Added text  
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
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 physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.14 
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw Consent 
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
 
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw from Investigational Product or 
Withdraw Consent  
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
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When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination or 
discontinuation (withdrawal of consent), an EOT visit must be 
performed as near as possible to her/his last dose of investigational 
product and the procedures, listed below, performed.  …  In these 
cases, the data will be recorded as EOT procedures in the CRF.  
 
 
Added table 
 
 
 
 
EOT procedures will be required whenever subjects 
discontinue treatment with investigational product.  The EOT 
visit and procedures listed below must be performed as close as 
possible to the subject’s last dose of investigational product.  
When a subject discontinues investigational product but 
continues with regularly scheduled study visits, the EOS visit 
will be completed later in the study as the subject’s final study 
visit.  The actual investigational product discontinuation 
scenario (Table 2) will determine the sequence of the EOT and 
EOS visits and procedures.  In some cases, the EOT visit and 
procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible 
to the subject’s last dose of investigational product.   
When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination 
(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.  ….  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 and EOS procedures in the 
CRF.  
Table 2: 
Early Discontinuation Scenarios 
 
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Investiga
tional 
Product 
Conse
nt 
Study 
Visit 
Status
EOT 
Visita 
EOS 
Visita 
Early 
Terminati
on 
Discontin
ued 
Withdr
awn 
No 
additi
onal 
visits 
excep
t 
EOT/E
OS 
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
Treatmen
t 
Discontin
uation 
Discontin
ued 
Active 
Regul
ar 
Visit 
Sched
ule 
Comp
lete 
as 
close 
as 
possi
ble to 
last 
dose 
IP 
Comp
lete 
at 
Final 
study 
visit 
Discontin
ued 
Semia
nnual 
contac
tb 
Telep
hone 
conta
ct 
every 
6 
mont
hs (±2 
weeks
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
 
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Some assessments noted below may be omitted if they have been 
completed within the 3 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT Visit: 
During the EOT Visit: 
• 
Subject questionnaires (see Section 12.2.6) 
• 
Conduct a DEXA bone density scan (selected study sites); 
document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for 
osteoporosis or osteopenia on the day of the scan, if applicable 
 
 
• 
Added text 
 
• 
Added text 
 
• 
Added text 
 
a Refer to Section 7.1.2 Schedule of Study Procedures for all procedures 
and evaluations required at the End of Treatment and End of Study Visits. 
b Outcomes data to be discussed or collected include data related to 
adjudicated hepatic and cardiovascular event-related data.  No additional 
data (e.g. AE, concomitant medication, etc) data will be collected, except 
as indicated in Section 12.1.6. 
Some assessments noted below may be omitted if they have been 
completed within the 6 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing 
Prior to the EOT/EOS Visit: 
During the EOT/EOS Visit 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
 Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Subject and Quality of Life  questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform TE (where available) using the Fibroscan® TE 
device (not required at EOT/EOS if done within 6 months) 
• 
Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
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• 
Added text 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites); not 
required at EOT/EOS if done within 6 months 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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 
 
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.  [Added text]  As appropriate, the Medical 
Monitor should be contacted. 
 
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.   
In the event of an inexplicable and acute (for example not 
explained by natural progression of the chronic disease) 
increase in alanine aminotransferase (ALT) to >3× baseline 
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(and >upper limit of normal [ULN]) or total bilirubin >2× 
baseline (and >ULN), the subject should be followed by repeat 
testing within 48 to 72 hours of the serum chemistry to confirm 
the abnormalities and to determine if they are increasing or 
decreasing. AE information should also be collected.  If 
symptoms persist or repeat testing shows ALT >3× baseline 
(and >ULN) or total bilirubin >2× baseline (and >ULN), 
subjects should be followed until resolution of the abnormality 
and as clinically indicated depending on other laboratory and 
clinical signs and symptoms. 
 
As appropriate, the Medical Monitor should be contacted. 
 
10.4 
Investigational Product Preparation 
The investigational product will be provided in bulk bottles and 
therefore may be repackaged in unit dose form for administration to 
subjects. 
 
Investigational Product Preparation 
The investigational product will be provided to the distribution 
center in bulk bottles and therefore may be repackaged in unit dose 
form for administration to subjects before shipping to the sites. 
 
11.1.2 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Resource utilization information 
will be collected from CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician 
visits (subject reported), and use of concomitant medications. 
 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Quality of life will be assessed by 
questionnaires (PBC-40, EQ-5D-5L, and FIS) 
administered annually.  Resource utilization information will 
be collected from the Medical and Surgical Treatment 
Procedures and Office Visit Log or other CRFs such as 
number, type and duration of hospitalizations, number of 
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• 
Added text 
outpatient physician visits (subject reported), and use of 
concomitant medications.  
• 
Endoscopy will be conducted at selected study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual 
study assessments or standard of care will be collected in 
the case report form to assess for the development of 
varix/varices 
11.1.2.2 
• 
Quality of Life questionnaires.   
• 
Quality of Life questionnaires.  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: 
a. PBC-40: The PBC-40 (Jacoby 2005) 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. 
b. EQ-5D-5L:  The Eq-5D-5L consists of 2 sections – the 
descriptive system and the visual analogue scales (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 
respondent’s self-rate 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). 
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c. 
Fatigue Impact Score (FIS):  The FIS is a validated 40-
question questionnaire organized into 3 dimensions:  
cognitive, physical, and social.  Each dimension has 5 
levels:  no problem, small problem, moderate problem, 
big problem, and extreme problem (Fisk 1994) 
11.1.2.3 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. The samples will be stored for up to 1 year after the 
end of the study and destroyed after 1 year if not analyzed. 
 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their 
involvement in the study.  IRB/IEC review and approval 
will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will 
be stored for up to 1 year after the end of the study and 
destroyed after 1 year if not analyzed. 
 
12.1.1.2 
Serious Adverse Event 
• 
Added text 
Serious Adverse Event 
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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12.1.4.2 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
  
All SAEs (including Potential Clinical Outcome Events that qualify 
as serious) must be reported to the medical monitor immediately 
(ie, within 24 hours) after the Investigator identifies the SAE…. 
 
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 investigational 
new drug (IND) safety reports (SUSARs) that occur during the 
study within the time frames required by each regulatory agency.  
The Investigator is responsible for submitting information on IND 
safety reports received from the Sponsor to her/his local IRB.  
Documentation of the submissions to IRBs and health authorities 
must be retained in the appropriate study file(s). 
 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
All SAEs occurring while subjects are receiving investigational 
product or are on an investigational product holiday (including 
Potential Clinical Outcome Events that qualify as serious) must be 
reported to the medical monitor immediately (ie, within 24 hours) 
after the Investigator identifies the SAE….  
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.  A SAE assessed with a possible, probable, or definite 
causal relationship to the investigational product and 
unexpected according to IB Reference Safety Information 
(RSI), is known as a suspected unexpected serious adverse 
reaction (SUSAR).  The Sponsor will notify the appropriate 
regulatory agencies as well as all participating Investigators of 
investigational new drug (IND) safety reports (SUSARs) that occur 
during the study within the time frames required by each regulatory 
agency.  The Investigator is responsible for submitting information 
on IND safety reports/SUSARs received from the Sponsor or 
Sponsor designee to her/his local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities must be retained in the 
appropriate study file(s). 
 
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12.1.6 
Notification of Post-Study SAEs 
• 
Added text 
 Notification of Post-Study SAEs 
SAEs that occur more than 30 days after a subject has 
discontinued study medication, and are not considered related 
to investigational product, must still be reported in the EDC 
system; however, these events are not required to be reported 
within 24 hours.  At a minimum, the SAE term, event start and 
end date, severity, relationship to investigational product, 
action taken with study medication, treatment, outcome, and 
potential endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event summary, SAE 
details) may also be required to be entered, when requested by 
the sponsor. 
 
12.1.8 
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments.  
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments. The Sponsor may also 
follow the health of an infant born subsequent to use of 
investigational product. 
 
12.2.2 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page …. 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page for findings that appear after consent, and on the 
medical history CRF for any finding present prior to consent…. 
12.2.5.1 
12.2.5.1  Subject Questionnaires 
 
12.2.6 Subject Questionnaires 
12.2.6/12.2.7 
12.2.6   Laboratory Assessments 
Subjects testing positive for urine drug screen will be excluded 
from the study. 
12.2.7 Laboratory Assessments 
Deleted text 
 
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Table 4  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids, thyroid hormones (T3, 
T4, TSH) 
 
 
Table 5  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids 
 
12.2.6 
Laboratory Assessments 
• 
Added text 
 
 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly visits based on serum chemistry and coagulation. 
 
12.2.7  Laboratory Assessments 
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. 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly (MELD scores only) and semi-annual visits based on 
serum chemistry and coagulation. 
 
13.1.5 
Additional Secondary Efficacy Analyses 
• 
Added text 
Additional Secondary Efficacy Analyses 
• 
Time to development of varix/varices 
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13.1.8 
Supportive Analysis 
Although the results of using matching are conditional only on the 
observed covariates, if one has the ability to measure many of the 
covariates that are believed to be related to the treatment 
assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained. 
 
Supportive Analysis 
Although the results of using matching controls are conditional 
only on the observed covariates, if one has the ability to measure 
many of the covariates that are believed to be related to the 
treatment assignment, then one can be fairly confident that 
approximately unbiased estimates for the treatment effect can be 
obtained. 
13.3 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study. In addition, the DSMC statistician 
will evaluate the sample size as described in Section 13.1.2.1. 
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.   
 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study.  
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.  The DSMC will document details about 
any unblinded subject data reviews in the closed session DSMC 
minutes, which will be made available to the Sponsor only after 
the database is locked and the trial is unblinded.   Cases of 
premature unblinding, as noted above, will also be reviewed by 
the DSMC.  
 
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16.2, Ethical 
Conduct of the 
Study 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles 
that have their origin in the Declaration of Helsinki (Seoul 
Revision, 2008) and are consistent with ICH/GCP, applicable 
regulatory requirements and the Sponsor’s policies. 
Ethical Conduct of the Study 
 The study will be performed in accordance with ethical principles 
and are consistent with ICH/GCP, local applicable regulatory 
requirements (in addition to Appendix C) and the Sponsor’s 
policies. 
19 
List of References 
• 
Added text 
List of References 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional 
impact of fatigue: initial validation of the fatigue impact scale. 
Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
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 Dec;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), 1622-1629. 
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. 
 
Appendix C 
• 
Added document 
Ethical Conduct according to the Declaration of Helsinki for 
Countries Participating Outside the US 
 
 
 
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1. 
TITLE PAGE 
 
 
Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 3b, Double-Blind, Randomized, Placebo-Controlled, Multicenter 
Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in 
Subjects with Primary Biliary Cirrhosis  
 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Amendment 1.1:  12 November 2015 
EudraCT Number:  2014-005012-42 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
USA 
 
TEL:  +1 858 652 6800 
FAX:  +1 858 558 5961 
 
 
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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Page 2
SPONSOR'S APPROVAL OF THE PROTOCOL
Reviewed and Approved by:
\e t-icv e[ tr
Date
 PhD
 Clinical Development
Intercept Pharmaceuticals, Inc.
Confi dential and Proprietary
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INVESTIGATOR’S AGREEMENT 
 
I have received and read the current version of the Investigational Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-302.  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 (CRFs) 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 747-302 and in accordance 
with Good Clinical Practice (CPMP/ICH/135/95), 21CFR Part 312 and all applicable regulatory 
requirements. 
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, PhD, Executive Director, Clinical Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
   
Email: 
 
SAE Fax: 
+1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
 
Or if Not Available: 
Contact: 
 MD,  Medical Director, Drug Safety,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Email: 
 (Pacific time zone) 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 (Pacific time zone) 
 
 
 
 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company:  Intercept Pharmaceuticals, Inc. 
Name of Investigational Product:  Obeticholic Acid (OCA) 
Name of Active Ingredient:  OCA; 6α-ethyl chenodeoxycholic acid (6-ECDCA); INT-747 
Title of Study:  A Phase 3b, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary 
Cirrhosis 
Study Number:  747-302 
Study Center(s):  Approximately 170 investigational study sites, globally 
Study Period (Years):  The study is event driven and total duration will be determined by the 
time required to accrue approximately 121 primary endpoint events, estimated to be 
approximately 8 years.  Subjects are expected to have a minimum follow-up time of 
approximately 6 years. 
Number of Subjects (planned):  Approximately 350 subjects 
Phase of Study:  Phase 3b 
Objectives:  
Primary 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care, on clinical outcomes in subjects with primary biliary cirrhosis (PBC) as measured by 
time to first occurrence of any of the following adjudicated events, derived as a composite event 
endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
Secondary 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above and also to include liver-related death. 
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To assess the effect of OCA compared to placebo on disease progression via the following: 
• Liver biochemistry  
• Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To assess the pharmacokinetics of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
Methodology: 
This Phase 3b, double-blind, randomized, placebo-controlled, multicenter study will evaluate the 
effect of OCA on clinical outcomes in subjects with PBC.  Subjects will be screened during a 
1 to 8 week Screening period prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm pretreatment alkaline phosphatase 
(ALP) and total bilirubin values (refer to Section 9.7.3).  Mean values for ALP and total bilirubin 
will be calculated using all available screening values.  Subjects who meet all inclusion criteria 
and none of the exclusion criteria will be randomized (1:1) to OCA or placebo treatment groups.  
The randomization will be stratified by ursodeoxycholic acid (UDCA) treatment (yes/no) and 
baseline bilirubin categories (>upper limit of normal [ULN]/ ≤ULN). 
Investigational product (OCA or matched placebo) will be taken orally, once daily.  
Investigational product will be initiated at 5 mg OCA or matched placebo.  After 3 months of 
treatment with investigational product, the dose may be increased (to the maximum dose of 
10 mg OCA or matched placebo, in a blinded manner) at the 3-month visit or any subsequent 
study visit based on tolerability.  Subjects will be seen at quarterly visits for the duration of the 
study. 
 
 
 
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Schematic Diagram:  
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; ULN = upper limit of normal 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with American Association for the 
Study of Liver Diseases [AASLD] and the European Association for the Study of the 
Liver [EASL] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the 
presence of ≥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 in 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 
2. A mean total bilirubin >ULN and ≤3x ULN and/or a mean ALP >5x ULN 
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past ≥3 months) or has been taking 
UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0 
5. Contraception:  Female subjects 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:   
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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• Double barrier method, ie, (a) condom (male or female) or (b) diaphragm, with 
spermicide; or  
• Intrauterine device (IUD); 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 subject)   
6. Must provide written informed consent and agree to comply with the study protocol 
Exclusion Criteria 
1.  History or presence of other concomitant liver diseases including:  
• Hepatitis C virus infection 
• Active hepatitis B infection; however, subjects 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 
• Nonalcoholic steatohepatitis 
• Gilbert’s Syndrome 
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including: 
• History of liver transplant, current placement on a liver transplant list, or current 
MELD score >12.  Subjects who are placed on a transplant list despite a relatively 
early disease stage (for example per regional guidelines) may be eligible as long as 
they do not meet any of the other exclusion criteria 
• Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
− Variceal bleed 
− Uncontrolled ascites  
− Encephalopathy  
− Spontaneous bacterial peritonitis  
• Known or suspected hepatocellular carcinoma 
• Prior transjugular intrahepatic portosystemic shunt procedure 
• Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine 
>2 mg/dL (178 μmol/L) 
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3. Mean total bilirubin >3x ULN  
4. Subjects who have undergone gastric bypass procedures (gastric lap band is 
acceptable) or ileal resection or plan to undergo either of these procedures 
5. Other medical conditions that may diminish life expectancy, including known cancers 
(except carcinomas in situ or other stable, relatively benign conditions such as 
chronic lymphatic leukemia) 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test), or lactating 
7. Known history of human immunodeficiency virus infection 
8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months) 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
14. UDCA naïve (unless contraindicated) 
Investigational Product, Dosage and Mode of Administration:  
OCA (5 mg or 10 mg tablets) 
Placebo (matching tablets) 
Duration of Treatment: 
It is estimated that subjects will be followed up for a minimum of 6 years.  The study is event 
driven and total duration of treatment will be determined by the time to accrue 121 total primary 
endpoint events. 
Duration of Subject Participation: 
It is estimated that subject participation will be a minimum of approximately 6 years. 
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Criteria for Evaluation: 
Primary Objectives 
Assessments 
Clinical outcomes 
• 
Death (all-cause) 
• 
Liver transplant 
• 
MELD score ≥15 
• 
Hospitalization (as defined by a stay of 24 hours or greater) for new 
onset or recurrence of: 
− 
Variceal bleed 
− 
Encephalopathy (as defined by a West Haven score of  ≥2) 
− 
Spontaneous bacterial peritonitis (confirmed by diagnostic 
paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic 
paracentesis at a frequency of at least twice in a month) 
• 
Hepatocellular carcinoma confirmed by 2 complimentary imaging 
modalities 
Secondary Objectives 
 
Individual components of the 
primary endpoint 
As listed above and including liver-related death 
Change in baseline liver 
biochemistry 
Liver biochemistry (see Table 5 for list of analytes to be tested)   
Inflammation and fibrosis 
IgM, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), 
fibroblast growth factor-19 (FGF-19), cytokeratin-18 (CK-18), enhance liver 
fibrosis (ELF), and Fibroscan® 
Clinical outcomes compared to 
historical controls 
Similar endpoints as used for the primary objective where available including 
liver transplant and death 
Pharmacokinetics 
OCA and its conjugates 
Health outcomes and economics 
research 
Including the following: 
Cost-effectiveness and resource utilization 
Quality of life (Fatigue Impact Score and EQ-5D-5L)  
Safety and tolerability 
Including the following: 
Treatment-emergent adverse events 
Clinical laboratory values 
 
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Statistical Methods:  
Sample Size Justification 
The following assumptions were used in sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.5 at 8 years with a hazard 
ratio of 0.60, and total study duration of 8 years, allowing for 2 years accrual and 
6 years of follow up 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to clinical outcomes. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: Randomized, Intent-to-Treat (ITT), Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical Control.  Descriptions of subject populations 
are provided in Section 13.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
Every event for enrolled subjects will be adjudicated by an independent committee. 
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Primary Efficacy Analysis 
The primary efficacy analysis will compare randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the ITT population.  The 2 treatment groups will 
be compared 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 determined based on a Cox regression model stratified by randomization strata to 
estimate the magnitude of the effect. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints are as follows: 
• Time to first occurrence of MELD score ≥15 
• Time to liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare randomized OCA to randomized placebo in 
ITT population with respect to the key secondary efficacy endpoints.  Only adjudicated events 
will be included in time-to-event analyses.  The comparison (hypothesis testing) will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of the OCA treatment group.  If the primary comparison is not 
statistically significant then comparison of the secondary endpoints will be considered as 
descriptive and exploratory. 
Other Efficacy Analyses 
The following secondary efficacy analyses will compare OCA to placebo on time to the 
following events: 
• Each component of the primary efficacy endpoint (except MELD score ≥15 which is 
listed above) 
• Development of varix/varices 
• Liver-related death 
• Liver-related death or liver transplant 
• Liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls. 
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Further details on efficacy, health outcomes, and pharmacokinetic analyses are specified in 
Section 13. 
Safety Analysis 
Safety data, including AEs, vitals, electrocardiogram, and clinical laboratory results will 
compare OCA and placebo using the Safety Population. 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Overview of Primary Biliary Cirrhosis and Obeticholic Acid ...................................22 
5.2. 
Mechanism of Action of Obeticholic Acid .................................................................22 
5.3. 
Nonclinical Experience with Obeticholic Acid ..........................................................23 
5.4. 
Clinical Experience with Obeticholic Acid ................................................................23 
5.5. 
Rationale for Study Design and Dose for Investigational Product .............................24 
5.5.1. 
Rational for Study Design ..........................................................................................24 
5.5.2. 
Rationale for Dose ......................................................................................................25 
5.5.2.1. 
Rationale for OCA Doses ...........................................................................................25 
5.5.2.2. 
Rationale for Control Groups .....................................................................................25 
5.6. 
Summary of Known Potential Risks with OCA .........................................................26 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................26 
6.1. 
Primary Objective .......................................................................................................26 
6.2. 
Secondary Objectives .................................................................................................27 
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 Subjects ....................................................................................................32 
7.3. 
Treatment Assignment ................................................................................................32 
7.4. 
Dose Titration Criteria ................................................................................................32 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................32 
7.5. 
Criteria for Study Termination ...................................................................................32 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................33 
8.1. 
Subject Population ......................................................................................................33 
8.2. 
Subject Inclusion Criteria ...........................................................................................33 
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8.3. 
Subject Exclusion Criteria ..........................................................................................34 
8.4. 
Subject Withdrawal from Investigational Product or Study Criteria ..........................35 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product ..........................35 
8.4.2. 
Other Reasons for Discontinuation of Investigational Product ..................................35 
8.4.2.1. 
Withdrawal of Consent ...............................................................................................36 
8.4.2.2. 
Lost to Follow-up .......................................................................................................36 
8.4.3. 
Subject Discontinuation Notification .........................................................................36 
9. 
TREATMENT OF SUBJECTS ..................................................................................37 
9.1. 
Investigational Product Treatment Regimen ..............................................................37 
9.1.1. 
Dose Adjustment Beginning at Month 3 ....................................................................37 
9.2. 
Concomitant Medications ...........................................................................................37 
9.2.1. 
Prohibited Medications ...............................................................................................38 
9.3. 
Treatment Compliance ................................................................................................38 
9.4. 
Randomization and Blinding ......................................................................................38 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures ...................................39 
9.5. 
Assignment of Site and Subject Numbers ..................................................................39 
9.5.1. 
Site Numbers ..............................................................................................................39 
9.5.2. 
Subject Numbers .........................................................................................................39 
9.6. 
Restrictions .................................................................................................................39 
9.7. 
Visit Procedures ..........................................................................................................40 
9.7.1. 
Visit Windows ............................................................................................................40 
9.7.2. 
Informed Consent Procedures.....................................................................................40 
9.7.3. 
Screening Procedures (1 to 8 Weeks prior to Day 0) .................................................41 
9.7.4. 
Day 0 Procedures (Randomization) ............................................................................42 
9.7.5. 
Safety Contact (Month 1, Month 2, and 2 Weeks Post-Titration [by 
telephone]): .................................................................................................................44 
9.7.6. 
Month 3 Procedures ....................................................................................................44 
9.7.7. 
Month 6 Procedures ....................................................................................................45 
9.7.8. 
Month 9 Procedures ....................................................................................................46 
9.7.9. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment .................................................................................................................47 
9.7.10. 
Month 12 Procedures ..................................................................................................47 
9.7.11. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 weeks]) ......................49 
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9.7.12. 
Month 6 Continued Follow-up Procedures (Semi-annually [±2 weeks]) ...................50 
9.7.13. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) .........................51 
9.7.14. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent ..................................52 
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 .......................................................55 
10.3. 
Investigational Product Storage ..................................................................................56 
10.4. 
Investigational Product Preparation ............................................................................56 
10.5. 
Investigational Product Administration ......................................................................56 
10.6. 
Investigational Product Accountability and Disposal .................................................56 
11. 
ASSESSMENT OF EFFICACY ................................................................................56 
11.1. 
Assessment of Efficacy ...............................................................................................56 
11.1.1. 
Primary Assessments ..................................................................................................56 
11.1.2. 
Secondary Assessments ..............................................................................................57 
11.1.2.1. 
Non-Invasive Assessments of Liver Fibrosis .............................................................57 
11.1.2.2. 
Other ...........................................................................................................................58 
11.1.2.3. 
Other Exploratory Evaluations ...................................................................................58 
11.1.2.4. 
Potential Clinical Outcome Events .............................................................................59 
12. 
ASSESSMENT OF SAFETY .....................................................................................59 
12.1. 
Adverse Events and Serious Adverse Events .............................................................59 
12.1.1. 
Definition of Adverse Events .....................................................................................59 
12.1.1.1. 
Adverse Event .............................................................................................................59 
12.1.1.2. 
Serious Adverse Event ................................................................................................59 
12.1.1.3. 
Treatment-Emergent Adverse Event ..........................................................................60 
12.1.2. 
Relationship to Investigational Product ......................................................................60 
12.1.3. 
Recording Adverse Event Severity .............................................................................61 
12.1.4. 
Reporting of Adverse Events and Serious Adverse Events ........................................61 
12.1.4.1. 
Reporting of Adverse Events ......................................................................................61 
12.1.4.2. 
Reporting of Serious Adverse Events .........................................................................61 
12.1.5. 
Additional Investigator Responsibilities for SAEs .....................................................62 
12.1.6. 
Notification of Post-Study SAEs ................................................................................63 
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12.1.7. 
Follow up of AEs and SAEs .......................................................................................63 
12.1.8. 
Pregnancy and Follow up ...........................................................................................63 
12.2. 
Other Safety Parameters .............................................................................................64 
12.2.1. 
Medical History/Demographics ..................................................................................64 
12.2.2. 
Physical Examination .................................................................................................64 
12.2.3. 
Vital Signs ..................................................................................................................64 
12.2.4. 
Electrocardiogram .......................................................................................................64 
12.2.5. 
Dual Emission X-Ray Absorptiometry .......................................................................64 
12.2.6. 
Subject Questionnaires ...............................................................................................64 
12.2.7. 
Laboratory Assessments .............................................................................................65 
13. 
STATISTICAL METHODS .......................................................................................67 
13.1. 
Efficacy Analysis ........................................................................................................67 
13.1.1. 
Analysis Populations ..................................................................................................67 
13.1.1.1. 
Comparability of Historical Controls .........................................................................67 
13.1.2. 
Determination of Sample Size ....................................................................................68 
13.1.2.1. 
Sample Size Re-Estimation Plan ................................................................................68 
13.1.3. 
Primary Efficacy Analysis ..........................................................................................69 
13.1.4. 
Key Secondary Efficacy Analyses ..............................................................................69 
13.1.5. 
Additional Secondary Efficacy Analyses ...................................................................70 
13.1.6. 
Exploratory Efficacy Analyses ...................................................................................71 
13.1.6.1. 
Responder Analyses ....................................................................................................71 
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints ................................................71 
13.1.8. 
Supportive Analysis ....................................................................................................71 
13.1.9. 
Alternative Primary Analysis .....................................................................................73 
13.1.10. 
Handling of Dropouts or Missing Data ......................................................................73 
13.1.10.1. Time to Event Endpoints ............................................................................................74 
13.1.10.2. Quantitative Endpoints ...............................................................................................74 
13.1.10.3. Responder Endpoints ..................................................................................................74 
13.1.11. 
Multiple Comparisons/Multiplicity ............................................................................74 
13.1.12. 
Examination of Subgroups .........................................................................................75 
13.2. 
Safety Analysis ...........................................................................................................75 
13.2.1. 
Adverse Events ...........................................................................................................75 
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13.2.2. 
Clinical Laboratory Evaluations .................................................................................76 
13.2.3. 
Additional Safety Analysis .........................................................................................76 
13.3. 
Data and Safety Monitoring Committee .....................................................................76 
13.4. 
Adjudication Committee .............................................................................................77 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................77 
14.1. 
Study Monitoring ........................................................................................................77 
14.2. 
Audits and Inspections ................................................................................................78 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................78 
16. 
ETHICS ......................................................................................................................78 
16.1. 
Ethics Review .............................................................................................................78 
16.2. 
Ethical Conduct of the Study ......................................................................................79 
16.3. 
Written Informed Consent ..........................................................................................79 
16.4. 
Subject Confidentiality and Data Protection ..............................................................79 
17. 
INVESTIGATOR OBLIGATIONS ...........................................................................80 
17.1. 
AE Reporting ..............................................................................................................80 
17.2. 
Protocol Deviations ....................................................................................................80 
17.3. 
Regulatory Documentation .........................................................................................80 
17.4. 
Ethics Review .............................................................................................................80 
17.5. 
Archiving and Record Retention ................................................................................81 
18. 
PUBLICATION POLICY ..........................................................................................81 
19. 
LIST OF REFERENCES ............................................................................................83 
APPENDIX A. LIST OF STUDY 747-302 OUTCOME EVENTS ...........................................84 
APPENDIX B. LIST OF STUDY 747-302 ANTICIPATED EVENTS ....................................85 
APPENDIX C. ETHICAL CONDUCT ACCORDING TO THE DECLARATION OF 
HELSINKI FOR COUNTRIES PARTICIPATING OUTSIDE THE 
US (DECLARATION OF HELSINKI, FORTELEZA, BRAZIL, 2013) .........86 
APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 
(DATED 29 APR 2015) ....................................................................................91 
APPENDIX E. 
SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 
(DATED 10 NOV 2015) .................................................................................125 
 
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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................29 
Table 2: 
Early Discontinuation Scenarios .................................................................................53 
Table 3: 
Relationship of Adverse Events to Investigational Product .......................................60 
Table 4: 
Severity of Adverse Events ........................................................................................61 
Table 5: 
List of Laboratory Analytes to be Tested ...................................................................66 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram Study 747-302 ............................................................................28 
 
 
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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 
CDCA 
chenodeoxycholic acid 
CI 
confidence interval 
CK-18 
cytokeratin-18 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
C-reactive protein 
DEXA 
dual-emission X-ray absorptiometry 
DSMC 
Data Safety Monitoring Committee 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
enhance liver fibrosis 
EOS 
end of study 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
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 
HDL 
high density lipoprotein 
IB 
Investigational Brochure 
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Abbreviation or Specialist Term 
Explanation 
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 
LDL 
low density lipoprotein 
LTSE 
Long-term safety extension 
MELD 
model of end stage liver disease  
MRS 
Mayo Risk Score 
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cirrhosis 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
the Sponsor 
Intercept Pharmaceuticals, Inc. 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
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 Primary Biliary Cirrhosis and Obeticholic Acid 
Primary Biliary Cirrhosis (PBC) 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, is currently the only 
treatment approved for PBC (Lindor 2009).  While UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of a poor clinical outcome due to PBC disease 
progression.  There is a clear unmet medical need for better therapies for patients with PBC that 
have an inadequate response to UDCA, or those who cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and effective. 
OCA is a modified bile acid and farnesoid X receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid (CDCA).  OCA is currently being developed in 
the United States (US) and Europe for the treatment of PBC and other chronic liver diseases.  
OCA has been granted Orphan Drug Designation in the US (09 Apr 2008) and Orphan Medicinal 
Product Designation in the European Union (27 Jul 2010) for the treatment of PBC. 
5.2. 
Mechanism of Action of Obeticholic Acid 
OCA is a 6α-ethyl derivative of the naturally occurring primary human bile acid CDCA, which is 
the endogenous ligand for FXR.  FXR is a ligand-dependent transcription factor that is part of 
the nuclear receptor superfamily.  FXR regulates a wide variety of target genes involved in the 
control of bile acid, lipid, and glucose homeostasis and in the regulation of immune responses. 
OCA’s potent FXR agonist effects are believed to account for the predominant efficacy of the 
investigational product.  Some of the pharmacological properties of OCA and other FXR 
agonists that have been elucidated in animal models of chronic liver disease relevant to the 
treatment of PBC include the following: 
• Improvement in hepatic choleresis with reduced inflammation and necrosis  
• Prevention and reversal of hepatic fibrosis 
The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and 
anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury 
and improved liver function in a cholestatic liver disease such as PBC. 
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5.3. 
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. 
5.4. 
Clinical Experience with Obeticholic Acid 
As of 31 January 2015, OCA has been evaluated in the clinic in 20 completed and ongoing 
studies, including subjects with other chronic liver diseases (eg, nonalcoholic steatohepatitis) and 
healthy subjects.  As of 31 January 2015, approximately 1650 subjects have received at least 
1 dose of OCA and of these, 432 were subjects with PBC with ≤5 years of OCA treatment.  
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. 
To date, the efficacy and safety of OCA in PBC has been evaluated in 2 placebo-controlled, 
double-blind, Phase 2 studies (747-201 and 747-202), and 1 placebo-controlled, double-blind 
Phase 3 study (747-301).  Following the double-blind phase, subjects in all 3 studies were 
eligible to continue with treatment in a long-term safety extension (LTSE) phase for up to 
5 years in Study 747-201, up to 1 year in Study 747-202, and up to 5 years in Study 747-301. 
Study 747-201 (59 subjects) 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 subjects) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in subjects 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 subjects) was a Phase 3, double-blind, placebo-controlled, parallel group 
study followed by an LTSE using OCA in subjects with PBC.  The primary endpoint for 
Study 747-301 was a composite endpoint based on the proportion of subjects reaching specific 
criteria for ALP and bilirubin (ALP <1.67x upper limit of normal [ULN] with a ≥15% reduction 
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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 10 mg OCA 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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is complete. 
5.5. 
Rationale for Study Design and Dose for Investigational Product 
5.5.1. 
Rational for Study Design 
OCA is a modified bile acid and FXR agonist that is derived from the primary human bile acid 
chenodeoxycholic acid.  The key mechanisms of action of OCA, including its choleretic, anti-
inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in 
attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. 
PBC is characterized by biochemical increases in ALP and GGT enzymes with or without 
elevations of hepatocellular transaminases and bilirubin (Lindor 2009).  Both the American 
Association for the Study of Liver Diseases (AASLD) (Lindor 2009) and the European 
Association for the Study of the Liver (EASL) (EASL 2009) guidelines base the biochemical 
component of PBC diagnosis on elevations of ALP.  In addition, a growing literature supports 
the use of biochemical endpoints, specifically serum ALP alone or with other parameters such as 
bilirubin, to manage subjects, test the efficacy of novel therapies in clinical studies, and gauge 
the risk of long-term adverse clinical outcomes in subjects with PBC (Beuers 2011, 
Momah 2012).  Data from the Global PBC Study Group (Lammers 2013), which has built a 
database tracking biochemical status and clinical outcomes in several thousand PBC subjects, 
provides evidence for the use of the composite biochemical endpoint of ALP and bilirubin as an 
acceptable surrogate endpoint. 
Study 747-301, a Phase 3 double-blind study, evaluated the safety and efficacy of OCA at doses 
of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability) and 10 mg and used 
a composite biochemical endpoint of ALP and bilirubin as a surrogate endpoint.  In this study, 
both treatment groups exhibited clinically meaningful improvements in liver biochemistry and 
were safe and generally well-tolerated.  Starting subjects on 5 mg OCA and titrating to 10 mg 
based on the clinical response appears to be an appropriate dosing strategy in subjects with PBC. 
Study 747-302 is a clinical outcomes study, supportive of Phase 3 Study 747-301 which was 
based on a surrogate biochemical endpoint, designed to confirm the clinical benefit of OCA 
treatment in patients with PBC.  A retrospective observational database (Global PBC Study 
Group [Lammers 2013]) of patients with PBC allowed for a rigorous patient-level meta-analysis 
and provided an opportunity for a robust assessment of ALP and bilirubin as viable surrogate 
biochemical parameters and a comprehensive understanding of the natural history of the PBC 
disease process.  Data from the Global PBC Study Group was also utilized to inform the design 
of the confirmatory outcomes study. 
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5.5.2. 
Rationale for Dose 
5.5.2.1. 
Rationale for OCA Doses 
The safety and tolerability of multiple doses of OCA have been established in subjects with PBC 
at doses up to 50 mg.  As demonstrated in the Phase 2 PBC studies (Studies 747-201 and 
747-202), OCA significantly reduced serum ALP levels at doses of 10 mg, 25 mg, and 50 mg, 
but with an increase in the incidence and severity of pruritus at higher dose levels.  The Phase 3 
PBC study subsequently evaluated the safety and efficacy of OCA at lower doses of 5 mg 
(titrated to 10 mg after 6 months based on efficacy and tolerability in the double-blind phase and 
after 3 months in the open-label phase) and 10 mg; both treatment groups exhibited clinically 
meaningful improvements in liver biochemistry and were safe and generally well tolerated.  
Based on these data, the intended commercial doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
The majority of efficacy results with OCA, in terms of change in alkaline phosphatase, was 
observed by 3 months and the time to treatment-emergent pruritus was typically 1 month or less 
in Study 747-301.  As such, Study 747-302 will evaluate the effect of OCA on clinical outcomes 
using the 5 mg OCA dose increasing to 10 mg OCA if tolerated. 
Based on these data, the intended commercial doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
Study 747-302 will evaluate the effect of OCA on clinical outcomes using the 5 mg OCA dose 
increasing to 10 mg OCA if tolerated. 
5.5.2.2. 
Rationale for Control Groups 
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 a standard of care 
effect.  Notably, accounting for the standard of care effect is critical when designing an 
outcome-based study conducted globally when there are regional differences in the treatment of 
subjects with PBC. 
Historical Control Group 
The available robust historical PBC observational datasets (UK-PBC and Global PBC Study 
Group) will also be leveraged to provide further comparative evaluation of the clinical benefit of 
OCA.  Each database includes >6000 patients with long-term follow-up. 
Comparison of OCA treatment to the historical controls may provide utility in addressing 
potential bias or confounds associated with the placebo arm.  For example, bias associated with 
the potential addition of commercial OCA and/or differences in long-term standard of care 
between the treatment arms including ancillary treatments and diagnostics. 
Therefore, further evaluation of the effect of OCA will compare OCA treatment versus historical 
controls, and will be supportive to placebo comparisons (ie, comparisons to historical and 
placebo controls will be evaluated separately). 
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5.6. 
Summary of Known Potential Risks with OCA 
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, but with a much 
lower frequency than that observed in subjects 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 subjects with chronic liver disease such as PBC, hepatic findings including increased 
transaminases and bilirubin and signs or symptoms of hepatic decompensation such as 
development of jaundice were observed mainly at the highest dose of OCA (50mg daily). 
Lipoprotein changes have also been observed with OCA dosing, including a decrease in high 
density lipoprotein (HDL) and an increase in low density lipoprotein (LDL).  Notably, in 
subjects 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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated subjects with the exception of a 
modest transient and early rise after initiation of treatment.   
6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care on clinical outcomes in subjects with PBC as measured by time to first occurrence of any 
of the following adjudicated events, derived as a composite event endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
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6.2. 
Secondary Objectives 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above and also to include liver-related death. 
To assess the effect of OCA compared to placebo on disease progression via the following: 
• Liver biochemistry 
• Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To assess the PK of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3b, double-blind, randomized, placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with bilirubin levels of >ULN and ≤3x ULN or ALP >5x.  
Subjects enrolled will be at higher risk of liver-related clinical complications. 
Approximately 350 subjects meeting all enrollment criteria will be recruited into the study over 
an approximate 2-year period, randomly allocated to treatment with either OCA or matching 
placebo once daily in a 1:1 ratio.  Subjects will be screened during a 1 to 8 week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples 
(at least 2 weeks apart) to confirm pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3).  Investigational product will be taken orally, once daily.  Investigational product 
will be initiated at 5 mg OCA or matched placebo.  The randomization will be stratified by 
UDCA treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN).  In addition to the 
placebo control arm, multiple historical control groups (concurrent and retrospective) will be 
used.  Following 3 months of treatment with investigational product, subjects should be titrated 
in a blinded manner (ie, subjects randomized to OCA will increase their dose to 10 mg OCA) 
based on tolerability.  It is anticipated that subjects will be followed for a minimum of 
approximately 6 years.  The study will continue until approximately 121 adjudicated primary 
endpoint events have been accrued in unique subjects, or until the Sponsor (eg, based on 
advisement by the Data Safety Monitoring Committee; DSMC) terminates the study. 
This study will be conducted at up to approximately 170 international study sites with experience 
in treating subjects with PBC.  Prospective subjects will be identified primarily from the hospital 
and/or physician’s database of subjects with PBC, or may be referred from other physicians.  
Subjects may self-refer to an Investigator if they become aware of the study through local, 
national, or international PBC subject societies, forums, and networks. 
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7.1.1. 
Study Design Diagram 
Figure 1: 
Schematic Diagram Study 747-302 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; ULN = upper limit of normal 
 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures  
 
Year 1 
Years 2 through End of Study 
 
Screening 
Visit 1a 
Screening 
Visit 2a 
Day 0 
Safety 
Contactb 
M 3 
M 6 
M 9 
M 12 
M 3 
continued 
follow-up 
M 6 
continued 
follow-up 
M 9 
continued 
follow-up 
M 12 
continued 
follow-up 
EOT/
EOSc 
Visit Windows (+/-)d 
3 to 8 wks 
prior to 
Day 0 
1 to 6 wks 
prior to 
Day 0 
 
±1 wk 
±2 
wks 
±2 
wks 
±2 
wks 
±2 
wks 
±2 
wks 
±2 wks 
±2 wks 
±2 wks 
±2 
wks 
STUDY PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/PBC Historye  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
Xe 
 
 
 
Xe 
X 
Vital Signs (including weight) 
Xf 
 
X 
 
X 
X 
X 
Xf 
 
X 
 
Xf 
Xf 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Subject Questionnaires 
(5-D Pruritus Scale and Pruritus 
VAS) 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Quality of Life Questionnaires  
(PBC-40, EQ-5D-5L, and FIS) g 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
TE Fibroscan®/DEXAh 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Endoscopyi 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Hepatic Ultrasoundj 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Physical Exam and Assessments for 
Mayo Risk and Child-Pugh Scoresk 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Adverse Events  
X 
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 
X 
Health Outcome Assessments l 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization/Treatment Assigned 
 
 
X 
 
 
 
 
 
 
 
 
 
 
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Table 1: 
Schedule of Study Procedures (Continued) 
 
Year 1 
Years 2 through End of Study 
 
Screening 
Visit 1a 
Screening 
Visit 2a 
Day 0 
Safety 
Contactb 
M 3 
M 6 
M 9 
M 12 
M 3 
continued 
follow-up 
M 6 
continued 
follow-up 
M 9 
continued 
follow-up 
M 12 
continued 
follow-up 
EOT/
EOSc 
Visit Windows (+/-)d 
3 to 8 wks 
prior to 
Day 0 
1 to 6 wks 
prior to 
Day 0 
 
±1 wk 
±2 
wks 
±2 
wks 
±2 
wks 
±2 
wks 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
±2 
wks 
Dose Titration (if applicable)m 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Dispense Investigational Productn 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
IP Accountability/Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSo 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
X 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Urine-based β-hCG Pregnancy Testp 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Chemistry/Hematology/Coagulation 
X 
Xa 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCA, C4, and FGF-19 (plasma) 
 
 
X 
 
X 
X 
Xq 
X 
 
 
 
X 
X 
Markers of Hepatic Fibrosis and/or 
Inflammationr 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Geneticss 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Blood Sample for Future Analysist 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
β-hCG = beta human chorionic gonadotropin; DEXA = dual-emission X-ray absorptiometry; EOS= End of Study; EOT = End of Treatment; FGF = fibroblast growth factor-19; 
FIS= Fatigue Impact Score; IP = Investigational Product; M = month, wk = week 
a All subjects will have the chemistry panel retested to ensure subjects have 2 ALP and bilirubin assessments at least 2 weeks apart to calculate the mean result for both analytes.  
The mean of all screening ALP and bilirubin assessments will be used to determine eligibility.  Samples for hematology and coagulation will not be collected at Screening 
Visit 2. 
b The subject should be contacted by telephone on a monthly basis in between at-clinic study visits at Month 1 and Month 2 (±1 week), and also 2 weeks post dose titration (up or 
down), to assess for AEs and concomitant medications and to verify that s/he is dosing as directed.   
c As soon as possible upon study discontinuation and as near as possible to last dose taken. 
d Visits should be based on Day 0 (not on the prior visit). 
e Medical history at Screening and the yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both.   
f Height will be collected at this visit. 
g The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2  and Section 12.2.6). 
h Transient elastography (TE) will be conducted at selected study sites where the Fibroscan® TE device is available.  Similarly, DEXA will be conducted at selected study sites 
where the DEXA device is available.   Please refer to Section 9.7.4 for additional information related to the allowed windows at Day 0 for these specific procedures.  
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i Endoscopy will be conducted at selected study sites where the device is available to assess for the presence of oesophageal varix/varices.  Please refer to Section 9.7.4 for 
additional information related to the allowed window at Day 0 for this specific procedure.  
j Ultrasound will be conducted to enhance HCC surveillance.  If a lesion is found, a second confirmatory image (eg, MRI) should be obtained.  Please refer to Section 9.7.4 for 
additional information related to the allowed windows at Day 0 for this specific procedure 
k 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 case report form.  Mayo Risk Score will be calculated based on central laboratory evaluations, diuretic use data, and peripheral edema assessment data captured in the CRF. 
l Health Outcome Assessments:  Data related to non-study related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
m After 3 months of treatment with investigational product, the dose should be increased (in a blinded manner) based on tolerability; this may occur at the Month 3 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed.   
n Subject to begin dosing on Day 1 
o The subject should be instructed to fast overnight (at least 8 hours) prior to each visit (except Screening Visit 1).  Fasting is required prior to all study visits, but water is 
permitted. 
p Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry.  If positive, a confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not be enrolled in the study.  (Additional testing may be conducted where required, regionally). 
q Only OCA PK samples will be collected at Month 9 at select study sites in a subset of subjects.  Please refer to Section 9.7.9 for the PK sampling schedule. 
r Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
s A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12 
t Please refer to Section 11.1.2.3 for description of the blood sample to be collected for future analysis. 
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7.1.3. 
Study Duration 
The study is event driven and total duration will be determined by the time required to accrue 
approximately 121 primary endpoint events, estimated to be approximately 8 years.  Subjects are 
expected to have a minimum follow-up time of approximately 6 years. 
7.2. 
Number of Subjects 
It is expected that approximately 350 subjects will be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
7.3. 
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate to 10 mg OCA (in a blinded 
manner) at the 3-month study visit or at any study visit thereafter depending on tolerability.   
7.4. 
Dose Titration Criteria 
After 3 months of treatment at the 5 mg dose, the dose of OCA will be increased to the 
maximum dose of 10 mg OCA or matched placebo (in a blinded manner) at the 3-month visit or 
any study visit following the 3-month visit based on tolerability of investigational product.  For 
those subjects that increased their dose to 10 mg, they may decrease his or her dose to 5 mg at 
any time during the study as considered appropriate (eg, tolerability), but should be titrated back 
to 10 mg based on tolerability and clinical judgment by the Investigator as soon as possible with 
the goal that all subjects remain on the 10-mg dose if tolerated. 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
Investigational product may be temporarily decreased (ie, from 10 mg to 5 mg daily, or by 
alternate day dosing) 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 
(5 mg or 10 mg) once the issues relating to the lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated events has accrued.  If a subject reaches an 
event, he or she should continue the regular visit schedule and continue taking investigational 
product as long as the Investigator assesses it as safe.  In general, subjects should be strongly 
encouraged to both stay on investigational product and remain in the study until study 
termination.   
7.5. 
Criteria for Study Termination 
The Sponsor 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 DSMC, it may be necessary to stop the study before all events have been accrued, and 
when subjects are still active on the study.  In addition, the Sponsor may terminate the study at 
an investigational site at any time (eg, poorly performing sites, as determined by the number of 
subjects enrolled or the quality of the study data). 
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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 subjects for the End of Study Visit.  The window of time for 
scheduling the visit will be based on a final projection of when the requisite 121 adjudicated 
events will have been accrued. 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Population 
This study will be conducted at approximately 170 international study sites with experience in 
treating patients with PBC.  Prospective subjects 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. 
Subject Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with AASLD and EASL practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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. 
2. A mean total bilirubin >ULN and ≤3x ULN and/or a mean ALP >5x ULN  
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking 
UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0. 
5. Contraception:  Female subjects 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:   
• Double barrier method, ie, (a) condom (male or female) or (b) diaphragm, with 
spermicide; or  
• Intrauterine device (IUD); or  
• Vasectomy (partner), or  
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• Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection, or 
• Abstinence, if in line with the preferred and usual lifestyle of the subject)   
6. Must provide written informed consent and agree to comply with the study protocol 
8.3. 
Subject Exclusion Criteria 
1. History or presence of other concomitant liver diseases including:  
• Hepatitis C virus infection 
• Active hepatitis B infection; however, subjects 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 
• Nonalcoholic steatohepatitis 
• Gilbert’s Syndrome  
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including:  
• History of liver transplant, current placement on a liver transplant list, or current 
MELD score >12.  Subjects who are placed on a transplant list despite a relatively 
early disease stage (for example per regional guidelines) may be eligible as long 
as they do not meet any of the other exclusion criteria. 
• Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
− Variceal bleed 
− Uncontrolled ascites 
− Encephalopathy  
− Spontaneous bacterial peritonitis  
• Known or suspected hepatocellular carcinoma 
• Prior transjugular intrahepatic portosystemic shunt procedure 
• Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine 
>2 mg/dL (178 μmol/L)  
3. Mean total bilirubin >3x ULN  
4. Subjects who have undergone gastric bypass procedures (gastric lap band is 
acceptable) or ileal resection or plan to undergo either of these procedures. 
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5. Other medical conditions that may diminish life expectancy, including known cancers 
(except carcinomas in situ or other stable, relatively benign conditions such as 
chronic lymphatic leukemia). 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test by the central laboratory), or lactating. 
7. Known history of human immunodeficiency virus infection. 
8. Medical conditions that may cause non-hepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months). 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study. 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0. 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components. 
14. UDCA naïve (unless contraindicated) 
8.4. 
Subject Withdrawal from Investigational Product or Study Criteria 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product 
If a female subject becomes pregnant, she must discontinue taking investigational product, but 
should continue with the study visit schedule.  The subject must be followed as considered 
appropriate by the Investigator and the medical monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an AE.  The subject may reinstate investigational 
product after delivery and cessation of breastfeeding (if applicable) at the discretion of the 
Investigator.  Subjects whose pregnancy is terminated early (planned or unplanned) may be 
permitted to resume participation in the study if termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotropin (β-hCG) test performed at the central laboratory. 
8.4.2. 
Other Reasons for Discontinuation of Investigational Product  
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.  If a subject reaches an event, 
he or she should continue the regular visit schedule and continue taking investigational product 
as long as the Investigator assesses it as safe.  Subjects who choose to discontinue investigational 
product prior to termination of the study need to also continue to follow the regular visit schedule 
through to study closure.  In general, subjects should be strongly encouraged to both stay on 
investigational product and remain in the study until study termination.  Early termination 
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procedures should only be conducted if the subject withdraws consent (See Section 9.7.14  Early 
Discontinuation and/or Early Termination Procedures). 
The following events are considered appropriate reasons for a subject to discontinue 
investigational product; however, these subjects are expected to continue in the study until study 
termination and the study will only terminate at the time when the needed number of adjudicated 
events has accrued (or at the discretion of the Sponsor): 
• The Investigator or Sponsor considers that it is advisable or in the best interest of the 
subject. 
• The occurrence of clinical or laboratory AEs considered by the Investigator to be 
clinically important. 
• Withdrawal of consent 
− Consent may be fully withdrawn 
− 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 potential 
adjudicated hepatic and/or cardiovascular events. 
The Investigator must notify the Sponsor study monitor by telephone or email as soon as 
possible if any subject prematurely withdraws from the study.   
8.4.2.1. 
Withdrawal of Consent 
If the subject 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 subjects 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 subject discontinuation.  This 
information and date must be recorded in the appropriate case report form (CRF).   
8.4.2.2. 
Lost to Follow-up 
If a subject fails to return to the clinic for a study visit, and the Investigator ceases to have 
contact with the subject, he or she will be withdrawn from the study. 
A reasonable effort must be made to contact the subject and determine the reason(s) why a 
subject 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 CRF.   
8.4.3. 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by telephone or email as soon as 
possible if any subject prematurely withdraws from the study.  The date when the subject is 
withdrawn and the reason for discontinuation must be recorded in the CRF.  If a subject is “lost 
to follow up” (fails to return for a visit), a reasonable effort should be made to contact the subject 
in order to determine why the subject failed to return.  This information must be documented in 
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the CRF.  If a subject is withdrawn from the study early (regardless of the cause), all of the 
EOT/EOS evaluations should be performed at the time of withdrawal, as appropriate (See 
Section 9.7.14 Early Discontinuation and/or Early Termination Procedures). 
9. 
TREATMENT OF SUBJECTS 
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:  placebo and OCA.  Investigational product will be 
administered orally, once daily for the duration of the study.  Each dose will be made up of 
1 tablet (ie, one 5 mg OCA tablet or one 10 mg OCA tablet, or matching placebo).   
Investigational product will be taken orally, once daily.  Subjects will be instructed to begin 
dosing on the day after the Day 0 visit (ie, on Day 1) and to take investigational product at 
approximately the same time each day.  Subjects must be instructed to swallow the tablet whole; 
they must not chew, divide, or crush the tablet. 
9.1.1. 
Dose Adjustment Beginning at Month 3 
After 3 months of treatment with investigational product, the dose of investigational product 
should be increased in a blinded manner and based on tolerability; this may occur at the Month 3 
visit, or at any study visit thereafter.  Titration above 10 mg OCA is not permitted.   
9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.1) 
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 CRF, as well as any dose or dose 
regimen changes that occur during the study.  Concomitant medications should be stable prior to 
Day 0.   
Subjects taking bile acid sequestrants (BAS) 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). 
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, 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. 
PBC Specific Therapy 
In general, Investigators will be encouraged to follow guidelines for care based upon local and 
institutional practice patterns and any relevant published practice guidelines.  Throughout the 
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course of the study, Investigators are expected to monitor subjects’ 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, subjects 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, subjects should be reminded to keep taking their blinded 
investigational product. 
9.2.1. 
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 and encourage the discontinuation of open-label OCA therapy.  However, if 
commercial OCA therapy remains, then investigational product should be discontinued to avoid 
potential double dosing.  Subjects that discontinue investigational product but continue 
commercial OCA therapy are expected to continue through the end of the study, and the study 
will only terminate at the time when the needed number of adjudicated events has accrued or at 
the discretion of the Sponsor.  Subjects will need to complete EOT procedures but continue with 
regularly scheduled visits until the study is terminated (See Section 9.7.14 Early Discontinuation 
and/or Early Termination Procedures). 
9.3. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Subjects should be instructed to retain all bottles of investigational product, even if empty, and to 
return them to the Investigator at the subsequent visit.  The Investigator or designee should 
perform investigational product accountability and, if applicable, follow up with the subject to 
retrieve any investigational product bottles that have not been returned.  
If the Investigator has concerns about a subject’s dosing compliance s/he should discuss this with 
the subject, assess the reasons for noncompliance and the likelihood that the subject will remain 
noncompliant, and notify the Sponsor accordingly. 
9.4. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Allocation to 1 of 
2 treatment groups (OCA or placebo) will occur on a 1:1 ratio across sites and will be stratified 
by UDCA treatment (yes/no) and mean baseline bilirubin categories (>ULN/≤ULN), as specified 
by the central laboratory.  The randomization will be based on a predefined randomization code 
(generated by the Sponsor or designee) using an interactive web response system (IWRS), which 
the Sponsor intends will serve as a computer-based subject registration system at Screening and 
Day 0.  The IWRS will serve as an investigational product inventory and management system 
and may be integrated with the study database.  
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The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide subject data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned (refer to Section 9.5.2, below) and 
investigational product dispensing information (ie, bottle number[s]) will be provided. 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects will be made available to the Investigator for 
emergency use only 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 is necessary for further medical management of the 
subject).  If it is not reasonable to inform the Medical Monitor in advance of unblinding the 
Investigator must promptly document in the subject’s source record and should subsequently 
contact the Medical Monitor to explain any premature unblinding of treatment assignment (such 
as unblinding which is necessary in order to treat an SAE). Procedures for unblinding a subject’s 
treatment will be provided separately to the Investigator.  Similarly, if the Medical Monitor 
breaks the blind for an individual subject for the purpose of evaluating an emergent safety issue, 
the Medical Monitor will document within trial documentation the rationale, circumstances, and 
the person or persons being informed about the unblinding. 
The Data and Safety Monitoring Committee (DSMC) will have access to the IWRS and will be 
able to unblind individual subjects.  Refer to Section 13.3 for further details regarding DSMC 
access to blinded and unblinded data.  The DSMC will document details about any unblinded 
subject data reviews in the closed session DSMC minutes, which will be made available to the 
Sponsor only after the database is locked and the trial is unblinded.   Cases of premature 
unblinding, as noted above, will also be reviewed by the DSMC.  
Access to treatment assignments will also be made available through the IWRS system to the 
appropriate named individual(s) responsible for reporting SAEs and suspected unexpected 
serious adverse reactions (SUSARs) to the Regulatory Authorities. 
9.5. 
Assignment of Site and Subject 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 subject data and to identify the site and or Investigator 
within study documents.  This number will be recorded in the CRF. 
9.5.2. 
Subject Numbers 
Subjects 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 3 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 trial is prohibited.   
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9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visits should be based on Day 0 (not on the prior visit), eg, Month 3 should ideally occur 
3 calendar months (±2 weeks) following Day 0.  The visit windows are as follows: 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening visit 1 interval is 3 to 8 weeks prior to Day 0.  Screening 
visit 2 interval is 1 to 6 weeks prior to Day 0 for screening visit 1.  
Screening visit 2 interval is 1 to 6 weeks prior to Day 0.  The visit 
window for Screening 2 visits allows for the repeat biochemistry 
tests to be collected at least two weeks after the initial biochemistry 
sample was collected, and will ensure ample time to receive lab 
results.  The overall Screening interval is up to 56 days, but 
screening procedures should not be performed during the last 
7 days of the window.  
Day 0 
This is the day of randomization.  On-treatment visit scheduling 
should be calculated from this point going forward.  (The first dose 
of investigational product should be taken the next day, on Day 1.) 
Months 3-12 
±2 week (14 days)  
Quarterly visits (Months 15 – EOS) 
±2 weeks (14 days) 
EOT 
(When subject discontinues investigational 
product) 
As soon as possible upon study discontinuation and as near as 
possible to last dose taken 
EOS 
(When subject terminates the study) 
The final study visit; EOS will occur concurrent with EOT if a 
subject discontinues study medication at the time the subject’s 
participation in the study ends (eg, withdrawal of consent or study 
termination by the Sponsor); EOS will occur after the EOT if the 
subject discontinues study medication  but continues in the study. 
EOS = end of study  EOT = end of treatment 
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk and benefit of the 
study to the subject and will provide him/her with a copy of the written information and 
informed consent form (ICF).  The subject will be given sufficient time to consider the study 
before deciding whether or not to participate.  The subject 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 s/he can withdraw from the study at any time.  The subject must be willing and 
able to provide written informed consent before entering the study.  The Investigator or a 
medically qualified designee is responsible for administering and documenting the written 
informed consent of the subject.  The subject will be given a copy of the written information and 
his/her signed and dated consent form. 
Any change in a subject’s consent status (eg, semi-annual telephone contact or medical record 
review) must be documented in a signed informed consent form or addendum.  The subject will 
be given a signed and dated copy of the consent document. 
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9.7.3. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 to 8 weeks prior to Day 0 to determine 
whether the subject meets all the inclusion criteria and none of the exclusion criteria.  Screening 
Visit 1 will occur 2 to 8 weeks prior to Day 0; Screening Visit 2 will occur 1 to 6 weeks prior to 
Day 0, depending on the date that the first serum chemistry sample was collected. Subjects who 
do not fulfill all eligibility criteria will not be enrolled in the study.  Subjects 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 3-digit Screening number assigned.   
Two Screening visits will occur from 1 to 8 weeks prior to Day 0 (as outlined below) allowing 
for the collection of repeated serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values: 
• All subjects will have 2 bilirubin and ALP assessments at least 2 weeks apart. 
• The mean of all available (at least 2; including both scheduled and 
unscheduled) bilirubin and ALP assessments will be used to determine eligibility 
(total bilirubin >ULN and ≤3x ULN and/or an ALP >5x ULN).   
Screening Visit 1 procedures are as follows: 
• The subject is to review and sign the ICF.  Informed consent must be obtained from 
the subject 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, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Assess and record any pretreatment-emergent AEs. 
• Record prior (if within 30 days of Screening) and current concomitant medications. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
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Screening Visit 2 procedures are as follows: 
• Verify inclusion and exclusion criteria for eligibility. 
• Assess and record any pretreatment-emergent AEs. 
• Record current concomitant medications. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry tests. 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
• In preparation for the dual-emission X-ray absorptiometry (DEXA) bone density scan 
to be done at Day 0 (selected study sites only), subjects who are taking calcium 
supplements should stop taking them for 48 hours before the scan.  If the subject is 
taking any medications for osteoporosis or osteopenia, s/he should not take them on 
the day of the scan. 
It is acceptable to repeat laboratory evaluations or other assessments or procedures within the 
Screening period (Weeks -8 to -1), as appropriate. 
9.7.4. 
Day 0 Procedures (Randomization) 
• Review inclusion and exclusion criteria for eligibility. 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure). 
• Subject and Quality of Life questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform transient elastography (TE; at selected study sites, where available) using the 
Fibroscan® TE device.  If TE has been done within 6 months of Day 0 and a 
report/adequate data are available, a pretreatment TE at Day 0 is not required.  If the 
TE cannot be performed on Day 0 (e.g., device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the screening visit window, as 
close as possible to the Day 0 visit, after subject eligibility has been confirmed. 
• Conduct a DEXA bone density scan (at selected study sites, where available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable.  If DEXA has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment DEXA at Day 0 is not required. If 
the DEXA cannot be performed on Day 0 (e.g., device/technician unavailability, 
scheduling issues, etc), the procedure may be completed within the screening visit 
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window, as close as possible to the Day 0 visit, after subject eligibility has been 
confirmed. 
• Perform an esophagogastroduodenoscopy (endoscopy; at selected study sites, where 
available) to assess the presence or absence of oesophageal varix/varices.  If an 
endoscopy has been done within 12 months of Day 0 and a report/adequate data are 
available, a pretreatment endoscopy at Day 0 is not required. If the endoscopy cannot 
be performed on Day 0 (e.g., device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening visit window, as close as 
possible to the Day 0 visit, after subject eligibility has been confirmed. 
− Subsequent endoscopies should be performed annually or per standard of care and 
the Investigator’s clinical judgment throughout the course of the study.  
Endoscopies should also be performed when platelet counts are <150 x 109 /L. 
• 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 Day 0 and a report/adequate data are available, a 
pretreatment ultrasound at Day 0 is not required. If the ultrasound cannot be 
performed on Day 0 (e.g., device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening visit window, as close as 
possible to the Day 0 visit, after subject eligibility has been confirmed. 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Assess and record any pretreatment-emergent AEs. 
• Review and record prior concomitant medications. 
• 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. 
• Randomize the subject only if s/he meets all inclusion criteria and no exclusion 
criteria. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
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• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and fibroblast growth factor-19 (FGF-19) 
− Markers of hepatic fibrosis and/or inflammation (including enhance liver fibrosis 
[ELF]) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Access the IWRS and dispense investigational product. 
• Instruct the subject to begin dosing on the day after the Day 0 visit (ie, on Day 1).  
Instruct the subject to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
9.7.5. 
Safety Contact (Month 1, Month 2, and 2 Weeks Post-Titration [by telephone]): 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Assess investigational product compliance. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 3 Procedures 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 and perform investigational product 
accountability. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests.  
• Obtain blood samples for: 
− OCA, C4, and FGF-19 
• Schedule the next visit and assess the subject’s supply of investigational product to 
ensure an adequate amount.  Access the IWRS and dispense investigational product if 
necessary. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 6 Procedures 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.6) 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 and perform investigational product 
accountability. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
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− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
• For subjects who will participate in the PK assessment and are taking BAS or 
aluminum hydroxide- or smectite-containing antacids, they should be instructed to 
not take their regular dose on the morning of the study visit.   
9.7.8. 
Month 9 Procedures 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate, and sitting blood pressure). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 and perform investigational product 
accountability. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
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• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• PK assessment in participating subjects at select study sites (see Section 9.7.9). 
• In preparation for the DEXA bone density scan to be done at the Month 12 visit 
(selected study sites only), subjects who are taking calcium supplements should stop 
taking them for 48 hours before the scan.  If the subject is taking any medications for 
osteoporosis or osteopenia, s/he should not take them on the day of the scan. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic Assessment 
At selected investigational sites, subjects will have the option to consent to participate in an 
additional OCA PK assessment.  PK samples will be used to support further analysis of OCA 
exposure-response in subjects with PBC.  This is optional and subjects may decline to participate 
without affecting their involvement in the rest of the study.  Consent to participate in the 
assessment can be given at any point during study participation prior to the Month 9 visit. 
Following collection of the Month 9 fasted samples (refer to Section 9.7.8 , subjects who are 
participating in the PK assessment will each receive a single dose of investigational product 
(blinded OCA or placebo tablet) with approximately 240 mL of water.  Subjects taking BAS or 
aluminum hydroxide- or smectite-containing antacids should be instructed to stagger their dosing 
of study medication and UDCA, ensuring at least 4 hours between doses of the BAS and/or these 
antacids and the study medication (and UDCA).   
Serial blood samples will be obtained for measurement of OCA and its conjugates prior to 
dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours post dose.  Samples should be collected 
within a window of ±5 minutes of the scheduled sample time.  Subjects should not drink 
additional water for 1 hour after taking the dose of investigational product and will remain fasted 
until the 4 hour sample is collected.  Lunch will be provided following collection of the 4 hour 
PK sample; the lunch will be a meal replacement drink.  Samples will be stored for up to 5 years 
after the end of the study and will be destroyed after 5 years if not analyzed. 
9.7.10. 
Month 12 Procedures 
• Perform a physical examination (including smoking and alcohol consumption habits). 
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• Assess and record vital signs (height ,weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Subject and Quality of Life questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform TE (at selected study sites, where available) using the Fibroscan® TE device. 
• Conduct a DEXA bone density scan (at selected study sites, where available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable. 
• Perform an endoscopy (at selected study sites, where available) to assess the presence 
or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 and perform investigational product 
accountability. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for: 
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− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 weeks]) 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 and perform investigational product 
accountability. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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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9.7.12. 
Month 6 Continued Follow-up Procedures (Semi-annually [±2 weeks]) 
• Assess and record vital signs (weight, oral temperature, sitting heart rate, respiratory 
rate and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.6) 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 (refer to Section 7.4). 
• Assess investigational product compliance and perform accountability. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− Markers of hepatic fibrosis and/or inflammation (including ELF). 
− Blood sample for future analysis (refer to Section 11.1.2.3). 
• At the semi-annual visit, in preparation for the DEXA bone density scan to be done at 
the annual visit (selected study sites only), subjects who are taking calcium 
supplements should stop taking them for 48 hours before the scan.  If the subject is 
taking any medications for osteoporosis or osteopenia, s/he should not take them on 
the day of the scan. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, and 
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− 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. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Assess and record vital signs (height, weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Subject and Quality of Life questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform TE (at selected study sites, where available) using the Fibroscan® TE device. 
• Conduct a DEXA bone density scan (selected study sites); document whether the 
subject stopped taking her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the scan, if applicable. 
• Perform an endoscopy (at selected study sites, where available) to assess the presence 
or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 (refer to Section 7.4). 
• Assess investigational product compliance and perform accountability. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
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• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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, 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. 
9.7.14. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent 
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects discontinue treatment with investigational 
product.  The EOT visit and procedures listed below must be performed as close as possible to 
the subject’s last dose of investigational product.  When a subject discontinues investigational 
product but continues with regularly scheduled study visits, the EOS visit will be completed later 
in the study as the subject’s final study visit.  The actual investigational product discontinuation 
scenario (Table 2) will determine the sequence of the EOT and EOS visits and procedures.  In 
some cases, the EOT visit and procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible to the subject’s last dose of 
investigational product.   
When a subject ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (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 subject 
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 and EOS procedures in the CRF.  
 
 
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Table 2: 
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 IP 
Treatment 
Discontinuation 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
Discontinued 
Semiannual 
contactb 
Telephone 
contact every 6 
months (±2 
weeks) 
Combined Visit, Completed as 
close as possible to last dose IP 
Discontinued 
Record 
review 
onlyb 
Record review 
only 
Combined visit 
Completed as close as possible 
to last dose IP 
Sponsor Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit 
Completed as close as possible 
to last dose IP 
Pregnancy 
Interrupted 
Retained 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
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; IP = investigational product 
a Refer to Section 7.1.2 Schedule of Study Procedures for all procedures and evaluations required at the End of 
Treatment and End of Study Visits. 
b Outcomes data to be discussed or collected include data related to adjudicated hepatic and cardiovascular event-
related data.  No additional data (e.g. AE, concomitant medication, etc) data will be collected, except as indicated 
in Section 12.1.6. 
Some assessments noted below may be omitted if they have been completed within the 6 months 
(or the timeframe otherwise specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT/EOS Visit: 
If possible to do before the visit, when scheduling the EOT/EOS visit, reiterate dosing 
instructions and advise the subject: 
• If applicable, NOT to take investigational product on the morning of the next visit, 
and  
• To bring the investigational product bottle(s); if applicable, s/he will dose at the 
clinic, and 
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• To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior to 
all study visits, but water is permitted. 
During the EOT/EOS Visit: 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Assess and record vital signs (height, weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead ECG. 
• Subject and Quality of Life questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform TE (where available) using the Fibroscan® TE device (not required at 
EOT/EOS if done within 6 months). 
• Conduct a DEXA bone density scan (selected study sites; not required at EOT/EOS if 
done within 6 months); document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites); not required at 
EOT/EOS if done within 6 months. 
• Perform physical examination and overall status assessment for calculation of Mayo 
Risk Score and Child-Pugh Assessments. 
− Presence/absence of peripheral edema 
− Presence (degree)/absence of ascites 
− Presence (degree)/absence of hepatic encephalopathy 
• Assess and record AEs; all ongoing “related” AEs must be followed until stable or 
resolved. 
• Review and record concomitant medications. 
• 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 and perform accountability; retrieve used 
bottles, accordingly, and document returns. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
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• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
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.   
In the event of an inexplicable and acute (for example not explained by natural progression of the 
chronic disease) increase in alanine aminotransferase (ALT) to >3× baseline (and >upper limit of 
normal [ULN]) or total bilirubin >2× baseline (and >ULN), the subject should be followed by 
repeat testing within 48 to 72 hours of the serum chemistry to confirm the abnormalities and to 
determine if they are increasing or decreasing.  AE information should also be collected.  If 
symptoms persist or repeat testing shows ALT >3× baseline (and >ULN) or total bilirubin 
>2× baseline (and >ULN), subjects should be followed until resolution of the abnormality and as 
clinically indicated depending on other laboratory and clinical signs and symptoms. 
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 5 mg or 10 mg OCA 
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 subject at each visit to provide enough tablets for daily 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. 
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10.3. 
Investigational Product Storage 
The investigational product should be stored in the containers in which they are received from 
the Sponsor’s supplier, at controlled room temperature, and protected from excess humidity. 
10.4. 
Investigational Product Preparation 
The investigational product will be provided to the distribution center in bulk bottles and 
therefore may be repackaged in unit dose form for administration to subjects before shipping to 
the sites. 
10.5. 
Investigational Product Administration 
Refer to Section 9.1. 
10.6. 
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 subject 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. 
11. 
ASSESSMENT OF EFFICACY 
11.1. 
Assessment of Efficacy  
11.1.1. 
Primary Assessments 
The following primary efficacy assessments will be measured: 
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
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• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of 2 or greater) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities. 
11.1.2. 
Secondary Assessments 
The following secondary efficacy assessments will be measured: 
• Liver-related death 
• Liver biochemistry (see Table 5 for list of analytes to be tested) 
• Biomarkers, including markers of hepatic fibrosis and/or inflammation, to be tested 
will include:  IgM, c-reactive protein (CRP), tumor necrosis factor-α (TNF-α), 
FGF-19, cytokeratin-18 (CK-18) and ELF, Fibroscan (and others as determined 
during the course of the study). 
• Data will be collected to inform quality of life and cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Quality of life will be 
assessed by questionnaires (PBC-40, EQ-5D-5L, and FIS) administered annually.  
Resource utilization information will be collected from the Medical and Surgical 
Treatment Procedures and Office Visit Log or other CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician visits (subject reported), 
and use of concomitant medications.  
• Endoscopy will be conducted at selected study sites where the device is available to 
assess for the presence of oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual study assessments or standard 
of care will be collected in the case report form to assess for the development of 
varix/varices. 
11.1.2.1. Non-Invasive Assessments of Liver Fibrosis 
• Blood samples for measurement of ELF™ test and other analytes will be collected.  
The ELF test assesses: hyaluronic acid (HA), procollagen-3 N-terminal peptide 
(P3NP), and a tissue inhibitor of metalloproteinase 1 (TIMP-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.   
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11.1.2.2. Other 
• OCA (and its conjugates) and C4 will be assayed. 
• Quality of Life questionnaires. 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 (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 respondent’s self-rate 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). 
− Fatigue Impact Scale (FIS):  The FIS is a validated 40 question questionnaire 
organized into 3 dimensions:  cognitive, physical, and social.  Each dimension has 
5 levels:  no problem, small problem, moderate problem, big problem, and 
extreme problem (Fisk 1994). 
11.1.2.3. Other Exploratory Evaluations 
• A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved 
in PBC will be conducted for subjects and at study sites willing to provide samples at 
Day 0, Month 12, and every other year at the yearly visits thereafter.  RNA 
expression resulting from treatment with OCA will be assessed at indicated 
timepoints during the study.   Subjects will be permitted to decline to provide a blood 
sample for the genetics study, without affecting their involvement in the study.  
IRB/IEC review and approval will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will be stored for up to 1 year 
after the end of the study and destroyed after 1 year if not analyzed. 
• Blood samples for future analysis of additional analytes, such as PBC autoantibodies 
and other cytokines and interleukins, may be assayed on an exploratory research 
basis.  Blood samples may also be used to assess other disease or investigational 
product characteristics.  Appropriate serum and plasma samples will be collected at 
selected time points during the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their involvement in the study.  IRB/IEC 
review and approval will be required and willing subjects must specifically consent to 
participate in this evaluation.  The samples will be stored for up to 1 year after the end 
of the study and destroyed after 1 year if not analyzed. 
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11.1.2.4. Potential Clinical Outcome Events 
The events listed in Appendix A 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 13.4) to confirm if they meet the criteria to be considered 
Clinical Outcome Events.  
12. 
ASSESSMENT OF SAFETY 
12.1. 
Adverse Events and Serious Adverse Events 
12.1.1. 
Definition of Adverse Events  
12.1.1.1. Adverse Event  
An AE is 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) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction. 
Subjects should be questioned in a general way, without leading the subject 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. 
12.1.1.2. 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-subject 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 subject 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. 
12.1.1.3. Treatment-Emergent Adverse Event  
A treatment-emergent AE (TEAE) is any event not present prior to the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
12.1.2. 
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 3.  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/serious adverse event (SAE) and the investigational product is 
determined to be “possible” or “probable” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 
Table 3: 
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 subject’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 
A reaction 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 subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
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12.1.3. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 4, must be entered on the AE CRF.  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 4: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Causing no limitation of usual activities; the subject may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the subject may experience annoying 
discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the subject may experience intolerable 
discomfort or pain. 
12.1.4. 
Reporting of Adverse Events and Serious Adverse Events 
12.1.4.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
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 subject’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE CRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product. 
12.1.4.2. 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 medical monitor.  
 MD, PhD 
Telephone:  
 (Pacific time zone) 
Email: 
 
SAE Fax:  +1 800 497 8521  
SAE Email:  sae@interceptpharma.com 
Alternate Contact: 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
 
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All SAEs occurring while subjects are receiving investigational product or are on an 
investigational product holiday (including Potential Clinical Outcome Events that qualify as 
serious) must be reported to the medical monitor immediately (ie, within 24 hours) after the 
Investigator identifies the SAE.  SAEs are reported by entering the SAE data into the electronic 
data capture (EDC) system.  Entering the SAE data into the EDC system will automatically 
notify the medical monitor of the event.  In the event that the EDC system is inaccessible, an 
SAE may be reported by telephone or fax using a paper SAE Report form.  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:  subject number and initials, a description of the event, at least one 
criterion classifying the event as serious and the name and title of the reporting individual.  
Additionally, judgment of causality by the Investigator must be provided as soon as possible to 
ensure timely reporting to regulatory authorities by the Sponsor or designee(s).  Following the 
initial report, any additional information obtained by the Investigator about the SAE must be 
reported promptly to the medical monitor.  Any supporting source documentation should be 
faxed to +1 800 497 8521 or emailed to sae@interceptpharma.com as soon as possible. 
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.  A SAE assessed 
with a possible, probable, or definite causal relationship to the investigational product and 
unexpected according to IB Reference Safety Information (RSI), is known as a suspected 
unexpected serious adverse reaction (SUSAR).  The Sponsor will notify the appropriate 
regulatory agencies as well as all participating Investigators of investigational new drug (IND) 
safety reports (SUSARs) that occur during the study within the time frames required by each 
regulatory agency.  The Investigator is responsible for submitting information on IND safety 
reports/SUSARs received from the Sponsor or Sponsor designee to her/his local EC/IRB.  
Documentation of the submissions to IRBs and health authorities must be retained in the 
appropriate study file(s). 
Potential Clinical Outcome Events (Appendix A) as well as Anticipated Events (Appendix B) 
will not undergo expeditious reporting to regulatory authorities. 
12.1.5. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the CRF 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 subject’s AE CRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the medical monitor, 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 subject 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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12.1.6. 
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 medical monitor should be notified 
immediately (ie, within 24 hours). 
All SAEs that occur within 30 days following the cessation of investigational product, whether 
or not they are related to the study, must be reported to the Sponsor within 24 hours by following 
the instructions provided in Section 12.1.4.2. 
SAEs that occur more than 30 days after a subject has discontinued study medication, and are not 
considered related to investigational product, must still be reported in the EDC system; however, 
these events are not required to be reported within 24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to investigational product, action taken with study 
medication, treatment, outcome, and potential endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event summary, SAE details) may also be required to be 
entered, when requested by the sponsor. 
12.1.7. 
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 subject 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 subject 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 CRF.  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. 
12.1.8. 
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 and the Sponsor must be notified within 24 hours of the Investigator’s learning of the 
pregnancy by completing the Pregnancy Notification Form and faxing or emailing to the Sponsor 
at +1 800 497 8521 or sae@interceptpharma.com.  
Safety will be monitored and assessed by AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and clinical laboratory assessments. The Sponsor may 
also follow the health of an infant born subsequent to use of investigational product. 
The subject may reinstate investigational product after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  Subjects whose pregnancy is terminated early 
(planned or unplanned) may be permitted to resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test (see Section 8.4.1). 
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12.2. 
Other Safety Parameters 
12.2.1. 
Medical History/Demographics 
A complete medical history and PBC disease-specific history will be obtained from the subject at 
Screening.  Smoking and alcohol consumption history and current habits will be recorded.  
Demographic characteristics (age, gender, race, and ethnicity) will be recorded. 
12.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the timepoints specified in the Schedule of Study Procedures (Section 7.1.2).  A basic physical 
examination should be performed, including all body systems pertinent to the subject.  Any 
clinically significant abnormality should be reported on the AE CRF page for findings that 
appear after consent, and on the medical history CRF for any finding present prior to consent.  
Information about smoking and alcohol consumption habits will be collected at the same 
(follow-up) timepoints as the physical exam. 
12.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits: height, weight, oral temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure.  When taking heart rate, respiratory rate, and blood 
pressure readings, subjects should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
12.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected at the Screening visit 1 and at EOT/EOS.  The 
Investigator or designee will review the 12-lead ECG and findings will be recorded in the CRF 
as normal, abnormal but not clinically significant, or abnormal and clinically significant.  Any 
clinically significant abnormality on ECGs should be reported on the AE CRF page.  
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 subject’s initials, Subject ID number, 
date, and time. 
12.2.5. 
Dual Emission X-Ray Absorptiometry 
A bone density assessment will be done using the DEXA scan. 
12.2.6. 
Subject Questionnaires 
Information about the subject’s PBC disease history (ie, date of diagnosis, treatment history, 
pruritus history, signs and symptoms, and including smoking history) will be collected during 
Screening.  At subsequent study visits (see Section 7.1.2), subjects will be asked to complete the 
following questionnaires; they may be asked to initial and date to document confirmation of their 
responses, and the questionnaires should be filed in the subject’s study records.  These may 
require transcription to the CRF by study site staff. 
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• 5-D Pruritus Questionnaire:  This is a questionnaire that has been validated in several 
different diseases.  It assesses symptoms in terms of 5 domains: degree, duration, 
direction, disability and distribution (Elman 2010). 
• Pruritus VAS:  A Visual Analogue Scale (VAS) will also be used to assess pruritus in 
individual subjects. 
12.2.7. 
Laboratory Assessments 
Subjects will be instructed to attend each of their study visits (except Screening) in a fasted state, 
and subjects should remain fasted until their blood samples have been collected.  At each visit, 
the Investigator or designee will verify that the subject has fasted for at least 8 hours and record 
fasting status in the source and CRF.  If the subject reports having eaten (water is permitted) 
within 8 hours, the Investigator or designee will document accordingly in the source and CRF 
and remind the subject that fasting is required prior to all study visits. 
Blood samples for serum chemistry and hematology will be collected at every visit as detailed in 
the Schedule of Study Procedures (Section 7.1.2).  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 by the central clinical laboratory in a study specific laboratory 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 subjects 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 5. 
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Table 5: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry  
Albumin, blood urea nitrogen (BUN), 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 very low density 
lipoprotein [VLDL] fractions and triglycerides[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, HBE [MCH], MCHC) 
Coagulation 
Prothrombin time (PT), partial thromboplastin time 
(PTT), international normalized ratio (INR) 
Urinalysis 
pH, specific gravity, total  protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, 
albumin, creatine, leucocytes, nitrates, 
albumin/creatine ratio (if positive) 
Biomarkers of Hepatic Fibrosis and/or Inflammation  
IgM, C-reactive protein (CRP), TNF-α, FGF-19, CK-
18, ELF, and others as determined during course of 
study  
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Genetics 
DNA including single-nucleotide polymorphisms 
(SNPs) that may be involved in PBC; RNA 
Blood Sample for Future Analysis 
PBC autoantibodies and other cytokines and 
interleukins TBD 
Other 
OCA (parent and conjugates [glyco and tauro]) and C4 
The Investigator should manage subjects with clinically significant lipoprotein abnormalities 
using local standard of care procedures as appropriate after assessing the individual subject’s 
total cardiovascular risk profile. 
Urine-based β-hCG pregnancy tests will be performed in female subjects of childbearing 
potential per protocol specified visits.  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 
subject will be followed, as outlined in Section 12.1.8 through pregnancy outcome. 
MELD scores, Child-Pugh score and MRS will be calculated at quarterly (MELD scores only) 
and semi-annual visits based on serum chemistry and coagulation. 
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13. 
STATISTICAL METHODS 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
hypothesis tests, will be prepared and approved by the Sponsor and its designees prior to study 
database lock, propensity score determination, and unblinding of the double-blind subject 
treatment assignments.  
13.1. 
Efficacy Analysis 
13.1.1. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
• The Randomized Population will include all randomized subjects. 
• The Intent-to-Treat (ITT) Population will include all randomized subjects who 
receive any amount of investigational product (OCA or placebo).  The ITT 
Population will be the primary population used for efficacy analyses.  Treatment 
assignment will be based on the randomized treatment. 
• The Safety Population will include all subjects who received any amount of 
investigational product (placebo or OCA).  The Safety Population will be the primary 
population used for safety analyses.  Treatment assignment will be based on the 
treatment actually received. 
• The PK population will include all OCA subjects who have at least one confirmed 
fasted analyzable sample.  Subjects must have been fasting for approximately 8 hours 
prior to the visit and must not have any major protocol deviations that potentially 
affect exposure levels.  The PK population will be used for OCA PK analyses.  
• The Overall Historical Control Population will include subjects from the United 
Kingdom (UK) -PBC Group and Global PBC Study Group databases with 
demonstrated comparability to randomized subjects in this clinical study (747-302) 
with respect to both subject characteristics and disease progression. 
• The UK-PBC Historical Control Population will include subjects from the UK-PBC 
Group databases with demonstrated comparability to randomized subjects in this 
clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
• The Global PBC Historical Control Population will include subjects from the Global 
PBC Study Group database with demonstrated comparability to randomized subjects 
in this clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
13.1.1.1. Comparability of Historical Controls 
Utilization of both historical control/observational databases (UK-PBC and Global PBC Study 
Group), with more than 6000 subjects each, allow for a rigorous subject level meta-analysis.  The 
historical databases include long-term follow up, detailed subject-level information such as 
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baseline clinical characteristics, longitudinal liver biochemistry, and long-term outcomes, and 
span a broad range of subject characteristics that may influence disease (disease state, age, 
gender, and regional differences in standard of care).  Historical controls from both databases 
will be chosen based on the same study inclusion/exclusion criteria where possible. 
13.1.2. 
Determination of Sample Size 
The following assumptions were used in sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.5 at 8 years with a hazard 
ratio of 0.60, and total study duration of 8 years, allowing for 2 years accrual and 
6 years of follow up. 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance. 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
13.1.2.1. Sample Size Re-Estimation Plan 
Conducting a long-term outcomes study given the low disease prevalence, relatively slow 
disease progression, and ethical considerations, which in combination will impact recruitment 
and event rates, is inherently difficult.  As stated in ICH E9, in long-term trials there is an 
opportunity to check the assumptions that underlay the original design and sample size 
calculations.  The power stated above depends on the total number of events.  Thus, the overall 
survival function can be estimated without unblinding. 
Therefore, starting approximately 2 years after the first subject is randomized, the aggregate 
event rate and sample size based on recruitment and retention will be evaluated in a blinded 
manner quarterly.  This evaluation will determine if any increases in number of subjects are 
required in order to obtain a total of 121 adjudicated events for the final analysis in the combined 
groups.  Specifically, the pooled number of events will be available during the study in a blinded 
manner, without any knowledge of the comparative efficacy in the treatment groups.  This 
method for evaluating the sample size does not inflate the type I error rate.  Additional subjects 
may be enrolled as appropriate. 
If after 4 years of accruing subjects, despite increases in the number of subjects, it is determined 
that at least an additional 2 years (ie, total study duration of at least 10 years) are needed to 
randomize sufficient subjects to achieve a total of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label OCA.  Previously randomized subjects will 
continue to be treated in a blinded manner with either OCA or matching placebo.  If this 
modification is implemented, the alternative primary efficacy analysis is specified is 
Section 13.1.9. 
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Any revised sample size or changes to treatment allocation will be justified and documented in a 
protocol amendment and in the CSR. 
13.1.3. 
Primary Efficacy Analysis 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
• Liver transplant 
• MELD score ≥15 
• Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
− Variceal bleed 
− Encephalopathy (as defined by a West Haven score of ≥2) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities. 
The primary efficacy analysis will compare randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the ITT population.  Only adjudicated events will 
be included in analyses.  The 2 treatment groups will be compared 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 determined based on a 
Cox regression model stratified by randomization strata to estimate the magnitude of the effect. 
13.1.4. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints will compare OCA to placebo on the following: 
• Time to first occurrence of MELD score ≥15 
• Time to liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare randomized OCA to randomized placebo in 
ITT population with respect to the key secondary efficacy endpoints.  Only adjudicated events 
will be included in time-to-event analyses.  The comparison (hypothesis testing) will be 
conducted as specified in Section 13.1.11 in a sequential closed testing gate-keeping procedure, 
provided that the primary efficacy endpoint comparison is statistically significant in favor of the 
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OCA treatment group.  If the primary comparison is not statistically significant then comparison 
of the secondary endpoints will be considered as descriptive and exploratory.  This procedure 
controls the study-wise type I error. 
The 2 treatment groups will be compared using the same methodology as specified for the 
primary efficacy analysis (Section 13.1.3). 
Analyses of change from Baseline to end of study in ALP and total bilirubin will be compared 
between treatment groups using analysis of covariance (ANCOVA) with change from Baseline 
as the dependent variable including treatment group and randomization stratification factor as 
fixed effects and the Baseline values as a covariate.  The same analysis will be carried out using 
percentage change from Baseline as the dependent variable. 
Descriptive statistics of the laboratory values will be summarized by treatment group.  The 
results, change from Baseline, and percentage change from Baseline values as well as estimates 
of least-square means, standard errors, and 95% CIs will be presented by treatment group.  
Estimates of the mean difference between treatment groups, the standard error of the difference, 
and 95% CI of the difference will be presented. 
13.1.5. 
Additional Secondary Efficacy Analyses 
The following time to event secondary efficacy analyses will compare randomized OCA versus 
randomized placebo using the ITT population: 
• Time to each component of the primary efficacy endpoint (except MELD score ≥15 
which is captured above) 
• Time to development of varix/varices 
• Time to liver-related death 
• Time to liver-related death or liver transplant 
• Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls as described below in Section 13.1.8. 
Analyses of changes in liver biochemistry (GGT, ALT, AST, conjugated bilirubin, albumin, and 
INR) will be summarized and analyzed using the same methodology as specified in 
Section 13.1.4 for the key secondary analyses of change in ALP and total bilirubin. 
Analyses of changes in MELD score, Child-Pugh score, Mayo Risk Score (MRS), IgM, CRP, 
TNF-α, FGF-19, CK-18, C4, and ELF score will be summarized and analyzed using the 
Wilcoxon Rank Sum Test to compare treatment groups.  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. 
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13.1.6. 
Exploratory Efficacy Analyses 
13.1.6.1. Responder Analyses 
The percentage of subjects with a decrease in ALP of ≥15% and ≥40% from Baseline will be 
summarized by treatment group.  In addition, the percentage of subjects with ALP ≤ULN will be 
summarized by treatment group. 
The percentage of subjects that meet the criteria of a responder based on each of the definitions 
below will be summarized by treatment group.  The response classification at baseline will also 
be included in the summary:  
• ALP ≤3x ULN and AST ≤2x ULN and total bilirubin ≤ULN (Corpechot 2008) 
• ALP ≤1.5x ULN and AST ≤1.5x ULN and total bilirubin ≤ULN (Corpechot 2011) 
• ALP ≤1.67x ULN and total bilirubin ≤ULN (Momah 2012) 
• Normal bilirubin (values ≤ULN) and normal albumin (values ≥lower limit of normal) 
(Kuiper 2009) 
• ALP ≤1.76 x ULN (Kumagi 2010) 
Responder analyses will compare treatment groups using a Cochran–Mantel–Haenszel test 
stratified by the randomization stratification factor.  Missing values will be considered as a 
non-responder.   
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints 
Sufficient data will be collected on resource utilization and quality of life to undertake 
cost-effectiveness analyses that are relevant to the major countries taking part in this study.  
Resource utilization data on hospitalizations, healthcare provider visits, and medications will be 
combined with appropriate national unit costs to calculate a cost per patient per year in the study. 
Quality of life data from patient-reported outcomes measures will be combined with survival 
data to calculate quality adjusted time in the study per patient.  Cost-effectiveness analyses will 
report the incremental cost per major clinical outcome averted, liver-related death averted, 
life-year gained and quality-adjusted life year gained, including OCA as part of usual care versus 
usual care without OCA.  Analyses will be conducted within the study and using a lifetime 
perspective.  A separate economic analysis plan will be prepared and reported separately from 
this protocol. 
13.1.8. 
Supportive Analysis 
Per the International Conference on Harmonisation (ICH) E10 guidance, “where no obvious 
single optimal external control exists, it may be advisable to study multiple external controls”.  
In order to address the risks associated with the inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare clinical outcomes in the OCA treatment arm to 
historical controls.   
In an attempt to avoid the inherent biases with historical controls and to maintain the integrity of 
this comparison, one can invoke matching methods to optimize comparability and find a 
historical control that is “similar” to a participating subject.  The historical database control 
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should be as similar as possible to the study population and should have been exposed to a 
similar standard of care (see Section 5.5.2.2). 
A propensity score can be used to reduce bias through matching, stratification, regression 
adjustment, or some combination.  Propensity scores use information from a pool of patients who 
do not participate in the study (historical controls) to identify what would have happened to 
participating subjects in the absence of the treatment.  By comparing how outcomes differ for 
treated subjects relative to historical controls, it is possible to estimate the effects of the 
treatment. 
Although it might be relatively simple to assign a historical control based on a single observable 
characteristic, in practice, if the matching process is to successfully mitigate potential bias, it has 
to be done considering a full range of covariates across which the treatment and historical 
controls might differ.  Although the results of using matching controls are conditional only on 
the observed covariates, if one has the ability to measure many of the covariates that are believed 
to be related to the treatment assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained.  Both UK-PBC Group and the 
Global PBC Study Group formally collect numerous covariates that could be used for propensity 
score estimation including standard of care, eg, UDCA. 
Historical controls will be chosen based on the same inclusion/exclusion criteria where possible. 
Propensity scores will be estimated using the available covariates that predict receiving the 
treatment.  Only covariates and not outcome variables will be included in the propensity score 
estimation.  Therefore, there is no chance of biasing results in favor of one treatment. 
The covariates and factors collected in the historical databases will be specified in the SAP. 
Propensity scores will be estimated first through a logistic regression model with treatment group 
as the dependent variable and the above covariates/factors as independent variables.  Then the 
stratum boundaries are determined based on the propensity score values for both groups (OCA 
population and control [historical and randomized placebo]) combined or in the OCA population 
or historical control group alone.  Based on recommendations in the literature, quintiles of the 
estimated propensity score from the combined group will be used to determine the stratum 
boundary cut-offs for the different strata. 
Outcome events collected in the historical database are:  death (liver-related and all-cause), liver 
transplant, hepatocellular carcinoma, and other.  Other is defined as cirrhosis or decompensation 
such as ascites, variceal bleed, and encephalopathy. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare randomized OCA-treated subjects in the ITT population and historical 
controls (Overall Historical Control Population: both the UK-PBC Group and Global PBC Study 
Group databases) on the following outcomes: 
• Time to death (all-cause) 
• Time to liver-related death 
• Time to liver transplant 
• Time to liver transplant or death (all-cause) 
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• Time to liver transplant or liver-related death 
• Time to hepatocellular carcinoma 
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 determined based on a Cox regression 
model stratified by randomization strata to estimate the magnitude of the effect. 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
13.1.9. 
Alternative Primary Analysis 
Based on sample size re-estimations, it may be determined that subjects will be enrolled to 
receive open-label OCA from that point forward, and the new primary efficacy analysis will 
become the comparison of all subjects in OCA population, to all control subjects (randomized 
placebo and historical controls) on time to liver transplant or death (all-cause) (see 
Section 13.1.2.1).  Similar statistical methodology as specified above in Section 13.1.8 for 
supportive analyses will be utilized. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare groups.  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 
determined based on a Cox regression model stratified by randomization strata to estimate the 
magnitude of the effect. 
In addition, the outcome events specified above in Section 13.1.8 will also be evaluated to 
compare all subjects in OCA population to all control subjects (randomized placebo and 
historical controls). 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
13.1.10. 
Handling of Dropouts or Missing Data 
Subjects who discontinue investigational product are expected to continue in the study until 
study termination. 
Missing data will be assumed to be missing at random.  In order to determine the effect of 
missing data on the analysis, efficacy endpoints will be analyzed using different methods of 
imputation as described below. 
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13.1.10.1. Time to Event Endpoints 
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 investigational product dosing). 
For analyses of the percentage of subjects with an event, subjects with no data after 
randomization will be considered to have an event. 
All time to event endpoints include only adjudicated events.  Sensitivity analyses may consider 
all events regardless of adjudication.  Events with discrepant adjudication will be analyzed using 
both results. 
13.1.10.2. Quantitative Endpoints 
For efficacy endpoints that utilize an ANCOVA model, observed cases will serve as the primary 
analysis.  Sensitivity analyses to assess the effect of missing data may be conducted where 
missing data is imputed using last observation carried forward. 
Sensitivity analyses of ANCOVA models will also be evaluated using a restricted maximum 
likelihood based mixed-effect repeated measures model where no imputations will be made for 
missing values.   
13.1.10.3. Responder Endpoints 
In an efficacy analysis in which subjects are classified as either a responder or a non-responder 
(binary outcome) based on dichotomizing a continuous variable, any subject who does not 
provide an assessment at the specified time point for the defining of response will be considered 
to be a non-responder.  That is, for the percentage of responders, the subject will be included in 
the denominator and will not contribute to the numerator. 
For sensitivity analyses using only “observed cases,” subjects who do not provide an assessment 
at the specified timepoint for the defining of response will not be included.  That is, for the 
percentage of responders, the subject will not be included in the numerator or the denominator. 
13.1.11. 
Multiple Comparisons/Multiplicity 
The key secondary efficacy endpoints are as follows: 
• Time to MELD score ≥15 
• Time to first occurrence of liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The hypothesis testing of key secondary analyses will compare placebo and OCA and will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of OCA.  If the primary comparison is not statistically significant 
then comparison of the secondary endpoints will be considered as descriptive and exploratory.  
This procedure controls the study-wise type I error.  
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• First (step 1) placebo and OCA will be compared with respect to the primary efficacy 
endpoint.  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• The time to MELD score ≥15 will be compared between placebo and OCA (step 2).  
If the comparison achieves statistical significance at 2-sided 0.05 level in favor of 
OCA group, then 
• The time to liver transplant or death (all-cause) will be compared between placebo 
and OCA (step 3).  If the comparison achieves statistical significance at 2-sided 
0.05 level in favor of OCA group, then 
• Change from Baseline in total bilirubin will be compared between placebo and OCA 
(step 4).  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• Change from Baseline in ALP at the end of study will be compared between placebo 
and OCA (step 5). 
If at any step defined above the comparison is not statistically significant at the 2-sided 
0.05 level then the remaining comparisons in the stated hierarchy will be considered descriptive 
and exploratory.  The study-wise type I error will be maintained with the above closed 
procedure. 
Additional efficacy endpoints will be analyzed; however hypothesis tests will be applied for 
descriptive and exploratory purposes only.   
13.1.12. 
Examination of Subgroups 
The primary and secondary efficacy endpoints will be analyzed for subject subgroups (eg, age, 
sex, and race) based on the ITT population.  Subgroups will be assessed at baseline and only if 
there are a sufficient number of subjects in each group (eg, >5 subjects per group). 
Baseline subgroups of interest are as follows:  age, age at PBC diagnosis, sex, race, body mass 
index, ALP level, bilirubin level, use of UDCA, years since diagnosis of PBC, and geographic 
region. 
13.2. 
Safety Analysis 
Safety data, including AEs and clinical laboratory observations, will be summarized by treatment 
group using the Safety Population. 
13.2.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary of Regulatory Activities.  Summary tables of 
treatment-emergent AEs will be provided.  The incidence of TEAEs will be tabulated by system 
organ class and preferred term for each treatment group, and by severity and relationship to 
treatment.  Tables of TEAEs leading to investigational product discontinuation and SAEs will be 
provided. 
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13.2.2. 
Clinical Laboratory Evaluations 
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will be 
presented for all study visits.  Changes from pretreatment to each study visit will also be 
summarized by treatment group. 
13.2.3. 
Additional Safety Analysis 
Additional safety assessments include vital signs and ECGs.  Descriptive statistics of the vital 
sign and ECG parameters will be presented by treatment group and study visit, as well as the 
change from pretreatment at each visit. 
In addition to potential clinical endpoint events, cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study and will be described separately. 
13.3. 
Data and Safety Monitoring Committee 
An independent DSMC will review safety data at periodic intervals from this study.  The DSMC 
will include internationally recognized hepatologists, pharmaceutical physicians, and a 
statistician.  All have considerable experience with clinical trial conduct and DSMCs, prior to 
joining the OCA DSMC.  Candidates are screened for conflicts of interest and any candidate 
found to have such a conflict is not offered membership.  Conflicts of interest are assessed 
regularly, and if members are found to have a new conflict of interest they would be replaced. 
The DSMC meets approximately quarterly at scheduled meetings and ad hoc meetings are 
convened, as appropriate.  The DSMC reviews all Intercept sponsored Phase 2 and 3 studies.  
Members of the DSMC will not be allowed to participate as investigators in this study and will 
not otherwise consult for the Sponsor. 
The DSMC will review data on a periodic basis to ensure the safe and proper treatment of 
subjects.  Based on review of these data, the DSMC will advise the Sponsor on the validity and 
scientific merit of continuing the study. 
The DSMC operates under an appropriate charter (in compliance with relevant regulatory 
guidance) that defines its organization and operation and includes specific procedures for each 
study.  The DSMC will prepare written minutes of both its open and closed sessions for each 
study.  The DSMC will document details about any unblinded subject data reviews in the closed 
session DSMC minutes, which will be made available to the Sponsor only after the database is 
locked and the trial is unblinded.   Cases of premature unblinding, as noted above, will also be 
reviewed by the DSMC.  
Data listings provided to the DSMC do not contain individual subject treatment information; 
however, the DSMC will have access to the database and may unblind individual subject data as 
appropriate.  Summary tables reviewed by the DSMC during closed sessions will include an 
overall column containing information regarding all subjects 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, Medical Dictionary for Regulatory Activities (MedDRA) coded AE, 
and AEs leading to early withdrawal of investigational product.  At each meeting, detailed 
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narratives of interval SAEs (including events resulting in death) are reviewed by the DSMC in 
addition to a cumulative list of all SAEs. 
The DSMC may request additional analyses if deemed necessary to fulfill the mission of the 
DSMC.  The DSMC will determine if an unscheduled meeting is necessary based on the 
additional data. 
All Investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DSMC relating to subject safety, which alter the 
conduct of this study.  The Investigators will inform the subjects of such actions and the 
protocol, PIS, and consent will be revised, as appropriate. 
13.4. 
Adjudication Committee 
All potential endpoint events will be reviewed by an adjudication committee before inclusion in 
the any analysis.  The adjudication of potential clinical endpoint events will include, but is not 
limited to:  available hospital reports, histology, discharge summaries, and death certificates.  
The assessment of events will be conducted in compliance with the protocol, study-specific 
procedures, manuals, Good Clinical Practice (GCP), and all other applicable regulatory 
requirements, including the archiving of essential documents.  A separate adjudication 
committee charter will document the entire data flow and process from committee membership, 
the reporting of events by the study site, reporting of the final assessment, supply of source 
documentation to the committee, the review of the events by the committee, and the working 
procedures of the committee.  The adjudication committee members will be independent 
hepatologists not involved in the study as investigators, DSMC members, or consultants.  All 
adjudication committee members will remain blinded to treatment group throughout the study. 
In addition to potential clinical endpoint events, cardiovascular events will also be adjudicated.  
The adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study and will be described separately. 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
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 subject’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 
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of dispensing investigational product, ECGs, etc) that support data entries in the CRF.  The CRF 
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 
subject's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
14.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC 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.   
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the CRF 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 14.2 for more details regarding the audit 
process. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF and/or other subject 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 the Sponsor before he or she can enroll 
any subject 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 subjects to the ethics committee 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 subjects for 
the study.  The protocol must be reapproved by the IRB or IEC upon receipt of amendments and 
annually, as local regulations require. 
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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.  
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, at a minimum annually, and after the study is complete. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles and are consistent with 
ICH/GCP, local applicable regulatory requirements (in addition to Appendix C), and the 
Sponsor’s policies. 
16.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated ICF 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 subject. 
16.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential and confidentiality of all subjects will be maintained.  Monitors (eg, 
CRA, medical monitor), auditors and inspectors will require access to a subject’s medical notes 
for the purpose of source document verification but the subject’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 subject’s names and identifying information (eg, subject’s 
hospital number, unique subject number).  This list will not be collected by the Sponsor. 
The written information sheet 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 subject 
number/randomization code/subject initials/site number, only. 
When personal data on subjects are stored or processed by computer, the data must be protected 
to prevent their disclosure to unauthorized third parties.  The pertinent sections of the data 
protection laws in which the country is being conducted will be complied with in full. 
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The written ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IEC/IRB may require direct access to parts of the hospital 
or study site records relevant to the study, including subject’s medical history. 
17. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the subjects 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 subjects, as applicable. 
17.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject 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 medical monitor. 
17.2. 
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 subject’s safety to be compromised if immediate action is not taken. 
17.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
• Approved ICF (all versions) 
• IRB/EC approvals (of protocol/amendments, subject questionnaires, etc) 
• Form FDA 1572  
• Current medical license 
• Curriculum vitae 
• Laboratory certification and reference ranges 
• Financial disclosure forms 
17.4. 
Ethics Review  
Please see Section 16.1 for the Investigator’s responsibilities regarding ethics review. 
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17.5. 
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 subject 
medical files (retained per country specific regulations), completed study subject log and 
confidential subject 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 prior to 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. 
18. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it Sponsors consistent 
with the Declaration of Helsinki (Seoul Revision 2008, 
[http://www.wma.net/en/30publications/10policies/b3/index.html, accessed May 22, 2013]).  
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 Study Registries (eg, clinicaltrials.gov):  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 (when available) 
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. 
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• 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:  The Sponsor, 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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19. 
LIST OF REFERENCES 
Beuers U, Lindor KD. A major step towards effective treatment evaluation in primary biliary 
cirrhosis. J Hepatol. 2011 Dec;55(6):1178-80. 
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and 
long term prognosis in primary biliary cirrhosis. Hepatology. 2008 Sep;48(3):871-877. 
Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: Biochemical response 
to treatment and prediction of long-term outcome. J Hepatol 2011;55:1361–1367. 
Elman S, Hynan L.S., Gabriel V, and Mayo M.J. The 5-D itch scale: a new measure of pruritus, 
British Journal of Dermatology 2010 162, pp587–593. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51:237-267. 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact of fatigue: initial validation of 
the fatigue impact scale. Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
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 Dec;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 
Nov;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. 
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 Apr;136(4):1281-7. 
Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict 
long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 
2010 Oct;105(10):2186-94. 
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Alkaline phosphatase values are a 
surrogate marker in prediction of transplant-free-survival in patients with primary biliary 
cirrhosis - an international, collaborative analysis.  J Hepatol. 2013; 58(Suppl):S388. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis: AASLD Practice 
Guidelines. Hepatology. 2009;50(1):291-308. 
Momah N, Silveira MG, Jorgensen R, et al. Optimizing biochemical markers as endpoints for 
clinical trials in primary biliary cirrhosis. Liver Int. 2012;32(5):790-795. 
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. 
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APPENDIX A. LIST OF STUDY 747-302 OUTCOME EVENTS 
Several of the specified clinical endpoints will also by definition (see Section 12.1) 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 12.1.4).  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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APPENDIX B.   LIST OF STUDY 747-302 ANTICIPATED EVENTS 
Jaundice  
Hepatic decompensation/failure 
Hypoalbuminemia 
Hyponatremia 
Splenomegaly 
Hepatorenal syndrome (renal failure in the setting of hepatic failure) 
Hepatopulmonary syndrome (pulmonary failure in the setting of hepatic failure) 
Fractures 
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APPENDIX C. ETHICAL CONDUCT ACCORDING TO THE 
DECLARATION OF HELSINKI FOR COUNTRIES 
PARTICIPATING OUTSIDE THE US (DECLARATION 
OF HELSINKI, FORTELEZA, BRAZIL, 2013) 
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Copyright 2013 American Medical Association. All rights reserved.
World Medical Association Declaration of Helsinki
Ethical Principles for Medical Research
Involving Human Subjects
World Medical Association
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1. The World Medical Association (WMA) has developed the Dec-
larationofHelsinkiasastatementofethicalprinciplesformedi-
cal research involving human subjects, including research on
identifiable human material and data.
The Declaration is intended to be read as a whole and each of
its constituent paragraphs should be applied with consider-
ation of all other relevant paragraphs.
2. ConsistentwiththemandateoftheWMA,theDeclarationisad-
dressed primarily to physicians. The WMA encourages others
who are involved in medical research involving human subjects
to adopt these principles.
General Principles
3. TheDeclarationofGenevaoftheWMAbindsthephysicianwith
the words, “The health of my patient will be my first consider-
ation,”andtheInternationalCodeofMedicalEthicsdeclaresthat,
“A physician shall act in the patient's best interest when provid-
ing medical care.”
4. It is the duty of the physician to promote and safeguard the
health,well-beingandrightsofpatients,includingthosewhoare
involvedinmedicalresearch.Thephysician'sknowledgeandcon-
science are dedicated to the fulfilment of this duty.
5. Medical progress is based on research that ultimately must in-
clude studies involving human subjects.
6. Theprimarypurposeofmedicalresearchinvolvinghumansub-
jects is to understand the causes, development and effects of
diseasesandimprovepreventive,diagnosticandtherapeuticin-
terventions (methods, procedures and treatments). Even the
bestproveninterventionsmustbeevaluatedcontinuallythrough
research for their safety, effectiveness, efficiency, accessibility
and quality.
7. Medicalresearchissubjecttoethicalstandardsthatpromoteand
ensure respect for all human subjects and protect their health
and rights.
8. Whiletheprimarypurposeofmedicalresearchistogeneratenew
knowledge, this goal can never take precedence over the rights
and interests of individual research subjects.
9. Itisthedutyofphysicianswhoareinvolvedinmedicalresearch
to protect the life, health, dignity, integrity, right to self-
determination,privacy,andconfidentialityofpersonalinforma-
tion of research subjects. The responsibility for the protection
ofresearchsubjectsmustalwaysrestwiththephysicianorother
health care professionals and never with the research subjects,
even though they have given consent.
10. Physiciansmustconsidertheethical,legalandregulatorynorms
andstandardsforresearchinvolvinghumansubjectsintheirown
countries as well as applicable international norms and stan-
dards.Nonationalorinternationalethical,legalorregulatoryre-
quirementshouldreduceoreliminateanyoftheprotectionsfor
research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that mini-
mises possible harm to the environment.
12. Medicalresearchinvolvinghumansubjectsmustbeconducted
onlybyindividualswiththeappropriateethicsandscientificedu-
cation, training and qualifications. Research on patients or
healthyvolunteersrequiresthesupervisionofacompetentand
appropriately qualified physician or other health care profes-
sional.
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13. Groups that are underrepresented in medical research should
be provided appropriate access to participation in research.
14. Physicians who combine medical research with medical care
should involve their patients in research only to the extent that
this is justified by its potential preventive, diagnostic or thera-
peuticvalueandifthephysicianhasgoodreasontobelievethat
participation in the research study will not adversely affect the
health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be en-
sured.
Risks, Burdens and Benefits
16. Inmedicalpracticeandinmedicalresearch,mostinterventions
involve risks and burdens.
Medical research involving human subjects may only be con-
ductediftheimportanceoftheobjectiveoutweighstherisksand
burdens to the research subjects.
17. All medical research involving human subjects must be pre-
ceded by careful assessment of predictable risks and burdens
to the individuals and groups involved in the research in com-
parisonwithforeseeablebenefitstothemandtootherindividu-
als or groups affected by the condition under investigation.
Measurestominimisetherisksmustbeimplemented.Therisks
mustbecontinuouslymonitored,assessedanddocumentedby
the researcher.
18. Physiciansmaynotbeinvolvedinaresearchstudyinvolvinghu-
mansubjectsunlesstheyareconfidentthattheriskshavebeen
adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive proof of definitive outcomes, physi-
cians must assess whether to continue, modify or immediately
stop the study.
Vulnerable Groups and Individuals
19. Somegroupsandindividualsareparticularlyvulnerableandmay
haveanincreasedlikelihoodofbeingwrongedorofincurringad-
ditional harm.
All vulnerable groups and individuals should receive specifi-
cally considered protection.
20. Medical research with a vulnerable group is only justified if the
research is responsive to the health needs or priorities of this
group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to ben-
efit from the knowledge, practices or interventions that result
from the research.
Scientific Requirements and Research Protocols
21. Medicalresearchinvolvinghumansubjectsmustconformtogen-
erally accepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as appropriate, ani-
mal experimentation. The welfare of animals used for research
must be respected.
22. The design and performance of each research study involving
human subjects must be clearly described and justified in a re-
search protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include
information regarding funding, sponsors, institutional affilia-
tions, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compen-
sating subjects who are harmed as a consequence of participa-
tion in the research study.
In clinical trials, the protocol must also describe appropriate ar-
rangements for post-trial provisions.
Research Ethics Committees
23. Theresearchprotocolmustbesubmittedforconsideration,com-
ment, guidance and approval to the concerned research ethics
committee before the study begins. This committee must be
transparent in its functioning, must be independent of the re-
searcher, the sponsor and any other undue influence and must
be duly qualified. It must take into consideration the laws and
regulations of the country or countries in which the research is
to be performed as well as applicable international norms and
standardsbutthesemustnotbeallowedtoreduceoreliminate
anyoftheprotectionsforresearchsubjectssetforthinthisDec-
laration.
The committee must have the right to monitor ongoing stud-
ies.Theresearchermustprovidemonitoringinformationtothe
committee, especially information about any serious adverse
events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of
thestudy,theresearchersmustsubmitafinalreporttothecom-
mittee containing a summary of the study’s findings and con-
clusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of re-
search subjects and the confidentiality of their personal infor-
mation.
Informed Consent
25. Participation by individuals capable of giving informed consent
as subjects in medical research must be voluntary. Although it
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2192
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may be appropriate to consult family members or community
leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving
informed consent, each potential subject must be adequately
informed of the aims, methods, sources of funding, any pos-
sible conflicts of interest, institutional affiliations of the re-
searcher,theanticipatedbenefitsandpotentialrisksofthestudy
and the discomfort it may entail, post-study provisions and any
other relevant aspects of the study. The potential subject must
be informed of the right to refuse to participate in the study or
to withdraw consent to participate at any time without repri-
sal. Special attention should be given to the specific informa-
tionneedsofindividualpotentialsubjectsaswellastothemeth-
ods used to deliver the information.
Afterensuringthatthepotentialsubjecthasunderstoodthein-
formation, the physician or another appropriately qualified in-
dividual must then seek the potential subject’s freely-given in-
formed consent, preferably in writing. If the consent cannot be
expressedinwriting,thenon-writtenconsentmustbeformally
documented and witnessed.
Allmedicalresearchsubjectsshouldbegiventheoptionofbeing
informed about the general outcome and results of the study.
27. When seeking informed consent for participation in a research
study the physician must be particularly cautious if the poten-
tial subject is in a dependent relationship with the physician or
mayconsentunderduress.Insuchsituationstheinformedcon-
sentmustbesoughtbyanappropriatelyqualifiedindividualwho
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving in-
formedconsent,thephysicianmustseekinformedconsentfrom
thelegallyauthorisedrepresentative.Theseindividualsmustnot
be included in a research study that has no likelihood of benefit
forthemunlessitisintendedtopromotethehealthofthegroup
represented by the potential subject, the research cannot in-
stead be performed with persons capable of providing in-
formed consent, and the research entails only minimal risk and
minimal burden.
29. When a potential research subject who is deemed incapable of
givinginformedconsentisabletogiveassenttodecisionsabout
participationinresearch,thephysicianmustseekthatassentin
addition to the consent of the legally authorised representa-
tive. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally in-
capable of giving consent, for example, unconscious patients,
may be done only if the physical or mental condition that pre-
ventsgivinginformedconsentisanecessarycharacteristicofthe
research group. In such circumstances the physician must seek
informedconsentfromthelegallyauthorisedrepresentative.If
nosuchrepresentativeisavailableandiftheresearchcannotbe
delayed,thestudymayproceedwithoutinformedconsentpro-
videdthatthespecificreasonsforinvolvingsubjectswithacon-
dition that renders them unable to give informed consent have
beenstatedintheresearchprotocolandthestudyhasbeenap-
provedbyaresearchethicscommittee.Consenttoremaininthe
researchmustbeobtainedassoonaspossiblefromthesubject
or a legally authorised representative.
31. Thephysicianmustfullyinformthepatientwhichaspectsoftheir
care are related to the research. The refusal of a patient to par-
ticipateinastudyorthepatient’sdecisiontowithdrawfromthe
study must never adversely affect the patient-physician rela-
tionship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or
similarrepositories,physiciansmustseekinformedconsentfor
its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracti-
cable to obtain for such research. In such situations the re-
search may be done only after consideration and approval of a
research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new inter-
vention must be tested against those of the best proven inter-
vention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary
to determine the efficacy or safety of an intervention
andthepatientswhoreceiveanyinterventionlesseffectivethan
thebestprovenone,placebo,ornointerventionwillnotbesub-
ject to additional risks of serious or irreversible harm as a result
of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. Inadvanceofaclinicaltrial,sponsors,researchersandhostcoun-
trygovernmentsshouldmakeprovisionsforpost-trialaccessfor
all participants who still need an intervention identified as ben-
eficialinthetrial.Thisinformationmustalsobedisclosedtopar-
ticipants during the informed consent process.
Research Registration and Publication and Dissemination
of Results
35. Every research study involving human subjects must be regis-
teredinapubliclyaccessibledatabasebeforerecruitmentofthe
first subject.
World Medical Association Declaration of Helsinki
Special Communication Clinical Review & Education
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36. Researchers, authors, sponsors, editors and publishers all have
ethical obligations with regard to the publication and dissemi-
nationoftheresultsofresearch.Researchershaveadutytomake
publicly available the results of their research on human sub-
jectsandareaccountableforthecompletenessandaccuracyof
their reports. All parties should adhere to accepted guidelines
for ethical reporting. Negative and inconclusive as well as posi-
tiveresultsmustbepublishedorotherwisemadepubliclyavail-
able. Sources of funding, institutional affiliations and conflicts
of interest must be declared in the publication. Reports of re-
search not in accordance with the principles of this Declaration
should not be accepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven inter-
ventions do not exist or other known interventions have been
ineffective, the physician, after seeking expert advice, with in-
formed consent from the patient or a legally authorised repre-
sentative, may use an unproven intervention if in the physi-
cian's judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should subse-
quently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be re-
corded and, where appropriate, made publicly available.
ARTICLE INFORMATION
Corresponding Author: World Medical
Association, 13, ch. du Levant, CIB - Bâtiment A,
01210 Ferney-Voltaire, France; wma@wma.net.
Published Online: October 19, 2013.
doi:10.1001/jama.2013.281053.
Disclaimer: ©2013 World Medical Association, Inc.
All Rights Reserved. All intellectual property rights
in the Declaration of Helsinki are vested in the
World Medical Association. The WMA has granted
JAMA exclusive rights to publish the
English-language version of the Declaration
through December 31, 2013.
Online-Only Content: Audio podcast is available at
www.jama.com.
Clinical Review & Education Special Communication
World Medical Association Declaration of Helsinki
2194
JAMA
November 27, 2013
Volume 310, Number 20
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Protocol 747-302 
Amendment 1.1:  12 Nov 2015
Page 91
 
Confidential and Proprietary 
APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 (DATED 29 APR 2015) 
Rationale 
The changes to the Original Version of the protocol, detailed below, modify the dose titration schedule based on observed efficacy and 
tolerability of OCA, address advice provided by regulatory agencies, and clarify questions raised by study site personnel currently 
using Original protocol version 1 dated 03 October 2014. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.  (Note:  Differences are denoted in bold font; Minor 
formatting changes are not listed) 
Section 
Original Text 
Revised Text 
Title Page 
Original:  03 October 2014 
Original:  03 October 2014 
Amendment 1:  xx April 2015 
Procedures in 
Case of 
Emergency 
Procedures in Case of Emergency 
 
Study Personnel Contact Information 
 
Or if Not 
Available 
Contact:
 MD, 
 & 
 Development, Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
Contact:
 MD, Medical Director, Drug Safety, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
Synopsis 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
≤1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 2 
weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
and total bilirubin values (refer to Section 9.7.3).   Subjects who 
meet all inclusion criteria and none of the exclusion criteria will be 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 2 
weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
and total bilirubin values (refer to Section 9.7.3).  Mean values for 
ALP and total bilirubin will be calculated using all available 
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Protocol 747-302
Amendment 1.1:  12 Nov 2015
Page 92
Confidential and Proprietary 
Section 
Original Text 
Revised Text 
randomized (1:1) to OCA or placebo treatment groups.  The 
randomization will be stratified by ursodeoxycholic acid (UDCA) 
treatment (yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ULN). 
 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 6 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 6-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
screening values.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment (yes/no) and baseline 
bilirubin categories (>upper limit of normal [ULN]/ ≤ULN). 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 3 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 3-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
Synopsis 
Inclusion Criteria 
2.  A mean total  bilirubin >ULN and ≤3x ULN or an ALP >5x 
ULN  
4.  Either is not taking UDCA (UDCA naïve or no UDCA dose in 
the past 3 months) or has been taking UDCA for at least 12 months 
with an approved, stable dose for ≥3 months prior to Day 0 
 
Inclusion Criteria 
2. A mean total bilirubin >ULN and ≤3x ULN and/or a mean 
ALP >5x ULN 
4.  Either is not taking UDCA (no UDCA dose in the past 
3 months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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Amendment 1.1:  12 Nov 2015
Page 93
 
Confidential and Proprietary 
Section 
Original Text 
Revised Text 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
contraception during the study and for 30 days after the end of 
treatment visit. 
 
5.  Contraception:  Female subjects 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: 
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
Synopsis 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
 
3. Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
4.  Other medical conditions that may diminish life expectancy to 
<2 years, including known cancers (except carcinomas in situ or 
other stable, relatively benign conditions such as chronic lymphatic 
leukemia) 
 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
3.  Mean total bilirubin >3x ULN 
 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
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Protocol 747-302 
Amendment 1.1:  12 Nov 2015
Page 94
 
Confidential and Proprietary 
Section 
Original Text 
Revised Text 
5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of screening (pretreatment) QT 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
5.  Deleted text 
Synopsis 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life 
 
 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life (Fatigue 
Impact Score and EQ-5D-
5L) 
 
Synopsis 
Statistical Methods: Other Efficacy Analyses 
• 
Added text 
Statistical Methods: Other Efficacy Analyses 
• 
Development of varix/varices 
4 
List of Abbreviations 
Added text 
 
List of Abbreviations 
EOS 
end of study 
 
5.4 
As of 31 March 2014, OCA has been evaluated in the clinic in 18 
completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 March 2014, a total of 1023 subjects have 
received at least one dose of OCA and of these, 414 (40%) were 
subjects with PBC.   
 
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 up to 4 years.  The LSTE phase of studies 
747-201 and 747-301 are ongoing; the LTSE phase of Study 747-
202 is complete 
As of 31 January 2015, OCA has been evaluated in the clinic in 20 
completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 January 2015, approximately 1650 subjects 
have received at least 1 dose of OCA and of these, 432 were 
subjects with PBC with ≤5 years of OCA treatment.   
 
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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is 
complete 
5.5.2.1 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg and 10 mg; both treatment 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg (titrated to 10 mg after 6 
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Protocol 747-302 
Amendment 1.1:  12 Nov 2015
Page 95
 
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Section 
Original Text 
Revised Text 
groups exhibited clinically meaningful improvements in liver 
biochemistry and were safe and generally well tolerated. 
 
months based on efficacy and tolerability in the double-blind 
phase and after 3 months in the open-label phase) and 10 mg; 
both treatment groups exhibited clinically meaningful 
improvements in liver biochemistry and were safe and generally 
well tolerated.  Based on these data, the intended commercial 
doses of OCA for the treatment of patients with PBC are 5 mg 
and 10 mg. 
The majority of efficacy results with OCA, in terms of change 
in alkaline phosphatase, was observed by 3 months and the 
time to treatment-emergent pruritus was typically 1 month or 
less in Study 747-301.  As such, Study 747-302 will evaluate the 
effect of OCA on clinical outcomes using the 5 mg OCA dose 
increasing to 10 mg OCA if tolerated. 
5.5.2.2. 
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons.   
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons (ie, comparisons to historical and placebo 
controls will be evaluated separately). 
5.6 
Additionally, consistent with nonclinical findings and the 
chemical characteristics of OCA (bile acid and detergent), an 
increase in liver function tests and hepatic AEs, including 
jaundice, were observed in subjects with liver disease at doses 
between 10 mg and 50 mg and in healthy volunteers who were 
treated at doses greater than 100 mg in Phase 1 multiple dose 
studies. 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  The clinical 
significance of these lipid findings remains unclear and is being 
studied further.  Notably, despite the observed decrease, HDL 
levels have generally remained within normal limits in subjects 
treated with OCA. 
• 
Deleted text 
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 subjects with chronic liver disease such as PBC, hepatic 
findings including increased transaminases and bilirubin and 
signs or symptoms of hepatic decompensation such as 
development of jaundice were observed mainly at the highest 
dose of OCA (50mg daily). 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  Notably, in subjects 
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Page 96
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Section 
Original Text 
Revised Text 
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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated 
subjects with the exception of a modest transient and early rise 
after initiation of treatment. 
7.1 
Overall Study Design 
…Subjects will be screened during a ≤1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3)….Following 6 months of treatment with 
investigational product, subjects should be titrated in a blinded 
manner (ie, subjects randomized to OCA will increase their dose to 
10 mg OCA) based on tolerability…. 
Overall Study Design 
…Subjects will be screened during a 1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to Section 9.7.3). 
….Following 3 months of treatment with investigational product, 
subjects should be titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose to 10 mg OCA) based 
on tolerability…. 
7.1.1 
Study Design Diagram
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
Study Design Diagram
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
7.1.2 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
1st column heading was “Screening Visit  x2) 
 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
Now 2 columns: 1st column now “Screening Visit 1” 
2nd column now Screening Visit 2 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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Visit Window ≤1 to 8 wks … 
Visit window in 2nd column added new text 
Added text 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnote a:   All subjects will have two 2 bilirubin assessments at 
least 2 weeks apart including those subjects who qualify based 
on ALP criteria.  For subjects that do not qualify based on 
ALP (ALP >5x ULN), the mean of the two 2 bilirubin 
assessments will be used to determine eligibility (total bilirubin 
>ULN and ≤3x ULN). 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2, and also 2 weeks post dose titration, to assess for AEs 
and concomitant medications and to verify that s/he is dosing as 
directed 
Footnote e:  Medical history at Screening will smoking and alcohol 
consumption history and current habits for both.   
Footnote g:  Subject Questionnaires include: Pruritus VAS, 5-D 
Pruritus Scale and Quality of Life questionnaires (See 
Section 11.1.2.2 and Section 12.2.5.1) 
 
 
 
3 to 8 wks… 
1 to 6 wks prior to Day 0 
 
Added Procedures: 
Quality of Life Questionnaires (PBC-40, EQ-5D-5L, and 
FIS) g  (Day 0, Annually, EOT/EOS) 
Endoscopy I (Day 0, annually, per standard of care) 
Hepatic Ultrasound (Day 0, Annually, EOT/EOS) 
Physical Exam and Assessments for Mayo Risk Score and Child-
Pugh (every 6 months) 
Health Outcome Assessments (All visits) 
Added Dose Titration at M3 
 
Footnote a:  All subjects will have the chemistry panel retested to 
ensure subjects have 2 ALP and bilirubin assessments at least 2 
weeks apart to calculate the mean result for both analytes.   
The mean of the all screening ALP and bilirubin assessments 
will be used to determine eligibility).  Samples for hematology 
and coagulation will not be collected at Screening visit 2. 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2 (±1 week), and also 2 weeks post dose titration (up or 
down), to assess for AEs and concomitant medications and to 
verify that s/he is dosing as directed.   
Footnote e:  Medical history at Screening and the yearly physical 
exam will include an assessment of smoking and alcohol 
consumption history and current habits for both.   
Footnote g:  The EQ-5D-5L and FIS Quality of Life 
questionnaires are validated for use in multiple languages. If 
a validated translation is not available in the local language 
required for a specific study subject, the data from that 
questionnaire will not be collected.    (See Section 11.1.2.2 and 
Section 12.2.6) 
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Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.   
 
Footnote i: Added text 
 
 
 
 
Footnote j:  Added text 
 
 
  
Footnote k:  Added text 
 
 
 
 
Footnote l:  Added text 
 
 
Footnote m:  After 6 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) 
based on tolerability; this may occur at the Month 6 visit, or at 
any study visit thereafter.  Titration above 10 mg OCA is not 
allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit.  Fasting is required prior to all 
study visits, but water is permitted. 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.  Please refer to Section 9.7.4 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote i:  Endoscopy will be conducted at selected study sites 
where the device is available to assess for the presence of 
oesophageal varix/varices.  Please refer to Section 9.7.4 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote j:  Ultrasound will be conducted to enhance HCC 
surveillance.  If a lesion is found, a second confirmatory 
image (eg, MRI) should be obtained.  Please refer to 
Section 9.7.4 for additional information related to the allowed 
windows at Day 0 for these specific procedures. 
Footnote k:  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 case report form.  Mayo Risk Score will be 
calculated based on central laboratory evaluations, diuretic 
use data, and peripheral edema assessment data captured in 
the CRF.  
Footnote l:  Health Outcome Assessments: Data related to non-
study related medical or surgical treatment procedures that 
the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the 
subject attended should be collected throughout the study. 
Footnote m:  After 3 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 3 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit (except Screening visit 1).  
Fasting is required prior to all study visits, but water is permitted. 
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Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at site.  If the blood 
test is also positive, the subject may not be enrolled in the study.  
(Additional testing may be conducted where required, 
regionally). 
 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not 
be enrolled in the study.  (Additional testing may be conducted 
where required, regionally). 
 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not 
change 
7.3 
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 6 month study visit or at 
any study visit thereafter depending on tolerability.   
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 3 month study visit or 
at any study visit thereafter depending on tolerability.   
7.4 
Dose Titration Criteria 
After 6 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
placebo (in a blinded manner) at the 6-month visit or any study visit 
following the 6-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
Dose Titration Criteria 
After 3 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
placebo (in a blinded manner) at the 3-month visit or any study visit 
following the 3-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
7.4.1 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, her or she should continue the regular 
visit schedule and continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination.  Early termination 
procedures should only be conducted if the subject withdraws 
consent. 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, he or she should continue the regular 
visit schedule and continue taking investigational product as long 
as the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination. 
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7.5 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all subjects have 
completed the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the Study/Early Termination Visit. 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all events have been 
accrued, and when subjects are still active on the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the End of Study Visit. 
8.2 
Subject Inclusion Criteria  
2.  A mean total bilirubin >ULN and ≤3x ULN or an ALP >5x 
ULN 
4.  Either is not taking UDCA (UDCA naïve or no UDCA 
dose in the past 3 months) or has been taking UDCA for at 
least 12 months with an approved, stable dose for ≥3 months 
prior to Day 0 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
contraception during the study and for 30 days after the end of 
treatment visit. 
Subject Inclusion Criteria 
2.  A mean total bilirubin >ULN and ≤3x ULN and/or a mean ALP 
>5x ULN  
4.  Either is not taking UDCA (no UDCA dose in the past 3 
months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
 
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8.3 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
3.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
4.  Other medical conditions that may diminish life expectancy 
to <2 years, including known cancers (except carcinomas in 
situ or other stable, relatively benign conditions such as chronic 
lymphatic leukemia) 
5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of Screening (pretreatment) QT 
 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test), or lactating 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example, per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
3.  Mean total bilirubin >3x ULN 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
 
5. Deleted text 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test by the central laboratory), or lactating 
8.4.1 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test. 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test performed at the central 
laboratory. 
8.4.2 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent. 
 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent (See Section 9.7.14 Early 
Discontinuation and/or Early Termination Procedures). 
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The following events are considered potential appropriate reasons 
for a subject to discontinue investigational product;…  
• 
Withdrawal of Consent 
- 
Added text 
 
 
 
 
 
 
The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study.   
The following events are considered appropriate reasons for a 
subject to discontinue investigational product; … 
• 
Withdrawal of Consent 
- 
Consent may be fully withdrawn 
- 
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 potential adjudicated hepatic and/or 
cardiovascular events 
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study.   
8.4.3 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study….This information must be documented in the CRF.  
If a subject is withdrawn from the study early (regardless of the 
cause), all of the end of treatment (EOT) evaluations should be 
performed at the time of withdrawal, as appropriate.  
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study….This information must be documented 
in the CRF.  If a subject is withdrawn from the study early 
(regardless of the cause), all of the (EOT/EOS) evaluations should 
be performed at the time of withdrawal, as appropriate (See 
Section 9.7.14 Early Discontinuation and/or Early Termination 
Procedures). 
9.1.1 
Dose Adjustment Beginning at Month 6 
After 6 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 6 visit, or at 
any study visit thereafter.   
Dose Adjustment Beginning at Month 3 
After 3 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 3 visit, or at 
any study visit thereafter.   
9.2 
Concomitant Medications 
Relevant information about all concomitant medications (including 
prescribed, over-the-counter, or herbal preparations) taken prior to 
(ie, within 30 days of Day 0) and during the study must be recorded 
Concomitant Medications 
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 
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in the source documents and CRF, as well as any dose or dose 
regimen changes that occur during the study.   
recorded in the source documents and CRF, as well as any dose or 
dose regimen changes that occur during the study. 
9.2.1 
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.   
 
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.  Subjects that discontinue investigational product 
but continue commercial OCA therapy are expected to 
continue through the end of the study, and the study will only 
terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.  Subjects 
will need to complete EOT procedures but continue with 
regularly scheduled visits until the study is terminated (See 
Section 9.7.14 Early Discontinuation and/or Early Termination 
Procedures). 
9.4 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN), 
as specified by the central laboratory.   
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and mean baseline bilirubin categories 
(>ULN/≤ULN), as specified by the central laboratory.   
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9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
• 
Added text - New section inserted. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects will be made 
available to the Investigator for emergency use only 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 is necessary for further medical management of the 
subject).  If it is not reasonable to inform the Medical Monitor 
in advance of unblinding the Investigator must promptly 
document in the subject’s source record and should 
subsequently contact the Medical Monitor to explain any 
premature unblinding of treatment assignment (such as 
unblinding which is necessary in order to treat an SAE). 
Procedures for unblinding a subject’s treatment will be 
provided separately to the Investigator.  Similarly, if the 
Medical Monitor breaks the blind for an individual subject for 
the purpose of evaluating an emergent safety issue, the Medical 
Monitor will document within trial documentation the 
rationale, circumstances, and the person or persons being 
informed about the unblinding. 
The Data and Safety Monitoring Committee (DSMC) will have 
access to the IWRS and will be able to unblind individual 
subjects.  Refer to Section 13.3 for further details regarding 
DSMC access to blinded and unblinded data.  The DSMC will 
document details about any unblinded subject data reviews in 
the closed session DSMC minutes, which will be made available 
to the Sponsor only after the database is locked and the trial is 
unblinded.   Cases of premature unblinding, as noted above, 
will also be reviewed by the DSMC.  
Access to treatment assignments will also be made available 
through the IWRS system to the appropriate named 
individual(s) responsible for reporting SAEs and suspected 
unexpected serious adverse reactions (SUSARs) to the 
Regulatory Authorities. 
 
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9.6 
Restrictions 
No additional restrictions. 
Restrictions 
Participation in another investigation product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the trial is prohibited. 
9.7.1 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Interval is ≤1 to 8 weeks prior to Day 
0, allowing for 2 Screening 2 visits to 
repeat biochemistry tests, and 
ensuring ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days. 
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2 week (7 days)  
Quarterly visits (Months 
15 – EOT) 
±2 weeks (14 days) 
EOT 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOT = end of treatment 
 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening visit 1 interval is 3 to 8 
weeks prior to Day 0 for screening 
visit 1.  Screening visit 2 interval is 
1 to 6 weeks prior to Day 0.   The 
visit window for Screening 2 visits 
allows for the repeat biochemistry 
tests to be collected at least two 
weeks after the initial biochemistry 
sample was collected, and will 
ensure ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days, but 
screening procedures should not be 
performed during the last 7 days of 
the window.  
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (14 days)  
Quarterly visits 
(Months 15 – EOS) 
±2 weeks (14 days) 
EOT 
(When subject 
discontinues 
investigational 
product) 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
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EOS 
(When subject 
terminates the study) 
The final study visit; EOS will 
occur concurrent with EOT if a 
subject discontinues study 
medication at the time the subject’s 
participation in the study ends (eg, 
withdrawal of consent or study 
termination by the Sponsor); EOS 
will occur after the EOT if the 
subject discontinues study 
medication  but continues in the 
study. 
EOT = end of treatment 
EOS = end of study 
9.7.2 
Informed Consent Procedures 
• 
Added text 
Informed Consent Procedures 
Any change in a subject’s consent status (eg, semi-annual 
telephone contact or medical record review) must be 
documented in a signed informed consent form or addendum.  
The subjects will be given a signed and dated copy of the 
consent document. 
9.7.3 
Screening Procedures (≤1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed ≤1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Subjects who 
do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects may be rescreened after 2 months; however, all Screening 
procedures should be repeated and a new 3-digit Screening number 
assigned.  
 
 
 
 
 
• 
All subjects will have 2 bilirubin and ALP 
assessments at least 2 weeks apart including those 
subjects who qualify based on ALP criteria. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Screening 
Visit 1 will occur 3 to 8 weeks prior to Day 0; Screening Visit 2 
will occur 1 to 6 weeks prior to Day 0, depending on the date 
that the first serum chemistry sample was collected. Subjects 
who do not fulfill all eligibility criteria will not be enrolled in the 
study.  Subjects 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 3-digit Screening number 
assigned. 
 
• 
All subjects will have 2 bilirubin and  ALP assessments at 
least 2 weeks apart 
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• 
For subjects that do not qualify based on ALP alone 
(ALP >5x  
ULN), the mean of the 2 bilirubin assessments will be 
used to determine eligibility (total bilirubin >ULN 
and ≤3x ULN). 
  
• 
Screening Visit procedures are as follows: 
• 
Record prior (if within 30 days of Day 0) and current 
concomitant medications 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual emission X ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
 
• 
Added text 
 
• 
For subjects that do not qualify based on ALP alone (ALP 
>5x ULN), the mean of all available (at least 2; 
including both scheduled and unscheduled) bilirubin 
assessments will be used to determine eligibility (total 
bilirubin >ULN and ≤3x ULN).   
• 
Screening Visit 1 procedures are as follows: 
• 
Record prior (if within 30 days of Screening) and current 
concomitant medications 
• 
Deleted text  
 
• 
Deleted text  
 
 
 
 
Screening Visit 2 procedures are as follows: 
• 
Verify inclusion and exclusion criteria for eligibility 
• 
Assess and record any pretreatment-emergent AEs 
• 
Record current concomitant medications 
• 
Verify that the subject has fasted for at least 8 hours 
- 
Record fasting status in the source and CRF 
- 
If the subject reports having eaten within 8 hours, 
document accordingly in the source and CRF and 
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remind the subject that fasting is required prior to all 
study visits 
• 
Obtain blood samples for serum chemistry tests 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual-emission X-ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
9.7.4 
Day 0 Procedures (Randomization) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE has 
been done within 3 months of Day 0 and a report/adequate data 
are available, a pretreatment TE at Day 0 is not required.   
 
 
 
• 
Conduct a DEXA bone density scan (at selected study sites, 
where available); document whether the subject stopped taking 
her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the 
scan, if applicable.  
 
Day 0 Procedures (Randomization) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6.) 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE 
has been done within 6 months of Day 0 and a 
report/adequate data are available, a pretreatment TE at 
Day 0 is not required.  If the TE cannot be performed on 
Day 0 (e.g., device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the 
screening visit window, as close as possible to the Day 0 
visit, after subject eligibility has been confirmed.   
• 
Conduct a DEXA bone density scan (at selected study 
sites, where available); document whether the subject 
stopped taking her/his calcium supplements for 48 hours 
before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable.  If DEXA 
has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment 
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• 
Added text 
 
 
 
 
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
 
 
DEXA at Day 0 is not required.  If DEXA cannot be 
performed on Day 0 (e.g., device/technician 
unavailability, scheduling issues, etc), the procedure 
may be completed within the screening visit window, as 
close as possible to the Day 0 visit, after subject 
eligibility has been confirmed. 
• 
Perform an esophagogastroduodenoscopy (endoscopy; 
at selected study sites, where available) to assess the 
presence or absence of oesophageal varix/varices. If an 
endoscopy has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment endoscopy at Day 0 is not required. If the 
endoscopy cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
- 
Subsequent endoscopies should be performed 
annually or per standard of care and the 
Investigator’s clinical judgment throughout 
the course of the study.  Endoscopies should 
also be performed when platelet counts are 
<150 x 109 /L. 
• 
Perform an ultrasound (if equipment is unavailable, 
sites should make every attempt to use available 
community referral sites) for HCC surveillance.  If an 
ultrasound has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment ultrasound at Day 0 is not required. If 
the ultrasound cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
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• 
Added text 
 
 
 
 
 
• 
Added text 
 
• 
Record prior (within 30 days of Day 0) and current  
concomitant medications 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
Review and record prior concomitant medications 
• 
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. 
9.7.6 
Month 3 Procedures 
• 
Added text 
• 
Added text 
Month 3 Procedures 
• 
Assess for dose titration, if eligible (refer to Section 7.4) 
• 
Obtain blood samples for: 
- 
OCA, C4, and FGF-19 
9.7.7 
 
Month 6 Procedures 
• 
Added text 
 
Month 6 Procedures 
• 
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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
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- 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.8 
Month 9 Procedures 
• 
Added text 
Month 9 Procedures 
• 
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 
9.7.9 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.9), subjects who are participating in the PK assessment 
will each receive a single dose of investigational product (10 mg 
OCA tablet) with approximately 240 mL of water. 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours postdose.  Subjects should not drink additional water 
for 1 hour after taking the dose of investigational product and will 
remain fasted until the 4 hour sample is collected.  Lunch will be 
provided following collection of the 4 hour PK sample; the lunch 
will be a meal replacement drink. 
 
 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.8), subjects who are participating in the PK assessment 
will each receive a single dose of investigational product (blinded 
OCA or placebo tablet) with approximately 240 mL of water. 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours post dose.  Samples should be collected within a 
window of ±5 minutes of the scheduled sample time.  Subjects 
should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until the 4 hour 
sample is collected.  Lunch will be provided following collection of 
the 4 hour PK sample; the lunch will be a meal replacement drink.  
Samples will be stored for up to 5 years after the end of the 
study and will be destroyed after 5 years if not analyzed. 
9.7.10 
 
Month 12 Procedures 
• 
Subject questionnaires (see Section 12.2.5.1) 
• 
Added text 
Month 12 Procedures 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
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• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.11 
Month 3 and Month 9 Continued Follow-up Procedures 
([±2 weeks]) 
Subjects should come to the study center for a quarterly study 
visit for a clinical laboratory evaluation to collect blood samples 
for calculation of MELD score.  If the subject is not able to 
come to the study center for a visit, home visits may be 
arranged on a per subject basis. 
Month 3 and Month 9 Continued Follow-up Procedures 
([±2 weeks]) 
• 
Deleted text 
• 
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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
9.7.12 
Month 6 Continue Follow-up Procedures (Semi-annually [±2 
weeks]) 
• 
Added text 
Month 6 Continue Follow-up Procedures (Semi-annually [±2 
weeks]) 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
Review and record any non-study related medical or 
surgical treatment procedures and any medically 
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relevant HCP or non-HCP related office visits that 
have occurred since the previous study visit 
9.7.13 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Added text  
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
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 physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.14 
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw Consent 
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
 
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw from Investigational Product or 
Withdraw Consent  
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
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When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination or 
discontinuation (withdrawal of consent), an EOT visit must be 
performed as near as possible to her/his last dose of investigational 
product and the procedures, listed below, performed.  …  In these 
cases, the data will be recorded as EOT procedures in the CRF.  
 
 
Added table 
 
 
 
 
 
 
 
EOT procedures will be required whenever subjects 
discontinue treatment with investigational product.  The EOT 
visit and procedures listed below must be performed as close as 
possible to the subject’s last dose of investigational product.  
When a subject discontinues investigational product but 
continues with regularly scheduled study visits, the EOS visit 
will be completed later in the study as the subject’s final study 
visit.  The actual investigational product discontinuation 
scenario (Table 2) will determine the sequence of the EOT and 
EOS visits and procedures.  In some cases, the EOT visit and 
procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible 
to the subject’s last dose of investigational product.   
When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination 
(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.  ….  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 and EOS procedures in the 
CRF.  
Table 2: 
Early Discontinuation Scenarios 
 
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Investiga
tional 
Product 
Conse
nt 
Study 
Visit 
Status 
EOT 
Visita 
EOS 
Visita 
Early 
Terminati
on 
Discontin
ued 
Withdr
awn 
No 
additi
onal 
visits 
except 
EOT/E
OS 
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
Treatmen
t 
Discontin
uation 
Discontin
ued 
Active 
Regul
ar 
Visit 
Sched
ule 
Comp
lete 
as 
close 
as 
possi
ble to 
last 
dose 
IP 
Comp
lete 
at 
Final 
study 
visit 
Discontin
ued 
Semian
nual 
contac
tb 
Telep
hone 
contac
t 
every 
6 
month
s (±2 
weeks
) 
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
 
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Some assessments noted below may be omitted if they have been 
completed within the 3 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing. 
 
 
 
 
Prior to the EOT Visit: 
During the EOT Visit: 
• 
Subject questionnaires (see Section 12.2.6) 
• 
Conduct a DEXA bone density scan (selected study sites); 
document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for 
osteoporosis or osteopenia on the day of the scan, if applicable 
 
 
• 
Added text 
 
• 
Added text 
 
• 
Added text 
 
 
a Refer to Section 7.1.2 Schedule of Study Procedures for all procedures 
and evaluations required at the End of Treatment and End of Study Visits. 
b Outcomes data to be discussed or collected include data related to 
adjudicated hepatic and cardiovascular event-related data.  No additional 
data (e.g. AE, concomitant medication, etc) data will be collected, except 
as indicated in Section 12.1.6. 
Some assessments noted below may be omitted if they have been 
completed within the 6 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing 
Prior to the EOT/EOS Visit: 
During the EOT/EOS Visit 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Subject and Quality of Life  questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform TE (where available) using the Fibroscan® TE 
device (not required at EOT/EOS if done within 6 months) 
• 
Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
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• 
Added text 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites); not 
required at EOT/EOS if done within 6 months 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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 
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.  [Added text]  As appropriate, the Medical 
Monitor should be contacted. 
 
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.   
In the event of an inexplicable and acute (for example not 
explained by natural progression of the chronic disease) 
increase in alanine aminotransferase (ALT) to >3× baseline 
(and >upper limit of normal [ULN]) or total bilirubin >2× 
baseline (and >ULN), the subject should be followed by repeat 
testing within 48 to 72 hours of the serum chemistry to confirm 
the abnormalities and to determine if they are increasing or 
decreasing. AE information should also be collected.  If 
symptoms persist or repeat testing shows ALT >3× baseline 
(and >ULN) or total bilirubin >2× baseline (and >ULN), 
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subjects should be followed until resolution of the abnormality 
and as clinically indicated depending on other laboratory and 
clinical signs and symptoms. 
 
As appropriate, the Medical Monitor should be contacted. 
10.4 
Investigational Product Preparation 
The investigational product will be provided in bulk bottles and 
therefore may be repackaged in unit dose form for administration to 
subjects. 
Investigational Product Preparation 
The investigational product will be provided to the distribution 
center in bulk bottles and therefore may be repackaged in unit dose 
form for administration to subjects before shipping to the sites. 
11.1.2 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Resource utilization information 
will be collected from CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician 
visits (subject reported), and use of concomitant medications.  
 
 
• 
Added text 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Quality of life will be assessed by 
questionnaires (PBC-40, EQ-5D-5L, and FIS) 
administered annually.  Resource utilization information will 
be collected from the Medical and Surgical Treatment 
Procedures and Office Visit Log or other CRFs such as 
number, type and duration of hospitalizations, number of 
outpatient physician visits (subject reported), and use of 
concomitant medications.  
• 
Endoscopy will be conducted at selected study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual 
study assessments or standard of care will be collected in 
the case report form to assess for the development of 
varix/varices 
11.1.2.2 
• 
Quality of Life questionnaires.   
• 
Quality of Life questionnaires.  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: 
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a. PBC-40: The PBC-40 (Jacoby 2005) 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. 
b. EQ-5D-5L:  The Eq-5D-5L consists of 2 sections – the 
descriptive system and the visual analogue scales (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 
respondent’s self-rate 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). 
c. 
Fatigue Impact Score (FIS):  The FIS is a validated 40-
question questionnaire organized into 3 dimensions:  
cognitive, physical, and social.  Each dimension has 5 
levels:  no problem, small problem, moderate problem, 
big problem, and extreme problem (Fisk 1994) 
11.1.2.3 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. The samples will be stored for up to 1 year after the 
end of the study and destroyed after 1 year if not analyzed. 
 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their 
involvement in the study.  IRB/IEC review and approval 
will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will 
be stored for up to 1 year after the end of the study and 
destroyed after 1 year if not analyzed. 
 
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12.1.1.2 
Serious Adverse Event 
• 
Added text 
Serious Adverse Event 
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 
12.1.4.2 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
  
All SAEs (including Potential Clinical Outcome Events that qualify 
as serious) must be reported to the medical monitor immediately 
(ie, within 24 hours) after the Investigator identifies the SAE…. 
 
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 investigational 
new drug (IND) safety reports (SUSARs) that occur during the 
study within the time frames required by each regulatory agency.  
The Investigator is responsible for submitting information on IND 
safety reports received from the Sponsor to her/his local IRB.  
Documentation of the submissions to IRBs and health authorities 
must be retained in the appropriate study file(s). 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
All SAEs occurring while subjects are receiving investigational 
product or are on an investigational product holiday (including 
Potential Clinical Outcome Events that qualify as serious) must be 
reported to the medical monitor immediately (ie, within 24 hours) 
after the Investigator identifies the SAE….  
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.  A SAE assessed with a possible, probable, or definite 
causal relationship to the investigational product and 
unexpected according to IB Reference Safety Information 
(RSI), is known as a suspected unexpected serious adverse 
reaction (SUSAR).  The Sponsor will notify the appropriate 
regulatory agencies as well as all participating Investigators of 
investigational new drug (IND) safety reports (SUSARs) that occur 
during the study within the time frames required by each regulatory 
agency.  The Investigator is responsible for submitting information 
on IND safety reports/SUSARs received from the Sponsor or 
Sponsor designee to her/his local EC/IRB.  Documentation of the 
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submissions to IRBs and health authorities must be retained in the 
appropriate study file(s). 
12.1.6 
Notification of Post-Study SAEs 
• 
Added text 
Notification of Post-Study SAEs 
SAEs that occur more than 30 days after a subject has 
discontinued study medication, and are not considered related 
to investigational product, must still be reported in the EDC 
system; however, these events are not required to be reported 
within 24 hours.  At a minimum, the SAE term, event start and 
end date, severity, relationship to investigational product, 
action taken with study medication, treatment, outcome, and 
potential endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event summary, SAE 
details) may also be required to be entered, when requested by 
the sponsor. 
12.1.8 
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments.  
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments. The Sponsor may also 
follow the health of an infant born subsequent to use of 
investigational product. 
12.2.2 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page …. 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page for findings that appear after consent, and on the 
medical history CRF for any finding present prior to consent…. 
12.2.5.1 
12.2.5.1  Subject Questionnaires 
 
12.2.6 Subject Questionnaires 
12.2.6/12.2.7 
12.2.6   Laboratory Assessments 
Subjects testing positive for urine drug screen will be excluded 
from the study. 
 
 
 
12.2.7 Laboratory Assessments 
Deleted text 
 
 
 
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Table 4  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids, thyroid hormones (T3, 
T4, TSH) 
Table 5  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids 
 
12.2.6 
Laboratory Assessments 
• 
Added text 
 
 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly visits based on serum chemistry and coagulation. 
12.2.7  Laboratory Assessments 
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. 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly (MELD scores only) and semi-annual visits based on 
serum chemistry and coagulation. 
13.1.5 
Additional Secondary Efficacy Analyses 
• 
Added text 
Additional Secondary Efficacy Analyses 
• 
Time to development of varix/varices 
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Section 
Original Text 
Revised Text 
13.1.8 
Supportive Analysis 
Although the results of using matching are conditional only on the 
observed covariates, if one has the ability to measure many of the 
covariates that are believed to be related to the treatment 
assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained. 
 
Supportive Analysis 
Although the results of using matching controls are conditional 
only on the observed covariates, if one has the ability to measure 
many of the covariates that are believed to be related to the 
treatment assignment, then one can be fairly confident that 
approximately unbiased estimates for the treatment effect can be 
obtained. 
13.3 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study. In addition, the DSMC statistician 
will evaluate the sample size as described in Section 13.1.2.1. 
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.   
 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study.  
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.  The DSMC will document details about 
any unblinded subject data reviews in the closed session DSMC 
minutes, which will be made available to the Sponsor only after 
the database is locked and the trial is unblinded.   Cases of 
premature unblinding, as noted above, will also be reviewed by 
the DSMC.  
16.2, Ethical 
Conduct of the 
Study 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles 
that have their origin in the Declaration of Helsinki (Seoul 
Revision, 2008) and are consistent with ICH/GCP, applicable 
regulatory requirements and the Sponsor’s policies. 
Ethical Conduct of the Study 
 The study will be performed in accordance with ethical principles 
and are consistent with ICH/GCP, local applicable regulatory 
requirements (in addition to Appendix C) and the Sponsor’s 
policies. 
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Section 
Original Text 
Revised Text 
19 
List of References 
• 
Added text 
List of References 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional 
impact of fatigue: initial validation of the fatigue impact scale. 
Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
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 Dec;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), 1622-1629. 
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. 
Appendix C 
• 
Added document 
Ethical Conduct according to the Declaration of Helsinki for 
Countries Participating Outside the US 
 
 
 
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APPENDIX E. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 (DATED 12 NOV 2015) 
Rationale 
The changes to Amendment 1 of the protocol, detailed below, include an additional exclusion criteria and changes to text precluding 
UDCA naïve subjects from entering the study and clarifying information showing that OCA may increase the exposure of narrow 
therapeutic index drugs that are substrates for CYP1A2, thus answering questions raised by regulatory authorities. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.1.  (Note:  Revised text in Amendment 1.1 is indicated in 
bold font, and the text deleted from Protocol Amendment 1 is crossed out in the table below. Minor formatting changes are not listed.) 
Section 
Original Text (Amendment 1, 29 April 2015) 
Revised Text (Amendment 1.1, 12 November 2015) 
Title Page 
Original:  03 October 2014 
Amendment 1:  29 APRIL 2015 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Amendment 1.1:  12 November 201 
Study Personnel 
Contact 
Information 
Mobile:      
 (Pacific time zone) 
Telephone: 
 
Telephone 
 
(deleted) 
Telephone: 
 
(deleted)   
Synopsis, 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
Synopsis, 
Statistical 
Methods:  
Sample Size 
Justification 
• 
5% of the subjects will have never been treated with UDCA; 
95% of the subjects will have been on UDCA for at least 1 
year 
(deleted) 
 
8.3 Subject 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
9.2 Concomitant 
Medications 
(insertion) 
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, showed weak effect 
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Section 
Original Text (Amendment 1, 29 April 2015) 
Revised Text (Amendment 1.1, 12 November 2015) 
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. 
12.1.4.2 
Reporting of 
Serious Adverse 
Event 
Mobile:      
 (Pacific time zone) 
Telephone: +1 858 964 1571 
(deleted) 
Telephone: 
   
13.1.2 
Determination of 
Sample Size 
5% of the subjects will have never been treated with UDCA; 95% 
of the subjects will have been on UDCA for at least 1 year 
(deleted) 
 
 
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1. 
TITLE PAGE 
 
 
Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 3b, Double-Blind, Randomized, Placebo-Controlled, Multicenter 
Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in 
Subjects with Primary Biliary Cirrhosis  
 
The COBALT Study 
Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) 
 
Version 3: 07 September 2016 
 
EudraCT Number: 2014-005012-42 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
USA 
 
TEL: +1 858 250 6398 
 
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 Investigational Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-302.  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 (CRFs) 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 747-302 and in accordance 
with Good Clinical Practice (CPMP/ICH/135/95), 21CFR Part 312 and all applicable regulatory 
requirements. 
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: 
 
SAE Fax: 
+1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
 
Or if Not Available: 
Contact: 
 MD, PhD, Executive Director, Clinical Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Email: 
 
 (Pacific time zone) 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 (Pacific time zone) 
 
 
 
 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company:  Intercept Pharmaceuticals, Inc. 
Name of Investigational Product:  Obeticholic Acid (OCA) 
Name of Active Ingredient:  OCA; 6α-ethyl chenodeoxycholic acid (6-ECDCA); INT-747 
Title of Study:  A Phase 3b, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary 
Cirrhosis 
Study Number:  747-302 
Study Center(s):  Approximately 170 investigational study sites, globally 
Study Period (Years):  The study is event driven and total duration will be determined by the 
time required to accrue approximately 121 primary endpoint events, estimated to be 
approximately 8 years.  Subjects are expected to have a minimum follow-up time of 
approximately 6 years. 
Number of Subjects (planned):  Approximately 350 subjects 
Phase of Study:  Phase 3b 
Objectives:  
Primary 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care, on clinical outcomes in subjects with primary biliary cirrhosis (PBC) as measured by 
time to first occurrence of any of the following adjudicated events, derived as a composite event 
endpoint:  
 Death (all-cause) 
 Liver transplant 
 Model of end stage liver disease (MELD) score ≥15 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
 Variceal bleed 
 Encephalopathy (as defined by a West Haven score of ≥2) 
 Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
 Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
Secondary 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above and also to include liver-related death. 
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To assess the effect of OCA compared to placebo on disease progression via the following: 
 Liver biochemistry  
 Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To assess the pharmacokinetics of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
Methodology: 
This Phase 3b, double-blind, randomized, placebo-controlled, multicenter study will evaluate the 
effect of OCA on clinical outcomes in subjects with PBC.  Subjects will be screened twice 
during a 1 to 8-week Screening period prior to entering the study to allow for the collection of 
repeat serum chemistry samples (at least 2 weeks apart) to confirm pretreatment alkaline 
phosphatase (ALP) and total bilirubin values (refer to Section 9.7.6).   
Investigational product will be taken orally, once daily for the majority of subjects; dose and 
frequency will be modified for subjects with cirrhosis (including subjects progressing to cirrhosis 
during the study) and classified as Child-Pugh B or C.  The randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment (yes/no) and baseline bilirubin categories (> upper limit 
of normal [ULN]/ ≤ ULN).   
Schematic Diagram:  
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for 
subjects on all dosing regimens, based on tolerability.  Subsequent dose titration(s) for subjects classified as 
Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after 
the previous dose titration. 
Dosing frequency will be determined by the presence or absence of cirrhosis and, if cirrhosis is 
present, by Child-Pugh Score as described below: 
 Non-cirrhotic subjects or subjects classified as Child-Pugh A at screening will receive 
5-mg OCA or matching placebo once daily for 3 months.  Subjects should titrate to a 
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maximum dose of 10-mg OCA once daily (or matching placebo) at the Month 3 visit or 
at any study visit following the Month 3 visit based on tolerability of the product.    
 For those subjects that up-titrate to 10 mg, dosing may be decreased to 5 mg at any time 
during the study as considered clinically appropriate (eg, based on tolerability). Subjects 
may be titrated back to a maximum dose of 10 mg once daily based on tolerability and 
clinical judgment of the Investigator.    
  Subjects who are cirrhotic and classified as Child-Pugh Class B or Child-Pugh Class C 
will initiate a modified treatment regimen with 5-mg OCA or matching placebo once 
weekly for at least 3 months.  Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5-mg OCA or matching placebo once daily, 
based on tolerability.  Subjects classified as Child-Pugh Class C should titrate to a 
maximum dose and frequency of 10-mg OCA or matching placebo twice weekly, based 
on tolerability.   
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score  
 
Planned Dosing Regimen 
Standard  
Modified  
Non-Cirrhotic/ 
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
5 mg once weekly 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weekly 
5 mg twice weekly 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weekly 
10 mg twice weekly 
Titration 3b 
(≥6 weeks after Titration 2) 
NA 
5 mg daily 
NA 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject 
tolerability and/or changes in cirrhosis status or Child-Pugh Score at any time during the study. 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with American Association for the 
Study of Liver Diseases [AASLD] and the European Association for the Study of the 
Liver [EASL] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the 
presence of ≥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 in 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 
2. A mean total bilirubin >ULN and ≤3× ULN and/or a mean ALP >5× ULN 
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3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past ≥3 months) or has been taking 
UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0 
5. Contraception:  Female subjects 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:   
 Double barrier method, ie, (a) condom (male or female) or (b) diaphragm, with 
spermicide; or  
 Intrauterine device (IUD); 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 subject   
6. Must provide written informed consent and agree to comply with the study protocol 
Exclusion Criteria 
1.  History or presence of other concomitant liver diseases including:  
 Hepatitis C virus infection 
 Active hepatitis B infection; however, subjects 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 
 Nonalcoholic steatohepatitis 
 Gilbert’s Syndrome 
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including: 
 
History of liver transplant, current placement on a liver transplant list, or current MELD 
score >12.  Subjects who are placed on a transplant list despite a relatively early disease 
stage (for example per regional guidelines) may be eligible as long as they do not meet 
any of the other exclusion criteria 
 Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
 Variceal bleed 
 Uncontrolled ascites  
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 Encephalopathy  
 Spontaneous bacterial peritonitis  
 Known or suspected hepatocellular carcinoma 
 Prior transjugular intrahepatic portosystemic shunt procedure 
 Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine 
>2 mg/dL (178 μmol/L) 
3. Mean total bilirubin >3× ULN  
4. Subjects who have undergone gastric bypass procedures (gastric lap band is 
acceptable) or ileal resection or plan to undergo either of these procedures 
5. Other medical conditions that may diminish life expectancy, including known cancers 
(except carcinomas in situ or other stable, relatively benign conditions such as 
chronic lymphatic leukemia) 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test), or lactating 
7. Known history of human immunodeficiency virus infection 
8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months) 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 
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-month 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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
14. UDCA naïve (unless contraindicated) 
Investigational Product, Dosage and Mode of Administration:  
OCA (5 mg or 10 mg tablets) 
Placebo (matching tablets) 
Duration of Treatment: 
It is estimated that subjects will be followed up for a minimum of 6 years.  The study is event 
driven and total duration of treatment will be determined by the time to accrue 121 total primary 
endpoint events. 
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Duration of Subject Participation: 
It is estimated that subject participation will be a minimum of approximately 6 years. 
Criteria for Evaluation: 
Primary Objectives 
Assessments 
Clinical outcomes 
 
Death (all-cause) 
 
Liver transplant 
 
MELD score ≥15 
 
Hospitalization (as defined by a stay of 24 hours or greater) for new 
onset or recurrence of: 
 
Variceal bleed 
 
Encephalopathy (as defined by a West Haven score of ≥2) 
 
Spontaneous bacterial peritonitis (confirmed by diagnostic 
paracentesis) 
 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic 
paracentesis at a frequency of at least twice in a month) 
 
Hepatocellular carcinoma confirmed by 2 complimentary imaging 
modalities 
Secondary Objectives 
 
Individual components of the 
primary endpoint 
As listed above and including liver-related death 
Change in baseline liver 
biochemistry 
Liver biochemistry (see Table 10:  for list of analytes to be tested)   
Inflammation and fibrosis 
IgM, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), 
fibroblast growth factor-19 (FGF-19), cytokeratin-18 (CK-18), enhance liver 
fibrosis (ELF), and Fibroscan® 
Clinical outcomes compared to 
historical controls 
Similar endpoints as used for the primary objective where available including 
liver transplant and death 
Pharmacokinetics 
OCA and its conjugates 
Health outcomes and economics 
research 
Including the following: 
Cost-effectiveness and resource utilization 
Quality of life (Fatigue Impact Score and EQ-5D-5L)  
Safety and tolerability 
Including the following: 
Treatment-emergent adverse events 
Clinical laboratory values 
 
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Statistical Methods:  
Sample Size Justification 
The following assumptions were used in sample size calculations:  
 Exponential survival curves, placebo survival estimate of 0.5 at 8 years with a hazard 
ratio of 0.60, and total study duration of 8 years, allowing for 2 years accrual and 
6 years of follow up 
 Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
 The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to clinical outcomes. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: Randomized, Intent-to-Treat (ITT), Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical Control.  Descriptions of subject populations 
are provided in Section 13.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
 Death (all-cause) 
 Liver transplant 
 Model of end stage liver disease (MELD) score ≥15 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
 Variceal bleed 
 Encephalopathy (as defined by a West Haven score of ≥2) 
 Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
 Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
Every event for enrolled subjects will be adjudicated by an independent committee. 
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Primary Efficacy Analysis 
The primary efficacy analysis will compare randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the ITT population.  The 2 treatment groups will 
be compared 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 determined based on a Cox regression model stratified by randomization strata to 
estimate the magnitude of the effect. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints are as follows: 
 Time to first occurrence of MELD score ≥15 
 Time to liver transplant or death (all-cause) 
 Change from Baseline in total bilirubin at end of study 
 Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare randomized OCA to randomized placebo in 
ITT population with respect to the key secondary efficacy endpoints.  Only adjudicated events 
will be included in time-to-event analyses.  The comparison (hypothesis testing) will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of the OCA treatment group.  If the primary comparison is not 
statistically significant then comparison of the secondary endpoints will be considered as 
descriptive and exploratory. 
Other Efficacy Analyses 
The following secondary efficacy analyses will compare OCA to placebo on time to the 
following events: 
 Each component of the primary efficacy endpoint (except MELD score ≥15 which is 
listed above) 
 Development of varix/varices 
 Liver-related death 
 Liver-related death or liver transplant 
 Liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls. 
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Further details on efficacy, health outcomes, and pharmacokinetic analyses are specified in 
Section 13. 
Safety Analysis 
Safety data, including AEs, vitals, electrocardiogram, and clinical laboratory results will 
compare OCA and placebo using the Safety Population. 
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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Overview of Primary Biliary Cirrhosis and Obeticholic Acid ...................................23 
5.2. 
Mechanism of Action of Obeticholic Acid .................................................................23 
5.3. 
Nonclinical Experience with Obeticholic Acid ..........................................................24 
5.4. 
Clinical Experience with Obeticholic Acid ................................................................24 
5.5. 
Rationale for Study Design and Dose for Investigational Product .............................25 
5.5.1. 
Rationale for Study Design .........................................................................................25 
5.5.2. 
Rationale for Dose ......................................................................................................26 
5.5.2.1. 
Rationale for OCA Doses ...........................................................................................26 
5.5.2.2. 
Rationale for Modified OCA Doses in Patients Classified with Child-Pugh B 
or Child-Pugh C Hepatic Impairment .........................................................................26 
5.5.2.3. 
Rationale for Control Groups .....................................................................................27 
5.6. 
Summary of Known Potential Risks with OCA .........................................................27 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................28 
6.1. 
Primary Objective .......................................................................................................28 
6.2. 
Secondary Objectives .................................................................................................28 
7. 
INVESTIGATIONAL PLAN .....................................................................................28 
7.1. 
Overall Study Design ..................................................................................................28 
7.1.1. 
Study Design Diagram ................................................................................................29 
7.1.2. 
Schedule of Study Procedures ....................................................................................30 
7.1.3. 
Study Duration ............................................................................................................35 
7.2. 
Number of Subjects ....................................................................................................35 
7.3. 
Planned Dosing Regimen ...........................................................................................35 
7.4. 
Dose Titration Criteria ................................................................................................36 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements .................................................38 
7.4.2. 
Safety Criteria for Adjustment or Stopping Doses .....................................................38 
7.5. 
Criteria for Study Termination ...................................................................................38 
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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................39 
8.1. 
Subject Population ......................................................................................................39 
8.2. 
Subject Inclusion Criteria ...........................................................................................39 
8.3. 
Subject Exclusion Criteria ..........................................................................................40 
8.4. 
Subject Withdrawal from Investigational Product or Study .......................................41 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product ..........................41 
8.4.2. 
Other Reasons for Discontinuation of Study or Investigational Product ...................41 
8.4.2.1. 
Elevated Liver Enzymes .............................................................................................42 
8.4.3. 
Withdrawal of Consent ...............................................................................................43 
8.4.4. 
Lost to Follow-up .......................................................................................................43 
8.4.5. 
Subject Discontinuation Notification .........................................................................43 
9. 
TREATMENT OF SUBJECTS ..................................................................................43 
9.1. 
Investigational Product Treatment Regimen ..............................................................43 
9.2. 
Concomitant Medications ...........................................................................................44 
9.2.1. 
Prohibited Medications ...............................................................................................44 
9.3. 
Treatment Compliance ................................................................................................45 
9.4. 
Randomization and Blinding ......................................................................................45 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures ...................................45 
9.5. 
Assignment of Site and Subject Numbers ..................................................................46 
9.5.1. 
Site Numbers ..............................................................................................................46 
9.5.2. 
Subject Numbers .........................................................................................................46 
9.6. 
Restrictions .................................................................................................................46 
9.7. 
Visit Procedures ..........................................................................................................47 
9.7.1. 
Visit Windows ............................................................................................................47 
9.7.2. 
Informed Consent Procedures.....................................................................................47 
9.7.3. 
Assessing Cirrhosis .....................................................................................................48 
9.7.4. 
Child-Pugh Score ........................................................................................................48 
9.7.5. 
Mayo Risk Score .........................................................................................................49 
9.7.6. 
Screening Procedures (1 to 8 Weeks prior to Day 0) .................................................49 
9.7.7. 
Day 0 Procedures (Randomization) ............................................................................51 
9.7.8. 
Month 1 Procedures: ...................................................................................................53 
9.7.9. 
Month 3 Procedures ....................................................................................................54 
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9.7.10. 
Post-Titration Visit Procedures: .................................................................................55 
9.7.11. 
Month 6 Procedures ....................................................................................................55 
9.7.12. 
Month 9 Procedures ....................................................................................................57 
9.7.13. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment .................................................................................................................57 
9.7.14. 
Month 12 Procedures ..................................................................................................58 
9.7.15. 
Month 3 and Month 9 Continued Follow-Up Procedures (±2 weeks) .......................59 
9.7.16. 
Month 6 Continued Follow-Up Procedures (Semi-annually [±2 weeks]) ..................60 
9.7.17. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) .........................61 
9.7.18. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent ..................................63 
9.7.19. 
Unscheduled Safety Visit ...........................................................................................66 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............66 
10.1. 
Investigational Product ...............................................................................................66 
10.2. 
Investigational Product Packaging and Labeling .......................................................66 
10.3. 
Investigational Product Storage ..................................................................................66 
10.4. 
Investigational Product Preparation ............................................................................66 
10.5. 
Investigational Product Administration ......................................................................67 
10.6. 
Investigational Product Accountability and Disposal .................................................67 
11. 
ASSESSMENT OF EFFICACY ................................................................................67 
11.1. 
Assessment of Efficacy ...............................................................................................67 
11.1.1. 
Primary Assessments ..................................................................................................67 
11.1.2. 
Secondary Assessments ..............................................................................................68 
11.1.2.1. 
Non-Invasive Assessments of Liver Fibrosis .............................................................68 
11.1.2.2. 
Other Secondary Assessments ....................................................................................68 
11.1.2.3. 
Other Exploratory Evaluations ...................................................................................69 
11.1.2.4. 
Potential Clinical Outcome Events .............................................................................69 
12. 
ASSESSMENT OF SAFETY .....................................................................................70 
12.1. 
Adverse Events and Serious Adverse Events .............................................................70 
12.1.1. 
Definition of Adverse Events .....................................................................................70 
12.1.1.1. 
Adverse Event .............................................................................................................70 
12.1.1.2. 
Serious Adverse Event ................................................................................................70 
12.1.1.3. 
Treatment-Emergent Adverse Event ..........................................................................71 
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12.1.2. 
Relationship to Investigational Product ......................................................................71 
12.1.3. 
Recording Adverse Event Severity .............................................................................71 
12.1.4. 
Reporting of Adverse Events and Serious Adverse Events ........................................72 
12.1.4.1. 
Reporting of Adverse Events ......................................................................................72 
12.1.4.2. 
Reporting of Serious Adverse Events .........................................................................72 
12.1.5. 
Suspected Liver-Related Clinical Outcome Events ....................................................73 
12.1.6. 
Additional Investigator Responsibilities for SAEs .....................................................73 
12.1.7. 
Notification of Post-Study SAEs ................................................................................74 
12.1.8. 
Follow-Up of AEs and SAEs ......................................................................................74 
12.1.9. 
Pregnancy and Follow up ...........................................................................................74 
12.2. 
Other Safety Parameters .............................................................................................75 
12.2.1. 
Medical History/Demographics ..................................................................................75 
12.2.2. 
Physical Examination .................................................................................................75 
12.2.3. 
Vital Signs ..................................................................................................................75 
12.2.4. 
Electrocardiogram .......................................................................................................75 
12.2.5. 
Dual Emission X-Ray Absorptiometry .......................................................................75 
12.2.6. 
Subject Questionnaires ...............................................................................................75 
12.2.7. 
Laboratory Assessments .............................................................................................76 
13. 
STATISTICAL METHODS .......................................................................................78 
13.1. 
Efficacy Analysis ........................................................................................................78 
13.1.1. 
Analysis Populations ..................................................................................................78 
13.1.1.1. 
Comparability of Historical Controls .........................................................................78 
13.1.2. 
Determination of Sample Size ....................................................................................79 
13.1.2.1. 
Sample Size Re-Estimation Plan ................................................................................79 
13.1.3. 
Primary Efficacy Analysis ..........................................................................................80 
13.1.4. 
Key Secondary Efficacy Analyses ..............................................................................80 
13.1.5. 
Additional Secondary Efficacy Analyses ...................................................................81 
13.1.6. 
Exploratory Efficacy Analyses ...................................................................................82 
13.1.6.1. 
Responder Analyses ....................................................................................................82 
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints ................................................82 
13.1.8. 
Supportive Analysis ....................................................................................................82 
13.1.9. 
Alternative Primary Analysis .....................................................................................84 
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13.1.10. 
Handling of Dropouts or Missing Data ......................................................................84 
13.1.10.1. Time to Event Endpoints ............................................................................................85 
13.1.10.2. Quantitative Endpoints ...............................................................................................85 
13.1.10.3. Responder Endpoints ..................................................................................................85 
13.1.11. 
Multiple Comparisons/Multiplicity ............................................................................85 
13.1.12. 
Examination of Subgroups .........................................................................................86 
13.2. 
Safety Analysis ...........................................................................................................86 
13.2.1. 
Adverse Events ...........................................................................................................86 
13.2.2. 
Clinical Laboratory Evaluations .................................................................................87 
13.2.3. 
Additional Safety Analysis .........................................................................................87 
13.2.4. 
Cardiovascular Adjudication Committee ...................................................................87 
13.3. 
Data Monitoring Committee .......................................................................................87 
13.4. 
Adjudication Committees ...........................................................................................88 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................89 
14.1. 
Study Monitoring ........................................................................................................89 
14.2. 
Audits and Inspections ................................................................................................89 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................89 
16. 
ETHICS ......................................................................................................................90 
16.1. 
Ethics Review .............................................................................................................90 
16.2. 
Ethical Conduct of the Study ......................................................................................90 
16.3. 
Written Informed Consent ..........................................................................................90 
16.4. 
Subject Confidentiality and Data Protection ..............................................................90 
17. 
INVESTIGATOR OBLIGATIONS ...........................................................................91 
17.1. 
AE Reporting ..............................................................................................................91 
17.2. 
Protocol Deviations ....................................................................................................91 
17.3. 
Regulatory Documentation .........................................................................................91 
17.4. 
Ethics Review .............................................................................................................92 
17.5. 
Archiving and Record Retention ................................................................................92 
18. 
PUBLICATION POLICY ..........................................................................................92 
LIST OF REFERENCES ...............................................................................................................94 
APPENDIX A. MODIFIED DOSING REGIMEN FOR SUBJECTS WITH CHILD-
PUGH B/C HEPATIC IMPAIRMENT ......................................................................96 
APPENDIX B. LIST OF STUDY 747-302 OUTCOME EVENTS ...........................................99 
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APPENDIX C. ETHICAL CONDUCT ACCORDING TO THE DECLARATION OF 
HELSINKI FOR COUNTRIES PARTICIPATING OUTSIDE THE US 
(DECLARATION OF HELSINKI, FORTELEZA, BRAZIL, 2013) ......................100 
APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 
(DATED 29 APR 2015) ...........................................................................................105 
APPENDIX E. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 
(DATED 12 NOV 2015) ..........................................................................................142 
APPENDIX F. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 (DATED 07 
SEPTEMBER 2016) .................................................................................................144 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures – Screening to Month 12 (Table 1 of 2) ....................30 
Table 2: 
Schedule of Study Procedures – Year 2 Through End of Study (Table 2 of 2) .........33 
Table 3: 
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score ..................................35 
Table 4: 
Determination of Dosing Regimen .............................................................................36 
Table 5: 
Changes in Dosing Regimen Due to Changes in Cirrhosis Status or 
Child-Pugh Score ........................................................................................................37 
Table 6: 
Child-Pugh Scoring System ........................................................................................49 
Table 7: 
Early Discontinuation Scenarios .................................................................................64 
Table 8: 
Relationship of Adverse Events to Investigational Product .......................................71 
Table 9: 
Severity of Adverse Events ........................................................................................72 
Table 10: List of Laboratory Analytes to be Tested ...................................................................77 
Table 11: Planned Dosing Regimen by Cirrhosis and Child-Pugh Score ..................................96 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram Study 747-302 ............................................................................29 
Figure 2: 
Dosing by Cirrhosis Status and Child-Pugh Score .....................................................96 
 
 
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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 
CAC 
Cardiovascular Adjudication Committee 
CDCA 
chenodeoxycholic acid 
CI 
confidence interval 
CK-18 
cytokeratin-18 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
C-reactive protein 
DEXA 
dual-emission X-ray absorptiometry 
DMC 
Data Monitoring Committee 
EASL 
European Association for the Study of the Liver 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
enhance liver fibrosis 
EOS 
end of study 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
FIS 
Fatigue Impact Scale 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
glyco-OCA 
glycine 6α-ethyl chenodeoxycholic acid 
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Abbreviation or Specialist Term 
Explanation 
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 
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 
LDL 
low density lipoprotein 
LTSE 
Long-term safety extension 
MACE 
Major adverse cardiovascular events 
MELD 
model of end stage liver disease  
MRS 
Mayo Risk Score 
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cholangitis (also known as primary biliary 
cirrhosis) 
PIS 
patient information sheet 
PK 
pharmacokinetic 
PSC 
primary sclerosing cholangitis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
SUSAR 
suspected unexpected serious adverse reactions 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
the Sponsor 
Intercept Pharmaceuticals, Inc. 
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Abbreviation or Specialist Term 
Explanation 
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 Primary Biliary Cirrhosis and Obeticholic Acid 
Primary biliary cholangitis, (PBC, also known as primary biliary cirrhosis) 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, is currently the only 
treatment approved for PBC (Lindor 2009).  While UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of a poor clinical outcome due to PBC disease 
progression.  There is a clear unmet medical need for better therapies for patients with PBC that 
have an inadequate response to UDCA, or those who cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and effective. 
OCA is a modified bile acid and farnesoid X receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid (CDCA).  OCA is currently being developed in 
the United States (US) and Europe for the treatment of PBC and other chronic liver diseases.  
OCA has been granted Orphan Drug Designation in the US (09 Apr 2008) and Orphan Medicinal 
Product Designation in the European Union (EU) (27 Jul 2010) for the treatment of PBC.  The 
United States Food and Drug Administration (FDA) has granted accelerated approval for Ocaliva 
for the treatment of PBC.  Ocaliva is not yet approved outside the United States for use in any 
indication. 
5.2. 
Mechanism of Action of Obeticholic Acid 
OCA is a 6α-ethyl derivative of the naturally occurring primary human bile acid CDCA, which is 
the endogenous ligand for FXR.  FXR is a ligand-dependent transcription factor that is part of 
the nuclear receptor superfamily.  FXR regulates a wide variety of target genes involved in the 
control of bile acid, lipid, and glucose homeostasis and in the regulation of immune responses. 
OCA’s potent FXR agonist effects are believed to account for the predominant efficacy of the 
investigational product.  Some of the pharmacological properties of OCA and other FXR 
agonists that have been elucidated in animal models of chronic liver disease relevant to the 
treatment of PBC include the following: 
 Improvement in hepatic choleresis with reduced inflammation and necrosis  
 Prevention and reversal of hepatic fibrosis 
The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and 
anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury 
and improved liver function in a cholestatic liver disease such as PBC. 
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5.3. 
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. 
5.4. 
Clinical Experience with Obeticholic Acid 
As of 31 Jan 2016, approximately 1726 subjects have received at least 1 dose of OCA. Of these, 
844 were healthy volunteers, 458 subjects had PBC, 330 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver disease (NAFLD), 33 subjects had alcoholic 
cirrhosis/portal hypertension, and 20 subjects 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. 
To date, the efficacy and safety of OCA in PBC has been evaluated in 2 placebo-controlled, 
double-blind, Phase 2 studies (747-201 and 747-202), and 1 placebo-controlled, double-blind 
Phase 3 study (747-301).  Following the double-blind phase, subjects in all 3 studies were 
eligible to continue with treatment in a long-term safety extension (LTSE) phase for up to 
5 years in Study 747-201, up to 1 year in Study 747-202, and up to 5 years in Study 747-301. 
Study 747-201 (59 subjects) 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 subjects) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in subjects 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 subjects) was a Phase 3, double-blind, placebo-controlled, parallel group 
study followed by an LTSE using OCA in subjects with PBC.  The primary endpoint for 
Study 747-301 was a composite endpoint based on the proportion of subjects reaching specific 
criteria for ALP and bilirubin (ALP <1.67× upper limit of normal [ULN] with a ≥15% reduction 
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and bilirubin ≤ULN).  Both OCA treatment groups met the primary endpoint of achieving a 
reduction in ALP to <1.67× 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 10 mg OCA 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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is complete. 
5.5. 
Rationale for Study Design and Dose for Investigational Product 
5.5.1. 
Rationale for Study Design 
OCA is a modified bile acid and FXR agonist that is derived from the primary human bile acid 
chenodeoxycholic acid.  The key mechanisms of action of OCA, including its choleretic, anti-
inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in 
attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. 
PBC is characterized by biochemical increases in ALP and GGT enzymes with or without 
elevations of hepatocellular transaminases and bilirubin (Lindor 2009).  Both the American 
Association for the Study of Liver Diseases (AASLD) (Lindor 2009) and the European 
Association for the Study of the Liver (EASL) (EASL 2009) guidelines base the biochemical 
component of PBC diagnosis on elevations of ALP.  In addition, a growing literature supports 
the use of biochemical endpoints, specifically serum ALP alone or with other parameters such as 
bilirubin, to manage subjects, test the efficacy of novel therapies in clinical studies, and gauge 
the risk of long-term adverse clinical outcomes in subjects with PBC (Beuers 2011, 
Momah 2012).  Data from the Global PBC Study Group (Lammers 2013), which has built a 
database tracking biochemical status and clinical outcomes in several thousand PBC subjects, 
provides evidence for the use of the composite biochemical endpoint of ALP and bilirubin as an 
acceptable surrogate endpoint. 
Study 747-301, a Phase 3 double-blind study, evaluated the safety and efficacy of OCA at doses 
of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability) and 10 mg and used 
a composite biochemical endpoint of ALP and bilirubin as a surrogate endpoint.  In this study, 
both treatment groups exhibited clinically meaningful improvements in liver biochemistry and 
were safe and generally well-tolerated.  As a result, starting subjects on 5 mg OCA and titrating 
to 10 mg based on tolerability and clinical response appears to be an appropriate dosing strategy 
in subjects with PBC.  
Study 747-302 is a clinical outcomes study, supportive of Phase 3 Study 747-301 which was 
based on a surrogate biochemical endpoint, designed to confirm the clinical benefit of OCA 
treatment in patients with PBC.  A retrospective observational database (Global PBC Study 
Group [Lammers 2013]) of patients with PBC allowed for a rigorous patient-level meta-analysis 
and provided an opportunity for a robust assessment of ALP and bilirubin as viable surrogate 
biochemical parameters and a comprehensive understanding of the natural history of the PBC 
disease process.  Data from the Global PBC Study Group was also utilized to inform the design 
of the confirmatory outcomes study. 
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5.5.2. 
Rationale for Dose 
5.5.2.1. 
Rationale for OCA Doses 
The safety and tolerability of multiple doses of OCA have been established in subjects with PBC 
at doses up to 50 mg.  As demonstrated in the Phase 2 PBC studies (Studies 747-201 and 
747-202), OCA significantly reduced serum ALP levels at doses of 10 mg, 25 mg, and 50 mg, 
but with an increase in the incidence and severity of pruritus at higher dose levels.  The Phase 3 
PBC study subsequently evaluated the safety and efficacy of OCA at lower doses of 5 mg 
(titrated to 10 mg after 6 months based on efficacy and tolerability in the double-blind phase and 
after 3 months in the open-label phase) and 10 mg; both treatment groups exhibited clinically 
meaningful improvements in liver biochemistry and were safe and generally well tolerated.  
Based on these data, the indicated commercial doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
The majority of efficacy results with OCA, in terms of change in alkaline phosphatase, was 
observed by 3 months and the time to treatment-emergent pruritus was typically 1 month or less 
in Study 747-301.  As such, Study 747-302 will evaluate the effect of OCA on clinical outcomes 
using the 5 mg OCA dose increasing to 10 mg OCA, if tolerated. 
5.5.2.2. 
Rationale for Modified OCA Doses in Patients Classified with Child-Pugh B or 
Child-Pugh C Hepatic Impairment 
 
Simulations using a physiologic PK model predicted changes in systemic and liver OCA 
concentrations associated with changes in the severity of hepatic impairment (Child-Pugh Score).  
Model simulations predicted that for mild (Child-Pugh A), moderate (Child-Pugh B), and severe 
(Child-Pugh C) hepatic impairment, total OCA plasma concentrations increase 1.4-, 8.0-, and 
13-fold relative to subjects 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 (Child-Pugh B and C) subjects treated with 
OCA in phase 1 and 2 studies experienced plasma OCA exposures >10-fold higher than those in 
healthy subjects, 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.  Collectively, 
the results from these analyses suggest that the doses of OCA administered to hepatically-impaired 
patients should be modestly lower than those for patients with normal hepatic function to achieve 
similar hepatic exposure.   
Per the approved FDA prescribing label, the recommended dosing regimen for OCA in subjects 
with moderate and severe hepatic impairment is a starting dose of 5-mg OCA once weekly.  
Dosage adjustments in subjects with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic 
impairment may be made after establishing tolerability at the lower dose (full modified dosing 
regimen is described in Appendix A).   
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5.5.2.3. 
Rationale for Control Groups 
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 a standard of care 
effect.  Notably, accounting for the standard of care effect is critical when designing an 
outcome-based study conducted globally when there are regional differences in the treatment of 
subjects with PBC. 
Historical Control Group 
The available robust historical PBC observational datasets (UK-PBC and Global PBC Study 
Group) will also be leveraged to provide further comparative evaluation of the clinical benefit of 
OCA.  Each database includes >6000 patients with long-term follow-up. 
Comparison of OCA treatment to the historical controls may provide utility in addressing 
potential bias or confounds associated with the placebo arm.  For example, bias associated with 
the potential addition of commercial OCA and/or differences in long-term standard of care 
between the treatment arms including ancillary treatments and diagnostics. 
Therefore, further evaluation of the effect of OCA will compare OCA treatment versus historical 
controls, and will be supportive to placebo comparisons (ie, comparisons to historical and 
placebo controls will be evaluated separately). 
5.6. 
Summary of Known Potential Risks with OCA 
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, but with a much 
lower frequency than that observed in subjects 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 subjects 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 
above 10 mg OCA.  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 (HDL) and an increase in low density lipoprotein (LDL).  Notably, in 
subjects 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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated subjects with the exception of a 
modest transient and early rise after initiation of treatment.   
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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care on clinical outcomes in subjects with PBC as measured by time to first occurrence of any 
of the following adjudicated events, derived as a composite event endpoint:  
 Death (all-cause) 
 Liver transplant 
 Model of end stage liver disease (MELD) score ≥15 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
 Variceal bleed 
 Encephalopathy (as defined by a West Haven score of ≥2) 
 Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
 Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities 
6.2. 
Secondary Objectives 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above and also to include liver-related death. 
To assess the effect of OCA compared to placebo on disease progression via the following: 
 Liver biochemistry 
 Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To assess the PK of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3b, double-blind, randomized, placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with bilirubin levels of >ULN and ≤3× ULN or ALP 
>5× ULN.  Subjects enrolled will be at higher risk of liver-related clinical complications. 
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Approximately 350 subjects meeting all enrollment criteria will be recruited into the study over 
an approximate 2-year period, randomly allocated to treatment with either OCA or matching 
placebo in a 1:1 ratio (Figure 1).  Subjects will be screened during a 1 to 8-week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples 
(at least 2 weeks apart) to confirm pretreatment ALP and total bilirubin values (refer to 
Section 9.7.6).  Randomization will be stratified by UDCA treatment (yes/no) and baseline 
bilirubin categories (>ULN/≤ULN).  In addition to the placebo control arm, multiple historical 
control groups (concurrent and retrospective) will be used.   
Investigational product will be taken orally, once daily.  Subjects who are non-cirrhotic or 
classified as Child-Pugh A at Screening will initiate investigational product once daily with 5-mg 
OCA or matching placebo.  Following 3 months of once daily treatment with investigational 
product, the dose should be titrated to a maximum 10 mg OCA or matching placebo once daily, 
based on tolerability (see Section 7.3).  
Subjects with cirrhosis (see Section 9.7.3) and classified as Child-Pugh Class B or Child-Pugh 
Class C will follow a modified dosing regimen, and will initiate investigational product once 
weekly with the 5-mg OCA or matching placebo dose.  In addition, these subjects will follow a 
modified titration plan, which is outlined in Appendix A. 
It is anticipated that subjects will be followed for a minimum of approximately 6 years.  The 
study will continue until approximately 121 adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor (eg, based on advisement by the Data 
Monitoring Committee; DMC) terminates the study. 
This study will be conducted at approximately 170 international study sites with experience in 
treating subjects with PBC.  Prospective subjects will be identified primarily from the hospital 
and/or physician’s database of subjects with PBC, or may be referred from other physicians.  
Subjects may self-refer to an Investigator if they become aware of the study through local, 
national, or international PBC subject societies, forums, and networks. 
7.1.1. 
Study Design Diagram 
Figure 1: 
Schematic Diagram Study 747-302 
  
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for 
subjects on all dosing regimens, based on tolerability.  Subsequent dose titration(s) for subjects classified as 
Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after 
the previous dose titration.
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures – Screening to Month 12 (Table 1 of 2) 
 
Screening Visits 
Day 0 
M 1 
M 3 
1-Month 
Post-Titration Visitb 
M 6 
M 9 
M 12 
1 
2a 
Visit Windows (+/-)c 
3 to 8 wk 
prior to 
Day 0 
1 to 6 wk 
prior to 
Day 0 
 
+1 wk 
±2 wk 
±1 wk 
±2 wk 
±2 wk 
±2 wk 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical/PBC Historyd  
X 
 
 
 
 
 
 
 
 
Cirrhosis Status Assessmente 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
Physical Exam  
X 
 
 
 
 
 
 
 
Xd 
Assessments for Mayo Risk Scoref 
X 
 
 
 
 
 
X 
 
X 
Assessments for Child-Pugh Scoreg 
X 
 
 
 
X 
 
X 
X 
X 
Vital Signs (including weight) 
Xh 
 
X 
 
X 
 
X 
X 
Xh 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
X 
Subject Questionnaires (5-D Pruritus Scale and 
Pruritus VAS) 
 
 
X 
 
 
 
X 
 
X 
Quality of Life Questionnaires (PBC-40, 
EQ-5D-5L, and FIS)i 
 
 
X 
 
 
 
 
 
X 
TE Fibroscan®/DEXAj 
 
 
X 
 
 
 
 
 
X 
Endoscopyk 
 
 
X 
 
 
 
 
 
X 
Hepatic Ultrasoundl 
 
X 
 
 
 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health Outcome Assessmentsm 
 
 
X 
 
X 
 
X 
X 
X 
Randomization/Treatment Assigned 
 
 
X 
 
 
 
 
 
 
Dose Titration: Standard Dosingn,o 
 
 
 
 
X 
 
X (if applicable) 
Dose Titration: Modified Dosing (if applicable)n,o 
 
 
 
 
X 
 
X 
X 
X  
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Table 1: 
Schedule of Study Procedures – Screening to Month 12 (Table 1 of 2) (Continued) 
 
Screening Visits 
Day 0 
M 1 
M 3 
1-Month 
Post-Titration Visitb 
M 6 
M 9 
M 12 
1 
2a 
Visit Windows (+/-)c 
3 to 8 wk 
prior to 
Day 0 
1 to 6 wk 
prior to 
Day 0 
 
+1 wk 
±2 wk 
±1 wk 
±2 wk 
±2 wk 
±2 wk 
Dispense Investigational Productp 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
IP Accountability/Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
Dosing Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSq 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
X 
Urine-based β-hCG Pregnancy Testr 
X 
 
X 
 
 
 
 
 
 
Chemistry/Hematology/ 
Coagulation 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
OCA, C4, and FGF-19 (plasma)  
 
 
X 
 
X 
 
X 
Xs 
X 
Markers of Hepatic Fibrosis and/or Inflammationt 
 
 
X 
 
 
 
X 
 
X 
Geneticsu 
 
 
X 
 
 
 
 
 
X 
Blood Sample for Future Analysisv 
 
 
X 
 
 
 
X 
 
X 
AE = adverse event; β-hCG = beta human chorionic gonadotropin; DEXA = dual-emission X-ray absorptiometry; EOS= End of Study; EOT = End of Treatment; 
FGF-19 = fibroblast growth factor-19; FIS = Fatigue Impact Scale; IP = Investigational Product; M = month, TE = transient elastography; VAS = Visual Analogue Scale; 
wk = week 
a All subjects will have the chemistry panel retested to ensure subjects have two ALP and bilirubin assessments at least 2 weeks apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and bilirubin assessments will be used to determine eligibility.  Samples for hematology and coagulation will not be collected at 
Screening Visit 2. 
b Post-Titration visits must be performed 1 month (+ 1 week) after any up-titration in dose and/or frequency in subjects following modified dosing due to Child-Pugh B and Child-
Pugh C hepatic impairment.  In subjects following the standard dosing regimen, the post-titration visit must be performed only after the first up-titration to 10 mg OCA or 
matching placebo, or after ≥3 months at a decreased dose or frequency. 
c Visits should be based on Day 0 (not on the prior visit) with the exception of the Post-Titration Visit, which is based on the date of titration. 
d Medical history at Screening and the yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both. 
e Presence or absence of cirrhosis should be assessed per Section 9.7.3.  Cirrhosis status should be repeated as clinically indicated. 
f Mayo Risk Score will be calculated based on central laboratory evaluations, diuretic use data, and peripheral edema assessment data captured in the CRF. 
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 Height will be collected at this visit. 
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i The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2 and Section 12.2.6). 
j Transient elastography (TE) will be conducted at selected study sites where the Fibroscan® TE device is available.  Similarly, DEXA will be conducted at selected study sites 
where the DEXA device is available.   Please refer to Section 9.7.7 for additional information related to the allowed windows at Day 0 for these specific procedures. 
k Endoscopy will be conducted at selected study sites where the device is available to assess for the presence of oesophageal varix/varices.  Please refer to Section 9.7.7 for 
additional information related to the allowed window at Day 0 for this specific procedure.  
l Ultrasound will be conducted to enhance HCC surveillance.  For all on study (eg, post-Day 0) ultrasounds: If a lesion is found, a second confirmatory image (eg, MRI) should be 
obtained to confirm if a study endpoint has been met. 
m Health Outcome Assessments: Data related to non-study related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
n Pre-titration tolerability assessment, which include a review of AEs and a review of safety laboratory results (eg, chemistry, hematology, and coagulation), must be completed 
by the Investigator before any up-titration can occur as defined in Section 7.4.1.  Lab results obtained within 2 months prior to any up-titration may be used for assessment.  
o Dose Titration is based on cirrhosis status (Section 9.7.3) and Child-Pugh Score (Section 9.7.4).  The initial dose titration of investigational product may occur at the Month 3 
visit, or any study visit thereafter for subjects on all dosing regimens, based on tolerability.  Subsequent dose titration(s) for subjects who are classified as Child-Pugh B or 
Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.  For complete modified dose titration criteria, refer 
to Appendix A. 
p Subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1) and to take investigational product at approximately the same time of day.  Subjects 
must be instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
q The subject 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. 
r Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry.  If positive, a confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not be enrolled in the study.  (Additional testing may be conducted where required, regionally). 
s Only OCA PK samples will be collected at Month 9 at select study sites in a subset of subjects.  Please refer to Section 9.7.13 for the PK sampling schedule. 
t Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
u A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12. 
v Please refer to Section 11.1.2.3 for description of the blood sample to be collected for future analysis. 
 
 
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Table 2: 
Schedule of Study Procedures – Year 2 Through End of Study (Table 2 of 2) 
 
Year 2 through End of Study 
 
M 3 
continued follow-up 
1-Month Post-
Titration Visita 
(if applicable) 
M 6 
continued follow-up 
M 9 
continued follow-up 
M 12 
continued follow-up 
EOT/ 
EOSb 
Visit Windows (+/-)c 
±2 wk 
+1 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
Physical Examd 
 
 
 
 
X 
X 
Assessment for Mayo Risk Scoree 
 
 
X 
 
X 
X 
Assessments for Child-Pugh Scoresf 
X 
 
X 
X 
X 
X 
Vital Signs (including weight) 
 
 
X 
 
Xg 
Xg 
12-Lead Electrocardiogram 
 
 
 
 
X 
X 
Subject Questionnaires (5-D Pruritus 
Scale and Pruritus VAS) 
 
 
X 
 
X 
X 
Quality of Life Questionnaires (PBC-40, 
EQ-5D-5L, and FIS)h 
 
 
 
 
X 
X 
TE Fibroscan®/DEXAi 
 
 
 
 
X 
X 
Endoscopyj 
 
 
 
 
X 
 
Hepatic Ultrasoundk 
 
 
 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
Health Outcome Assessmentsl 
X 
 
X 
X 
X 
X 
Dose Titration (if applicable)m,n 
X 
 
X 
X 
X 
 
Dispense Investigational Product 
X 
 
X 
X 
X 
 
IP Accountability/Compliance 
X 
X 
X 
X 
X 
X 
Dosing Diary 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSo 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
X 
X 
Chemistry/Hematology/Coagulation 
X 
X 
X 
X 
X 
X 
OCA, C4, and FGF-19 (plasma) 
 
 
 
 
X 
X 
Markers of Hepatic Fibrosis and/or 
Inflammationp 
 
 
X 
 
X 
X 
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Table 2: 
Schedule of Study Procedures – Year 2 Through End of Study (Table 2 of 2) (Continued) 
 
Year 2 through End of Study 
 
M 3 
continued follow-up 
1-Month Post-
Titration Visita 
(if applicable) 
M 6 
continued follow-up 
M 9 
continued follow-up 
M 12 
continued follow-up 
EOT/ 
EOSb 
Visit Windows (+/-)c 
±2 wk 
+1 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
Geneticsq 
 
 
 
 
X 
 
Blood Sample for Future Analysisr 
 
 
X 
 
X 
X 
AE = adverse event; β-hCG = beta human chorionic gonadotropin; DEXA = dual-emission X-ray absorptiometry; EOS= End of Study; EOT = End of Treatment; 
FGF-19 = fibroblast growth factor-19; FIS = Fatigue Impact Scale; IP = Investigational Product; M = month, TE = transient elastography; VAS = Visual Analogue Scale; 
wk = week 
a  In subjects following the standard dosing regimen, the post-titration visit must be performed only after the first up-titration to 10 mg OCA or matching placebo, or after 
≥3 months at a decreased dose or frequency.  Post-titration visits must be performed 1 month ± 1 week after any up-titration in dose and/or frequency in subjects following 
modified dosing due to Child-Pugh B and Child-Pugh C hepatic impairment.   
b  As soon as possible upon study discontinuation and as near as possible to last dose taken. 
c Visits should be based on Day 0 (not on the prior visit) with the exception of the Post-Titration Visit, which is based on the date of titration. 
d The yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both. 
e Mayo Risk Score will be calculated based on central laboratory evaluations, diuretic use data, and peripheral edema assessment data captured in the CRF. 
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 case report form. 
g Height will be collected at this visit. 
h  The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2 and Section 12.2.6). 
i Transient elastography (TE) will be conducted at selected study sites where the Fibroscan® TE device is available.  Similarly, DEXA will be conducted at selected study sites 
where the DEXA device is available.  Not required if done within 6 months of visit. 
j  Endoscopy will be conducted at selected study sites where the device is available to assess for the presence of oesophageal varix/varices. 
k  Ultrasound will be conducted to enhance HCC surveillance.  For all on study (e.g. post-day 0) ultrasounds: If a lesion is found, a second confirmatory image (eg, MRI) should be 
obtained to confirm if a study endpoint has been met. 
l  Health Outcome Assessments: Data related to non-study related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
m  Pre-titration tolerability assessment, which include a review of AEs and a review of safety laboratory results (eg, chemistry, hematology, and coagulation), must be completed 
by the Investigator before any up-titration can occur as defined in Section 7.4.1.  Lab results obtained within 2 months prior to any up-titration may be used for assessment.   
n  Dose Titration is based on cirrhosis status (see Section 9.7.3) and Child-Pugh Score (Section 9.7.4).  The initial dose titration of investigational products may occur at the Month 
3 visit, or any study visit thereafter for subjects on all dosing regimens, based on tolerability.  Subsequent dose titration(s) for subjects who are classified as Child-Pugh B or 
Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.  For complete modified dose titration criteria, refer 
to Appendix A. 
o  The subject should be instructed to fast overnight (at least 8 hours) prior to each visit.  Fasting is required prior to all study visits, but water is permitted. 
p  Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
q  A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12. 
r Please refer to Section 11.1.2.3 for description of the blood sample to be collected for future analysis.
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7.1.3. 
Study Duration 
The study is event driven and total duration will be determined by the time required to accrue 
approximately 121 primary endpoint events, estimated to be approximately 8 years.  Subjects are 
expected to have a minimum follow-up time of approximately 6 years. 
7.2. 
Number of Subjects 
It is expected that approximately 350 subjects will be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
7.3. 
Planned Dosing Regimen 
Subjects will be randomized to treatment with either OCA or matching placebo in a 1:1 ratio.  
Subjects will be dosed according to their cirrhosis status (as defined in Section 9.7.3) and 
applicable Child-Pugh Score (see Section 9.7.4) as outlined in Table 3.  
Subjects who are non-cirrhotic or classified as Child-Pugh A at screening will receive 5 mg OCA 
or matching placebo once daily for 3 months.  Subjects should titrate to a maximum dose of 10 
mg OCA once daily (or matching placebo) at the Month 3 visit or at any study visit following the 
Month 3 visit based on tolerability of the product.  A review of safety laboratory results (eg, 
chemistry, hematology, and coagulation) obtained no more than 2 months prior to the planned 
up-titration visit must be completed as part of the product tolerability assessment before 
up-titration can occur (see Section 7.4.1).   
For those subjects that up-titrate to 10 mg, dose may be decreased to 5 mg at any time during the 
study as considered clinically appropriate (eg, tolerability). Subjects may be titrated back up to a 
maximum dose of 10 mg once daily based on tolerability and clinical judgment of the 
Investigator.  A review of safety laboratory results obtained within 2 months of the planned 
up-titration visit date is not required prior to re-challenging a subject up to 10 mg once daily 
dosing, as long as the decrease in dose/dosing frequency was less than 3 months in duration.  
Table 3: 
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Scheduled Dosing Regimen 
Standard  
Modifiedd  
Non-Cirrhotic/ 
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
5 mg once weekly 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weeklyc 
5 mg twice weeklyc 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weeklyc 
10 mg twice weeklyc 
Titration 3b 
(≥6 weeks after Titration 2) 
NA 
5 mg daily 
NA 
a Starting dose based on subject’s cirrhosis status and Child-Pugh score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject 
tolerability and/or changes in cirrhosis status or Child-Pugh score at any time during the study (see Section 7.4). 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
d Refer to Appendix A  for additional instructions regarding subjects following the Modified Dosing Regimen. 
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The dosing regimen should be determined as described in Table 4.  Investigators should follow 
the dosing/titration schedule as shown in Table 3. 
Table 4: 
Determination of Dosing Regimen 
Cirrhosis? 
No 
Yes 
Yes 
Yes 
Child-Pugh Score 
Any 
A 
B 
C 
Dosing Regimen 
Standard 
Modified for Child-Pugh B 
Modified for Child-Pugh C 
7.4. 
Dose Titration 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 subject’s cirrhosis status (using histology or 
non-histological methods as defined in Section 9.7.3 and Section 9.7.4) or Child-Pugh Score.   
Scheduled Dose Titration - The first dose titration for any subject may occur no earlier than 
3 months following initiation of OCA or matching placebo.  Subsequent titrations in dose or 
dosing frequency for subjects following the Modified Dosing Regimens may occur no earlier 
than 6 weeks (via an unscheduled visit or regular visit- see Appendix A) following an 
up-titration. 
Tolerability Dose Titration - Investigators may decrease the dosing frequency or dose for any 
subject at any time during the study, as considered clinically appropriate (eg, tolerability; see 
Section 7.4.2).   
Dose Titration due to Change in Cirrhosis or Child-Pugh Score - When subjects demonstrate 
a change in cirrhosis status (as assessed per Section 9.7.3) or Child-Pugh Score (Section 9.7.4), 
dosing should be reassessed and the dosing regimen modified appropriately.  Changes to the 
dosing regimen are not mandatory and should be based on clinical judgment as well as change in 
cirrhosis status.  Table 5  provides an overview of the possible changes in dosing regimen due to 
changes in cirrhosis or Child-Pugh 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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Table 5: 
Changes in Dosing Regimen Due to Changes in Cirrhosis Status or 
Child-Pugh Score 
 
Original Status 
New Statusa 
Non-cirrhotic OR  
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Non-cirrhotic or  
Child-Pugh A 
No Change 
10 mg daily  5 mg daily 
5 mg daily No change or 10 mg 
twice weeklyb 
5 mg or 10 mg daily  10 mg 
twice weeklyb 
Child-Pugh B 
5 mg daily  10 mg daily  
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 
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 subject begins dosing with the new dosing regimen, titration should occur as described for that dosing 
regimen in Section 7.3 or Appendix A.  
b Dosing per the twice weekly schedule must be at least 3 days apart. 
Subjects who exhibit development of cirrhosis at any point in the study should be assessed per 
Section 9.7.3.  If the presence of cirrhosis is confirmed and the subject’s Child-Pugh score is 
either B or C, the appropriate modified dosing regimen should be followed.  The dose or 
frequency of investigational product should be down-titrated to the next lowest dosing frequency 
in the appropriate modified dosing regimen unless the subject is currently taking a dose and 
frequency also specified in the modified dosing regimen and the Investigator determines that it is 
clinically appropriate for the subject to continue at that dose (Appendix A). 
Subjects with pre-existing cirrhosis who demonstrate a change in the Child-Pugh Score from A 
to B or C at any point in the study should also have their dosing modified per the appropriate 
dosing regimen (Appendix A).  
Subjects who demonstrate an improvement in cirrhosis status or in Child-Pugh Score from B to 
A, or from Child-Pugh C to B, may be eligible to transition to the standard dosing regimen or the 
modified dosing for Child-Pugh B, respectively, based on tolerability.  Prior to any dosing 
change, subjects must meet pre-titration assessment requirements for dosing as described in 
Section 7.4.1. 
Child-Pugh Scores will be calculated at all quarterly study visits. All associated visit data 
(including central laboratory results) should be entered into the eCRF in a timely fashion to 
confirm that the subject’s Child Pugh Score has not changed.  If a change in cirrhosis status (as 
defined in Section 9.7.3) and/or Child-Pugh Score is observed independent of a study visit, the 
subject 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. 
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Subjects’ dose and dosing frequency may be titrated up or down within the appropriate dosing 
regimen based on the calculated Child-Pugh Scores.  Up-titration should be done per Investigator 
discretion and be guided by the pre-titration tolerability assessments. 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements 
Tolerability of investigational product must be assessed prior to titrating a subject to a higher 
dose.  A review of adverse events and safety laboratory results (eg, chemistry, hematology, and 
coagulation) obtained within 2 months of the up-titration visit must be performed as part of the 
investigational product tolerability assessment, prior to any planned up-titration in study 
medication (eg, Month 3, Month 6).  Safety laboratory results obtained at the Month 1 visit (for 
titration at Month 3) or at the 1 Month Post-Titration Assessment visit (for titration prior to or at 
the subsequent quarterly visit) are acceptable for review purposes; however, 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 subject to a higher 
dose.  
To be eligible for a dose up-titration: 
 Subjects 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.  
 There must be no clinically significant increase (as determined by the investigator) in the 
subject’s liver function tests.  Subjects whose total bilirubin is >2× baseline (and >ULN) 
cannot be up-titrated, and additional unscheduled safety visit procedures, outlined in 
Section 9.7.19, should be implemented, as required. 
7.4.2. 
Safety Criteria for Adjustment or Stopping Doses 
Investigational product may be temporarily decreased (eg, from 10 mg to 5 mg daily, or 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 that 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 when the needed number of adjudicated events has accrued.  If a subject reaches an 
event, he or she should continue the regular visit schedule and continue taking investigational 
product as long as the Investigator assesses it as safe.  In general, subjects should be strongly 
encouraged to both stay on investigational product and remain in the study until study 
termination.   
7.5. 
Criteria for Study Termination 
The Sponsor 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 DMC, it may be necessary to stop the study before all events have been accrued, and 
when subjects are still active on the study.  In addition, the Sponsor may terminate the study at 
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an investigational site at any time (eg, poorly performing sites, as determined by the number of 
subjects 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 subjects for the End of Study Visit.  The window of time for 
scheduling the visit will be based on a final projection of when the requisite 121 adjudicated 
events will have been accrued. 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Population 
This study will be conducted at approximately 170 international study sites with experience in 
treating patients with PBC.  Prospective subjects 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. 
Subject Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with AASLD and EASL practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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. 
2. A mean total bilirubin >ULN and ≤3× ULN and/or a mean ALP >5× ULN  
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking 
UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0. 
5. Contraception:  Female subjects 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:   
 Double-barrier method, ie, (a) condom (male or female) or (b) diaphragm, with 
spermicide; or  
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 Intrauterine device (IUD); 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 subject)   
6. Must provide written informed consent and agree to comply with the study protocol 
8.3. 
Subject Exclusion Criteria 
1. History or presence of other concomitant liver diseases including:  
 Hepatitis C virus infection 
 Active hepatitis B infection; however, subjects 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 
 Nonalcoholic steatohepatitis 
 Gilbert’s Syndrome  
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including:  
 History of liver transplant, current placement on a liver transplant list, or current 
MELD score >12.  Subjects who are placed on a transplant list despite a relatively 
early disease stage (for example per regional guidelines) may be eligible as long 
as they do not meet any of the other exclusion criteria. 
 Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
 Variceal bleed 
 Uncontrolled ascites 
 Encephalopathy  
 Spontaneous bacterial peritonitis  
 Known or suspected hepatocellular carcinoma 
 Prior transjugular intrahepatic portosystemic shunt procedure 
 Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine 
>2 mg/dL (178 μmol/L)  
3. Mean total bilirubin >3× ULN  
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4. Subjects who have undergone gastric bypass procedures (gastric lap band is 
acceptable) or ileal resection or plan to undergo either of these procedures. 
5. Other medical conditions that may diminish life expectancy, including known cancers 
(except carcinomas in situ or other stable, relatively benign conditions such as 
chronic lymphatic leukemia). 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test by the central laboratory), or lactating. 
7. Known history of human immunodeficiency virus infection. 
8. Medical conditions that may cause non-hepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months). 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study. 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0. 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components. 
14. UDCA naïve (unless contraindicated) 
8.4. 
Subject Withdrawal from Investigational Product or Study 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product 
If a female subject becomes pregnant, she must discontinue taking investigational product, but 
should continue with the study visit schedule.  The subject must be followed as considered 
appropriate by the Investigator and the medical monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an AE.  The subject may reinstate investigational 
product after delivery and cessation of breastfeeding (if applicable) at the discretion of the 
Investigator.  Subjects whose pregnancy is terminated early (planned or unplanned) may be 
permitted to resume participation in the study if termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotropin (β-hCG) test performed at the central laboratory. 
8.4.2. 
Other Reasons for Discontinuation of Study or Investigational Product  
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.  If a subject reaches an event, 
he or she should continue the regular visit schedule and continue taking investigational product 
as long as the Investigator assesses it as safe.  Subjects who choose to discontinue investigational 
product prior to termination of the study need to also continue to follow the regular visit schedule 
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through to study closure.  In general, subjects should be strongly encouraged to both stay on 
investigational product and remain in the study until study termination.  Early termination 
procedures should only be conducted if the subject withdraws consent (See Section 9.7.18 Early 
Discontinuation and/or Early Termination Procedures). 
The following events are considered appropriate reasons for a subject to discontinue 
investigational product; however, these subjects are expected to continue in the study until study 
termination and the study will only terminate at the time when the needed number of adjudicated 
events has accrued (or at the discretion of the Sponsor): 
 Subject begins treatment with commercially available OCA 
 The Investigator or Sponsor considers that it is advisable or in the best interest of the 
subject. 
 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 subject 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 potential 
adjudicated hepatic and/or cardiovascular events. 
Subjects who undergo a liver transplant during the course of the study must discontinue 
investigational product and discontinue the study visit schedule.  However, these subjects 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.  
The Investigator must notify the Sponsor study monitor by telephone or email as soon as 
possible if any subject prematurely withdraws from the study.   
8.4.2.1. 
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. 
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8.4.3. 
Withdrawal of Consent 
If the subject 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 subjects 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 subject discontinuation.  This 
information and date must be recorded in the appropriate case report form (CRF).   
8.4.4. 
Lost to Follow-up 
If a subject fails to return to the clinic for a study visit, and the Investigator ceases to have 
contact with the subject, he or she will be withdrawn from the study. 
A reasonable effort must be made to contact the subject and determine the reason(s) why a 
subject 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 CRF.   
8.4.5. 
Subject Discontinuation Notification  
The Investigator must notify the Sponsor study monitor by telephone or email as soon as 
possible if any subject prematurely withdraws from the study.  The date when the subject is 
withdrawn and the reason for discontinuation must be recorded in the CRF.  If a subject is “lost 
to follow up” (fails to return for a visit), a reasonable effort should be made to contact the subject 
in order to determine why the subject failed to return.  This information must be documented in 
the CRF.  If a subject is withdrawn from the study early (regardless of the cause), all of the 
EOT/EOS evaluations should be performed at the time of withdrawal, as appropriate (See 
Section 9.7.18, Early Discontinuation and/or Early Termination Procedures).  
9. 
TREATMENT OF SUBJECTS 
9.1. 
Investigational Product Treatment Regimen 
The term investigational product refers to either OCA (provided as part of this clinical study) or 
matching 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 5 mg OCA tablet or one 
10 mg OCA tablet, or matching placebo).   
Investigational product will be taken orally, up to once daily, for the duration of the study.   
All subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1) and 
to take investigational product at approximately the same time of day.  Subjects must be 
instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
At each study visit where the daily dose of investigational product is administered at the site, all 
assessments, except for the post-dose collection of blood samples for the subset of subjects 
participating in the Month 9 PK assessment, must be completed before administration of 
investigational product. 
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9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.1) 
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 CRF, as well as any dose or dose 
regimen changes that occur during the study.  Concomitant medications should be stable prior to 
Day 0.   
Drug Interactions 
Subjects 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 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 Investigator’s Brochure (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 with OCA that may be observed in study subjects. 
PBC Specific Therapy 
In general, 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 subjects’ 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, subjects 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, subjects should be reminded to keep taking their blinded 
investigational product. 
9.2.1. 
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.  Subjects who continue with commercial OCA therapy must discontinue study 
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medication and are expected to continue through the end of the study (see Section 7.4.2).  The 
study will only terminate at the time when the needed number of adjudicated events has accrued 
or at the discretion of the Sponsor.  Subjects will need to complete EOT procedures but continue 
with regularly scheduled visits until the study is terminated (see Section 9.7.18 Early 
Discontinuation and/or Early Termination Procedures). 
9.3. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Subjects should be instructed to complete a dosing diary to help monitor compliance to the 
prescribed dosing regimen.  Subjects should be instructed to retain all bottles of investigational 
product, even if empty, and to return them to the Investigator at the subsequent visit.  The 
Investigator or designee should perform investigational product accountability and, if applicable, 
follow up with the subject to retrieve any investigational product bottles that have not been 
returned.  
If the Investigator has concerns about a subject’s dosing compliance s/he should discuss this with 
the subject, assess the reasons for noncompliance and the likelihood that the subject will remain 
noncompliant, and notify the Sponsor accordingly.    
9.4. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Allocation to one of 
two treatment groups (OCA or placebo) will occur on a 1:1 ratio across sites and will be 
stratified by UDCA treatment (yes/no) and mean baseline bilirubin categories (>ULN/≤ULN), as 
specified by the central laboratory.  The randomization will be based on a predefined 
randomization code (generated by the Sponsor or designee) using an interactive web response 
system (IWRS), which the Sponsor intends will serve as a computer-based subject registration 
system at Screening and Day 0.  The IWRS will serve as an investigational product inventory 
and management system and may be integrated with the study database.  
The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide subject data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned (refer to Section 9.5.2, below) and 
investigational product dispensing information (ie, bottle number[s]) will be provided. 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects 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 subject).  If it 
is not reasonable to inform the Medical Monitor in advance of the unblinding, the Investigator 
must promptly document in the subject’s record the rationale for unblinding and should 
subsequently contact the Medical Monitor to explain any premature unblinding of treatment 
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assignment.  Procedures for unblinding a subject’s treatment will be provided separately to the 
Investigator.  Similarly, if the Medical Monitor breaks the blind for an individual subject for the 
purpose of evaluating an emergent safety issue, the Medical Monitor will document within trial 
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 subjects.  Refer to Section 13.3 for further details regarding DMC access to 
blinded and unblinded data.  The DMC will document details about any unblinded subject data 
reviews in the closed session DMC minutes, which will be made available to the Sponsor only 
after the database is locked and the trial 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 Subject 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 subject data and to identify the site and or Investigator 
within study documents.  This number will be recorded in the CRF. 
9.5.2. 
Subject Numbers 
Subjects 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 trial is prohibited.   
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9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visits should be based on Day 0 (not on the prior visit), eg, Month 3 should ideally occur 
3 calendar months (± 2 weeks) following Day 0.  The visit windows are as follows: 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening Visit 1 interval is 3 to 8 weeks prior to Day 0.  Screening 
Visit 2 interval is 1 to 6 weeks prior to Day 0.  The visit window for 
Screening 2 visits allows for the repeat biochemistry tests to be 
collected at least two weeks after the initial biochemistry sample 
was collected and will ensure ample time to receive lab results.  
The overall Screening interval is up to 56 days, but screening 
procedures should not be performed during the last 7 days of the 
window.  
Day 0 
This is the day of randomization.  On-treatment visit scheduling 
should be calculated from this point going forward. (The first dose 
of investigational product should be taken the next day, on Day 1.) 
Month 1  
+1 week (7 days)  
Titration Visit – Standard Dosing Regimen 
≥Month 3 
Titration Visit 1 – Modified Dosing 
Regimen 
≥Month 3 
Titration Visit 2 – Modified Dosing 
Regimen 
≥6 weeks after Titration Visit 1 
Titration Visit 3 – Modified Dosing 
Regimen (Child-Pugh B ONLY) 
≥6 weeks after Titration Visit 2 
Post-Titration Visit 
1 month (+1week [7 days]) from date of titration or after ≥3 months 
at a decreased dose or frequency   
Month 3 to Month 12 
±2 weeks (14 days)  
Quarterly visits (Months 15 to EOS) 
±2 weeks (14 days) 
EOT 
(When subject discontinues investigational 
product) 
As soon as possible upon study discontinuation and as near as 
possible to last dose taken 
EOS 
(When subject terminates the study) 
The final study visit; EOS will occur concurrent with EOT if a 
subject discontinues study medication at the time the subject’s 
participation in the study ends (eg, withdrawal of consent or study 
termination by the Sponsor); EOS will occur after the EOT if the 
subject discontinues study medication but continues in the study. 
EOS = end of study; EOT = end of treatment  
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk and benefit of the 
study to the subject and will provide him/her with a copy of the written information and 
informed consent form (ICF).  The subject will be given sufficient time to consider the study 
before deciding whether or not to participate.  The subject will be informed that participation is 
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voluntary and that her/his future medical treatment will not be compromised by participation in 
the study and that s/he can withdraw from the study at any time.  The subject must be willing and 
able to provide written informed consent before entering the study.  The Investigator or a 
medically qualified designee is responsible for administering and documenting the written 
informed consent of the subject.  The subject will be given a copy of the written information and 
his/her signed and dated consent form. 
Any change in a subject’s consent status (eg, semi-annual telephone contact or medical record 
review) must be documented in a signed informed consent form or addendum.  The subject will 
be given a signed and dated copy of the consent document. 
9.7.3. 
Assessing Cirrhosis 
To determine which dosing regimen subjects should follow, the presence or absence of 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 is defined as a subject 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  
 elevation in prothrombin time /INR (not due to antithrombotic agent use), or 
 elevated bilirubin (2× ULN) 
Subjects who exhibit no evidence of cirrhosis by the above methods of assessment will be dosed 
using the Standard Dosing Regimen, while those who do exhibit evidence of cirrhosis by one or 
more of the above methods will be dosed using the Modified Dosing Regimen according to their 
Child-Pugh Score calculated in the electronic case report form (eCRF) (see Appendix A, 
Section 7.3, Table 3 and Table 4). 
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. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is calculated and reported within the electronic data 
capture (EDC) system based on data entered into the eCRF adding the scores from the 5 factors 
outlined in Table 6  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 
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10 and above is Grade C (severe, decompensated disease).  Calculation of the Child-Pugh 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.  It is important to note 
that subjects must have confirmed cirrhosis as assessed by one or more of the above criteria 
(Section 9.7.3) prior to applying the calculated Child-Pugh score for dosing.  Investigators will 
be responsible for determining the appropriate dosing regimen based on both the cirrhosis status 
and the Child-Pugh score (Table 6).  Any change in cirrhosis status or Child-Pugh Score will 
necessitate re-evaluation of the dosing regimen. 
Table 6: 
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) 
9.7.5. 
Mayo Risk Score 
Mayo Risk Score (MRS) (Dickson 1989) is calculated and reported within the EDC system 
based on data entered into the eCRF.  Calculation of MRS includes investigator assessment of 
peripheral edema and the use of diuretic therapy, which will be assessed during adverse event 
and concomitant medicine review at the scheduled visits and entered into the eCRF, as well as 
total bilirubin, albumin, and prothrombin time results obtained from the central laboratory data. 
9.7.6. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 week to 8 weeks prior to Day 0 to 
determine whether the subject meets all the inclusion criteria and none of the exclusion criteria.  
Screening Visit 1 will occur 3 weeks to 8 weeks prior to Day 0; Screening Visit 2 will occur 
1 week to 6 weeks prior to Day 0, depending on the date that the first serum chemistry sample 
was collected. Subjects who do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects may be rescreened after 2 months have elapsed from the date of their most recent 
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screening visit procedure; however, all Screening procedures (including obtaining informed 
consent) should be repeated and a new three-digit Screening number assigned.   
Two Screening visits will occur from 1 to 8 weeks prior to Day 0 (as outlined below) allowing 
for the collection of repeated serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values: 
 All subjects will have 2 bilirubin and ALP assessments at least 2 weeks apart. 
 The mean of all available (at least 2; including both scheduled and 
unscheduled) bilirubin and ALP assessments will be used to determine eligibility 
(total bilirubin >ULN and ≤3× ULN and/or an ALP >5× ULN).   
Screening Visit 1 procedures are as follows: 
 The subject is to review and sign the ICF.  Informed consent must be obtained from 
the subject 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  
 Assess for the presence/absence of cirrhosis. 
 Verify inclusion and exclusion criteria for eligibility. 
 Perform a physical examination.  
 Perform assessments for calculation of Child-Pugh Score 
 Perform assessment for calculation of Mayo Risk Score. 
 Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Perform a standard 12-lead electrocardiogram (ECG). 
 Assess and record any pretreatment-emergent AEs. 
 Record prior (if within 30 days of Screening) and current concomitant medications. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 Obtain urine sample for urinalysis. 
 Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
 The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
Screening Visit 2 procedures are as follows: 
 Verify inclusion and exclusion criteria for eligibility. 
 Perform an ultrasound for hepatocellular carcinoma (HCC) surveillance (if equipment 
is unavailable, sites should make every attempt to use available community referral 
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sites).  If an ultrasound has been done within 12 months of Screening Visit 2, and a 
report/adequate data are available, a pretreatment ultrasound at Screening Visit 2 is 
not required.  If the ultrasound cannot be performed at Screening Visit 2 (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. 
 Assess and record any pretreatment-emergent AEs. 
 Record current concomitant medications. 
 Verify that the subject has fasted for at least 8 hours. 
 Record fasting status in the source and CRF. 
 If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
 Obtain blood samples for serum chemistry tests. 
 The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
 In preparation for the dual-emission X-ray absorptiometry (DEXA) bone density scan 
to be done at Day 0 (selected study sites only), subjects who are taking calcium 
supplements should stop taking them for 48 hours before the scan.  If the subject is 
taking any medications for osteoporosis or osteopenia, s/he should not take them on 
the day of the scan. 
It is acceptable to repeat laboratory evaluations or other assessments or procedures within the 
Screening period (Weeks -8 to -1), as appropriate. 
9.7.7. 
Day 0 Procedures (Randomization) 
 Review inclusion and exclusion criteria for eligibility. 
 Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
 Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
 Perform transient elastography (TE; at selected study sites, where available) using the 
Fibroscan® TE device.  If TE has been done within 6 months of Day 0 and a 
report/adequate data are available, a pretreatment TE at Day 0 is not required.  If the 
TE cannot be performed on Day 0 (eg, device/technician unavailability, scheduling 
issues, TE data is needed to inform cirrhosis assessment, etc), the procedure may be 
completed within the screening visit window, at Screening Visit 1 (if data is needed 
for cirrhosis assessment) or as close as possible to the Day 0 visit, preferably, after 
subject eligibility has been confirmed. 
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 Conduct a DEXA bone density scan (at selected study sites, where available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable.  If DEXA has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment DEXA at Day 0 is not required. If 
the DEXA cannot be performed on Day 0 (eg, device/technician unavailability, 
scheduling issues, etc), the procedure may be completed within the screening visit 
window, as close as possible to the Day 0 visit, preferably, after subject eligibility has 
been confirmed. 
 Perform an esophagogastroduodenoscopy (endoscopy; at selected study sites, where 
available) to assess the presence or absence of oesophageal varix/varices.  If an 
endoscopy has been done within 12 months of Day 0 and a report/adequate data are 
available, a pretreatment endoscopy at Day 0 is not required. If the endoscopy cannot 
be performed on Day 0 (eg, device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening visit window, as close as 
possible to the Day 0 visit, preferably, after subject eligibility has been confirmed. 
 Subsequent endoscopies should be performed annually or per standard of care and 
the Investigator’s clinical judgment throughout the course of the study.  
Endoscopies should also be performed when platelet counts are <150 × 109 /L. 
 Assess and record any pretreatment-emergent AEs. 
 Review and record prior concomitant medications. 
 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 subject only if s/he meets all inclusion criteria and no exclusion 
criteria. 
 Verify that the subject has fasted for at least 8 hours. 
 Record fasting status in the source and CRF 
 If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
 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 tests. 
 Obtain blood samples for:  
 OCA, C4, and fibroblast growth factor-19 (FGF-19) 
 Markers of hepatic fibrosis and/or inflammation (including enhance liver fibrosis 
[ELF]) 
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 Genetics (see Section 11.1.2.3) 
 Blood sample for future analysis (refer to Section 11.1.2.3)  
 Access the IWRS and dispense investigational product 
 Instruct the subject to begin dosing on the day after the Day 0 visit (ie, on Day 1).  
Instruct the subject to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
 Provide the subject with a dosing diary to document his or her dosing. 
 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
 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. 
Month 1 Procedures: 
 Assess and record AEs 
 Review and record concomitant medications. 
 Assess investigational product compliance, perform investigational product 
accountability, and review dosing diary with the subject. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 Provide the subject with a dosing diary to document his or her dosing. 
 In the event it is not feasible for the subject to return to the site for the above 
referenced procedures, the following alternative visit procedures are available to help 
ensure compliance with the Month 1 visit requirements: 
 At the Day 0 visit, the subject can be provided with the central laboratory 
collection kit and shipping materials associated with the Month 1 visit, and have 
the laboratory specimen collection performed at his or her local doctor’s office or 
designated laboratory collection center.  The subject must also be contacted via 
telephone at the Month 1 visit time point to assess AEs, review concomitant 
medications, and assess investigational product compliance. 
 If all other options for the collection of the Month 1 laboratory samples have been 
exhausted, the use of a local laboratory for the Month 1 samples would be 
accepted for this visit although any laboratory data obtained from a local 
laboratory will not be captured in the eCRF or included in the study analysis.  A 
copy of the local laboratory report would need to be provided to the investigator 
for review and available in the source records.  The subject must also be contacted 
via telephone at the Month 1 visit time point to assess AEs, review concomitant 
medications, and assess investigational product compliance. 
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 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
 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. 
Month 3 Procedures 
 Perform assessments for calculation of Child-Pugh Score. 
 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. 
 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, and review dosing diary with the subject. 
 Assess for dose titration, if eligible (refer to Section 7.4). 
 Verify that the subject has fasted for at least 8 hours. 
 Record fasting status in the source and CRF 
 If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests.  
 Obtain blood samples for: 
 OCA, C4, and FGF-19 
 Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
 Provide the subject with a dosing diary to document his or her dosing. 
 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
 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 
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 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. 
Post-Titration Visit Procedures: 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Assess investigational product compliance, perform investigational product 
accountability, and review dosing diary with the subject. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 Provide the subject with a dosing diary to document his or her dosing. 
 In the event it is not feasible for the subject to return the site for the above referenced 
procedures, the following alternative visit procedures are available, to help ensure 
compliance with the Post-Titration visit requirements: 
- At the Up-titration Visit, the subject can be provided with the central laboratory 
collection kit and shipping materials associated with the Post-Titration visit, and 
have the laboratory specimen collection performed at his or her local doctor’s 
office or designated laboratory collection center.  The subject must also be 
contacted via telephone at the Post-Titration Visit time point to assess AEs, 
review concomitant medications, and assess investigational product compliance. 
- If all other options for the collection of the Post-Titration laboratory samples have 
been exhausted, the use of a local laboratory for the Post-Titration samples would 
be accepted for this visit although any laboratory data obtained from a local 
laboratory will not be captured in the eCRF or included in the study analysis.  A 
copy of the local laboratory report would need to be provided to the investigator 
for review and available in the source records.  The subject must also be contacted 
via telephone at the Post-Titration Visit time point to assess AEs, review 
concomitant medications, and assess investigational product compliance. 
 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
- 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. 
Month 6 Procedures  
 Perform assessment for calculation of Mayo Risk Score. 
 Perform assessments for calculation of Child-Pugh Score. 
 Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
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 Subject questionnaires (see Section 12.2.6) 
 Assess and record AEs. 
 Review and record concomitant medications. 
 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, and review dosing diary with the subject. 
 Assess for dose titration, if eligible (refer to Section 7.4). 
 Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
 Verify that the subject has fasted for at least 8 hours. 
 Record fasting status in the source and CRF. 
 If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 Obtain blood samples for:  
 OCA, C4, and FGF-19 
 Markers of hepatic fibrosis and/or inflammation (including ELF) 
 Blood sample for future analysis (refer to Section 11.1.2.3)  
 Provide the subject with a dosing diary to document his or her dosing. 
 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
 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. 
 For subjects who will participate in the PK assessment and are taking BAS or 
aluminum hydroxide- or smectite-containing antacids, they should be instructed to 
not take their regular dose on the morning of the study visit.   
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9.7.12. 
Month 9 Procedures 
 Perform assessments for calculation of Child-Pugh Score. 
 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. 
 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, and review dosing diary with the subject. 
 Assess for dose titration, if eligible (refer to Section 7.4). 
 Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
 Verify that the subject has fasted for at least 8 hours. 
 Record fasting status in the source and CRF. 
 If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 PK assessment in participating subjects at select study sites (see Section 9.7.13). 
 In preparation for the DEXA bone density scan to be done at the Month 12 visit 
(selected study sites only), subjects who are taking calcium supplements should stop 
taking them for 48 hours before the scan.  If the subject is taking any medications for 
osteoporosis or osteopenia, s/he should not take them on the day of the scan. 
 Provide the subject with a dosing diary to document his or her dosing. 
 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
 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. 
9.7.13. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic Assessment 
At selected investigational sites, subjects will have the option to consent to participate in an 
additional OCA PK assessment.  PK samples will be used to support further analysis of OCA 
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exposure-response in subjects with PBC.  This is optional and subjects may decline to participate 
without affecting their involvement in the rest of the study.  Consent to participate in the 
assessment can be given at any point during study participation prior to the Month 9 visit.  
Subjects who are following the Child-Pugh B and Child-Pugh C modified dosing regimen may 
participate in the PK assessment and will dose in the clinic at this visit even if the previous dose 
was taken less than 3 days prior; however, every attempt should be made to schedule the 
Month 9 PK visit according to the subject’s established dosing schedule. 
Following collection of the Month 9 fasted samples (refer to Section 9.7.12, subjects who are 
participating in the PK assessment will each receive a single dose of investigational product 
(blinded OCA or placebo tablet) with approximately 240 mL of water.  Subjects taking BAS or 
aluminum hydroxide- or smectite-containing antacids should be instructed to stagger their dosing 
of study medication and UDCA, ensuring at least 4 hours between doses of the BAS and/or these 
antacids and the study medication (and UDCA).   
Serial blood samples will be obtained for measurement of OCA and its conjugates prior to 
dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours post dose.  Samples should be collected 
within a window of ±5 minutes of the scheduled sample time.  Subjects should not drink 
additional water for 1 hour after taking the dose of investigational product and will remain fasted 
until the 4-hour sample is collected.  Lunch will be provided following collection of the 4 hour 
PK sample; the lunch will be a meal replacement drink with no other food allowed until after the 
final 6-hour post-dose sample is collected.  Samples will be stored for up to 5 years after the end 
of the study and will be destroyed after 5 years if not analyzed. 
9.7.14. 
Month 12 Procedures 
 Perform a physical examination (including smoking and alcohol consumption habits). 
 Perform assessment for calculation of Mayo Risk Score. 
 Perform assessments for calculation of Child-Pugh Score. 
 Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Perform a standard 12-lead electrocardiogram (ECG). 
 Quality of Life and Subject questionnaires and (see Section 11.1.2.2 
and Section 12.2.6). 
 Perform TE (at selected study sites, where available) using the Fibroscan® TE device. 
 Conduct a DEXA bone density scan (at selected study sites, where available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable. 
 Perform an endoscopy (at selected study sites, where available) to assess the presence 
or absence of oesophageal varix/varices. 
 Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
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 Assess and record AEs. 
 Review and record concomitant medications. 
 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, and review dosing diary with the subject. 
 Assess for dose titration, if eligible (refer to Section 7.4). 
 Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
 Verify that the subject has fasted for at least 8 hours. 
 Record fasting status in the source and CRF. 
 If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
 Obtain urine sample for urinalysis. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 Obtain blood samples for: 
 OCA, C4, and FGF-19 
 Markers of hepatic fibrosis and/or inflammation (including ELF) 
 Genetics (see Section 11.1.2.3) 
 Blood sample for future analysis (refer to Section 11.1.2.3)  
 Provide the subject with a dosing diary to document his or her dosing. 
 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
 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. 
9.7.15. 
Month 3 and Month 9 Continued Follow-Up Procedures (±2 weeks) 
 Perform assessments for calculation of Child-Pugh Score. 
 Assess and record AEs. 
 Review and record concomitant medications. 
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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, and review dosing diary with the subject. 
 Assess for dose titration, if eligible (refer to Section 7.4). 
 Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
 Verify that the subject has fasted for at least 8 hours. 
 Record fasting status in the source and CRF. 
 If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 Provide the subject with a dosing diary to document his or her dosing. 
 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
 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. 
9.7.16. 
Month 6 Continued Follow-Up Procedures (Semi-annually [±2 weeks]) 
 Perform assessment for calculation of Mayo Risk Score. 
 Perform assessments for calculation of Child-Pugh Score. 
 Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate 
and sitting blood pressure). 
 Subject questionnaires (see Section 12.2.6) 
 Assess and record AEs. 
 Review and record concomitant medications. 
 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 (refer to Section 7.4). 
 Assess investigational product compliance, perform accountability, and review dosing 
diary with the subject. 
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 Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
 Verify that the subject has fasted for at least 8 hours. 
 Record fasting status in the source and CRF. 
 If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 Obtain blood samples for:  
 Markers of hepatic fibrosis and/or inflammation (including ELF). 
 Blood sample for future analysis (refer to Section 11.1.2.3). 
 At the semi-annual visit, in preparation for the DEXA bone density scan to be done at 
the annual visit (selected study sites only), subjects who are taking calcium 
supplements should stop taking them for 48 hours before the scan.  If the subject is 
taking any medications for osteoporosis or osteopenia, s/he should not take them on 
the day of the scan. 
 Provide the subject with a dosing diary to document his or her dosing. 
 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
 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 
9.7.17. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
 Perform a physical examination (including smoking and alcohol consumption habits). 
 Perform assessment for calculation of Mayo Risk Score. 
 Perform assessments for calculation of Child-Pugh Score. 
 Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Perform a standard 12-lead electrocardiogram (ECG). 
 Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
 Perform TE (at selected study sites, where available) using the Fibroscan® TE device. 
 Conduct a DEXA bone density scan (selected study sites); document whether the 
subject stopped taking her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the scan, if applicable. 
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 Perform an endoscopy (at selected study sites, where available) to assess the presence 
or absence of oesophageal varix/varices. 
 Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
 Assess and record AEs. 
 Review and record concomitant medications. 
 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 (refer to Section 7.4). 
 Assess investigational product compliance, perform accountability, and review dosing 
diary with the subject. 
 Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product. 
 Verify that the subject has fasted for at least 8 hours. 
 Record fasting status in the source and CRF. 
 If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
 Obtain urine sample for urinalysis. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 Obtain blood samples for:  
 OCA, C4, and FGF-19 
 Markers of hepatic fibrosis and/or inflammation (including ELF) 
 Genetics (see Section 11.1.2.3) 
 Blood sample for future analysis (refer to Section 11.1.2.3)  
 Provide the subject with a dosing diary to document his or her dosing. 
 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
 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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9.7.18. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent 
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects discontinue treatment with investigational 
product.  The EOT visit and procedures listed below must be performed as close as possible to 
the subject’s last dose of investigational product.  When a subject discontinues investigational 
product but continues with regularly scheduled study visits, the EOS visit will be completed later 
in the study as the subject’s final study visit.  The actual investigational product discontinuation 
scenario (Table 7) will determine the sequence of the EOT and EOS visits and procedures.  In 
some cases, the EOT visit and procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible to the subject’s last dose of 
investigational product.   
When a subject ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (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 subject 
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 and EOS procedures in the CRF.  
 
 
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Table 7: 
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 IP 
Treatment 
Discontinuationb 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
Discontinued 
Semiannual 
contactc 
Telephone 
contact every 6 
months (±2 
weeks) 
Combined Visit, Completed as 
close as possible to last dose IP 
Discontinued 
Record review 
onlyc 
Record review 
only 
Combined visit 
Completed as close as possible 
to last dose IP 
Sponsor 
Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit 
Completed as close as possible 
to last dose IP 
Pregnancy 
Interrupted 
Retained 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
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; IP = investigational product 
a Refer to Section 7.1.2 Schedule of Study Procedures, Table 2 for all procedures and evaluations required at the 
End of Treatment and End of Study Visits.  
b   Includes initiation of commercially available OCA. 
c Outcomes data to be discussed or collected include data related to adjudicated hepatic and cardiovascular event-
related data.  No additional data (e.g. AE, concomitant medication, etc) data will be collected, except as indicated 
in Section 12.1.7. 
Some assessments noted below may be omitted if they have been completed within the 6 months 
(or the timeframe otherwise specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT/EOS Visit: 
If possible to do before the visit, when scheduling the EOT/EOS visit, reiterate dosing 
instructions and advise the subject: 
 If applicable, NOT to take investigational product on the morning of the next visit, 
and  
 To bring the investigational product bottle(s); if applicable, s/he will dose at the 
clinic, and 
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 To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior to 
all study visits, but water is permitted. 
During the EOT/EOS Visit: 
 Perform a physical examination (including smoking and alcohol consumption habits). 
 Perform assessment for calculation of Mayo Risk Score. 
 Perform assessments for calculation of Child-Pugh Score. 
 Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
 Perform a standard 12-lead ECG. 
 Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
 Perform TE (where available) using the Fibroscan® TE device (not required at 
EOT/EOS if done within 6 months). 
 Conduct a DEXA bone density scan (selected study sites; not required at EOT/EOS if 
done within 6 months); document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable. 
 Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites); not required at 
EOT/EOS if done within 6 months. 
 Assess and record AEs; all ongoing “related” AEs must be followed until stable or 
resolved. 
 Review and record concomitant medications. 
 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 accountability, and review dosing 
diary with the subject; retrieve used bottles, accordingly, and document returns. 
 Verify that the subject has fasted for at least 8 hours. 
 Record fasting status in the source and CRF. 
 If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
 Obtain urine sample for urinalysis. 
 Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
 Obtain blood samples for:  
 OCA, C4, and FGF-19 
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 Markers of hepatic fibrosis and/or inflammation (including ELF) 
 Blood sample for future analysis (refer to Section 11.1.2.3)  
9.7.19. 
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.   
In the event of an inexplicable and acute (for example not explained by natural progression of the 
chronic disease) increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
or total bilirubin is observed during the course of the study, refer to Section 8.4.2.1 to confirm 
whether an unscheduled safety visit is required. 
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 5 mg or 10 mg OCA 
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 subject at each visit to provide enough tablets for daily 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 
The 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 Preparation 
The investigational product will be provided to the distribution center in bulk bottles and 
therefore may be repackaged in unit dose form for administration to subjects before shipping to 
the sites. 
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10.5. 
Investigational Product Administration 
Refer to Section 9.1. 
10.6. 
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 subject 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. 
11. 
ASSESSMENT OF EFFICACY 
11.1. 
Assessment of Efficacy  
11.1.1. 
Primary Assessments 
The following primary efficacy assessments will be measured: 
 Death (all-cause) 
 Liver transplant 
 Model of end stage liver disease (MELD) score ≥15 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
 Variceal bleed 
 Encephalopathy (as defined by a West Haven score of 2 or greater) 
 Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
 Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities. 
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11.1.2. 
Secondary Assessments 
The following secondary efficacy assessments will be measured: 
 Liver-related death 
 Liver biochemistry (see Table 10 for list of analytes to be tested) 
 Biomarkers, including markers of hepatic fibrosis and/or inflammation, to be tested 
will include:  IgM, c-reactive protein (CRP), tumor necrosis factor-α (TNF-α), 
FGF-19, cytokeratin-18 (CK-18) and ELF, Fibroscan (and others as determined 
during the course of the study). 
 Data will be collected to inform quality of life and cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Quality of life will be 
assessed by questionnaires (PBC-40, EQ-5D-5L, and FIS) administered annually.  
Resource utilization information will be collected from the Medical and Surgical 
Treatment Procedures and Office Visit Log or other CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician visits (subject reported), 
and use of concomitant medications.  
 Endoscopy will be conducted at selected study sites where the device is available to 
assess for the presence of oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual study assessments or standard 
of care will be collected in the case report form to assess for the development of 
varix/varices. 
11.1.2.1. Non-Invasive Assessments of Liver Fibrosis 
 Blood samples for measurement of ELF™ test and other analytes will be collected.  
The ELF test assesses: hyaluronic acid (HA), procollagen-3 N-terminal peptide 
(P3NP), and a tissue inhibitor of metalloproteinase 1 (TIMP-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.   
11.1.2.2. Other Secondary Assessments 
 OCA (OCA, tauro-OCA, glyco-OCA, total OCA, OCA glucuronide) and C4 will be 
assayed to determine bioanalytical concentrations.  Additional analyses may include 
other conjugates or metabolites not yet identified.   
 Quality of Life questionnaires. 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 (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 respondent’s self-rate 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). 
 Fatigue Impact Scale (FIS):  The FIS is a validated 40 question questionnaire 
organized into 3 dimensions:  cognitive, physical, and social.  Each dimension has 
5 levels:  no problem, small problem, moderate problem, big problem, and 
extreme problem (Fisk 1994). 
11.1.2.3. Other Exploratory Evaluations 
 A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved 
in PBC will be conducted for subjects and at study sites willing to provide samples at 
Day 0, Month 12, and every other year at the yearly visits thereafter.  RNA 
expression resulting from treatment with OCA will be assessed at indicated 
timepoints during the study.   Subjects will be permitted to decline to provide a blood 
sample for the genetics study, without affecting their involvement in the study.  
IRB/IEC review and approval will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will be stored for up to 1 year 
after the end of the study and destroyed after 1 year if not analyzed. 
 Blood samples for future analysis of additional analytes, such as PBC autoantibodies 
and other cytokines and interleukins, may be assayed on an exploratory research 
basis.  Blood samples may also be used to assess other disease or investigational 
product characteristics.  Appropriate serum and plasma samples will be collected at 
selected time points during the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their involvement in the study.  IRB/IEC 
review and approval will be required and willing subjects must specifically consent to 
participate in this evaluation.  The samples will be stored for up to 1 year after the end 
of the study and destroyed after 1 year if not analyzed. 
11.1.2.4. Potential Clinical Outcome Events 
The events listed in Appendix A  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 13.4) 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 
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 13.4. 
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12. 
ASSESSMENT OF SAFETY 
12.1. 
Adverse Events and Serious Adverse Events 
12.1.1. 
Definition of Adverse Events  
12.1.1.1. Adverse Event  
An AE is 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) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction. 
Subjects should be questioned in a general way, without leading the subject 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. 
12.1.1.2. 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-subject 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 subject 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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12.1.1.3. Treatment-Emergent Adverse Event  
A treatment-emergent AE (TEAE) is any event not present prior to the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
12.1.2. 
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/serious adverse event (SAE) and the investigational product is 
determined to be “possible” or “probable” 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 subject’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 
A reaction 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 subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
12.1.3. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 9, must be entered on the AE CRF.  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 
Causing no limitation of usual activities; the subject may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the subject may experience annoying 
discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the subject may experience intolerable 
discomfort or pain. 
12.1.4. 
Reporting of Adverse Events and Serious Adverse Events 
12.1.4.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
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 subject’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE CRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product. 
12.1.4.2. 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 be reported by: 
 E-mail to the SAE email address:  sae@interceptpharma.com 
 Fax using a paper SAE report form:  +1 800 497 8521 
 Telephone:  +1 858 964 1571  
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:   
 Subject 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 
investigational new drug (IND) 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 +1 800 497 8521 or 
emailed to sae@interceptpharma.com as soon as possible.   
The Investigator is responsible for submitting information on IND 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 IECs/IRBs must be retained in 
the appropriate study file(s).  As instructed by the Sponsor, IND 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 12.1.5.  
12.1.5. 
Suspected Liver-Related Clinical Outcome Events 
Specified liver-related clinical outcome events may, by definition (see Section 12.1.1.2) qualify 
as SAEs.  The Sponsor must be notified of any SAEs within 24 hours of the site becoming aware 
of the event (see Section 12.1.4.2).  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. 
For liver-related clinical outcome events could also meet the criteria of a SUSAR, which would 
necessitate unblinding for expedited reporting, please refer to Section 11.1.2.4. 
The Sponsor will consider the following list of clinical outcome events (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), hepatic encephalopathy (preferred term: hepatic encephalopathy),  and 
spontaneous bacterial peritonitis (preferred term: peritonitis bacterial). 
12.1.6. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the CRF 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 subject’s AE CRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the medical monitor, the Investigator 
should provide input into the SAE narrative and provide timely information to ensure prompt 
follow up and closure of the SAE report. 
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The Investigator and supporting personnel responsible for subject 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. 
12.1.7. 
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 SAE must be reported to the Sponsor 
immediately (ie, within 24 hours). 
All SAEs that occur within 30 days following the cessation of investigational product, 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 12.1.4.2. 
SAEs that occur more than 30 days after a subject has discontinued study medication, and are not 
considered related to investigational product, must still be reported in the EDC system; however, 
these events are not required to be reported within 24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to investigational product, action taken with study 
medication, treatment, outcome, and potential endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event summary, SAE details) may also be required to be 
entered, when requested by the sponsor. 
12.1.8. 
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 subject 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 subject 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 CRF.  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. 
12.1.9. 
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 investigational 
product and the Sponsor must be notified within 24 hours of the Investigator’s learning of the 
pregnancy by completing the Pregnancy Notification Form and faxing or emailing to the Sponsor 
at +1 800 497 8521 or sae@interceptpharma.com.  
Safety will be monitored and assessed by AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and clinical laboratory assessments. The Sponsor may 
also follow the health of an infant born subsequent to use of investigational product. 
The subject may reinstate investigational product after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  Subjects whose pregnancy is terminated early 
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(planned or unplanned) may be permitted to resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test (see Section 8.4.1). 
12.2. 
Other Safety Parameters 
12.2.1. 
Medical History/Demographics 
A complete medical history and PBC disease-specific history will be obtained from the subject at 
Screening.  Smoking and alcohol consumption history and current habits will be recorded.  
Demographic characteristics (age, gender, race, and ethnicity) will be recorded. 
12.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the timepoints specified in the Schedule of Study Procedures (Section 7.1.2).  A basic physical 
examination should be performed, including all body systems pertinent to the subject.  Any 
clinically significant abnormality should be reported on the AE CRF page for findings that 
appear after consent, and on the medical history CRF for any finding present prior to consent.  
Information about smoking and alcohol consumption habits will be collected at the same 
(follow-up) timepoints as the physical exam. 
12.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits: height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure.  When taking heart rate, respiratory rate, and blood 
pressure readings, subjects should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
12.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected at the Screening Visit 1, Month 12, and at EOT/EOS.  
The Investigator or designee will review the 12-lead ECG and findings will be recorded in the 
CRF as normal, abnormal but not clinically significant, or abnormal and clinically significant.  
Any clinically significant abnormality on ECGs should be reported on the AE CRF page.  
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 subject’s initials, Subject ID number, 
date, and time. 
12.2.5. 
Dual Emission X-Ray Absorptiometry 
A bone density assessment will be done using the DEXA scan. 
12.2.6. 
Subject Questionnaires 
Information about the subject’s PBC disease history (ie, date of diagnosis, treatment history, 
pruritus history, signs and symptoms, and including smoking history) will be collected during 
Screening.  At subsequent study visits (see Section 7.1.2), subjects will be asked to complete the 
following questionnaires; they may be asked to initial and date to document confirmation of their 
responses, and the questionnaires should be filed in the subject’s study records.  These may 
require transcription to the CRF by study site staff. 
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 5-D Pruritus Questionnaire:  This is a questionnaire that has been validated in several 
different diseases.  It assesses symptoms in terms of 5 domains: degree, duration, 
direction, disability and distribution (Elman 2010). 
 Pruritus VAS:  A Visual Analogue Scale (VAS) will also be used to assess pruritus in 
individual subjects. 
12.2.7. 
Laboratory Assessments 
Subjects will be instructed to attend each of their study visits (except Screening) in a fasted state, 
and subjects should remain fasted until their blood samples have been collected.  At each visit, 
the Investigator or designee will verify that the subject has fasted for at least 8 hours and record 
fasting status in the source and CRF.  If the subject reports having eaten (water is permitted) 
within 8 hours, the Investigator or designee will document accordingly in the source and CRF 
and remind the subject that fasting is required prior to all study visits. 
Blood samples for serum chemistry and hematology will be collected at every visit as detailed in 
the Schedule of Study Procedures (Section 7.1.2).  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 by the central clinical laboratory in a study specific laboratory 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 subjects 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 10. 
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Table 10: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry  
Albumin, blood urea nitrogen (BUN), 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 very low density 
lipoprotein [VLDL] fractions and triglycerides[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 
Prothrombin time (PT), partial thromboplastin time 
(PTT), international normalized ratio (INR) 
Urinalysis 
pH, specific gravity, total protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, 
albumin, creatine, leucocytes, nitrates, 
albumin/creatine ratio (if positive) 
Biomarkers of Hepatic Fibrosis and/or Inflammation  
IgM, C-reactive protein (CRP), TNF-α, FGF-19, CK-
18, ELF, and others as determined during course of 
study  
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Genetics 
DNA including single-nucleotide polymorphisms 
(SNPs) that may be involved in PBC; RNA 
Blood Sample for Future Analysis 
PBC autoantibodies and other cytokines and 
interleukins TBD 
Other 
OCA (parent and conjugates [glyco and tauro]) and C4 
The Investigator should manage subjects with clinically significant lipoprotein abnormalities 
using local standard of care procedures as appropriate after assessing the individual subject’s 
total cardiovascular risk profile. 
Urine-based β-hCG pregnancy tests will be performed in female subjects of childbearing 
potential per protocol specified visits.  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 
subject will be followed, as outlined in Section 12.1.9 through pregnancy outcome. 
MELD scores, Child-Pugh score, and MRS will be calculated at screening, and at quarterly 
(MELD and Child-Pugh scores) or semi-annual (MRS) visits based on serum chemistry and 
coagulation. 
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13. 
STATISTICAL METHODS 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
hypothesis tests, will be prepared and approved by the Sponsor and its designees prior to study 
database lock, propensity score determination, and unblinding of the double-blind subject 
treatment assignments.  
13.1. 
Efficacy Analysis 
13.1.1. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
 The Randomized Population will include all randomized subjects. 
 The Intent-to-Treat (ITT) Population will include all randomized subjects who 
receive any amount of investigational product (OCA or placebo).  The ITT 
Population will be the primary population used for efficacy analyses.  Treatment 
assignment will be based on the randomized treatment. 
 The Safety Population will include all subjects who received any amount of 
investigational product (placebo or OCA).  The Safety Population will be the primary 
population used for safety analyses.  Treatment assignment will be based on the 
treatment actually received. 
 The PK population will include all OCA subjects who have at least one confirmed 
fasted analyzable sample.  Subjects must have been fasting for approximately 8 hours 
prior to the visit and must not have any major protocol deviations that potentially 
affect exposure levels.  The PK population will be used for OCA PK analyses.  
 The Overall Historical Control Population will include subjects from the United 
Kingdom (UK) -PBC Group and Global PBC Study Group databases with 
demonstrated comparability to randomized subjects in this clinical study (747-302) 
with respect to both subject characteristics and disease progression. 
 The UK-PBC Historical Control Population will include subjects from the UK-PBC 
Group databases with demonstrated comparability to randomized subjects in this 
clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
 The Global PBC Historical Control Population will include subjects from the Global 
PBC Study Group database with demonstrated comparability to randomized subjects 
in this clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
13.1.1.1. Comparability of Historical Controls 
Utilization of both historical control/observational databases (UK-PBC and Global PBC Study 
Group), with more than 6000 subjects each, allow for a rigorous subject level meta-analysis.  The 
historical databases include long-term follow up, detailed subject-level information such as 
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baseline clinical characteristics, longitudinal liver biochemistry, and long-term outcomes, and 
span a broad range of subject characteristics that may influence disease (disease state, age, 
gender, and regional differences in standard of care).  Historical controls from both databases 
will be chosen based on the same study inclusion/exclusion criteria where possible. 
13.1.2. 
Determination of Sample Size 
The following assumptions were used in sample size calculations:  
 Exponential survival curves, placebo survival estimate of 0.5 at 8 years with a hazard 
ratio of 0.60, and total study duration of 8 years, allowing for 2 years accrual and 
6 years of follow up. 
 Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
 The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance. 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
13.1.2.1. Sample Size Re-Estimation Plan 
Conducting a long-term outcomes study given the low disease prevalence, relatively slow 
disease progression, and ethical considerations, which in combination will impact recruitment 
and event rates, is inherently difficult.  As stated in ICH E9, in long-term trials there is an 
opportunity to check the assumptions that underlay the original design and sample size 
calculations.  The power stated above depends on the total number of events.  Thus, the overall 
survival function can be estimated without unblinding. 
Therefore, starting approximately 2 years after the first subject is randomized, the aggregate 
event rate and sample size based on recruitment and retention will be evaluated in a blinded 
manner quarterly.  This evaluation will determine if any increases in number of subjects are 
required in order to obtain a total of 121 adjudicated events for the final analysis in the combined 
groups.  Specifically, the pooled number of events will be available during the study in a blinded 
manner, without any knowledge of the comparative efficacy in the treatment groups.  This 
method for evaluating the sample size does not inflate the type I error rate.  Additional subjects 
may be enrolled as appropriate. 
If after 4 years of accruing subjects, despite increases in the number of subjects, it is determined 
that at least an additional 2 years (ie, total study duration of at least 10 years) are needed to 
randomize sufficient subjects to achieve a total of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label OCA.  Previously randomized subjects will 
continue to be treated in a blinded manner with either OCA or matching placebo.  If this 
modification is implemented, the alternative primary efficacy analysis is specified is 
Section 13.1.9. 
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Any revised sample size or changes to treatment allocation will be justified and documented in a 
protocol amendment and in the CSR. 
13.1.3. 
Primary Efficacy Analysis 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
 Death (all-cause) 
 Liver transplant 
 MELD score ≥15 
 Hospitalization (as defined by a stay of 24 hours or greater) for new onset or 
recurrence of: 
 Variceal bleed 
 Encephalopathy (as defined by a West Haven score of ≥2) 
 Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
 Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
 Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities. 
The primary efficacy analysis will compare randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the ITT population.  Only adjudicated events will 
be included in analyses.  The 2 treatment groups will be compared 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 determined based on a 
Cox regression model stratified by randomization strata to estimate the magnitude of the effect. 
13.1.4. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints will compare OCA to placebo on the following: 
 Time to first occurrence of MELD score ≥15 
 Time to liver transplant or death (all-cause) 
 Change from Baseline in total bilirubin at end of study 
 Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare randomized OCA to randomized placebo in 
ITT population with respect to the key secondary efficacy endpoints.  Only adjudicated events 
will be included in time-to-event analyses.  The comparison (hypothesis testing) will be 
conducted as specified in Section 13.1.11 in a sequential closed testing gate-keeping procedure, 
provided that the primary efficacy endpoint comparison is statistically significant in favor of the 
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OCA treatment group.  If the primary comparison is not statistically significant then comparison 
of the secondary endpoints will be considered as descriptive and exploratory.  This procedure 
controls the study-wise type I error. 
The 2 treatment groups will be compared using the same methodology as specified for the 
primary efficacy analysis (Section 13.1.3). 
Analyses of change from Baseline to end of study in ALP and total bilirubin will be compared 
between treatment groups using analysis of covariance (ANCOVA) with change from Baseline 
as the dependent variable including treatment group and randomization stratification factor as 
fixed effects and the Baseline values as a covariate.  The same analysis will be carried out using 
percentage change from Baseline as the dependent variable. 
Descriptive statistics of the laboratory values will be summarized by treatment group.  The 
results, change from Baseline, and percentage change from Baseline values as well as estimates 
of least-square means, standard errors, and 95% CIs will be presented by treatment group.  
Estimates of the mean difference between treatment groups, the standard error of the difference, 
and 95% CI of the difference will be presented. 
13.1.5. 
Additional Secondary Efficacy Analyses 
The following time to event secondary efficacy analyses will compare randomized OCA versus 
randomized placebo using the ITT population: 
 Time to each component of the primary efficacy endpoint (except MELD score ≥15 
which is captured above) 
 Time to development of varix/varices 
 Time to liver-related death 
 Time to liver-related death or liver transplant 
 Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls as described below in Section 13.1.8. 
Analyses of changes in liver biochemistry (GGT, ALT, AST, conjugated bilirubin, albumin, and 
INR) will be summarized and analyzed using the same methodology as specified in 
Section 13.1.4 for the key secondary analyses of change in ALP and total bilirubin. 
Analyses of changes in MELD score, Child-Pugh score, Mayo Risk Score (MRS), IgM, CRP, 
TNF-α, FGF-19, CK-18, C4, and ELF score will be summarized and analyzed using the 
Wilcoxon Rank Sum Test to compare treatment groups.  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. 
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13.1.6. 
Exploratory Efficacy Analyses 
13.1.6.1. Responder Analyses 
The percentage of subjects with a decrease in ALP of ≥15% and ≥40% from Baseline will be 
summarized by treatment group.  In addition, the percentage of subjects with ALP ≤ULN will be 
summarized by treatment group. 
The percentage of subjects that meet the criteria of a responder based on each of the definitions 
below will be summarized by treatment group.  The response classification at baseline will also 
be included in the summary:  
 ALP ≤3× ULN and AST ≤2× ULN and total bilirubin ≤ULN (Corpechot 2008) 
 ALP ≤1.5× ULN and AST ≤1.5× ULN and total bilirubin ≤ULN (Corpechot 2011) 
 ALP ≤1.67× ULN and total bilirubin ≤ULN (Momah 2012) 
 Normal bilirubin (values ≤ULN) and normal albumin (values ≥lower limit of normal) 
(Kuiper 2009) 
 ALP ≤1.76× ULN (Kumagi 2010) 
Responder analyses will compare treatment groups using a Cochran–Mantel–Haenszel test 
stratified by the randomization stratification factor.  Missing values will be considered as a 
non-responder.   
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints 
Sufficient data will be collected on resource utilization and quality of life to undertake 
cost-effectiveness analyses that are relevant to the major countries taking part in this study.  
Resource utilization data on hospitalizations, healthcare provider visits, and medications will be 
combined with appropriate national unit costs to calculate a cost per patient per year in the study. 
Quality of life data from patient-reported outcomes measures will be combined with survival 
data to calculate quality adjusted time in the study per patient.  Cost-effectiveness analyses will 
report the incremental cost per major clinical outcome averted, liver-related death averted, 
life-year gained and quality-adjusted life year gained, including OCA as part of usual care versus 
usual care without OCA.  Analyses will be conducted within the study and using a lifetime 
perspective.  A separate economic analysis plan will be prepared and reported separately from 
this protocol. 
13.1.8. 
Supportive Analysis 
Per the International Conference on Harmonisation (ICH) E10 guidance, “where no obvious 
single optimal external control exists, it may be advisable to study multiple external controls”.  
In order to address the risks associated with the inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare clinical outcomes in the OCA treatment arm to 
historical controls.   
In an attempt to avoid the inherent biases with historical controls and to maintain the integrity of 
this comparison, one can invoke matching methods to optimize comparability and find a 
historical control that is “similar” to a participating subject.  The historical database control 
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should be as similar as possible to the study population and should have been exposed to a 
similar standard of care (see Section 5.5.2.3). 
A propensity score can be used to reduce bias through matching, stratification, regression 
adjustment, or some combination.  Propensity scores use information from a pool of patients who 
do not participate in the study (historical controls) to identify what would have happened to 
participating subjects in the absence of the treatment.  By comparing how outcomes differ for 
treated subjects relative to historical controls, it is possible to estimate the effects of the 
treatment. 
Although it might be relatively simple to assign a historical control based on a single observable 
characteristic, in practice, if the matching process is to successfully mitigate potential bias, it has 
to be done considering a full range of covariates across which the treatment and historical 
controls might differ.  Although the results of using matching controls are conditional only on 
the observed covariates, if one has the ability to measure many of the covariates that are believed 
to be related to the treatment assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained.  Both UK-PBC Group and the 
Global PBC Study Group formally collect numerous covariates that could be used for propensity 
score estimation including standard of care, eg, UDCA. 
Historical controls will be chosen based on the same inclusion/exclusion criteria where possible. 
Propensity scores will be estimated using the available covariates that predict receiving the 
treatment.  Only covariates and not outcome variables will be included in the propensity score 
estimation.  Therefore, there is no chance of biasing results in favor of one treatment. 
The covariates and factors collected in the historical databases will be specified in the SAP. 
Propensity scores will be estimated first through a logistic regression model with treatment group 
as the dependent variable and the above covariates/factors as independent variables.  Then the 
stratum boundaries are determined based on the propensity score values for both groups (OCA 
population and control [historical and randomized placebo]) combined or in the OCA population 
or historical control group alone.  Based on recommendations in the literature, quintiles of the 
estimated propensity score from the combined group will be used to determine the stratum 
boundary cut-offs for the different strata. 
Outcome events collected in the historical database are:  death (liver-related and all-cause), liver 
transplant, hepatocellular carcinoma, and other.  Other is defined as cirrhosis or decompensation 
such as ascites, variceal bleed, and encephalopathy. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare randomized OCA-treated subjects in the ITT population and historical 
controls (Overall Historical Control Population: both the UK-PBC Group and Global PBC Study 
Group databases) on the following outcomes: 
 Time to death (all-cause) 
 Time to liver-related death 
 Time to liver transplant 
 Time to liver transplant or death (all-cause) 
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 Time to liver transplant or liver-related death 
 Time to hepatocellular carcinoma 
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 determined based on a Cox regression 
model stratified by randomization strata to estimate the magnitude of the effect. 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
13.1.9. 
Alternative Primary Analysis 
Based on sample size re-estimations, it may be determined that subjects will be enrolled to 
receive open-label OCA from that point forward, and the new primary efficacy analysis will 
become the comparison of all subjects in OCA population, to all control subjects (randomized 
placebo and historical controls) on time to liver transplant or death (all-cause) (see 
Section 13.1.2.1).  Similar statistical methodology as specified above in Section 13.1.8 for 
supportive analyses will be utilized. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare groups.  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 
determined based on a Cox regression model stratified by randomization strata to estimate the 
magnitude of the effect. 
In addition, the outcome events specified above in Section 13.1.8 will also be evaluated to 
compare all subjects in OCA population to all control subjects (randomized placebo and 
historical controls). 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
13.1.10. 
Handling of Dropouts or Missing Data 
Subjects who discontinue investigational product are expected to continue in the study until 
study termination. 
Missing data will be assumed to be missing at random.  In order to determine the effect of 
missing data on the analysis, efficacy endpoints will be analyzed using different methods of 
imputation as described below. 
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13.1.10.1. Time to Event Endpoints 
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 investigational product dosing). 
For analyses of the percentage of subjects with an event, subjects with no data after 
randomization will be considered to have an event. 
All time to event endpoints include only adjudicated events.  Sensitivity analyses may consider 
all events regardless of adjudication.  Events with discrepant adjudication will be analyzed using 
both results. 
13.1.10.2. Quantitative Endpoints 
For efficacy endpoints that utilize an ANCOVA model, observed cases will serve as the primary 
analysis.  Sensitivity analyses to assess the effect of missing data may be conducted where 
missing data is imputed using last observation carried forward. 
Sensitivity analyses of ANCOVA models will also be evaluated using a restricted maximum 
likelihood based mixed-effect repeated measures model where no imputations will be made for 
missing values.   
13.1.10.3. Responder Endpoints 
In an efficacy analysis in which subjects are classified as either a responder or a non-responder 
(binary outcome) based on dichotomizing a continuous variable, any subject who does not 
provide an assessment at the specified time point for the defining of response will be considered 
to be a non-responder.  That is, for the percentage of responders, the subject will be included in 
the denominator and will not contribute to the numerator. 
For sensitivity analyses using only “observed cases,” subjects who do not provide an assessment 
at the specified timepoint for the defining of response will not be included.  That is, for the 
percentage of responders, the subject will not be included in the numerator or the denominator. 
13.1.11. 
Multiple Comparisons/Multiplicity 
The key secondary efficacy endpoints are as follows: 
 Time to MELD score ≥15 
 Time to first occurrence of liver transplant or death (all-cause) 
 Change from Baseline in total bilirubin at end of study 
 Change from Baseline in ALP at end of study 
The hypothesis testing of key secondary analyses will compare placebo and OCA and will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of OCA.  If the primary comparison is not statistically significant 
then comparison of the secondary endpoints will be considered as descriptive and exploratory.  
This procedure controls the study-wise type I error.  
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 First (step 1) placebo and OCA will be compared with respect to the primary efficacy 
endpoint.  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
 The time to MELD score ≥15 will be compared between placebo and OCA (step 2).  
If the comparison achieves statistical significance at 2-sided 0.05 level in favor of 
OCA group, then 
 The time to liver transplant or death (all-cause) will be compared between placebo 
and OCA (step 3).  If the comparison achieves statistical significance at 2-sided 
0.05 level in favor of OCA group, then 
 Change from Baseline in total bilirubin will be compared between placebo and OCA 
(step 4).  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
 Change from Baseline in ALP at the end of study will be compared between placebo 
and OCA (step 5). 
If at any step defined above the comparison is not statistically significant at the 2-sided 
0.05 level then the remaining comparisons in the stated hierarchy will be considered descriptive 
and exploratory.  The study-wise type I error will be maintained with the above closed 
procedure. 
Additional efficacy endpoints will be analyzed; however, hypothesis tests will be applied for 
descriptive and exploratory purposes only.   
13.1.12. 
Examination of Subgroups 
The primary and secondary efficacy endpoints will be analyzed for subject subgroups (eg, age, 
sex, and race) based on the ITT population.  Subgroups will be assessed at baseline and only if 
there are a sufficient number of subjects in each group (eg, >5 subjects per group). 
Baseline subgroups of interest are as follows:  age, age at PBC diagnosis, sex, race, body mass 
index, ALP level, bilirubin level, use of UDCA, years since diagnosis of PBC, and geographic 
region. 
13.2. 
Safety Analysis 
Safety data, including AEs and clinical laboratory observations, will be summarized by treatment 
group using the Safety Population. 
13.2.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary of Regulatory Activities.  Summary tables of 
treatment-emergent AEs will be provided.  The incidence of TEAEs will be tabulated by system 
organ class and preferred term for each treatment group, and by severity and relationship to 
treatment.  Tables of TEAEs leading to investigational product discontinuation and SAEs will be 
provided. 
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13.2.2. 
Clinical Laboratory Evaluations 
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will be 
presented for all study visits.  Changes from pretreatment to each study visit will also be 
summarized by treatment group. 
13.2.3. 
Additional Safety Analysis 
Additional safety assessments include vital signs and ECGs.  Descriptive statistics of the vital 
sign and ECG parameters will be presented by treatment group and study visit, as well as the 
change from pretreatment at each visit. 
13.2.4. 
Cardiovascular Adjudication Committee 
In addition to potential clinical endpoint events, cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study. Adjudicated cardiovascular events include core 
major adverse cardiovascular events (MACE) (cardiovascular death, nonfatal myocardial 
infarction, and nonfatal stroke) and expanded MACE (unstable angina requiring hospitalization, 
transient ischemic attack, peripheral or coronary revascularization procedures, hospitalization for 
congestive heart failure).  Other events potentially related to adverse cardiovascular outcomes 
may be included in the Cardiovascular Adjudication Committee (CAC) Charter for adjudication.  
The adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study (see Section 13.4). 
13.3. 
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 subjects.  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 subject treatment information; 
however, the DMC will have access to the database and may unblind individual subject data as 
appropriate.  Summary tables reviewed by the DMC during closed sessions will include an 
overall column containing information regarding all subjects and separate treatment columns 
with ‘dummy’ labels, ie, the actual treatment groups are used, but are not identified.  Data 
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reviewed during the meetings will include, at a minimum, disposition, demographics, exposure, 
clinical laboratory results, Medical Dictionary for Regulatory Activities (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 subject safety, which alter the 
conduct of this study.  The Investigators will inform the subjects of such actions and the 
protocol, patient information sheet (PIS), and consent will be revised, as appropriate. 
13.4. 
Adjudication Committees 
All suspected liver-related clinical outcomes, 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 subject 
treatment or site-specific information.  The assessment of events will be conducted in 
compliance with study-specific procedures, manuals, good clinical practice (GCP), and all other 
applicable regulatory requirements, including the archiving of essential documents.    
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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
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 subject’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 CRF.  The CRF 
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 
subject's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
14.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC 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.   
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the CRF 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 14.2 for more details regarding the audit 
process. 
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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF and/or other subject 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 the Sponsor before he or she can enroll 
any subject 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 subjects to the ethics committee 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 subjects for 
the study.  The protocol must be reapproved by the IRB or 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.  
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, at a minimum annually, and after the study is complete. 
16.2. 
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. 
16.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated ICF 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 subject. 
16.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential and confidentiality of all subjects will be maintained.  Monitors (eg, 
CRA, medical monitor), auditors and inspectors will require access to a subject’s medical notes 
for the purpose of source document verification but the subject’s confidentiality will be 
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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 subject’s names and identifying information (eg, subject’s 
hospital number, unique subject number).  This list will not be collected by the Sponsor. 
The written information sheet 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 subject 
number/randomization code/subject initials/site number, only. 
When personal data on subjects are stored or processed by computer, the data must be protected 
to prevent their disclosure to unauthorized third parties.  The pertinent sections of the data 
protection laws in which the country is being conducted will be complied with in full. 
The written ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IEC/IRB may require direct access to parts of the hospital 
or study site records relevant to the study, including subject’s medical history. 
17. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the subjects 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 subjects, as applicable. 
17.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject 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 medical monitor. 
17.2. 
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 subject’s safety to be compromised if immediate action is not taken. 
17.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
 Approved ICF (all versions) 
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 IRB/EC approvals (of protocol/amendments, subject questionnaires, etc) 
 Form FDA 1572  
 Current medical license 
 Curriculum vitae 
 Laboratory certification and reference ranges 
 Financial disclosure forms 
17.4. 
Ethics Review  
Please see Section 16.1 for the Investigator’s responsibilities regarding ethics review. 
17.5. 
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 subject 
medical files (retained per country specific regulations), completed study subject log and 
confidential subject 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 prior to 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. 
18. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it sponsors consistent 
with the Declaration of Helsinki (Seoul Revision 2008, 
[http://www.wma.net/en/30publications/10policies/b3/index.html, accessed May 22, 2013]).  
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. 
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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 Study Registries (eg, 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 (when available) 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:  The Sponsor, 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. 
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 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. 
LIST OF REFERENCES 
Beuers U, Lindor KD. A major step towards effective treatment evaluation in primary biliary 
cirrhosis. J Hepatol. 2011;55(6):1178-80. 
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and 
long term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871-877. 
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. 
Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: Biochemical response 
to treatment and prediction of long-term outcome. J Hepatol. 2011;55:1361–1367. 
Dickson ER, Grambsch PM, Fleming TR, et al.  Prognosis in primary biliary cirrhosis:  Model 
for decision making.  Hepatology. 1989;10(1):1-7. 
Elman S, Hynan L.S., Gabriel V, and Mayo M.J. The 5-D itch scale: a new measure of pruritus, 
British Journal of Dermatology. 2010;162,587–593. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51:237-267. 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact of fatigue: initial validation of 
the fatigue impact scale. Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
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. 
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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. 
Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict 
long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 
2010;105(10):2186-94. 
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Alkaline phosphatase values are a 
surrogate marker in prediction of transplant-free-survival in patients with primary biliary 
cirrhosis - an international, collaborative analysis.  J Hepatol. 2013; 58(Suppl):S388. 
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. 
Momah N, Silveira MG, Jorgensen R, et al. Optimizing biochemical markers as endpoints for 
clinical trials in primary biliary cirrhosis. Liver Int. 2012;32(5):790-795. 
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. 
 
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APPENDIX A. MODIFIED DOSING REGIMEN FOR SUBJECTS WITH 
CHILD-PUGH B/C HEPATIC IMPAIRMENT 
Overview of Modified Dosing Regimen for Subjects with Child-Pugh B or C Hepatic 
Impairment 
An overview of the modified dosing regimen for subjects with Child-Pugh Class B or 
Child-Pugh Class C is presented in Figure 2 and Table 11. 
Subjects who are cirrhotic and classified as Child-Pugh Class B or Child-Pugh Class C will 
initiate a modified treatment regimen with 5 mg OCA or matching placebo once weekly for at 
least 3 months.  Subjects classified as Child-Pugh Class B should eventually titrate to a 
maximum dose of 5 mg OCA or matching placebo once daily, based on tolerability.  Subjects 
classified as Child-Pugh Class C should titrate to a maximum dose and frequency of 10 mg OCA 
or matching placebo twice weekly. 
Figure 2: 
Dosing by Cirrhosis Status and Child-Pugh Score 
 
a  Cirrhosis may be assessed by histology or non-histological methods as defined in Section 9.7.3. 
BIW = twice weekly; QW = once weekly 
Table 11: 
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Modified Dosing Regimen 
Child-Pugh B 
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg once weekly 
5 mg once weekly 
Titration 1b  
(≥Month 3) 
5 mg twice weeklyc 
5 mg twice weeklyc 
Titration 2b  
(≥6 weeks after Titration 1) 
10 mg twice weeklyc 
10 mg twice weeklyc 
Titration 3b 
(≥6 weeks after Titration 2) 
5 mg daily 
NA 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b  Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject 
tolerability and/or changes in cirrhosis status or Child-Pugh Score at any time during the study. 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
Modified Dosing Regimen for Subjects with Child-Pugh B Hepatic Impairment 
Subjects with cirrhosis and classified as Child-Pugh B at Screening will follow a modified 
dosing schedule receiving 5 mg OCA or matching placebo once weekly as described in Figure 2.  
After a minimum of 3 months dosing once weekly with 5 mg OCA or matching placebo, and 
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following review of the pre-titration laboratory results to assess safety and tolerability, the dosing 
frequency of 5 mg OCA or matching placebo should be increased to twice weekly (at least 3 
days apart).  Subjects who have maintained the twice weekly dosing frequency for a minimum of 
at least 6 weeks, and meet the dose titration criteria, should up-titrate to twice weekly dosing 
with 10 mg OCA or matching placebo.  Subjects with at least 6 weeks of twice weekly dosing at 
10 mg OCA or matching placebo, and meeting dose titration criteria, should up-titrate to the 
maximum allowed dose of 5 mg OCA or matching placebo once daily.  
Investigators may decrease the dosing frequency (back to once or twice weekly) or dose for any 
subject at any time during the study, as considered clinically appropriate (eg, tolerability). 
Modified Dosing Regimen for Subjects with Child-Pugh C Hepatic Impairment 
Subjects with cirrhosis and classified as Child-Pugh C at Screening will follow a modified 
dosing schedule receiving 5 mg OCA or matching placebo once weekly as described in Figure 2.  
After a minimum of 3 months dosing once weekly with 5 mg OCA or matching placebo, and 
following review of the pre-titration laboratory results to assess safety and tolerability, the dosing 
frequency of 5 mg OCA or matching placebo should be increased to twice weekly (at least three 
days apart).  Subjects who have maintained the twice weekly dosing frequency for a minimum of 
at least 6 weeks, and meet the dose titration criteria, should up-titrate to the maximum allowed 
dose of 10 mg OCA or matching placebo twice weekly.   
Investigators may decrease the dosing frequency (back to once weekly) or dose for any subject at 
any time during the study, as considered clinically appropriate (eg, tolerability).   
Dose Titration due to Change in Cirrhosis or Child-Pugh Score 
Subjects on a modified dosing regimen who demonstrate a change in cirrhosis status and/or 
Child-Pugh Score should have their dose of investigational product modified to match their 
current status per the appropriate dosing regimen (see Section 7.4, Table 5); however, changes to 
the dosing regimen are not mandatory and should be based on clinical judgment as well as 
changes in status. Changes in Child-Pugh Score that result from a transient, explainable change 
in laboratory parameters should be documented appropriately, and should not necessarily result 
in a change to the dosing regimen.  Investigators may contact the medical monitor at any time to 
discuss potential changes to dosing.   
Possible scenarios for dosing modifications include: 
 Subjects who develop cirrhosis during the course of the trial with a classification of 
Child-Pugh B or C 
 Subjects with pre-existing cirrhosis who demonstrate a change in the Child-Pugh Score 
from A to B or C at any point in the study   
 Improvement in classification of Child-Pugh Score from C to B  
 Improvement in classification of Child-Pugh Score from B to A; these subjects may be 
eligible to transition to the standard dosing regimen 
Subjects may titrate dose and dosing frequency up or down as appropriate, within the appropriate 
dosing regimen.  Up-titration should be done per Investigator discretion and be guided by the 
pre-titration tolerability assessments outlined in Section 7.4.1.  A 1-Month Post-Titration 
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Assessment must be performed any time a subject’s dose or frequency is up-titrated (see 
Section 7.1.2 and Section 9.7.10). 
Unscheduled Titration Visit, Optional Visit 
An unscheduled up-titration visit may be scheduled for as early as 6 weeks after the initial 
titration visit (or subsequent titration visit) occurs for subjects who are following the modified 
dosing regimen.  The visit procedures required for the unscheduled titration visit are outlined 
below.  Subjects who up titrate at an unscheduled visit will continue to follow the regular visit 
schedule for all other study visits.   
For subjects who up titrate at an unscheduled visit the following procedures will be performed: 
 Assess and record AEs. 
 Review and record concomitant medications. 
 Perform the pre-Titration Tolerability Assessment as outlined in Section 7.4.1. 
 Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
 Provide the subject with a dosing diary to document his or her dosing. 
 Schedule the next visit, reiterate dosing instructions, and advise the subject: 
- 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. 
For subjects who up titrate at an unscheduled visit: The + 1-week window week related to the 
1-Month Post-Titration visit can be extended for up to an additional 5 weeks to allow for the 
post-titration assessment to be performed during one of the subject’s regularly scheduled 
study visits.  If the window is extended past +1 week allowed visit window, at a minimum, a 
telephone safety contact should then be performed 1-month post-titration. 
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APPENDIX B. LIST OF STUDY 747-302 OUTCOME EVENTS 
Several of the specified clinical endpoints will also by definition (see Section 12.1) 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 12.1.4).  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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APPENDIX C. ETHICAL CONDUCT ACCORDING TO THE 
DECLARATION OF HELSINKI FOR COUNTRIES 
PARTICIPATING OUTSIDE THE US (DECLARATION 
OF HELSINKI, FORTELEZA, BRAZIL, 2013) 
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Copyright 2013 American Medical Association. All rights reserved.
World Medical Association Declaration of Helsinki
Ethical Principles for Medical Research
Involving Human Subjects
World Medical Association
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1. The World Medical Association (WMA) has developed the Dec-
larationofHelsinkiasastatementofethicalprinciplesformedi-
cal research involving human subjects, including research on
identifiable human material and data.
The Declaration is intended to be read as a whole and each of
its constituent paragraphs should be applied with consider-
ation of all other relevant paragraphs.
2. ConsistentwiththemandateoftheWMA,theDeclarationisad-
dressed primarily to physicians. The WMA encourages others
who are involved in medical research involving human subjects
to adopt these principles.
General Principles
3. TheDeclarationofGenevaoftheWMAbindsthephysicianwith
the words, “The health of my patient will be my first consider-
ation,”andtheInternationalCodeofMedicalEthicsdeclaresthat,
“A physician shall act in the patient's best interest when provid-
ing medical care.”
4. It is the duty of the physician to promote and safeguard the
health,well-beingandrightsofpatients,includingthosewhoare
involvedinmedicalresearch.Thephysician'sknowledgeandcon-
science are dedicated to the fulfilment of this duty.
5. Medical progress is based on research that ultimately must in-
clude studies involving human subjects.
6. Theprimarypurposeofmedicalresearchinvolvinghumansub-
jects is to understand the causes, development and effects of
diseasesandimprovepreventive,diagnosticandtherapeuticin-
terventions (methods, procedures and treatments). Even the
bestproveninterventionsmustbeevaluatedcontinuallythrough
research for their safety, effectiveness, efficiency, accessibility
and quality.
7. Medicalresearchissubjecttoethicalstandardsthatpromoteand
ensure respect for all human subjects and protect their health
and rights.
8. Whiletheprimarypurposeofmedicalresearchistogeneratenew
knowledge, this goal can never take precedence over the rights
and interests of individual research subjects.
9. Itisthedutyofphysicianswhoareinvolvedinmedicalresearch
to protect the life, health, dignity, integrity, right to self-
determination,privacy,andconfidentialityofpersonalinforma-
tion of research subjects. The responsibility for the protection
ofresearchsubjectsmustalwaysrestwiththephysicianorother
health care professionals and never with the research subjects,
even though they have given consent.
10. Physiciansmustconsidertheethical,legalandregulatorynorms
andstandardsforresearchinvolvinghumansubjectsintheirown
countries as well as applicable international norms and stan-
dards.Nonationalorinternationalethical,legalorregulatoryre-
quirementshouldreduceoreliminateanyoftheprotectionsfor
research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that mini-
mises possible harm to the environment.
12. Medicalresearchinvolvinghumansubjectsmustbeconducted
onlybyindividualswiththeappropriateethicsandscientificedu-
cation, training and qualifications. Research on patients or
healthyvolunteersrequiresthesupervisionofacompetentand
appropriately qualified physician or other health care profes-
sional.
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13. Groups that are underrepresented in medical research should
be provided appropriate access to participation in research.
14. Physicians who combine medical research with medical care
should involve their patients in research only to the extent that
this is justified by its potential preventive, diagnostic or thera-
peuticvalueandifthephysicianhasgoodreasontobelievethat
participation in the research study will not adversely affect the
health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be en-
sured.
Risks, Burdens and Benefits
16. Inmedicalpracticeandinmedicalresearch,mostinterventions
involve risks and burdens.
Medical research involving human subjects may only be con-
ductediftheimportanceoftheobjectiveoutweighstherisksand
burdens to the research subjects.
17. All medical research involving human subjects must be pre-
ceded by careful assessment of predictable risks and burdens
to the individuals and groups involved in the research in com-
parisonwithforeseeablebenefitstothemandtootherindividu-
als or groups affected by the condition under investigation.
Measurestominimisetherisksmustbeimplemented.Therisks
mustbecontinuouslymonitored,assessedanddocumentedby
the researcher.
18. Physiciansmaynotbeinvolvedinaresearchstudyinvolvinghu-
mansubjectsunlesstheyareconfidentthattheriskshavebeen
adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive proof of definitive outcomes, physi-
cians must assess whether to continue, modify or immediately
stop the study.
Vulnerable Groups and Individuals
19. Somegroupsandindividualsareparticularlyvulnerableandmay
haveanincreasedlikelihoodofbeingwrongedorofincurringad-
ditional harm.
All vulnerable groups and individuals should receive specifi-
cally considered protection.
20. Medical research with a vulnerable group is only justified if the
research is responsive to the health needs or priorities of this
group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to ben-
efit from the knowledge, practices or interventions that result
from the research.
Scientific Requirements and Research Protocols
21. Medicalresearchinvolvinghumansubjectsmustconformtogen-
erally accepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as appropriate, ani-
mal experimentation. The welfare of animals used for research
must be respected.
22. The design and performance of each research study involving
human subjects must be clearly described and justified in a re-
search protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include
information regarding funding, sponsors, institutional affilia-
tions, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compen-
sating subjects who are harmed as a consequence of participa-
tion in the research study.
In clinical trials, the protocol must also describe appropriate ar-
rangements for post-trial provisions.
Research Ethics Committees
23. Theresearchprotocolmustbesubmittedforconsideration,com-
ment, guidance and approval to the concerned research ethics
committee before the study begins. This committee must be
transparent in its functioning, must be independent of the re-
searcher, the sponsor and any other undue influence and must
be duly qualified. It must take into consideration the laws and
regulations of the country or countries in which the research is
to be performed as well as applicable international norms and
standardsbutthesemustnotbeallowedtoreduceoreliminate
anyoftheprotectionsforresearchsubjectssetforthinthisDec-
laration.
The committee must have the right to monitor ongoing stud-
ies.Theresearchermustprovidemonitoringinformationtothe
committee, especially information about any serious adverse
events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of
thestudy,theresearchersmustsubmitafinalreporttothecom-
mittee containing a summary of the study’s findings and con-
clusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of re-
search subjects and the confidentiality of their personal infor-
mation.
Informed Consent
25. Participation by individuals capable of giving informed consent
as subjects in medical research must be voluntary. Although it
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may be appropriate to consult family members or community
leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving
informed consent, each potential subject must be adequately
informed of the aims, methods, sources of funding, any pos-
sible conflicts of interest, institutional affiliations of the re-
searcher,theanticipatedbenefitsandpotentialrisksofthestudy
and the discomfort it may entail, post-study provisions and any
other relevant aspects of the study. The potential subject must
be informed of the right to refuse to participate in the study or
to withdraw consent to participate at any time without repri-
sal. Special attention should be given to the specific informa-
tionneedsofindividualpotentialsubjectsaswellastothemeth-
ods used to deliver the information.
Afterensuringthatthepotentialsubjecthasunderstoodthein-
formation, the physician or another appropriately qualified in-
dividual must then seek the potential subject’s freely-given in-
formed consent, preferably in writing. If the consent cannot be
expressedinwriting,thenon-writtenconsentmustbeformally
documented and witnessed.
Allmedicalresearchsubjectsshouldbegiventheoptionofbeing
informed about the general outcome and results of the study.
27. When seeking informed consent for participation in a research
study the physician must be particularly cautious if the poten-
tial subject is in a dependent relationship with the physician or
mayconsentunderduress.Insuchsituationstheinformedcon-
sentmustbesoughtbyanappropriatelyqualifiedindividualwho
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving in-
formedconsent,thephysicianmustseekinformedconsentfrom
thelegallyauthorisedrepresentative.Theseindividualsmustnot
be included in a research study that has no likelihood of benefit
forthemunlessitisintendedtopromotethehealthofthegroup
represented by the potential subject, the research cannot in-
stead be performed with persons capable of providing in-
formed consent, and the research entails only minimal risk and
minimal burden.
29. When a potential research subject who is deemed incapable of
givinginformedconsentisabletogiveassenttodecisionsabout
participationinresearch,thephysicianmustseekthatassentin
addition to the consent of the legally authorised representa-
tive. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally in-
capable of giving consent, for example, unconscious patients,
may be done only if the physical or mental condition that pre-
ventsgivinginformedconsentisanecessarycharacteristicofthe
research group. In such circumstances the physician must seek
informedconsentfromthelegallyauthorisedrepresentative.If
nosuchrepresentativeisavailableandiftheresearchcannotbe
delayed,thestudymayproceedwithoutinformedconsentpro-
videdthatthespecificreasonsforinvolvingsubjectswithacon-
dition that renders them unable to give informed consent have
beenstatedintheresearchprotocolandthestudyhasbeenap-
provedbyaresearchethicscommittee.Consenttoremaininthe
researchmustbeobtainedassoonaspossiblefromthesubject
or a legally authorised representative.
31. Thephysicianmustfullyinformthepatientwhichaspectsoftheir
care are related to the research. The refusal of a patient to par-
ticipateinastudyorthepatient’sdecisiontowithdrawfromthe
study must never adversely affect the patient-physician rela-
tionship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or
similarrepositories,physiciansmustseekinformedconsentfor
its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracti-
cable to obtain for such research. In such situations the re-
search may be done only after consideration and approval of a
research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new inter-
vention must be tested against those of the best proven inter-
vention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary
to determine the efficacy or safety of an intervention
andthepatientswhoreceiveanyinterventionlesseffectivethan
thebestprovenone,placebo,ornointerventionwillnotbesub-
ject to additional risks of serious or irreversible harm as a result
of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. Inadvanceofaclinicaltrial,sponsors,researchersandhostcoun-
trygovernmentsshouldmakeprovisionsforpost-trialaccessfor
all participants who still need an intervention identified as ben-
eficialinthetrial.Thisinformationmustalsobedisclosedtopar-
ticipants during the informed consent process.
Research Registration and Publication and Dissemination
of Results
35. Every research study involving human subjects must be regis-
teredinapubliclyaccessibledatabasebeforerecruitmentofthe
first subject.
World Medical Association Declaration of Helsinki
Special Communication Clinical Review & Education
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36. Researchers, authors, sponsors, editors and publishers all have
ethical obligations with regard to the publication and dissemi-
nationoftheresultsofresearch.Researchershaveadutytomake
publicly available the results of their research on human sub-
jectsandareaccountableforthecompletenessandaccuracyof
their reports. All parties should adhere to accepted guidelines
for ethical reporting. Negative and inconclusive as well as posi-
tiveresultsmustbepublishedorotherwisemadepubliclyavail-
able. Sources of funding, institutional affiliations and conflicts
of interest must be declared in the publication. Reports of re-
search not in accordance with the principles of this Declaration
should not be accepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven inter-
ventions do not exist or other known interventions have been
ineffective, the physician, after seeking expert advice, with in-
formed consent from the patient or a legally authorised repre-
sentative, may use an unproven intervention if in the physi-
cian's judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should subse-
quently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be re-
corded and, where appropriate, made publicly available.
ARTICLE INFORMATION
Corresponding Author: World Medical
Association, 13, ch. du Levant, CIB - Bâtiment A,
01210 Ferney-Voltaire, France; wma@wma.net.
Published Online: October 19, 2013.
doi:10.1001/jama.2013.281053.
Disclaimer: ©2013 World Medical Association, Inc.
All Rights Reserved. All intellectual property rights
in the Declaration of Helsinki are vested in the
World Medical Association. The WMA has granted
JAMA exclusive rights to publish the
English-language version of the Declaration
through December 31, 2013.
Online-Only Content: Audio podcast is available at
www.jama.com.
Clinical Review & Education Special Communication
World Medical Association Declaration of Helsinki
2194
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November 27, 2013
Volume 310, Number 20
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APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 (DATED 29 APR 2015) 
Rationale 
The changes to the Original Version of the protocol, detailed below, modify the dose titration schedule based on observed efficacy and 
tolerability of OCA, address advice provided by regulatory agencies, and clarify questions raised by study site personnel currently 
using Original protocol version 1 dated 03 October 2014. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.  (Note:  Differences are denoted in bold font; Minor 
formatting changes are not listed) 
Section 
Original Text 
Revised Text 
Title Page 
Original:  03 October 2014 
Original:  03 October 2014 
Amendment 1:  xx April 2015 
Procedures in 
Case of 
Emergency 
 
Procedures in Case of Emergency 
 
Study Personnel Contact Information 
 
Or if Not 
Available 
Contact:
 MD, 
 & 
 Development, Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
 
Contact:
 MD, Medical Director, Drug Safety, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
Synopsis 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
≤1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 2 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 2 
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Section 
Original Text 
Revised Text 
weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
and total bilirubin values (refer to Section 9.7.3).   Subjects who 
meet all inclusion criteria and none of the exclusion criteria will be 
randomized (1:1) to OCA or placebo treatment groups.  The 
randomization will be stratified by ursodeoxycholic acid (UDCA) 
treatment (yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 6 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 6-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
 
weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
and total bilirubin values (refer to Section 9.7.3).  Mean values for 
ALP and total bilirubin will be calculated using all available 
screening values.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment (yes/no) and baseline 
bilirubin categories (>upper limit of normal [ULN]/ ≤ ULN). 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 3 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 3-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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Section 
Original Text 
Revised Text 
Synopsis 
Inclusion Criteria 
2.  A mean total  bilirubin >ULN and ≤3× ULN or an ALP 
>5×ULN  
4.  Either is not taking UDCA (UDCA naïve or no UDCA dose in 
the past 3 months) or has been taking UDCA for at least 12 months 
with an approved, stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
contraception during the study and for 30 days after the end of 
treatment visit. 
 
Inclusion Criteria 
2. A mean total bilirubin >ULN and ≤3× ULN and/or a mean 
ALP >5× ULN 
4.  Either is not taking UDCA (no UDCA dose in the past 
3 months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects 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:   
 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
 
Intrauterine device (IUD); 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 subject)  
 
Synopsis 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
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3. Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
4.  Other medical conditions that may diminish life expectancy to 
<2 years, including known cancers (except carcinomas in situ or 
other stable, relatively benign conditions such as chronic lymphatic 
leukemia) 
5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of screening (pretreatment) QT 
 
 
3.  Mean total bilirubin >3× ULN 
 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
5.  Deleted text 
Synopsis 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life 
 
 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life (Fatigue 
Impact Score and EQ-5D-
5L) 
 
Synopsis 
Statistical Methods: Other Efficacy Analyses 
 
Added text 
Statistical Methods: Other Efficacy Analyses 
 
Development of varix/varices 
4 
List of Abbreviations 
Added text 
 
List of Abbreviations 
EOS 
 end of study 
 
5.4 
As of 31 March 2014, OCA has been evaluated in the clinic in 18 
completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 March 2014, a total of 1023 subjects have 
received at least one dose of OCA and of these, 414 (40%) were 
subjects with PBC.   
As of 31 January 2015, OCA has been evaluated in the clinic in 20 
completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 January 2015, approximately 1650 subjects 
have received at least 1 dose of OCA and of these, 432 were 
subjects with PBC with ≤5 years of OCA treatment.   
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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 up to 4 years.  The LSTE phase of studies 
747-201 and 747-301 are ongoing; the LTSE phase of Study 747-
202 is complete 
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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is 
complete 
5.5.2.1 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg and 10 mg; both treatment 
groups exhibited clinically meaningful improvements in liver 
biochemistry and were safe and generally well tolerated. 
 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg (titrated to 10 mg after 6 
months based on efficacy and tolerability in the double-blind 
phase and after 3 months in the open-label phase) and 10 mg; 
both treatment groups exhibited clinically meaningful 
improvements in liver biochemistry and were safe and generally 
well tolerated.  Based on these data, the intended commercial 
doses of OCA for the treatment of patients with PBC are 5 mg 
and 10 mg. 
The majority of efficacy results with OCA, in terms of change 
in alkaline phosphatase, was observed by 3 months and the 
time to treatment-emergent pruritus was typically 1 month or 
less in Study 747-301.  As such, Study 747-302 will evaluate the 
effect of OCA on clinical outcomes using the 5 mg OCA dose 
increasing to 10 mg OCA if tolerated. 
 
5.5.2.2. 
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons.   
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons (ie, comparisons to historical and placebo 
controls will be evaluated separately). 
 
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5.6 
Additionally, consistent with nonclinical findings and the 
chemical characteristics of OCA (bile acid and detergent), an 
increase in liver function tests and hepatic AEs, including 
jaundice, were observed in subjects with liver disease at doses 
between 10 mg and 50 mg and in healthy volunteers who were 
treated at doses greater than 100 mg in Phase 1 multiple dose 
studies. 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  The clinical 
significance of these lipid findings remains unclear and is being 
studied further.  Notably, despite the observed decrease, HDL 
levels have generally remained within normal limits in subjects 
treated with OCA. 
 
Deleted text 
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 subjects with chronic liver disease such as PBC, hepatic 
findings including increased transaminases and bilirubin and 
signs or symptoms of hepatic decompensation such as 
development of jaundice were observed mainly at the highest 
dose of OCA (50mg daily). 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  Notably, in subjects 
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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated 
subjects with the exception of a modest transient and early rise 
after initiation of treatment. 
7.1 
Overall Study Design 
…Subjects will be screened during a ≤1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3)….Following 6 months of treatment with 
investigational product, subjects should be titrated in a blinded 
manner (ie, subjects randomized to OCA will increase their dose to 
10 mg OCA) based on tolerability…. 
Overall Study Design 
…Subjects will be screened during a 1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to Section 9.7.3). 
….Following 3 months of treatment with investigational product, 
subjects should be titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose to 10 mg OCA) based 
on tolerability…. 
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7.1.1 
Study Design Diagram 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
Study Design Diagram 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
7.1.2 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
1st column heading was “Screening Visit  x2) 
 
Visit Window ≤1 to 8 wks … 
Visit window in 2nd column added new text 
Added text 
 
 
 
 
 
 
 
 
 
 
 
 
Footnote a:   All subjects will have two 2 bilirubin assessments at 
least 2 weeks apart including those subjects who qualify based 
on ALP criteria.  For subjects that do not qualify based on 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
Now 2 columns: 1st column now “Screening Visit 1” 
2nd column now Screening Visit 2 
3 to 8 wks… 
1 to 6 wks prior to Day 0 
 
Added Procedures: 
Quality of Life Questionnaires (PBC-40, EQ-5D-5L, and 
FIS) g  (Day 0, Annually, EOT/EOS) 
Endoscopy I (Day 0, annually, per standard of care) 
Hepatic Ultrasound (Day 0, Annually, EOT/EOS) 
Physical Exam and Assessments for Mayo Risk Score and Child-
Pugh (every 6 months) 
Health Outcome Assessments (All visits) 
Added Dose Titration at M3 
Footnote a All subjects will have the chemistry panel retested 
to ensure subjects have 2 ALP and bilirubin assessments at 
least 2 weeks apart to calculate the mean result for both 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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ALP (ALP >5× ULN), the mean of the two 2 bilirubin 
assessments will be used to determine eligibility (total bilirubin 
>ULN and ≤3× ULN). 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2, and also 2 weeks post dose titration, to assess for AEs 
and concomitant medications and to verify that s/he is dosing as 
directed 
Footnote e:  Medical history at Screening will smoking and alcohol 
consumption history and current habits for both.   
 
Footnote g:  Subject Questionnaires include: Pruritus VAS, 5-D 
Pruritus Scale and Quality of Life questionnaires (See 
Section 11.1.2.2 and Section 12.2.5.1) 
 
 
 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.   
 
 
Footnote i: Added text 
 
 
Footnote j:  Added text 
 
 
 
 
Footnote k:  Added text 
analytes.   The mean of the all screening ALP and bilirubin 
assessments will be used to determine eligibility).  Samples for 
hematology and coagulation will not be collected at Screening 
visit 2. 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2 (± 1 week), and also 2 weeks post dose titration (up or 
down), to assess for AEs and concomitant medications and to 
verify that s/he is dosing as directed.   
Footnote e:  Medical history at Screening and the yearly physical 
exam will include an assessment of smoking and alcohol 
consumption history and current habits for both.   
Footnote g:  The EQ-5D-5L and FIS Quality of Life 
questionnaires are validated for use in multiple languages. If 
a validated translation is not available in the local language 
required for a specific study subject, the data from that 
questionnaire will not be collected.    (See Section 11.1.2.2 and 
Section 12.2.6) 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.  Please refer to Section 9.7.7 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote i: Endoscopy will be conducted at selected study sites 
where the device is available to assess for the presence of 
oesophageal varix/varices.  Please refer to Section 9.7.7 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote j:  Ultrasound will be conducted to enhance HCC 
surveillance.  If a lesion is found, a second confirmatory 
image (eg, MRI) should be obtained.  Please refer to 
Section 9.7.7 for additional information related to the allowed 
windows at Day 0 for these specific procedures. 
Footnote k:  Child-Pugh Score will be calculated based on 
ascites assessment, hepatic encephalopathy grade, and central 
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Footnote l:  Added text 
 
 
 
Footnote m:  After 6 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 6 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit.  Fasting is required prior to all 
study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at site.  If the blood 
test is also positive, the subject may not be enrolled in the study.  
(Additional testing may be conducted where required, 
regionally). 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
laboratory evaluations per the Child-Pugh scoring system 
noted in the case report form.  Mayo Risk Score will be 
calculated based on central laboratory evaluations, diuretic 
use data, and peripheral edema assessment data captured in 
the CRF.  
Footnote l:  Health Outcome Assessments: Data related to non-
study related medical or surgical treatment procedures that 
the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the 
subject attended should be collected throughout the study. 
Footnote m:  After 3 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 3 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit (except Screening visit 1).  
Fasting is required prior to all study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not 
be enrolled in the study.  (Additional testing may be conducted 
where required, regionally). 
 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
 
7.3 
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 6 month study visit or at 
any study visit thereafter depending on tolerability.   
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 3 month study visit or 
at any study visit thereafter depending on tolerability.   
7.4 
Dose Titration Criteria 
After 6 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
Dose Titration Criteria 
After 3 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
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placebo (in a blinded manner) at the 6-month visit or any study visit 
following the 6-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
placebo (in a blinded manner) at the 3-month visit or any study visit 
following the 3-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
7.4.1 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, her or she should continue the regular 
visit schedule and continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination.  Early termination 
procedures should only be conducted if the subject withdraws 
consent. 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, he or she should continue the regular 
visit schedule and continue taking investigational product as long 
as the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination. 
7.5 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all subjects have 
completed the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the Study/Early Termination Visit. 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all events have been 
accrued, and when subjects are still active on the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the End of Study Visit. 
8.2 
Subject Inclusion Criteria  
2.  A mean total bilirubin >ULN and ≤3× ULN or an ALP >5× 
ULN 
4.  Either is not taking UDCA (UDCA naïve or no UDCA 
dose in the past 3 months) or has been taking UDCA for at 
least 12 months with an approved, stable dose for ≥3 months 
prior to Day 0 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
Subject Inclusion Criteria 
2.  A mean total bilirubin >ULN and ≤3× ULN and/or a mean ALP 
>5× ULN  
4.  Either is not taking UDCA (no UDCA dose in the past 3 
months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
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contraception during the study and for 30 days after the end of 
treatment visit. 
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:   
 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
 
Intrauterine device (IUD); 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 subject)  
 
 
8.3 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
3.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
4.  Other medical conditions that may diminish life expectancy 
to <2 years, including known cancers (except carcinomas in 
situ or other stable, relatively benign conditions such as chronic 
lymphatic leukemia) 
 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example, per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
3.  Mean total bilirubin >3× ULN 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
 
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5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of Screening (pretreatment) QT 
 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test), or lactating 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
 
5. Deleted text 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test by the central laboratory), or lactating 
 
8.4.1 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test. 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test performed at the central 
laboratory. 
8.4.2 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent. 
 
 
The following events are considered potential appropriate reasons 
for a subject to discontinue investigational product;…  
 
Withdrawal of Consent 
- 
Added text 
 
 
 
 
 
 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent (See Section 9.7.18 Early 
Discontinuation and/or Early Termination Procedures). 
 
The following events are considered appropriate reasons for a 
subject to discontinue investigational product; … 
 
Withdrawal of Consent 
- 
Consent may be fully withdrawn 
- 
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 potential adjudicated hepatic and/or 
cardiovascular events 
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The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study.   
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study.   
8.4.3 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study….This information must be documented in the CRF.  
If a subject is withdrawn from the study early (regardless of the 
cause), all of the end of treatment (EOT) evaluations should be 
performed at the time of withdrawal, as appropriate.  
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study….This information must be documented 
in the CRF.  If a subject is withdrawn from the study early 
(regardless of the cause), all of the (EOT/EOS) evaluations should 
be performed at the time of withdrawal, as appropriate (See 
Section 9.7.18 Early Discontinuation and/or Early Termination 
Procedures). 
9.1.1 
Dose Adjustment Beginning at Month 6 
After 6 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 6 visit, or at 
any study visit thereafter.   
Dose Adjustment Beginning at Month 3 
After 3 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 3 visit, or at 
any study visit thereafter.   
9.2 
Concomitant Medications 
Relevant information about all concomitant medications (including 
prescribed, over-the-counter, or herbal preparations) taken prior to 
(ie, within 30 days of Day 0) and during the study must be recorded 
in the source documents and CRF, as well as any dose or dose 
regimen changes that occur during the study.   
Concomitant Medications 
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 CRF, as well as any dose or 
dose regimen changes that occur during the study. 
9.2.1 
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.   
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.  Subjects that discontinue investigational product 
but continue commercial OCA therapy are expected to 
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continue through the end of the study, and the study will only 
terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.  Subjects 
will need to complete EOT procedures but continue with 
regularly scheduled visits until the study is terminated (See 
Section 9.7.18 Early Discontinuation and/or Early Termination 
Procedures). 
 
9.4 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN), 
as specified by the central laboratory.   
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and mean baseline bilirubin categories 
(>ULN/≤ULN), as specified by the central laboratory.   
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
 
Added text - New section inserted. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects will be made 
available to the Investigator for emergency use only 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 is necessary for further medical management of the 
subject).  If it is not reasonable to inform the Medical Monitor 
in advance of unblinding the Investigator must promptly 
document in the subject’s source record and should 
subsequently contact the Medical Monitor to explain any 
premature unblinding of treatment assignment (such as 
unblinding which is necessary in order to treat an SAE). 
Procedures for unblinding a subject’s treatment will be 
provided separately to the Investigator.  Similarly, if the 
Medical Monitor breaks the blind for an individual subject for 
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the purpose of evaluating an emergent safety issue, the Medical 
Monitor will document within trial documentation the 
rationale, circumstances, and the person or persons being 
informed about the unblinding. 
The Data and Safety Monitoring Committee (DSMC) will have 
access to the IWRS and will be able to unblind individual 
subjects.  Refer to Section 13.3 for further details regarding 
DSMC access to blinded and unblinded data.  The DSMC will 
document details about any unblinded subject data reviews in 
the closed session DSMC minutes, which will be made available 
to the Sponsor only after the database is locked and the trial is 
unblinded.   Cases of premature unblinding, as noted above, 
will also be reviewed by the DSMC.  
Access to treatment assignments will also be made available 
through the IWRS system to the appropriate named 
individual(s) responsible for reporting SAEs and suspected 
unexpected serious adverse reactions (SUSARs) to the 
Regulatory Authorities. 
9.6 
Restrictions 
No additional restrictions. 
Restrictions 
Participation in another investigation product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the trial is prohibited. 
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9.7.1 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Interval is ≤1 to 8 weeks prior to Day 
0, allowing for 2 Screening 2 visits to 
repeat biochemistry tests, and 
ensuring ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days. 
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (7 days)  
Quarterly visits (Months 
15 – EOT) 
±2 weeks (14 days) 
EOT 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOT = end of treatment 
 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening visit 1 interval is 3 to 8 
weeks prior to Day 0 for screening 
visit 1.  Screening visit 2 interval is 
1 to 6 weeks prior to Day 0.   The 
visit window for Screening 2 visits 
allows for the repeat biochemistry 
tests to be collected at least two 
weeks after the initial biochemistry 
sample was collected, and will 
ensure ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days, but 
screening procedures should not be 
performed during the last 7 days of 
the window.  
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (14 days)  
Quarterly visits 
(Months 15 – EOS) 
±2 weeks (14 days) 
EOT 
(When subject 
discontinues 
investigational 
product) 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOS 
(When subject 
terminates the study) 
The final study visit; EOS will 
occur concurrent with EOT if a 
subject discontinues study 
medication at the time the subject’s 
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participation in the study ends (eg, 
withdrawal of consent or study 
termination by the Sponsor); EOS 
will occur after the EOT if the 
subject discontinues study 
medication  but continues in the 
study. 
EOT = end of treatment 
EOS = end of study 
 
9.7.2 
Informed Consent Procedures 
 
Added text 
Informed Consent Procedures 
Any change in a subject’s consent status (eg, semi-annual 
telephone contact or medical record review) must be 
documented in a signed informed consent form or addendum.  
The subjects will be given a signed and dated copy of the 
consent document. 
9.7.3 
Screening Procedures (≤1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed ≤1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Subjects who 
do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects may be rescreened after 2 months; however, all Screening 
procedures should be repeated and a new 3-digit Screening number 
assigned.  
 
 
 
 
 
 
All subjects will have 2 bilirubin and ALP 
assessments at least 2 weeks apart including those 
subjects who qualify based on ALP criteria. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Screening 
Visit 1 will occur 3 to 8 weeks prior to Day 0; Screening Visit 2 
will occur 1 to 6 weeks prior to Day 0, depending on the date 
that the first serum chemistry sample was collected. Subjects 
who do not fulfill all eligibility criteria will not be enrolled in the 
study.  Subjects 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 3-digit Screening number 
assigned. 
 
 
All subjects will have 2 bilirubin and  ALP assessments at 
least 2 weeks apart 
 
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 
For subjects that do not qualify based on ALP alone 
(ALP >5×  
ULN), the mean of the 2 bilirubin assessments will be 
used to determine eligibility (total bilirubin >ULN 
and ≤3× ULN). 
  
 
 
 
Screening Visit procedures are as follows: 
 
Record prior (if within 30 days of Day 0) and current 
concomitant medications 
 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
 
In preparation for the dual emission X ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
 
 
 
Added text 
 
 
For subjects that do not qualify based on ALP alone (ALP 
>5× ULN), the mean of all available (at least 2; 
including both scheduled and unscheduled) bilirubin 
assessments will be used to determine eligibility (total 
bilirubin >ULN and ≤3× ULN).   
 
 
 
 
Screening Visit 1 procedures are as follows: 
 
Record prior (if within 30 days of Screening) and current 
concomitant medications 
 
Deleted text  
 
 
Deleted text 
 
 
 
 
 
 
Screening Visit 2 procedures are as follows: 
 
Verify inclusion and exclusion criteria for eligibility 
 
Assess and record any pretreatment-emergent AEs 
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 
Record current concomitant medications 
 
Verify that the subject has fasted for at least 8 hours 
- 
Record fasting status in the source and CRF 
- 
If the subject reports having eaten within 8 hours, 
document accordingly in the source and CRF and 
remind the subject that fasting is required prior to all 
study visits 
 
Obtain blood samples for serum chemistry tests 
 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
 
In preparation for the dual-emission X-ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
9.7.4 
Day 0 Procedures (Randomization) 
 
Subject questionnaires (see Section 12.2.5.1) 
 
 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE has 
been done within 3 months of Day 0 and a report/adequate data 
are available, a pretreatment TE at Day 0 is not required.   
 
 
 
Day 0 Procedures (Randomization) 
 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6.) 
 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE 
has been done within 6 months of Day 0 and a 
report/adequate data are available, a pretreatment TE at 
Day 0 is not required.  If the TE cannot be performed on 
Day 0 (e.g., device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the 
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 
 Conduct a DEXA bone density scan (at selected study sites, 
where available); document whether the subject stopped taking 
her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the 
scan, if applicable.  
 
 
 
 
 
 
 
 
Added text 
 
 
 
 
 
 
 
 
 
 
 
screening visit window, as close as possible to the Day 0 
visit, after subject eligibility has been confirmed.   
 
 Conduct a DEXA bone density scan (at selected study 
sites, where available); document whether the subject 
stopped taking her/his calcium supplements for 48 hours 
before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable.  If DEXA 
has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment 
DEXA at Day 0 is not required.  If DEXA cannot be 
performed on Day 0 (e.g., device/technician 
unavailability, scheduling issues, etc), the procedure 
may be completed within the screening visit window, as 
close as possible to the Day 0 visit, after subject 
eligibility has been confirmed. 
 
Perform an esophagogastroduodenoscopy (endoscopy; 
at selected study sites, where available) to assess the 
presence or absence of oesophageal varix/varices. If an 
endoscopy has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment endoscopy at Day 0 is not required. If the 
endoscopy cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
- 
Subsequent endoscopies should be performed 
annually or per standard of care and the 
Investigator’s clinical judgment throughout 
the course of the study.  Endoscopies should 
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 
Added text 
 
 
 
 
 
 
 
 
 
Added text 
 
 
 
 
 
 
 
Added text 
 
 
Record prior (within 30 days of Day 0) and current  
concomitant medications 
also be performed when platelet counts are 
<150 × 109 /L. 
 
Perform an ultrasound (if equipment is unavailable, 
sites should make every attempt to use available 
community referral sites) for HCC surveillance.  If an 
ultrasound has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment ultrasound at Day 0 is not required. If 
the ultrasound cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
 
 Review and record prior concomitant medications 
 
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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9.7.6 
Month 3 Procedures 
 
Added text 
 
Added text 
Month 3 Procedures 
 
Assess for dose titration, if eligible (refer to Section 7.4) 
 
Obtain blood samples for: 
- 
OCA, C4, and FGF-19 
9.7.7 
 
Month 6 Procedures 
 
Added text 
 
Month 6 Procedures 
 
 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 
 
Mayo Clinic Score and Child-Pugh Assessment 
 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.8 
Month 9 Procedures 
 
Added text 
Month 9 Procedures 
 
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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9.7.9 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.9), subjects who are participating in the PK assessment 
will each receive a single dose of investigational product (10 mg 
OCA tablet) with approximately 240 mL of water. 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours postdose.  Subjects should not drink additional water 
for 1 hour after taking the dose of investigational product and will 
remain fasted until the 4 hour sample is collected.  Lunch will be 
provided following collection of the 4 hour PK sample; the lunch 
will be a meal replacement drink. 
 
 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.12), subjects who are participating in the PK 
assessment will each receive a single dose of investigational 
product (blinded OCA or placebo tablet) with approximately 240 
mL of water. 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours post dose.  Samples should be collected within a 
window of ±5 minutes of the scheduled sample time.  Subjects 
should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until the 4 hour 
sample is collected.  Lunch will be provided following collection of 
the 4 hour PK sample; the lunch will be a meal replacement drink.  
Samples will be stored for up to 5 years after the end of the 
study and will be destroyed after 5 years if not analyzed. 
9.7.10 
 
Month 12 Procedures 
 
Subject questionnaires (see Section 12.2.5.1) 
 
 
Added text 
Month 12 Procedures 
 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
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o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.11 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
Subjects should come to the study center for a quarterly study 
visit for a clinical laboratory evaluation to collect blood samples 
for calculation of MELD score.  If the subject is not able to 
come to the study center for a visit, home visits may be 
arranged on a per subject basis. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
 
Deleted text 
 
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 
 
Mayo Clinic Score and Child-Pugh Assessment 
9.7.12 
Month 6 Continue Follow-up Procedures (Semi-annually [±2 
weeks]) 
 
Added text 
Month 6 Continue Follow-up Procedures (Semi-annually [±2 
weeks]) 
 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
 
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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9.7.13 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
 
Subject questionnaires (see Section 12.2.5.1) 
 
 
Added text  
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
 
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 physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.14 
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw Consent 
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw from Investigational Product or 
Withdraw Consent  
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
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Added text 
 
 
 
 
 
 
 
 
When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination or 
discontinuation (withdrawal of consent), an EOT visit must be 
performed as near as possible to her/his last dose of investigational 
product and the procedures, listed below, performed.  …  In these 
cases, the data will be recorded as EOT procedures in the CRF.  
 
 
Added table 
 
 
 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects 
discontinue treatment with investigational product.  The EOT 
visit and procedures listed below must be performed as close as 
possible to the subject’s last dose of investigational product.  
When a subject discontinues investigational product but 
continues with regularly scheduled study visits, the EOS visit 
will be completed later in the study as the subject’s final study 
visit.  The actual investigational product discontinuation 
scenario  
Table 7: 
Early Discontinuation Scenarios 
(Table 7) will determine the sequence of the EOT and EOS 
visits and procedures.  In some cases, the EOT visit and 
procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible 
to the subject’s last dose of investigational product.   
When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination 
(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.  ….  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 and EOS procedures in the 
CRF.  
Table 2: 
Early Discontinuation Scenarios 
 
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Investiga
tional 
Product 
Conse
nt 
Study 
Visit 
Status 
EOT 
Visita 
EOS 
Visita 
Early 
Terminati
on 
Discontin
ued 
Withdr
awn 
No 
additi
onal 
visits 
excep
t 
EOT/E
OS 
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
Treatmen
t 
Discontin
uation 
Discontin
ued 
Active 
Regul
ar 
Visit 
Sched
ule 
Comp
lete 
as 
close 
as 
possi
ble to 
last 
dose 
IP 
Comp
lete 
at 
Final 
study 
visit 
Discontin
ued 
Semia
nnual 
contac
tb 
Telep
hone 
conta
ct 
every 
6 
mont
hs (±2 
weeks
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
 
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Some assessments noted below may be omitted if they have been 
completed within the 3 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT Visit: 
During the EOT Visit: 
 
Subject questionnaires (see Section 12.2.6) 
 
Conduct a DEXA bone density scan (selected study sites); 
document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for 
osteoporosis or osteopenia on the day of the scan, if applicable 
 
 
 
Added text 
 
 
Added text 
 
 
Added text 
 
a Refer to Section 7.1.2 Schedule of Study Procedures for all procedures 
and evaluations required at the End of Treatment and End of Study Visits. 
b Outcomes data to be discussed or collected include data related to 
adjudicated hepatic and cardiovascular event-related data.  No additional 
data (e.g. AE, concomitant medication, etc) data will be collected, except 
as indicated in Section 12.1.7. 
Some assessments noted below may be omitted if they have been 
completed within the 6 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing 
Prior to the EOT/EOS Visit: 
During the EOT/EOS Visit 
 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
 
 Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
 
Subject and Quality of Life  questionnaires (see Section 
11.1.2.2 and Section 12.2.6) 
 
Perform TE (where available) using the Fibroscan® TE 
device (not required at EOT/EOS if done within 6 months) 
 
Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
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 
Added text 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites); not 
required at EOT/EOS if done within 6 months 
 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
 
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 
 
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.  [Added text]  As appropriate, the Medical 
Monitor should be contacted. 
 
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.   
In the event of an inexplicable and acute (for example not 
explained by natural progression of the chronic disease) 
increase in alanine aminotransferase (ALT) to >3× baseline 
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(and >upper limit of normal [ULN]) or total bilirubin >2× 
baseline (and >ULN), the subject should be followed by repeat 
testing within 48 to 72 hours of the serum chemistry to confirm 
the abnormalities and to determine if they are increasing or 
decreasing. AE information should also be collected.  If 
symptoms persist or repeat testing shows ALT >3× baseline 
(and >ULN) or total bilirubin >2× baseline (and >ULN), 
subjects should be followed until resolution of the abnormality 
and as clinically indicated depending on other laboratory and 
clinical signs and symptoms. 
 
As appropriate, the Medical Monitor should be contacted. 
 
10.4 
Investigational Product Preparation 
The investigational product will be provided in bulk bottles and 
therefore may be repackaged in unit dose form for administration to 
subjects. 
 
Investigational Product Preparation 
The investigational product will be provided to the distribution 
center in bulk bottles and therefore may be repackaged in unit dose 
form for administration to subjects before shipping to the sites. 
 
11.1.2 
Secondary Assessments 
 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Resource utilization information 
will be collected from CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician 
visits (subject reported), and use of concomitant medications.  
 
Secondary Assessments 
 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Quality of life will be assessed by 
questionnaires (PBC-40, EQ-5D-5L, and FIS) 
administered annually.  Resource utilization information will 
be collected from the Medical and Surgical Treatment 
Procedures and Office Visit Log or other CRFs such as 
number, type and duration of hospitalizations, number of 
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 
Added text 
outpatient physician visits (subject reported), and use of 
concomitant medications.  
 
Endoscopy will be conducted at selected study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual 
study assessments or standard of care will be collected in 
the case report form to assess for the development of 
varix/varices 
11.1.2.2 
 
Quality of Life questionnaires.   
 
Quality of Life questionnaires.  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: 
a. PBC-40: The PBC-40 (Jacoby 2005) 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. 
b. EQ-5D-5L:  The Eq-5D-5L consists of 2 sections – the 
descriptive system and the visual analogue scales (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 
respondent’s self-rate 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). 
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c. 
Fatigue Impact Score (FIS):  The FIS is a validated 40-
question questionnaire organized into 3 dimensions:  
cognitive, physical, and social.  Each dimension has 5 
levels:  no problem, small problem, moderate problem, 
big problem, and extreme problem (Fisk 1994) 
11.1.2.3 
 Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. The samples will be stored for up to 1 year after the 
end of the study and destroyed after 1 year if not analyzed. 
 
 Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their 
involvement in the study.  IRB/IEC review and approval 
will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will 
be stored for up to 1 year after the end of the study and 
destroyed after 1 year if not analyzed. 
 
12.1.1.2 
Serious Adverse Event 
 
Added text 
Serious Adverse Event 
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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12.1.4.2 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
  
All SAEs (including Potential Clinical Outcome Events that qualify 
as serious) must be reported to the medical monitor immediately 
(ie, within 24 hours) after the Investigator identifies the SAE…. 
 
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 investigational 
new drug (IND) safety reports (SUSARs) that occur during the 
study within the time frames required by each regulatory agency.  
The Investigator is responsible for submitting information on IND 
safety reports received from the Sponsor to her/his local IRB.  
Documentation of the submissions to IRBs and health authorities 
must be retained in the appropriate study file(s). 
 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
All SAEs occurring while subjects are receiving investigational 
product or are on an investigational product holiday (including 
Potential Clinical Outcome Events that qualify as serious) must be 
reported to the medical monitor immediately (ie, within 24 hours) 
after the Investigator identifies the SAE….  
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.  A SAE assessed with a possible, probable, or definite 
causal relationship to the investigational product and 
unexpected according to IB Reference Safety Information 
(RSI), is known as a suspected unexpected serious adverse 
reaction (SUSAR).  The Sponsor will notify the appropriate 
regulatory agencies as well as all participating Investigators of 
investigational new drug (IND) safety reports (SUSARs) that occur 
during the study within the time frames required by each regulatory 
agency.  The Investigator is responsible for submitting information 
on IND safety reports/SUSARs received from the Sponsor or 
Sponsor designee to her/his local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities must be retained in the 
appropriate study file(s). 
 
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12.1.6 
Notification of Post-Study SAEs 
 
Added text 
 Notification of Post-Study SAEs 
SAEs that occur more than 30 days after a subject has 
discontinued study medication, and are not considered related 
to investigational product, must still be reported in the EDC 
system; however, these events are not required to be reported 
within 24 hours.  At a minimum, the SAE term, event start and 
end date, severity, relationship to investigational product, 
action taken with study medication, treatment, outcome, and 
potential endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event summary, SAE 
details) may also be required to be entered, when requested by 
the sponsor. 
 
12.1.8 
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments.  
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments. The Sponsor may also 
follow the health of an infant born subsequent to use of 
investigational product. 
 
12.2.2 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page …. 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page for findings that appear after consent, and on the 
medical history CRF for any finding present prior to consent…. 
12.2.5.1 
12.2.5.1  Subject Questionnaires 
 
12.2.6 Subject Questionnaires 
12.2.6/12.2.7 
12.2.6   Laboratory Assessments 
Subjects testing positive for urine drug screen will be excluded 
from the study. 
12.2.7 Laboratory Assessments 
Deleted text 
 
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Table 4  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids, thyroid hormones (T3, 
T4, TSH) 
 
Table 5  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids 
 
12.2.6 
Laboratory Assessments 
 
Added text 
 
 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly visits based on serum chemistry and coagulation. 
 
12.2.7  Laboratory Assessments 
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. 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly (MELD scores only) and semi-annual visits based on 
serum chemistry and coagulation. 
 
13.1.5 
Additional Secondary Efficacy Analyses 
 
Added text 
Additional Secondary Efficacy Analyses 
 
Time to development of varix/varices 
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13.1.8 
Supportive Analysis 
Although the results of using matching are conditional only on the 
observed covariates, if one has the ability to measure many of the 
covariates that are believed to be related to the treatment 
assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained. 
 
Supportive Analysis 
Although the results of using matching controls are conditional 
only on the observed covariates, if one has the ability to measure 
many of the covariates that are believed to be related to the 
treatment assignment, then one can be fairly confident that 
approximately unbiased estimates for the treatment effect can be 
obtained. 
13.3 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study. In addition, the DSMC statistician 
will evaluate the sample size as described in Section 13.1.2.1. 
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.   
 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study.  
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.  The DSMC will document details about 
any unblinded subject data reviews in the closed session DSMC 
minutes, which will be made available to the Sponsor only after 
the database is locked and the trial is unblinded.   Cases of 
premature unblinding, as noted above, will also be reviewed by 
the DSMC.  
 
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16.2, Ethical 
Conduct of the 
Study 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles 
that have their origin in the Declaration of Helsinki (Seoul 
Revision, 2008) and are consistent with ICH/GCP, applicable 
regulatory requirements and the Sponsor’s policies. 
Ethical Conduct of the Study 
 The study will be performed in accordance with ethical principles 
and are consistent with ICH/GCP, local applicable regulatory 
requirements (in addition to Appendix C) and the Sponsor’s 
policies. 
19 
List of References 
 
Added text 
List of References 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional 
impact of fatigue: initial validation of the fatigue impact scale. 
Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
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 Dec;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), 1622-1629. 
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. 
 
Appendix C 
 
Added document 
Ethical Conduct according to the Declaration of Helsinki for 
Countries Participating Outside the US 
 
 
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APPENDIX E.  SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 (DATED 12 NOV 2015) 
Rationale 
The changes to Amendment 1 of the protocol, detailed below, generated specifically for regulatory authority requests, include an 
additional exclusion criteria and changes to text precluding UDCA naïve subjects from entering the study and clarifying information 
showing that OCA may increase the exposure of narrow therapeutic index drugs that are substrates for CYP1A2, thus answering 
questions raised by regulatory authorities. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.1.  (Note:  Revised text in Amendment 1.1 is indicated in 
bold font, and the text deleted from Protocol Amendment 1 is crossed out in the table below. Minor formatting changes are not listed.) 
Section 
Original Text (Amendment 1, 29 April 2015) 
Revised Text (Amendment 1.1, 12 November 2015) 
Title Page 
Original:  03 October 2014 
Amendment 1:  29 APRIL 2015 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Amendment 1.1:  12 November 201 
Study Personnel 
Contact 
Information 
Mobile:      
 (Pacific time zone) 
Telephone: 
 
Telephone 
 
(deleted) 
Telephone: 
 
(deleted)   
Synopsis, 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
Synopsis, 
Statistical 
Methods:  
Sample Size 
Justification 
 
5% of the subjects will have never been treated with UDCA; 
95% of the subjects will have been on UDCA for at least 1 
year 
(deleted) 
 
8.3 Subject 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
9.2 Concomitant 
Medications 
(insertion) 
The effect of OCA on drug metabolizing enzymes has been 
evaluated in both in vitro and clinical studies.  The PK profile 
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of caffeine, a sensitive CYP1A2 substrate, 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. 
12.1.4.2 
Reporting of 
Serious Adverse 
Event 
Mobile:      
 (Pacific time zone) 
Telephone: +1 858 964 1571 
(deleted) 
Telephone: 
   
13.1.2 
Determination of 
Sample Size 
5% of the subjects will have never been treated with UDCA; 95% 
of the subjects will have been on UDCA for at least 1 year 
(deleted) 
 
 
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APPENDIX F. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 (DATED 07 SEPTEMBER 2016) 
Rationale 
The changes to Version 3 of the protocol, include dosing adjustments based on Child-Pugh scoring, additional exclusion criteria, 
changes to text precluding UDCA-naïve subjects from entering the study.  
Please note that the Sponsor has renamed protocol “amendments” to “versions”, therefore all future revisions that require a revised 
protocol will have an associated “version” number. The table below includes substantial revisions made to Protocol 747-302 under 
Version 3, which encompass the revisions captured in Protocol Amendment 1.1. Revised text in Version 3 is indicated in bold font, 
and the text deleted from Protocol Amendment 1.1 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 (Amendment 1.1, 
29 April 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology 
...  Mean values for ALP and total bilirubin 
will be calculated using all available 
screening values.  Subjects who meet all 
inclusion criteria and none of the exclusion 
criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The 
randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment 
(yes/no) and baseline bilirubin categories 
(>upper limit of normal [ULN]/ ≤ULN). 
Investigational product (OCA or matched 
placebo) will be taken orally, once daily.  
Investigational product will be initiated at 5 
mg OCA or matched placebo.  After 3 
months of treatment with investigational 
product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched 
placebo, in a blinded manner) at the 3-
month visit or any subsequent study visit 
based on tolerability.  Subjects will be seen 
at quarterly visits for the duration of the 
study. 
...  Investigational product will be taken orally, once daily 
for the majority of subjects; dose and frequency will be 
modified for subjects with cirrhosis (including subjects 
progressing to cirrhosis during the study) and 
classified as Child-Pugh B or C.  The randomization will 
be stratified by ursodeoxycholic acid (UDCA) treatment 
(yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
To incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores, 
to align with the 
recommended dosing 
regimen found in the 
Ocaliva US Package Insert 
for patients with hepatic 
impairment. 
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29 April 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology. 
7.1.1, Study 
Design Diagram, 
Figure 1 
Schematic diagram
 
Updated schematic diagram 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.  Subsequent dose titration(s) for subjects 
classified as Child Pugh B or Child-Pugh C and 
following a modified dosing schedule may occur no 
earlier than 6 weeks after the previous dose titration 
Incorporate updated dosing 
scheme to reflect addition of 
Child-Pugh scoring. 
Synopsis, 
Methodology 
(insertion) 
Dosing frequency will be determined by the presence 
or absence of cirrhosis and, if cirrhosis is present, by 
Child-Pugh Score as described below: 
• 
Non-cirrhotic subjects or subjects classified as 
Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects 
should titrate to a maximum dose of 10-mg OCA once 
daily (or matching placebo) at the Month 3 visit or at 
any study visit following the Month 3 visit based on 
tolerability of the product.    
• 
For those subjects that up-titrate to 10 mg, dosing 
may be decreased to 5 mg at any time during the study 
as considered clinically appropriate (eg, based on 
tolerability). Subjects may be titrated back to a 
maximum dose of 10 mg once daily based on 
tolerability and clinical judgment of the Investigator.    
• 
 Subjects who are cirrhotic and classified as Child-
Pugh Class B or Child-Pugh Class C will initiate a 
modified treatment regimen with 5-mg OCA or 
matching placebo once weekly for at least 3 months.  
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5-mg OCA or 
Revised methodology to 
incorporate the changes in 
dosing for subjects based on 
the Child-Pugh Scores. 
 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
matching placebo once daily, based on tolerability.  
Subjects classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 10-mg 
OCA or matching placebo twice weekly, based on 
tolerability. 
Includes New Table: Planned Dosing Regimen by 
Cirrhosis and Child-Pugh Score 
5.1, Overview 
(insertion) 
The United States Food and Drug Administration 
(FDA) has granted accelerated approval for OcalivaTM 
for the treatment of PBC.  Ocaliva is not yet approved 
outside the United States for use in any indication. 
Language updated as OCA 
is approved in the US with 
the trade name Ocaliva. 
5.5.2.2, Rationale 
for Modified OCA 
Doses in Patients 
Classified with 
Child-Pugh B or 
Child-Pugh C 
Hepatic 
Impairment 
(Insertion) 
New section: Rationale for Modified OCA Doses in 
Patients Classified with Child-Pugh B or Child-Pugh C 
Hepatic Impairment 
Simulations using a physiologic PK model predicted 
changes in systemic and liver OCA concentrations 
associated with changes in the severity of hepatic 
impairment (Child-Pugh score).  Model simulations 
predicted that for mild (Child-Pugh A), moderate 
(Child-Pugh B), and severe (Child-Pugh C) hepatic 
impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to subjects 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 (Child-Pugh B and C) 
subjects treated with OCA in phase 1 and 2 studies 
experienced plasma OCA exposures >10-fold higher 
than those in healthy subjects, no apparent impact on 
the overall safety profile was observed, consistent with 
Provide the rationale to 
incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores 
into the protocol. 
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Justification for Change 
only a modest increase in liver exposure of OCA 
associated with hepatic impairment.  Collectively, the 
results from these analyses and those from bile acids in 
the literature suggest that the doses of OCA 
administered to hepatically-impaired patients should 
be modestly lower than those for patients with normal 
hepatic function to achieve similar hepatic exposure.   
Per the approved FDA prescribing label, the 
recommended dosing regimen for OCA in subjects 
with moderate and severe hepatic impairment is a 
starting dose of 5-mg OCA once weekly.   Dosage 
adjustments in subjects with moderate (Child-Pugh B) 
or severe (Child-Pugh C) hepatic impairment may be 
made after establishing tolerability at the lower dose 
(full modified dosing regimen is described in 
Appendix A). 
5.6, Summary of 
Known Potential 
Risks with OCA 
(Insertion) 
…These findings were seen more frequently with doses 
above 10 mg OCA.  In addition, cholecystitis, including 
acute cholecystitis, was reported in association with 
treatment with OCA. 
Added two AE terms 
reported in the updated 
Investigator’s Brochure. 
7.1, Overall Study 
Design 
…Investigational product will be initiated 
at 5 mg OCA or matched placebo.   
Following 3 months of treatment with 
investigational product, subjects should be 
titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose 
to 10 mg OCA) based on tolerability 
Investigational product will be taken orally, once daily.  
Subjects who are non-cirrhotic or classified as Child-
Pugh A at Screening will initiate investigational 
product once daily with 5-mg OCA or matching 
placebo. Following 3 months of once daily treatment with 
investigational product, the dose should be titrated to a 
maximum 10 mg OCA or matching placebo once daily, 
based on tolerability (see Section 7.3).  
Subjects with cirrhosis and classified as Child-Pugh 
Class B or Child-Pugh Class C will follow a modified 
dosing regimen, and will initiate investigational 
product once weekly with the 5-mg OCA or matching 
placebo dose.  In addition, these subjects will follow a 
modified titration plan, which is outlined in 
Appendix A.  
Amend the protocol to 
incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
7.1.2, Table 1, 
Schedule of Study 
Procedures – 
Screening to 
Month 12 (Table 1 
of 2), 9.3, 
Treatment 
compliance 
Safety Contact 
This visit has been deleted. 
Replaced with the 1 Month 
Post-Titration Visit. 
(Insertion) 
Added the following visits: 
 
Month 1 
 
1 Month Post-Titration Visit 
Visits were added to 
accommodate the updated 
dosing and titration regimen 
based on subject’s 
Child-Pugh Scores. 
bThe subject should be contacted by 
telephone on a monthly basis in between at-
clinic study visits at Month 1 and Month 2 
(± 1 week), and also 2 weeks post dose 
titration (up or down), to assess for AEs and 
concomitant medications and to verify that 
s/he is dosing as directed. 
cAs soon as possible upon study 
discontinuation and as near as possible to 
last dose taken. 
nSubject to begin dosing on Day 1 
Deleted. 
Result of table being 
updated for the dosing and 
titration regimen based on 
subject’s Child-Pugh Scores. 
(Insertion) 
Added the following study procedures: 
 
Cirrhosis Status Assessmente 
 
Assessments for Child-Pugh Scoresg 
 
Dose Titration: Standard Dosingn,o 
 
Dose Titration: Modified Dosing n,o 
 
Dosing Diary 
Study procedures were 
added to accommodate the 
updated dosing/titration 
regimen.  Dosing diary was 
added to improve 
compliance. 
(Insertion) 
Added the following footnotes: 
 
bSafety Post-Titration visits must be performed 
1 month + 1 week after any up-titration in dose 
and/or 
frequency 
in 
subjects 
following 
modified dosing due to Child-Pugh B and 
Child-Pugh C hepatic impairment.  In subjects 
following the standard dosing regimen, the 
post-titration visit must be performed only after 
Added footnotes provide 
clarity regarding 
assessments and visits based 
on the evaluation of 
Child-Pugh scores.  
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the first up-titration to 10 mg OCA or matching 
placebo, or after ≥3 months at a decreased dose 
or frequency. 
 
ePresence or absence of cirrhosis should be 
assessed per Section 9.7.3.  Cirrhosis status 
should be repeated as clinically indicated. 
 
fMayo Risk Score will be calculated based on 
central laboratory evaluations, diuretic use data, 
and peripheral edema assessment data captured 
in the CRF. 
 
gChild-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. 
 
nPre-titration tolerability assessment, which 
include a review of AEs and a review of safety 
laboratory results (eg, chemistry, hematology, 
and coagulation), must be completed by the 
Investigator before any up-titration can occur as 
defined in Section 7.4.1.  Lab results obtained 
within 2 months prior to any up-titration may be 
used for assessment. 
 
oDose Titration is based on cirrhosis status 
(Section 9.7.3) 
and 
Child-Pugh 
score 
(Section 7.3).  The initial dose titration of 
investigational product may occur at the Month 
3 visit, or any study visit thereafter for subjects 
on all dosing regimens, based on tolerability.  
Subsequent dose titration(s) for subjects who 
are classified as Child-Pugh B or Child-Pugh C 
and following a modified dosing schedule may 
occur no earlier than 6 weeks after the previous 
dose titration.  For complete modified dose 
titration criteria, refer to Appendix A. 
 
pSubjects will be instructed to begin dosing on 
the day after the Day 0 visit (ie, on Day 1) and 
to take investigational product at approximately 
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the same time of day.  Subjects must be 
instructed to swallow the tablet whole; they 
must not chew, divide, or crush the tablet. 
7.1.2, Table 2, 
Schedule of Study 
Procedures – Year 
2 Through End of 
Study (Table 2 of 
2) 
 
New table- Schedule of Study Procedures – Year 2 
Through End of Study (Table 2 of 2) 
Divided Schedule of Study 
Procedures into 2 tables, 
updated to include visits 
added per updated 
dosing/titration information.   
7.3, Planned 
Dosing Regimen 
7.3 Treatment Assignment 
Subjects will receive either placebo or 5 mg 
OCA and should titrate to 10 mg OCA (in a 
blinded manner) at the 3-month study visit 
or at any study visit thereafter depending on 
tolerability. 
7.3 Planned Dosing Regimen 
Subjects will be randomized to treatment with either 
OCA or matching placebo in a 1:1 ratio.  Subjects will 
be dosed according to their cirrhosis status (as defined 
in Section 9.7.3) and applicable Child-Pugh Score (see 
Section 9.7.4) as outlined in Table 3.  
Subjects who are non-cirrhotic or classified as 
Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects 
should titrate to a maximum dose of 10-mg OCA once 
daily (or matching placebo) at the Month 3 visit or at 
any study visit following the Month 3 visit based on 
tolerability of the product.  A review of safety 
laboratory results (eg, chemistry, hematology, and 
coagulation) obtained no more than 2 months prior to 
the planned up-titration visit must be completed as 
part of the product tolerability assessment before up-
titration can occur (see Section 7.4.1).   
For those subjects that up-titrate to 10 mg, dose may 
be decreased to 5 mg at any time during the study as 
considered clinically appropriate (eg, tolerability). 
Subjects may be titrated back up to a maximum dose 
of 10 mg once daily based on tolerability and clinical 
judgment of the Investigator.  A review of safety 
laboratory results obtained within 2 months of the 
planned up-titration visit date is not required prior to 
Section renamed to reflect 
changes in titration and 
dosing for subjects with 
hepatic impairment. 
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re-challenging a subject up to 10 mg once daily dosing, 
as long as the decrease in dose/dosing frequency was 
less than 3 months in duration. 
(Insertion) 
New:  Table 3: Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
Tables added to clarify 
changes in titration and 
dosing. 
New:  Table 4: Determination of Dosing Regimen 
7.4 Dose Titration 
Criteria 
After 3 months of treatment at the 5 mg 
dose, the dose of OCA will be increased to 
the maximum dose of 10 mg OCA or 
matched placebo (in a blinded manner) at 
the 3-month visit or any study visit 
following the 3 month visit based on 
tolerability of investigational product.   
 
For those subjects that increased their dose 
to 10 mg, they may decrease his or her dose 
to 5 mg at any time during the study as 
considered appropriate (eg, tolerability), but 
should be titrated back to 10 mg based on 
tolerability and clinical judgment by the 
Investigator as soon as possible with the 
goal that all subjects remain on the 10-mg 
dose if tolerated 
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 
subject’s cirrhosis status (using histology or 
non-histological methods as defined in Section 9.7.3 
and Section 9.7.4) or Child-Pugh Score.   
Scheduled Dose Titration - The first dose titration for 
any subject may occur no earlier than 3 months 
following initiation of OCA or matching placebo.  
Subsequent titrations in dose or dosing frequency for 
subjects following the Modified Dosing Regimens may 
occur no earlier than 6 weeks (via an unscheduled visit 
or regular visit- see Appendix A) following an 
up-titration. 
Tolerability Dose Titration - Investigators may 
decrease the dosing frequency or dose for any subject at 
any time during the study, as considered clinically 
appropriate (eg, tolerability; see Section 7.4.2).   
Dose Titration due to Change in Cirrhosis or 
Child-Pugh Score - When subjects demonstrate a 
change in cirrhosis status (as assessed per 
Section 9.7.3) or Child-Pugh Score (Section 9.7.4), 
dosing should be reassessed and the dosing regimen 
modified appropriately.  Changes to the dosing 
regimen are not mandatory and should be based on 
clinical judgment as well as change in cirrhosis status.  
Table 5 provides an overview of the possible changes in 
dosing regimen due to changes in cirrhosis or Child-
Entire section revised to 
reflect changes in titration 
and dosing. 
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Pugh 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.  
7.4 Dose Titration 
Criteria 
(Insertion) 
New: Table 5:  Changes in Dosing Regimen Due to 
Changes in Cirrhosis Status or Child-Pugh Score 
Section and table added to 
provide dosing guidelines to 
investigators. 
7.4 Dose Titration 
Criteria 
(Insertion) 
Subjects who exhibit development of cirrhosis at any 
point in the study should be assessed per Section 9.7.3.  
If the presence of cirrhosis is confirmed and the 
subject’s Child-Pugh score is either B or C, the 
appropriate modified dosing regimen should be 
followed.  The dose or frequency of investigational 
product should be down-titrated to the next lowest 
dosing frequency in the appropriate modified dosing 
regimen unless the subject is currently taking a dose 
and frequency also specified in the modified dosing 
regimen and the investigator determines that it is 
clinically appropriate for the subject to continue at 
that dose (Appendix A). 
Subjects with pre-existing cirrhosis who demonstrate a 
change in the Child-Pugh Score from A to B or C at 
any point in the study should also have their dosing 
modified per the appropriate dosing regimen 
(Appendix A).  
Subjects who demonstrate an improvement in 
cirrhosis status or in Child-Pugh Score from B to A, or 
from Child-Pugh C to B, may be eligible to transition 
to the standard dosing regimen or the modified dosing 
for Child-Pugh B, respectively, based on tolerability.  
Prior to any dosing change, subjects must meet 
pre-titration assessment requirements for dosing as 
described in Section 7.4.1. 
Child-Pugh Scores will be calculated at all quarterly 
study visits. All associated visit data (including central 
laboratory results) should be entered into the eCRF in 
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a timely fashion to confirm that the subject’s Child 
Pugh Score has not changed.  If a change in cirrhosis 
status (as defined in Section 9.7.3) and/or Child-Pugh 
Score is observed independent of a study visit, the 
subject 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. 
Subjects’ dose and dosing frequency may be titrated 
up or down within the appropriate dosing regimen 
based on the calculated Child-Pugh Scores.  Up-
titration should be done per Investigator discretion 
and be guided by the pre-titration tolerability 
assessments. 
7.4.1, 
Pre-Titration 
Tolerability 
Assessment 
Requirements 
(Insertion) 
7.4.1  Pre-Titration Assessment Requirements 
Tolerability of investigational product must be 
assessed prior to titrating a subject to a higher dose.  A 
review of adverse events and safety laboratory results 
(eg, chemistry, hematology, and coagulation) obtained 
within 2 months of the up-titration visit must be 
performed as part of the investigational product 
tolerability assessment, prior to any planned up-
titration in study medication (eg, Month 3, Month 6).  
Safety laboratory results obtained at the Month 1 visit 
(for titration at Month 3) or at the 1 Month 
Post-Titration Assessment visit (for titration prior to 
or at the subsequent quarterly visit) are acceptable for 
review purposes; however, 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 subject to a higher dose.  
To be eligible for a dose up-titration: 
• 
Subjects should not be experiencing significant 
AEs that are suspected to be related to investigational 
Section added to provide 
guidance for assessing 
subject tolerability prior to 
titration. 
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product (eg, severe pruritus) or displaying other 
symptoms that may indicate intolerability of 
investigational product.  
• 
There must be no clinically significant increase (as 
determined by the investigator) in the subject’s liver 
function tests.  Subjects whose total bilirubin is 
>2× baseline (and >ULN) cannot be up-titrated, and 
additional unscheduled safety visit procedures, 
outlined in Section 9.7.19, should be implemented, as 
required 
8.4.2, Other 
Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
(Insertion) 
 
• 
Subject begins treatment with commercially 
available OCA 
… safety concerns and related to study drug 
• 
Consent may be fully withdrawn (in which case the 
subject discontinues both investigational product and 
study visits and procedures) 
…Subjects who undergo a liver transplant during the 
course of the study must discontinue investigational 
product and discontinue the study visit schedule.  
However, these subjects 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. 
Added text as Ocaliva is 
commercially available in 
the US and therefore 
subjects may be 
discontinued if they began 
off-study treatment with 
Ocaliva.   
8.4.2.1, Elevated 
Liver Enzymes 
(Insertion) 
New Section:  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 
Section added to incorporate 
monitoring of liver test 
results during the study. 
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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. 
9.1, 
Investigational 
Product Treatment 
Regimen 
9.1.1 Dose Adjustment Beginning at 
Month 3 
After 3 months of treatment with 
investigational product, the dose of 
investigational product should be increased 
in a blinded manner and based on 
tolerability; this may occur at the Month 3 
visit, or at any study visit thereafter.  
Titration above 10 mg OCA is not 
permitted. 
At each study visit where the daily dose of 
investigational product is administered at the site, all 
assessments, except for the post-dose collection of 
blood samples for the subset of subjects participating 
in the Month 9 PK assessment, must be completed 
before administration of investigational product. 
Section revised to reflect 
changes in titration and 
dosing. 
9.2, Concomitant 
Medications 
Subjects taking bile acid sequestrants 
(BAS) 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). 
 
New sub-heading:   
Drug Interactions 
Subjects 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 INR levels, therefore, INR should be 
monitored and the dosage of warfarin adjusted, as 
Section revised to provide 
additional information on 
drug-drug interactions with 
OCA. 
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needed during treatment with OCA and after cessation 
of OCA, to maintain the target INR range.  
(…) Information related to additional drug-drug 
interaction (DDI) studies is available in the current 
version of the Investigator’s Brochure (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 with OCA that may 
be observed in study subjects. 
9.2.1, Prohibited 
Medications 
… the Investigator should be cognizant of 
the possibility of double dosing and 
encourage the discontinuation of open-label 
OCA therapy.  However, if commercial 
OCA therapy remains, then investigational 
product should be discontinued to avoid 
potential double dosing.  Subjects that 
discontinue investigational product but 
continue commercial OCA therapy are 
expected to continue through the end of the 
study, and the … 
… the Investigator should be cognizant of the possibility 
of double dosing.  Subjects who continue with 
commercial OCA therapy must discontinue study 
medication and are expected to continue through the end 
of the study.  … 
Ocaliva is commercially 
available in the US and, 
therefore, subjects wishing 
to take commercially 
available drug are not 
discouraged, but they must 
discontinue study 
medication. 
9.7.1, Visit 
Windows 
(insertion) 
Added the following visit windows: 
 
Month 1 (+1 week [7 days]) 
 
Titration Visit – Standard Dosing Regimen 
(≥Month 3) 
 
Titration Visit 1 – Modified Dosing Regimen 
(≥Month 3) 
 
Titration Visit 2 – Modified Dosing Regimen 
(≥6 weeks after Titration Visit 1) 
 
Titration Visit 3 – Modified Dosing Regimen 
(Child-Pugh B ONLY) (≥6 weeks after 
Titration Visit 2) 
 
Post-Titration Visit, (+1week [7 days]) from 
date of titration or after ≥3 months at a 
decreased dose or frequency) 
Added visits to 
accommodate the updated 
dosing/titration scheme. 
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9.7.3, Assessing 
Cirrhosis 
(Insertion) 
New: 9.7.3. Assessing Cirrhosis 
To determine which dosing regimen subjects should 
follow, the presence or absence of 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 
is defined as a subject 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  
 
elevation in prothrombin time /INR (not 
due to antithrombotic agent use), or 
 
elevated bilirubin (2× ULN) 
Subjects who exhibit no evidence of cirrhosis by the 
above methods of assessment will be dosed using the 
Standard Dosing Regimen, while those who do exhibit 
evidence of cirrhosis by one or more of the above 
methods will be dosed using the Modified Dosing 
Regimen according to their Child-Pugh Score 
calculated in the electronic case report form (eCRF) 
(see  Appendix A). 
Added section to assess 
cirrhosis as this assessment 
will determine the 
acceptable dosing regimen 
based on a subject’s 
Child-Pugh score.  
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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, Child-Pugh 
Score 
(Insertion) 
9.7.4. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is 
calculated and reported within the electronic data 
capture (EDC) system based on data entered into the 
eCRF adding the scores from the 5 factors outlined in 
Table 6 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 
Child-Pugh 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.   
It is important to note that subjects must have 
confirmed cirrhosis as assessed by one or more of the 
above criteria (Section 9.7.3) prior to applying the 
calculated Child-Pugh score for dosing.  Investigators 
will be responsible for determining the appropriate 
dosing regimen based on both the cirrhosis status and 
the Child-Pugh score (Table 6).  Any change in 
cirrhosis status or Child-Pugh Score will necessitate 
re-evaluation of the dosing regimen 
Section added to provide 
Investigators with 
information on the 
Child-Pugh scoring system. 
9.7.4, Child-Pugh 
Score 
(Insertion) 
Table 6 (New)  Child-Pugh Scoring System 
 
9.7.6, Screening 
Procedures (1 to 8 
(Insertion) 
The following procedures were added: 
Screening Visit 1 procedures are as follows: 
 
Provide the subject with a dosing diary to 
Procedures added to assess 
cirrhosis. 
 
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Weeks prior to 
Day 0) 
document his or her dosing 
 
Assess for the presence/absence of cirrhosis 
 
Perform status assessment for calculation of 
Mayo Risk Score 
Screening Visit 2 procedures are as follows: 
 
Perform an ultrasound for hepatocellular 
carcinoma (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 Visit 2, and a report/adequate data are 
available, a pretreatment ultrasound at Screening 
Visit 2 is not required.  If the ultrasound cannot 
be performed at Screening Visit 2 (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. 
9.7.7, Day 0 
Procedures 
(Randomization) 
9.7.4. 
Day 0 Procedures 
• 
Perform an ultrasound for 
hepatocellular carcinoma (HCC) 
surveillance (if equipment is unavailable, 
… 
• 
Perform physical examination and 
overall status assessment for calculation of 
Mayo Risk Score and Child-Pugh 
Assessments. 
 Presence/absence of peripheral edema 
 Presence (degree)/absence of ascites 
 Presence (degree)/absence of hepatic 
encephalopathy 
9.7.7: Day 0 Procedures (Randomization) 
• 
Provide the subject with a dosing diary to 
document his or her dosing. 
 
Updated visit to 
accommodate the updated 
dosing/titration scheme. 
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9.7.8, Month 1 
Procedures 
9.7.5 Safety Contact (Month 1, Month 2, 
and 2 Weeks Post-Titration [by telephone]) 
9.7.8 Month 1 Procedures 
• 
Provide the subject with a dosing diary to 
document his or her dosing. 
• 
In the event it is not feasible for the subject to 
return to the site for the above referenced procedures, 
the following alternative visit procedures are available 
to help ensure compliance with the Month 1 visit 
requirements: 
- 
At the Day 0 visit, the subject can be provided 
with the central laboratory collection kit and shipping 
materials associated with the Month 1 visit, … 
- 
If all other options for the collection of the Month 
1 laboratory samples have been exhausted, the use of a 
local laboratory for the Month 1 samples would be 
accepted for this visit although any laboratory data 
obtained from a local laboratory will not be captured 
in the eCRF or included in the study analysis.  … 
 
Revised section to include 
the new Month 1 visit 
procedures.  
9.7.9, Month 3 
procedures, 
9.7.11, Month 6 
Procedures, 
9.7.12, Month 9, 
9.7.14, Month 12 
Procedures  
(Insertion) 
• 
Perform assessments for calculation of Child-Pugh 
Score 
Added procedure to 
accommodate the updated 
dosing/titration scheme. 
9.7.9 thru 9.7.17 
(Insertion) 
If up titration will occur at this visit, complete the pre-
titration visit and visit related assessments as outlined 
to ensure all procedures required for dose titration 
eligibility have been met, including the required review 
of the dose titration laboratory parameters. 
 
Provide the subject with a dosing diary to 
document his or her dosing 
Text added to clarify 
procedures required before 
up-titration. 
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 
… review dosing diary with the subject 
9.7.10, Post 
Titration Visit 
Procedures 
(Insertion) 
New: 9.7.10. Post Titration Visit Procedures 
• 
Assess and record AEs. 
• 
Review and record concomitant medications. 
• 
Assess investigational product compliance, 
perform investigational product accountability, and 
review dosing diary with the subject. 
• 
Obtain blood samples for serum chemistry, 
hematology, and coagulation tests. 
• 
Provide the subject with a dosing diary to 
document his or her dosing. 
• 
In the event it is not feasible for the subject to 
return the site for the above referenced procedures, 
the following alternative visit procedures are available, 
to help ensure compliance with the Post-Titration visit 
requirements: 
- 
At the Up-titration Visit, the subject can be 
provided with the central laboratory collection kit 
and shipping materials associated with the Post-
Titration visit, and have the laboratory specimen 
collection performed at his or her local doctor’s 
office or designated laboratory collection center.  
The subject must also be contacted via telephone 
at the Post-Titration Visit time point to assess 
AEs, review concomitant medications, and assess 
investigational product compliance. 
- 
If all other options for the collection of the 
Post-Titration laboratory samples have been 
exhausted, the use of a local laboratory for the 
Post Titration samples would be accepted for this 
visit although any laboratory data obtained from 
a local laboratory will not be captured in the 
eCRF or included in the study analysis.  A copy of 
the local laboratory report would need to be 
Added visit to accommodate 
the updated dosing/titration 
scheme. 
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provided to the investigator for review and 
available in the source records.  The subject must 
also be contacted via telephone at the Post-
Titration Visit time point to assess AEs, review 
concomitant medications, and assess 
investigational product compliance. 
• 
Schedule the next visit, reiterate dosing 
instructions, and advise the subject: 
- 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… 
9.7.13, Month 9 
Procedures for 
Subjects 
Participating in 
Pharmacokinetic 
Assessment 
(Insertion) 
…Subjects who are following the Child-Pugh B and 
Child-Pugh C modified dosing regimen may 
participate in the PK assessment and will dose in the 
clinic at this visit even if the previous dose was taken 
less than 3 days prior; however, every attempt should 
be made to schedule the Month 9 PK visit according to 
the subject’s established dosing schedule. 
Clarify that subjects with 
hepatic impairment may 
continue to participate in the 
PK assessment. 
9.7.13, Month 9 
Procedures for 
Subjects 
Participating in 
Pharmacokinetic 
Assessment 
…Lunch will be provided following 
collection of the 4 hour PK sample; the 
lunch will be a meal replacement drink… 
…Lunch will be provided following collection of the 4 
hour PK sample; the lunch will be a meal replacement 
drink with no other food allowed until after the final 6-
hour post dose sample is collected… 
Clarify PK collection 
procedures. 
 
11.1.2.2, Other 
Secondary 
Assessments 
• 
OCA (and its conjugates) and C4 will 
be assayed 
• 
OCA (OCA, tauro-OCA, glyco-OCA, total OCA, 
OCA glucuronide) and C4 will be assayed to determine 
bioanalytical concentrations.  Additional analyses may 
include other conjugates or metabolites not yet 
identified. 
Clarify the analytes to be 
measured for the PK 
analyses. 
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Original Text (Amendment 1.1, 
29 April 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
11.1.2.4, Potential 
Clinical Outcome 
Events 
(Insertion) 
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 13.4. 
Revised to clarify that 
potential clinical outcome 
events meeting the criteria 
of a SUSAR will not be 
reported to regulatory 
authorities expeditiously.  
12.1.4.2 Reporting 
of Serious 
Adverse Event 
In agreeing to the provisions of this 
protocol, the Investigator accepts all legal 
responsibilities for immediate reporting of 
SAEs to the medical monitor. 
All SAEs occurring while subjects are 
receiving investigational product or are on 
an investigational product holiday 
(including Potential Clinical Outcome 
Events that qualify as serious) must be 
reported to the medical monitor 
immediately (ie, within 24 hours) after the 
Investigator identifies the SAE.  SAEs are 
reported by entering the SAE data into the 
electronic data capture (EDC) system.  
Entering the SAE data into the EDC system 
will automatically notify the medical 
monitor of the event.  In the event that the 
EDC system is inaccessible, an SAE may 
be reported by telephone or fax using a 
paper SAE Report form.  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 
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 be reported by: 
• 
E-mail to the SAE email address:  
sae@interceptpharma.com 
• 
Fax using a paper SAE report form:  
+1 800 497 8521 
• 
Telephone:  +1 858 964 1571  
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:   
• 
Subject number  
Updated guidance for 
reporting SAEs. 
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Justification for Change 
information should be provided at the time 
of the initial report:   
subject number and initials, a description of 
the event, at least one criterion classifying 
the event as serious and the name and title 
of the reporting individual.  Additionally, 
judgment of causality by the Investigator 
must be provided as soon as possible to 
ensure timely reporting to regulatory 
authorities by the Sponsor or designee(s).  
Following the initial report, any additional 
information obtained by the Investigator 
about the SAE must be reported promptly 
to the medical monitor.  Any supporting 
source documentation should be faxed to 
+1 800 497 8521 or emailed to 
sae@interceptpharma.com as soon as 
possible. 
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.  A 
SAE assessed with a possible, probable, or 
definite causal relationship to the 
investigational product and unexpected 
according to IB Reference Safety 
Information (RSI), is known as a suspected 
unexpected serious adverse reaction 
(SUSAR).  The Sponsor will notify the 
appropriate regulatory agencies as well as 
all participating Investigators of 
investigational new drug (IND) safety 
reports (SUSARs) that occur during the 
study within the time frames required by 
• 
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 Sponsor will notify the appropriate regulatory 
agencies as well as all participating Investigators of 
investigational new drug (IND) 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 
+1 800 497 8521 or emailed to 
sae@interceptpharma.com as soon as possible.   
The Investigator is responsible for submitting 
information on IND 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 
IECs/IRBs must be retained in the appropriate study 
file(s).  As instructed by the Sponsor, IND 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 12.1.5. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
each regulatory agency.  The Investigator is 
responsible for submitting information on 
IND safety reports/SUSARs received from 
the Sponsor or Sponsor designee to her/his 
local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities 
must be retained in the appropriate study 
file(s). 
Potential Clinical Outcome Events 
(Appendix A) as well as Anticipated Events 
(Appendix B) will not undergo expeditious 
reporting to regulatory authorities 
Section 12.1.5, 
Suspected Liver-
related Clinical 
Outcome Events 
Clinical Outcome Events (Appendix A) as 
well as Anticipated Events (Appendix B) 
will not undergo expeditous reporting. 
12.1.5 Suspected Liver-Related Clinical Outcome 
Events 
Specified liver-related clinical outcome events may, by 
definition (see Section 12.1.1.2) qualify as SAEs.  The 
Sponsor must be notified of any SAEs within 24 hours 
of the site becoming aware of the event (see 
Section 12.1.4.2).  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. 
Given that the liver-related clinical outcome events 
could also meet the criteria of a SUSAR, please refer to 
Section 11.1.2.4. 
The Sponsor will consider the following list of clinical 
outcome events (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 
Updated section to account 
for events related to hepatic 
impairment. 
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Justification for Change 
haemorrhage), hepatic encephalopathy (preferred 
term: hepatic encephalopathy), spontaneous bacterial 
and peritonitis (preferred term: peritonitis bacterial). 
13.2.4, 
Cardiovascular 
Adjudication 
Committee 
13.2.3 
(…) 
In addition to potential clinical endpoint 
events, cardiovascular events will be 
adjudicated.  The adjudication of these 
events will be handled separately from the 
adjudication of events for assessment of the 
primary endpoint in this study and will be 
described separately. 
New Section: Cardiovascular Adjudication Committee 
In addition to potential clinical endpoint events, 
cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately 
from the adjudication of events for assessment of the 
primary endpoint in this study. Adjudicated 
cardiovascular events include core major adverse 
cardiovascular events (MACE) (cardiovascular death, 
nonfatal myocardial infarction, and nonfatal stroke) 
and expanded MACE (unstable angina requiring 
hospitalization, transient ischemic attack, peripheral 
or coronary revascularization procedures, 
hospitalization for congestive heart failure).  Other 
events potentially related to adverse cardiovascular 
outcomes may be included in the Cardiovascular 
Adjudication Committee (CAC) Charter for 
adjudication.  The adjudication of these events will be 
handled separately from the adjudication of events for 
assessment of the primary endpoint in this study (see 
Section 13.4). 
Committee added to assess 
cardiovascular events in 
subjects during the study. 
13.4, Adjudication 
Committee 
All potential endpoint events will be 
reviewed by an adjudication committee 
before inclusion in the any analysis.  The 
adjudication of potential clinical endpoint 
events will include, but is not limited to:  
available hospital reports, histology, 
discharge summaries, and death certificates.  
The assessment of events will be conducted 
in compliance with the protocol, study-
specific procedures, manuals, Good 
Clinical Practice (GCP), and all other 
applicable regulatory requirements, 
including the archiving of essential 
All suspected liver-related clinical outcomes, 
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 
Committee  
S added to assess liver 
impairment in subjects 
during the study. 
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Justification for Change 
documents.  A separate adjudication 
committee charter will document the entire 
data flow and process from committee 
membership, the reporting of events by the 
study site, reporting of the final assessment, 
supply of source documentation to the 
committee, the review of the events by the 
committee, and the working procedures of 
the committee.  The adjudication committee 
members will be independent hepatologists 
not involved in the study as investigators, 
DSMC members, or consultants.  All 
adjudication committee members will 
remain blinded to treatment group 
throughout the study. 
In addition to potential clinical endpoint 
events, cardiovascular events will also be 
adjudicated.  The adjudication of these 
events will be handled separately from the 
adjudication of events for assessment of the 
primary endpoint in this study and will be 
described separately. 
• 
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 subject treatment or site-
specific information.  The assessment of events will be 
conducted in compliance with study-specific 
procedures, manuals, good clinical practice (GCP), 
and all other applicable regulatory requirements, 
including the archiving of essential documents. 
Appendix A, 
Modified Dosing 
Regimen for 
Subjects with 
Child-Pugh B/C 
(Insertion) 
New: APPENDIX A. MODIFIED DOSING 
REGIMEN FOR SUBJECTS WITH CHILD-PUGH 
B/C HEPATIC IMPAIRMENT 
Added section to describe 
changes in dosing and 
titration for subjects 
assessed as cirrhotic 
Child-Pugh B or Child-Pugh 
C. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Hepatic 
Impairment 
Appendix B, LIST 
OF STUDY 747-
302 OUTCOME 
EVENTS 
Was Appendix A 
Now Appendix B 
The hepatic dosing appendix 
became Appendix A 
Appendix C 
LIST OF STUDY 747-302 ANTICIPATED 
EVENTS 
Deleted 
Replaced by Appendix A, 
more comprehensive 
description of the outcome 
events. 
 
Page 50 of 1682


 
1. 
TITLE PAGE 
 
Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cholangitis 
 
THE COBALT STUDY 
Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) 
 
Version 3.1:  21 December 2016 
 
(For FDA Review Only) 
 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA  92121 
USA 
 
TEL: +1 858 250 6398 
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 Investigational Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-302.  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 747-302 and in accordance 
with Good Clinical Practice (CPMP/ICH/135/95), 21CFR Part 312 and all applicable regulatory 
requirements. 
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: 
 
SAE Fax: 
+1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
 
Or if Not Available: 
Contact: 
 MD, PhD Medical Director, Clinical Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Email: 
 
 (Pacific time zone) 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 (Pacific time zone) 
 
 
 
 
 
 
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Protocol 747-302 
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Page 5
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product: 
Obeticholic Acid (OCA) 
Name of Active Ingredient: 
Obeticholic acid (OCA); 6α-ethyl-chenodeoxycholic acid; (6-ECDCA); INT-747 
Title of Study:  
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Effect of 
Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary Cholangitis 
Investigators and/or Study Center(s):  
Approximately 170 investigational study sites, globally. 
Studied Period (years):  
The study is event driven and total duration will be determined by the 
time required to accrue approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects are expected to have a 
minimum follow-up time of approximately 6 years. 
Phase of Development:   
Phase 4 
 
 
Objectives: 
Primary  
To assess the effect of OCA compared to placebo, in conjunction with established local standard of care, on 
clinical outcomes in subjects with primary biliary cirrhosis (PBC) as measured by time to first occurrence of any 
of the following adjudicated events, derived as a composite event endpoint:  
• 
Death (all-cause) 
• 
Liver transplant 
• 
Model of end stage liver disease (MELD) score ≥15 
• 
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 (confirmed by diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of 
at least twice in a month) 
• 
Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities unless confirmed by 
biopsy 
Secondary  
To assess the effect of OCA compared to placebo on time to first occurrence of each individual component of 
the primary endpoint as listed above  
To assess the effect of OCA compared to placebo on time to first occurrence of liver related death. 
To assess the effect of OCA compared to placebo on progression to cirrhosis To assess the effect of OCA 
compared to placebo on disease progression via the following: 
• 
Liver biochemistry  
• 
Markers of inflammation and fibrosis 
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Protocol 747-302
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To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To characterize the pharmacokinetics of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource utilization, and 
quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
Methodology:
This Phase 4, double-blind, randomized, placebo-controlled, multicenter study will evaluate the effect of OCA 
on clinical outcomes in subjects with PBC.  Subjects will be screened twice during a 1 to 8-week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples (at least 2 weeks 
apart) to confirm pretreatment alkaline phosphatase (ALP) and total bilirubin values (refer to Section 9.7.6). 
Investigational product will be taken orally, once daily for the majority of subjects; dose and frequency will be 
modified for subjects with cirrhosis (including subjects progressing to cirrhosis during the study) and classified 
as Child-Pugh B or C.  The randomization will be stratified by ursodeoxycholic acid (UDCA) treatment (yes/no) 
and baseline bilirubin categories (> upper limit of normal [ULN]/ ≤ ULN). 
Schematic Diagram:  
 
 
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for subjects on all dosing 
regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for subjects classified as Child-Pugh B or 
Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration. 
 
Dosing frequency will be determined by the presence or absence of cirrhosis and, if cirrhosis is present, by 
Child-Pugh Score as described below: 
• 
Non-cirrhotic subjects or subjects classified as Child-Pugh A at screening will receive 5-mg OCA 
or matching placebo once daily for 3 months.  Subjects should titrate to a maximum dose of 10-mg 
OCA once daily (or matching placebo) at the Month 3 visit or at any study visit following the 
Month 3 visit based on tolerability and biochemical response of the product.    
• 
For those subjects that up-titrate to 10 mg, dosing may be decreased to 5 mg at any time during the 
study as considered clinically appropriate (eg, based on tolerability). Subjects may be titrated back 
to a maximum dose of 10 mg once daily based on tolerability and clinical judgment of the 
Investigator.    
• 
Subjects who are cirrhotic and classified as Child-Pugh Class B or Child-Pugh Class C will initiate 
a modified treatment regimen with 5-mg OCA or matching placebo once weekly for at least 
3 months.  Subjects classified as Child-Pugh Class B should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once daily, based on tolerability and biochemical response.  
Subjects classified as Child-Pugh Class C should titrate to a maximum dose and frequency of 
10-mg OCA or matching placebo twice weekly, based on tolerability and biochemical response. 
 
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Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Planned Dosing Regimen 
Standard 
Modified 
Non-Cirrhotic/ 
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
5 mg once weekly 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weekly 
5 mg twice weekly 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weekly 
10 mg twice weekly 
Titration 3b 
(≥6 weeks after Titration 2) 
NA 
5 mg daily 
NA 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or Child-Pugh Score at any time during the study. 
Number of Subjects (planned):  
Approximately 428 subjects 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver 
Diseases [AASLD] and the European Association for the Study of the Liver [EASL] practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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 
2. A mean total bilirubin >ULN and ≤5× ULN and/or a mean ALP >3× ULN 
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past ≥3 months) or has been taking UDCA for at 
least 12 months with a stable dose for ≥3 months prior to Day 0 
5. Contraception:  Female subjects of childbearing potential must use ≥1 effective method of 
contraception during the study and until 30 days following the last dose of investigational product.  
Effective methods of contraception are considered to be those listed below: 
• 
Barrier method, ie, (a) condom (male or female) or (b) diaphragm, with spermicide 
• 
Intrauterine device (IUD) 
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection) 
• 
Abstinence, if in line with the preferred and usual lifestyle of the subject   
6. Must provide written informed consent and agree to comply with the study protocol 
Exclusion Criteria 
1. History or presence of other concomitant liver diseases including: 
• 
Hepatitis C virus infection 
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• 
Active hepatitis B infection; however, subjects 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 
• 
Nonalcoholic steatohepatitis 
• 
Gilbert's Syndrome 
2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including: 
• 
History of liver transplant, current placement on a liver transplant list, or current MELD score >12.  
Subjects who are placed on a transplant list despite a relatively early disease stage (for example per 
regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria 
• 
Cirrhosis with complications, including history (within the past 12 months) or presence of: 
− 
Variceal bleed 
− 
Uncontrolled ascites  
− 
Encephalopathy  
− 
Spontaneous bacterial peritonitis 
• 
Known or suspected hepatocellular carcinoma 
• 
Prior transjugular intrahepatic portosystemic shunt procedure 
• 
Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine >2 mg/dL 
(178 μmol/L) 
3. Mean total bilirubin >5× ULN  
4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal 
resection or plan to undergo either of these procedures 
5. Other medical conditions that may diminish life expectancy, including known cancers (except 
carcinomas in situ or other stable, relatively benign conditions such as chronic lymphatic leukemia) 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed 
by a positive serum pregnancy test), or lactating 
7. Known history of human immunodeficiency virus infection 
8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 
3 months) 
9. Other clinically significant medical conditions that are not well controlled or for which medication 
needs are anticipated to change during the study 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 
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-month 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. History of known or suspected clinically significant hypersensitivity to OCA or any of its components 
14. UDCA naïve (unless contraindicated) 
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Investigational Product, Dosage and Mode of Administration:  
OCA (5 mg or 10 mg tablets) 
Reference Therapy, Dosage and Mode of Administration:  
Placebo (matching tablets) 
Duration of Treatment:  
It is expected that subjects will be followed up for a minimum of 6 years.  The study is event driven and total 
duration of treatment will be determined by the time to accrue 127 total primary endpoint events. 
Criteria for Evaluation: 
Primary Objectives 
Assessments 
Clinical outcomes 
• 
Death (all-cause) 
• 
Liver transplant 
• 
MELD score ≥15 
• 
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 (confirmed by 
diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring 
therapeutic paracentesis at a frequency of at least twice in a 
month) 
• 
Hepatocellular carcinoma confirmed by 2 complimentary 
imaging modalities unless confirmed by biopsy 
Secondary Objectives 
 
Individual components of the 
primary endpoint 
As listed above and including liver-related death 
Progression to cirrhosis 
Clinical, laboratory, or radiological evidence of cirrhosis and/or liver 
stiffness (i.e., Fibroscan® TE) confirmed by biopsy unless not medically 
indicated 
Change in baseline liver 
biochemistry 
Liver biochemistry (see Table 10) for list of analytes to be tested  
Inflammation and fibrosis 
IgM, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), 
fibroblast growth factor-19 (FGF-19), cytokeratin-18 (CK-18), enhanced 
liver fibrosis (ELF), and Fibroscan® TE 
Clinical outcomes compared to 
historical controls 
Similar endpoints as used for the primary objective where available 
including liver transplant and death 
Pharmacokinetics 
OCA and its conjugates 
Health outcomes and economics 
research 
Including the following: 
Cost-effectiveness and resource utilization 
Quality of life (Fatigue Impact Score and EQ-5D-5L)  
Safety and tolerability 
Including the following: 
Treatment-emergent adverse events 
Clinical laboratory values 
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Statistical Methods: 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the data: Intent-to-
Treat (ITT), Safety, PK, Overall Historical Control, UKPBC Historical Control, and the Global PBC Historical 
Control.  Descriptions of subject populations are provided in Section 13.1.1. 
Efficacy Analyses 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the time to first occurrence of one of the following:  
• 
Death (all-cause) 
• 
Liver transplant 
• 
Model of end stage liver disease (MELD) score ≥15 
• 
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 (confirmed by diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of 
at least twice in a month) 
• 
Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities unless confirmed by 
biopsy 
All events will be adjudicated by an independent committee. 
Primary Efficacy Analysis 
The primary efficacy analysis will compare OCA to placebo with respect to the primary efficacy endpoint using 
the ITT population.  The 2 treatment groups will be compared 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 its 95% CI will be determined based 
on a Cox regression model stratified by randomization strata to estimate the magnitude of the effect. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints are as follows: 
• 
Time to first occurrence of MELD score ≥15 
• 
Time to liver transplant or death (all-cause) 
• 
Change from Baseline in total bilirubin at end of study 
• 
Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare OCA to placebo in the ITT population with respect to the key 
secondary efficacy endpoints.  Only adjudicated events will be included in time-to-event analyses.  The 
comparison (hypothesis testing) will be conducted in a sequential closed testing gate-keeping procedure (in the 
order in which the key secondary endpoints are stated above), provided that the primary efficacy endpoint 
comparison is statistically significant in favor of the OCA treatment group.  If the primary comparison is not 
statistically significant then comparison of the secondary endpoints will be considered as descriptive and 
exploratory. 
Other Efficacy Analyses 
The following secondary efficacy analyses will compare OCA to placebo on time to the following events: 
• 
Each component of the primary efficacy endpoint (except MELD score ≥15 which is listed above) 
• 
Development of varix/varices 
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• 
Liver-related death 
• 
Liver-related death or liver transplant 
• 
Liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these secondary 
efficacy analyses.  Similar endpoints, where available, will be analyzed to compare OCA to historical controls. 
Progression to cirrhosis will be assessed in the subset of subjects considered non-cirrhotic at baseline using 
available medical history, clinical, and laboratory assessments as well as baseline transient elastography (TE) 
where available. Specifically, subjects with no clinical, laboratory, or radiological evidence of cirrhosis at 
baseline and/or a TE liver stiffness of <16.9 kPa (Corpechot 2012) will be considered non-cirrhotic.  
Progression to cirrhosis will be assessed by the development of clinical, laboratory, or radiological evidence of 
cirrhosis and/or when liver stiffness increases to ≥16.9 kPa during the trial in which case histological 
progression to cirrhosis should be confirmed by biopsy unless not medically indicated. Using this definition for 
progression to cirrhosis, the percentage of non-cirrhotic subjects progressing to cirrhosis during the treatment 
period will be summarized by treatment group and compared using a Cochran–Mantel–Haenszel test stratified 
by the randomization stratification factor.  
Analyses for the histological assessment conducted as part of the biopsy sub-study are defined in Appendix C. 
Further details on efficacy, health outcomes, and pharmacokinetic analyses are specified in Section 13. 
Safety Analyses 
Safety data, including AEs, vitals, electrocardiogram, and clinical laboratory results will be summarized by 
treatment group for the Safety Population. 
Sample Size Justification 
The following assumptions were used in sample size calculations:  
• 
Exponential survival curves, placebo survival estimate of 0.6 at 8 years with a hazard ratio of 0.60, 
and total study duration of 10 years (from first subject enrolled), allowing for 4 years subject 
accrual and 6 years of follow-up 
• 
Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• 
The 2 groups will be compared using a 2-sided log rank test at the 5% level of significance 
• 
Two interim analyses and one final analysis are planned 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 127 events (both 
groups combined) will provide 80% power to demonstrate a statistically significant difference between OCA 
and placebo on time to clinical outcomes. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 428 subjects 
will be enrolled to attain 127 events. 
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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.............................19 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Overview of Primary Biliary Cirrhosis and Obeticholic Acid ...................................22 
5.2. 
Mechanism of Action of Obeticholic Acid .................................................................22 
5.3. 
Nonclinical Experience with Obeticholic Acid ..........................................................23 
5.4. 
Clinical Experience with Obeticholic Acid ................................................................23 
5.5. 
Rationale for Study Design and Dose for Investigational Product .............................24 
5.5.1. 
Rationale for Study Design .........................................................................................24 
5.5.2. 
Rationale for Dose ......................................................................................................25 
5.5.2.1. 
Rationale for OCA Dose .............................................................................................25 
5.5.2.2. 
Rationale for Modified OCA Doses in Patients Classified with Child-Pugh B 
or Child-Pugh C Hepatic Impairment .........................................................................25 
5.5.2.3. 
Rationale for Control Groups .....................................................................................25 
5.6. 
Summary of Known Potential Risks with OCA .........................................................26 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................27 
6.1. 
Primary Objective .......................................................................................................27 
6.2. 
Secondary Objectives .................................................................................................27 
7. 
INVESTIGATIONAL PLAN .....................................................................................28 
7.1. 
Overall Study Design ..................................................................................................28 
7.1.1. 
Study Design Diagram ................................................................................................29 
7.1.2. 
Schedule of Study Procedures ....................................................................................30 
7.1.3. 
Study Duration ............................................................................................................35 
7.2. 
Number of Subjects ....................................................................................................35 
7.3. 
Planned Dosing Regimen ...........................................................................................35 
7.4. 
Dose Titration Criteria ................................................................................................36 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements .................................................38 
7.4.2. 
Safety Criteria for Adjustment or Stopping Doses .....................................................38 
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7.5. 
Criteria for Study Termination ...................................................................................39 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................39 
8.1. 
Subject Population ......................................................................................................39 
8.2. 
Subject Inclusion Criteria ...........................................................................................39 
8.3. 
Subject Exclusion Criteria ..........................................................................................40 
8.4. 
Subject Withdrawal from Investigational Product or Study .......................................42 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product ..........................42 
8.4.1.1. 
Severe Drug-Induced Liver Injury ..............................................................................42 
8.4.1.2. 
Liver Transplantation ..................................................................................................42 
8.4.2. 
Reasons for Mandatory Interruption of Investigational Product ................................42 
8.4.2.1. 
Pregnancy ...................................................................................................................42 
8.4.3. 
Other Reasons for Discontinuation of Study or Investigational Product ...................43 
8.4.3.1. 
Elevated Liver Enzymes .............................................................................................43 
8.4.4. 
Withdrawal of Consent ...............................................................................................44 
8.4.5. 
Lost to Follow-Up.......................................................................................................44 
8.4.6. 
Subject Discontinuation Notification .........................................................................44 
9. 
TREATMENT OF SUBJECTS ..................................................................................44 
9.1. 
Investigational Product Treatment Regimen ..............................................................44 
9.2. 
Concomitant Medications ...........................................................................................45 
9.2.1. 
Prohibited Medications ...............................................................................................46 
9.3. 
Treatment Compliance ................................................................................................46 
9.4. 
Randomization and Blinding ......................................................................................46 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures ...................................46 
9.5. 
Assignment of Site and Subject Numbers ..................................................................47 
9.5.1. 
Site Numbers ..............................................................................................................47 
9.5.2. 
Subject Numbers .........................................................................................................47 
9.6. 
Restrictions .................................................................................................................47 
9.7. 
Visit Procedures ..........................................................................................................48 
9.7.1. 
Visit Windows ............................................................................................................48 
9.7.2. 
Informed Consent Procedures.....................................................................................48 
9.7.3. 
Assessing Cirrhosis .....................................................................................................49 
9.7.3.1. 
Determination for Dosing Regimen ............................................................................49 
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9.7.3.2. 
Progression to Cirrhosis ..............................................................................................50 
9.7.4. 
Child-Pugh Score ........................................................................................................50 
9.7.5. 
Mayo Risk Score .........................................................................................................51 
9.7.6. 
Screening Procedures (1 to 8 Weeks prior to Day 0) .................................................51 
9.7.7. 
Day 0 Procedures (Randomization) ............................................................................53 
9.7.8. 
Month 1 Procedures ....................................................................................................54 
9.7.9. 
Month 3 Procedures ....................................................................................................55 
9.7.10. 
Post-Titration Visit Procedures ...................................................................................56 
9.7.11. 
Month 6 Procedures ....................................................................................................57 
9.7.12. 
Month 9 Procedures ....................................................................................................58 
9.7.13. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment .................................................................................................................59 
9.7.14. 
Month 12 Procedures ..................................................................................................60 
9.7.15. 
Month 3 and Month 9 Continued Follow-Up Procedures (±2 weeks) .......................61 
9.7.16. 
Month 6 Continued Follow-Up Procedures (Semi-annually [±2 weeks]) ..................62 
9.7.17. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) .........................63 
9.7.18. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent ..................................64 
9.7.19. 
Unscheduled Safety Visit ...........................................................................................67 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............67 
10.1. 
Investigational Product ...............................................................................................67 
10.2. 
Investigational Product Packaging and Labeling .......................................................67 
10.3. 
Investigational Product Storage ..................................................................................68 
10.4. 
Investigational Product Preparation ............................................................................68 
10.5. 
Investigational Product Administration ......................................................................68 
10.6. 
Investigational Product Accountability and Disposal .................................................68 
11. 
ASSESSMENT OF EFFICACY ................................................................................68 
11.1. 
Assessment of Efficacy ...............................................................................................68 
11.1.1. 
Primary Assessments ..................................................................................................68 
11.1.2. 
Secondary Assessments ..............................................................................................69 
11.1.2.1. 
Non-Invasive Assessments of Liver Fibrosis .............................................................70 
11.1.2.2. 
Other Secondary Assessments ....................................................................................70 
11.1.2.3. 
Other Exploratory Evaluations ...................................................................................70 
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11.1.2.4. 
Potential Clinical Outcome Events .............................................................................71 
12. 
ASSESSMENT OF SAFETY .....................................................................................71 
12.1. 
Adverse Events and Serious Adverse Events .............................................................71 
12.1.1. 
Definitions of Adverse Events ....................................................................................71 
12.1.1.1. 
Adverse Event .............................................................................................................71 
12.1.1.2. 
Serious Adverse Event ................................................................................................72 
12.1.1.3. 
Treatment-Emergent Adverse Event ..........................................................................72 
12.1.2. 
Relationship to Investigational Product ......................................................................72 
12.1.3. 
Recording Adverse Event Severity .............................................................................73 
12.1.4. 
Reporting of Adverse Events and Serious Adverse Events ........................................73 
12.1.4.1. 
Reporting of Adverse Events ......................................................................................73 
12.1.4.2. 
Reporting of Serious Adverse Events .........................................................................74 
12.1.5. 
Suspected Liver-Related Clinical Outcome Events ....................................................75 
12.1.6. 
Additional Investigator Responsibilities for SAEs .....................................................75 
12.1.7. 
Notification of Post-Study SAEs ................................................................................75 
12.1.8. 
Follow-Up of AEs and SAEs ......................................................................................76 
12.1.9. 
Pregnancy and Follow up ...........................................................................................76 
12.2. 
Other Safety Parameters .............................................................................................77 
12.2.1. 
Medical History/Demographics ..................................................................................77 
12.2.2. 
Physical Examination .................................................................................................77 
12.2.3. 
Vital Signs ..................................................................................................................77 
12.2.4. 
Electrocardiogram .......................................................................................................77 
12.2.5. 
Dual Emission X-Ray Absorptiometry .......................................................................77 
12.2.6. 
Subject Questionnaires ...............................................................................................77 
12.2.7. 
Laboratory Assessments .............................................................................................78 
13. 
STATISTICAL METHODS .......................................................................................80 
13.1. 
Efficacy Analysis ........................................................................................................80 
13.1.1. 
Analysis Populations ..................................................................................................80 
13.1.1.1. 
Comparability of Historical Controls .........................................................................80 
13.1.2. 
Determination of Sample Size ....................................................................................81 
13.1.2.1. 
Sample Size Monitoring .............................................................................................81 
13.1.3. 
Primary Efficacy Analysis ..........................................................................................81 
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13.1.4. 
Key Secondary Efficacy Analyses ..............................................................................82 
13.1.5. 
Additional Secondary Efficacy Analyses ...................................................................83 
13.1.5.1. 
Association of Biochemistry with Clinical Outcomes and Clinical Benefit ..............84 
13.1.6. 
Exploratory Efficacy Analyses ...................................................................................84 
13.1.6.1. 
Responder Analyses ....................................................................................................84 
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints ................................................84 
13.1.8. 
Supportive Analysis ....................................................................................................85 
13.1.9. 
Handling of Dropouts or Missing Data ......................................................................86 
13.1.9.1. 
Time to Event Endpoints ............................................................................................87 
13.1.9.2. 
Quantitative Endpoints ...............................................................................................87 
13.1.9.3. 
Responder Endpoints ..................................................................................................87 
13.1.10. 
Multiple Comparisons/Multiplicity ............................................................................87 
13.1.11. 
Examination of Subgroups .........................................................................................88 
13.1.12. 
Continuous Monitoring and Interim Analyses ...........................................................88 
13.2. 
Safety Analysis ...........................................................................................................89 
13.2.1. 
Adverse Events ...........................................................................................................89 
13.2.2. 
Clinical Laboratory Evaluations .................................................................................89 
13.2.3. 
Additional Safety Analysis .........................................................................................89 
13.2.4. 
Cardiovascular Adjudication Committee ...................................................................89 
13.3. 
Data Monitoring Committee .......................................................................................89 
13.4. 
Adjudication Committees ...........................................................................................90 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................91 
14.1. 
Study Monitoring ........................................................................................................91 
14.2. 
Audits and Inspections ................................................................................................91 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................92 
16. 
ETHICS ......................................................................................................................92 
16.1. 
Ethics Review .............................................................................................................92 
16.2. 
Ethical Conduct of the Study ......................................................................................92 
16.3. 
Written Informed Consent ..........................................................................................93 
16.4. 
Subject Confidentiality and Data Protection ..............................................................93 
17. 
INVESTIGATOR OBLIGATIONS ...........................................................................93 
17.1. 
AE Reporting ..............................................................................................................94 
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17.2. 
Protocol Deviations ....................................................................................................94 
17.3. 
Regulatory Documentation .........................................................................................94 
17.4. 
Ethics Review .............................................................................................................94 
17.5. 
Archiving and Record Retention ................................................................................94 
18. 
PUBLICATION POLICY ..........................................................................................95 
19. 
LIST OF REFERENCES ............................................................................................97 
APPENDIX A. MODIFIED DOSING REGIMEN FOR SUBJECTS WITH CHILD-
PUGH B/C HEPATIC IMPAIRMENT ......................................................................99 
APPENDIX B. ETHICAL CONDUCT ACCORDING TO THE DECLARATION OF 
HELSINKI FOR COUNTRIES PARTICIPATING OUTSIDE THE US 
(DECLARATION OF HELSINKI, FORTELEZA, BRAZIL, 2013) ......................102 
APPENDIX C. BIOPSY SUB-STUDY OF PROTOCOL 747-302:  A PHASE 4, 
DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
MULTICENTER STUDY EVALUATING THE EFFECT OF 
OBETICHOLIC ACID ON CLINICAL OUTCOMES IN SUBJECTS 
WITH PRIMARY BILIARY CHOLANGITIS ........................................................107 
APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 
(DATED 29 APR 2015) ...........................................................................................109 
APPENDIX E. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 
(DATED 12 NOV 2015) ..........................................................................................146 
APPENDIX F. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 (DATED 07 
SEPTEMBER 2016) .................................................................................................148 
APPENDIX G. SUMMARY OF CHANGES:  PROTOCOL VERSION 3.1 (DATED 
23 DECEMBER 2016) .............................................................................................172 
 
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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) .......................30 
Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) ............33 
Table 3: 
Planned Dosing Regimen by Cirrhosis and Child Pugh Score ...................................36 
Table 4: 
Determination of Dosing Regimen .............................................................................36 
Table 5: 
Changes in Dosing Regimen Due to Changes in Cirrhosis Status or 
Child-Pugh Score ........................................................................................................37 
Table 6: 
Child-Pugh Scoring System ........................................................................................50 
Table 7: 
Early Discontinuation Scenarios .................................................................................65 
Table 8: 
Relationship of Adverse Events to Investigational Product .......................................73 
Table 9: 
Severity of Adverse Events ........................................................................................73 
Table 10: List of Laboratory Analytes to be Tested ...................................................................79 
Table 11: Planned Dosing Regimen by Cirrhosis and Child-Pugh Score ..................................99 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram Study 747-302 ............................................................................29 
Figure 2: 
Dosing by Cirrhosis Status and Child-Pugh Score .....................................................99 
  
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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 
CAC 
Cardiovascular Adjudication Committee 
CDCA 
chenodeoxycholic acid 
CI 
confidence interval 
CK-18 
cytokeratin-18 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
C-reactive protein 
DEXA 
dual-emission X-ray absorptiometry 
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 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
FIS 
Fatigue Impact Scale 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
glyco-OCA 
glycine 6α-ethyl chenodeoxycholic acid 
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Abbreviation or Specialist Term 
Explanation 
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 
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 
LDL 
low-density lipoprotein 
LTSE 
long-term safety extension 
MACE 
major adverse cardiovascular events 
MELD 
model of end stage liver disease  
MRS 
Mayo Risk Score 
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cholangitis (also known as primary biliary 
cirrhosis) 
PIS 
patient information sheet 
PK 
pharmacokinetic 
PSC 
primary sclerosing cholangitis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
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. 
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Abbreviation or Specialist Term 
Explanation 
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 Primary Biliary Cirrhosis and Obeticholic Acid 
Primary biliary cholangitis, (PBC, also known as primary biliary cirrhosis) 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, is currently the only 
treatment approved for PBC (Lindor 2009).  While UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of a poor clinical outcome due to PBC disease 
progression.  There is a clear unmet medical need for better therapies for patients with PBC that 
have an inadequate response to UDCA, or those who cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and effective. 
OCA is a modified bile acid and farnesoid X receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid (CDCA).  OCA is currently being developed in 
the United States (US) and Europe for the treatment of PBC and other chronic liver diseases.  
OCA has been granted Orphan Drug Designation in the US (09 Apr 2008) and Orphan Medicinal 
Product Designation in the European Union (EU) (27 Jul 2010) for the treatment of PBC.  The 
United States Food and Drug Administration (FDA) has granted accelerated approval for Ocaliva 
for the treatment of PBC.  Ocaliva is not yet approved outside the United States for use in any 
indication.  
5.2. 
Mechanism of Action of Obeticholic Acid 
OCA is a 6α-ethyl derivative of the naturally occurring primary human bile acid CDCA, which is 
the endogenous ligand for FXR.  FXR is a ligand-dependent transcription factor that is part of 
the nuclear receptor superfamily.  FXR regulates a wide variety of target genes involved in the 
control of bile acid, lipid, and glucose homeostasis and in the regulation of immune responses. 
OCA’s potent FXR agonist effects are believed to account for the predominant efficacy of the 
investigational product.  Some of the pharmacological properties of OCA and other FXR 
agonists that have been elucidated in animal models of chronic liver disease relevant to the 
treatment of PBC include the following: 
• Improvement in hepatic choleresis with reduced inflammation and necrosis  
• Prevention and reversal of hepatic fibrosis 
The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and 
anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury 
and improved liver function in a cholestatic liver disease such as PBC. 
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5.3. 
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. 
5.4. 
Clinical Experience with Obeticholic Acid 
As of 31 Jan 2016, approximately 1726 subjects have received at least 1 dose of OCA. Of these, 
844 were healthy volunteers, 458 subjects had PBC, 330 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver disease (NAFLD), 33 subjects had alcoholic 
cirrhosis/portal hypertension, and 20 subjects 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. 
To date, the efficacy and safety of OCA in PBC has been evaluated in 2 placebo-controlled, 
double-blind, Phase 2 studies (747-201 and 747-202), and 1 placebo-controlled, double-blind 
Phase 3 study (747-301).  Following the double-blind phase, subjects in all 3 studies were 
eligible to continue with treatment in a long-term safety extension (LTSE) phase for up to 
5 years in Study 747-201, up to 1 year in Study 747-202, and up to 5 years in Study 747-301. 
Study 747-201 (59 subjects) 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 subjects) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in subjects 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 subjects) was a Phase 3, double-blind, placebo-controlled, parallel group 
study followed by an LTSE using OCA in subjects with PBC.  The primary endpoint for 
Study 747-301 was a composite endpoint based on the proportion of subjects reaching specific 
criteria for ALP and bilirubin (ALP <1.67× upper limit of normal [ULN] with a ≥15% reduction 
and bilirubin ≤ULN).  Both OCA treatment groups met the primary endpoint of achieving a 
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reduction in ALP to <1.67× 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 10 mg OCA 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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is complete. 
5.5. 
Rationale for Study Design and Dose for Investigational Product 
5.5.1. 
Rationale for Study Design 
OCA is a modified bile acid and FXR agonist that is derived from the primary human bile acid 
chenodeoxycholic acid.  The key mechanisms of action of OCA, including its choleretic, anti-
inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in 
attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. 
PBC is characterized by biochemical increases in ALP and GGT enzymes with or without 
elevations of hepatocellular transaminases and bilirubin (Lindor 2009).  Both the American 
Association for the Study of Liver Diseases (AASLD) (Lindor 2009) and the European 
Association for the Study of the Liver (EASL) (EASL 2009) guidelines base the biochemical 
component of PBC diagnosis on elevations of ALP.  In addition, a growing literature supports 
the use of biochemical endpoints, specifically serum ALP alone or with other parameters such as 
bilirubin, to manage subjects, test the efficacy of novel therapies in clinical studies, and gauge 
the risk of long-term adverse clinical outcomes in subjects with PBC (Beuers 2011, 
Momah 2012).  Data from the Global PBC Study Group (Lammers 2013), which has built a 
database tracking biochemical status and clinical outcomes in several thousand PBC subjects, 
provides evidence for the use of the composite biochemical endpoint of ALP and bilirubin as an 
acceptable surrogate endpoint. 
Study 747-301, a Phase 3 double-blind study, evaluated the safety and efficacy of OCA at doses 
of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability) and 10 mg and used 
a composite biochemical endpoint of ALP and bilirubin as a surrogate endpoint.  In this study, 
both treatment groups exhibited clinically meaningful improvements in liver biochemistry and 
were safe and generally well-tolerated.  As a result, starting subjects on 5 mg OCA and titrating 
to 10 mg based on tolerability and clinical response appears to be an appropriate dosing strategy 
in subjects with PBC.  
Study 747-302 is a clinical outcomes study, supportive of Phase 3 Study 747-301 which was 
based on a surrogate biochemical endpoint, designed to confirm the clinical benefit of OCA 
treatment in patients with PBC.  A retrospective observational database (Global PBC Study 
Group [Lammers 2013]) of patients with PBC allowed for a rigorous patient-level meta-analysis 
and provided an opportunity for a robust assessment of ALP and bilirubin as viable surrogate 
biochemical parameters and a comprehensive understanding of the natural history of the PBC 
disease process.  Data from the Global PBC Study Group was also utilized to inform the design 
of the confirmatory outcomes study. 
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5.5.2. 
Rationale for Dose 
5.5.2.1. 
Rationale for OCA Dose 
The safety and tolerability of multiple doses of OCA have been established in subjects with PBC 
at doses up to 50 mg.  As demonstrated in the Phase 2 PBC studies (Studies 747-201 and 
747-202), OCA significantly reduced serum ALP levels at doses of 10 mg, 25 mg, and 50 mg, 
but with an increase in the incidence and severity of pruritus at higher dose levels.  The Phase 3 
PBC study subsequently evaluated the safety and efficacy of OCA at lower doses of 5 mg 
(titrated to 10 mg after 6 months based on efficacy and tolerability in the double-blind phase and 
after 3 months in the open-label phase) and 10 mg; both treatment groups exhibited clinically 
meaningful improvements in liver biochemistry and were safe and generally well tolerated.  
Based on these data, the indicated commercial doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
The majority of efficacy results with OCA, in terms of change in alkaline phosphatase, was 
observed by 3 months and the time to treatment-emergent pruritus was typically 1 month or less 
in Study 747-301.  As such, Study 747-302 will evaluate the effect of OCA on clinical outcomes 
using the 5 mg OCA dose increasing to 10 mg OCA, if tolerated. 
5.5.2.2. 
Rationale for Modified OCA Doses in Patients Classified with Child-Pugh B or 
Child-Pugh C Hepatic Impairment 
Simulations using a physiologic PK model predicted changes in systemic and liver OCA 
concentrations associated with changes in the severity of hepatic impairment (Child-Pugh Score).  
Model simulations predicted that for mild (Child-Pugh A), moderate (Child-Pugh B), and severe 
(Child-Pugh C) hepatic impairment, total OCA plasma concentrations increase 1.4-, 8.0-, and 
13-fold relative to subjects 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 (Child-Pugh B and C) subjects treated 
with OCA in phase 1 and 2 studies experienced plasma OCA exposures >10-fold higher than 
those in healthy subjects, 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.  Collectively, the results from these analyses suggest that the doses of OCA 
administered to hepatically-impaired patients should be modestly lower than those for patients 
with normal hepatic function to achieve similar hepatic exposure.   
Per the approved FDA prescribing label, the recommended dosing regimen for OCA in subjects 
with moderate and severe hepatic impairment is a starting dose of 5-mg OCA once weekly.  
Dosage adjustments in subjects with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic 
impairment may be made after establishing tolerability at the lower dose (full modified dosing 
regimen is described in Appendix A).   
5.5.2.3. 
Rationale for Control Groups  
Placebo Control Group 
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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 a standard of care 
effect.  Notably, accounting for the standard of care effect is critical when designing an 
outcome-based study conducted globally when there are regional differences in the treatment of 
subjects with PBC. 
Historical Control Group 
The available robust historical PBC observational datasets (UK-PBC and Global PBC Study 
Group) will also be leveraged to provide further comparative evaluation of the clinical benefit of 
OCA.  Each database includes >6000 patients with long-term follow-up. 
Comparison of OCA treatment to the historical controls may provide utility in addressing 
potential bias or confounds associated with the placebo arm.  For example, bias associated with 
the potential addition of commercial OCA and/or differences in long-term standard of care 
between the treatment arms including ancillary treatments and diagnostics. 
Therefore, further evaluation of the effect of OCA will compare OCA treatment versus historical 
controls, and will be supportive to placebo comparisons (ie, comparisons to historical and 
placebo controls will be evaluated separately). 
5.6. 
Summary of Known Potential Risks with OCA 
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, but with a much 
lower frequency than that observed in subjects with PBC. 
An increase in liver enzymes and hepatic AEs, including jaundice, were observed in subjects 
with liver disease at OCA doses between 10 mg and 50 mg and in healthy subjects who were 
treated at doses ≥100 mg in Phase 1, multiple-dose studies. 
In subjects 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 
above 10 mg OCA.  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 (HDL) and an increase in low density lipoprotein (LDL).  Notably, in 
subjects 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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated subjects with the exception of a 
modest transient and early rise after initiation of treatment.   
Refer to the IB for additional information regarding the known potential risks with the 
investigational product. 
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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care on clinical outcomes in subjects with PBC as measured by time to first occurrence of any 
of the following adjudicated events, derived as a composite event endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities unless 
confirmed by biopsy 
6.2. 
Secondary Objectives 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above and also to include liver-related death. 
To characterize the effect of OCA compared to placebo on progression to cirrhosis.    
To assess the effect of OCA compared to placebo on disease progression via the following: 
• Liver biochemistry 
• Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To assess the PK of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 4, double-blind, randomized, placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with bilirubin levels of >ULN and ≤5× ULN and/or ALP 
>3× ULN.  Subjects enrolled will be at higher risk of liver-related clinical complications. 
Approximately 428 subjects meeting all enrollment criteria will be recruited into the study over 
an approximate 4-year period, randomly allocated to treatment with either OCA or matching 
placebo in a 1:1 ratio (Figure 1).  Subjects will be screened during a 1 to 8-week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples 
(at least 2 weeks apart) to confirm pretreatment ALP and total bilirubin values (refer to 
Section 9.7.6).  Randomization will be stratified by UDCA treatment (yes/no) and baseline 
bilirubin categories (>ULN/≤ULN).  In addition to the placebo control arm, multiple historical 
control groups (concurrent and retrospective) will be used.   
  Subjects will be dosed according to their cirrhosis status and Child-Pugh Score. Subjects who 
are non-cirrhotic or classified as Child-Pugh A at Screening will initiate investigational product 
once daily with 5-mg OCA or matching placebo.  Following 3 months of once daily treatment 
with investigational product, the dose should be titrated to a maximum 10 mg OCA or matching 
placebo once daily, based on tolerability and biochemical response (see Section 7.3).  
Subjects with cirrhosis (see Section 9.7.3) and classified as Child-Pugh Class B or Child-Pugh 
Class C will follow a modified dosing regimen, and will initiate investigational product once 
weekly with the 5-mg OCA or matching placebo dose.  In addition, these subjects will follow a 
modified titration plan, which is outlined in Appendix A. 
It is anticipated that subjects will be followed for a minimum of approximately 6 years.  The 
study will continue until approximately 127 adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor (eg, based on advisement by the Data 
Monitoring Committee; DMC) terminates the study. 
This study will be conducted at approximately 170 international study sites with experience in 
treating subjects with PBC.  Prospective subjects will be identified primarily from the hospital 
and/or physician’s database of subjects with PBC, or may be referred from other physicians.  
Subjects may self-refer to an Investigator if they become aware of the study through local, 
national, or international PBC subject societies, forums, and networks. 
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7.1.1.
Study Design Diagram 
Figure 1: 
Schematic Diagram Study 747-302 
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for 
subjects on all dosing regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for 
subjects classified as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier 
than 6 weeks after the previous dose titration 
 
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) 
 
Screening Visits 
Day 0 
M 1 
M 3 
1-Month 
Post-Titration 
Visitb 
M 6 
M 9 
M 12 
1 
2a 
Visit Windows (+/-)c 
3 to 8 wk 
prior to 
Day 0 
1 to 6 wk 
prior to 
Day 0 
 
+1 
wk 
±2 
wk 
±1 wk 
±2 wk 
±2 
wk 
±2 wk 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical/PBC Historyd  
X 
 
 
 
 
 
 
 
 
Cirrhosis Status Assessmente 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
Physical Exam  
X 
 
 
X 
 
X 
X 
 
Xd 
Assessments for Mayo Risk Scoref 
X 
 
 
 
 
 
X 
 
X 
Assessments for Child-Pugh Scoreg 
X 
 
 
 
X 
 
X 
X 
X 
Vital Signs (including weight) 
Xh 
 
X 
 
X 
 
X 
X 
Xh 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
X 
Subject Questionnaires (5-D Pruritus Scale and 
Pruritus VAS) 
 
 
X 
 
 
 
X 
 
X 
Quality of Life Questionnaires (PBC-40, 
EQ-5D-5L, and FIS)i 
 
 
X 
 
 
 
 
 
X 
Fibroscan® TEj 
 
 
X 
 
 
 
X 
 
X 
DEXAk 
 
 
X 
 
 
 
 
 
X 
Endoscopyl 
 
 
X 
 
 
 
 
 
X 
Hepatic Ultrasoundm 
 
X 
 
 
 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health Outcome Assessmentsn 
 
 
X 
 
X 
 
X 
X 
X 
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Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) (Continued) 
 
Screening Visits 
Day 0 
M 1 
M 3 
1-Month 
Post-Titration 
Visitb 
M 6 
M 9 
M 12 
1 
2a 
Visit Windows (+/-)c 
3 to 8 wk 
prior to 
Day 0 
1 to 6 wk 
prior to 
Day 0 
 
+1 
wk 
±2 
wk 
±1 wk 
±2 wk 
±2 
wk 
±2 wk 
Randomization/Treatment Assigned 
 
 
X 
 
 
 
 
 
 
Dose Titration: Standard Dosingo,p 
 
 
 
 
X 
 
X (if applicable) 
Dose Titration: Modified Dosing (if applicable)o,p 
 
 
 
 
X 
 
X 
X 
X  
Dispense Investigational Productq 
 
 
X 
 
X 
 
X 
X 
X 
IP Accountability/Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
Dosing Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSr 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
X 
Urine-based β-hCG Pregnancy Tests 
X 
 
X 
 
 
 
 
 
 
Chemistry/Hematology/Coagulation 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
OCA, C4, and FGF-19 (plasma)  
 
 
X 
 
X 
 
X 
Xt 
X 
Markers of Hepatic Fibrosis and/or Inflammationu 
 
 
X 
 
 
 
X 
 
X 
Geneticsv 
 
 
X 
 
 
 
 
 
X 
Blood Sample for Future Analysisw 
 
 
X 
 
 
 
X 
 
X 
AE = adverse event; β-hCG = beta human chorionic gonadotropin; DEXA = dual-emission X-ray absorptiometry; EOS= End of Study; EOT = End of Treatment; 
FGF-19 = fibroblast growth factor-19; FIS = Fatigue Impact Scale; IP = Investigational Product; M = month, TE = transient elastography; VAS = Visual Analogue Scale; 
wk = week 
a All subjects will have the chemistry panel retested to ensure subjects have two ALP and bilirubin assessments at least 2 weeks apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and bilirubin assessments will be used to determine eligibility.  Samples for hematology and coagulation will not be collected at 
Screening Visit 2. 
b Post-Titration visits must be performed 1 month (+ 1 week) after any up-titration in dose and/or frequency in subjects following modified dosing due to Child-Pugh B and Child-
Pugh C hepatic impairment.  In subjects following the standard dosing regimen, the post-titration visit must be performed only after the first up-titration to 10 mg OCA or 
matching placebo, or after ≥3 months at a decreased dose or frequency. 
c Visits should be based on Day 0 (not on the prior visit) with the exception of the Post-Titration Visit, which is based on the date of titration. 
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d Medical history at Screening and the yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both. 
e Presence or absence of cirrhosis should be assessed per Section 9.7.3.  Cirrhosis status should be repeated as clinically indicated. 
f Mayo Risk Score will be calculated based on central laboratory evaluations, diuretic use data, and peripheral edema assessment data captured in the eCRF. 
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 Height will be collected at this visit. 
i The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2 and Section 12.2.6). 
j Transient elastography (TE) will be conducted at 6-month intervals at all study sites where the Fibroscan® TE device is available.  Please refer to Section 9.7.7 for additional 
information related to the allowed windows at Day 0 for this procedure. 
k DEXA will be conducted at 12-month intervals at all study sites where the DEXA device is available.  Please refer to Section 9.7.7 for additional information related to the 
allowed windows at Day 0 for this procedure. 
l Endoscopy will be conducted at selected study sites where the device is available to assess for the presence of oesophageal varix/varices.  Please refer to Section 9.7.7 for 
additional information related to the allowed window at Day 0 for this specific procedure.  
m Ultrasound will be conducted to enhance HCC surveillance.  For all on study (eg, post-Day 0) ultrasounds: unless HCC has already confirmed by biopsy, a second confirmatory 
image (eg, MRI) should be obtained to confirm if a study endpoint has been met.   
n Health Outcome Assessments: Data related to non-study related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
o Pre-titration tolerability assessment, which include a review of AEs and a review of safety laboratory results (eg, chemistry, hematology, and coagulation), must be completed 
by the Investigator before any up-titration can occur as defined in Section 7.4.1.  Lab results obtained within 2 months prior to any up-titration may be used for assessment.  
p Dose Titration is based on cirrhosis status (Section 9.7.3) and Child-Pugh Score (Section 9.7.4).  The initial dose titration of investigational product may occur at the Month 3 
visit, or any study visit thereafter for subjects on all dosing regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for subjects who are classified 
as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.  For complete modified dose 
titration criteria, refer to Appendix A. 
q Subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1) and to take investigational product at approximately the same time of day.  Subjects 
must be instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
r The subject 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. 
s Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry.  If positive, a confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not be enrolled in the study.  (Additional testing may be conducted where required, regionally). 
t Only OCA PK samples will be collected at Month 9 at select study sites in a subset of subjects.  Please refer to Section 9.7.13 for the PK sampling schedule. 
u Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
v A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12.  If a baseline (e.g. Day 0) genetic sample is not obtained, subsequent genetic samples are not required to be collected during the course of the study. 
w Please refer to Section 11.1.2.3 for description of the blood sample to be collected for future analysis. 
 
 
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Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) 
 
Year 2 through End of Study 
 
M 3 
continued follow-up 
1-Month Post-
Titration Visita 
(if applicable) 
M 6 
continued follow-up 
M 9 
continued follow-up 
M 12 
continued follow-up 
EOT/ 
EOSb 
Visit Windows (+/-)c 
±2 wk 
+1 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
Physical Examd 
 
X 
 
 
X 
X 
Assessment for Mayo Risk Scoree 
 
 
X 
 
X 
X 
Assessments for Child-Pugh Scoresf 
X 
 
X 
X 
X 
X 
Vital Signs (including weight) 
 
 
X 
 
Xg 
Xg 
12-Lead Electrocardiogram 
 
 
 
 
X 
X 
Subject Questionnaires (5-D Pruritus 
Scale and Pruritus VAS) 
 
 
X 
 
X 
X 
Quality of Life Questionnaires (PBC-40, 
EQ-5D-5L, and FIS)h 
 
 
 
 
X 
X 
Fibroscan®TEi 
 
 
X 
 
X 
X 
DEXAj 
 
 
 
 
X 
X 
Endoscopyk 
 
 
 
 
X 
 
Hepatic Ultrasoundl 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
Health Outcome Assessmentsm 
X 
 
X 
X 
X 
X 
Dose Titration (if applicable)n,o 
X 
 
X 
X 
X 
 
Dispense Investigational Product 
X 
 
X 
X 
X 
 
IP Accountability/Compliance 
X 
X 
X 
X 
X 
X 
Dosing Diary 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSp 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
X 
X 
Chemistry/Hematology/Coagulation 
X 
X 
X 
X 
X 
X 
 
 
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Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) (Continued) 
 
Year 2 through End of Study 
OCA, C4, and FGF-19 (plasma) 
 
 
 
 
X 
X 
Markers of Hepatic Fibrosis and/or 
Inflammationq 
 
 
X 
 
X 
X 
Geneticsr 
 
 
 
 
X 
 
Blood Sample for Future Analysiss 
 
 
X 
 
X 
X 
AE = adverse event; β-hCG = beta human chorionic gonadotropin; DEXA = dual-emission X-ray absorptiometry; EOS= End of Study; EOT = End of Treatment; 
FGF-19 = fibroblast growth factor-19; FIS = Fatigue Impact Scale; IP = Investigational Product; M = month, TE = transient elastography; VAS = Visual Analogue Scale; 
wk = week 
a  In subjects following the standard dosing regimen, the post-titration visit must be performed only after the first up-titration to 10 mg OCA or matching placebo, or after 
≥3 months at a decreased dose or frequency.  Post-titration visits must be performed 1 month ± 1 week after any up-titration in dose and/or frequency in subjects following 
modified dosing due to Child-Pugh B and Child-Pugh C hepatic impairment.   
b  As soon as possible upon study discontinuation and as near as possible to last dose taken. 
c Visits should be based on Day 0 (not on the prior visit) with the exception of the Post-Titration Visit, which is based on the date of titration. 
d The yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both. 
e Mayo Risk Score will be calculated based on central laboratory evaluations, diuretic use data, and peripheral edema assessment data captured in the CRF. 
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 case report form. 
g Height will be collected at this visit. 
h  The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2 and Section 12.2.6). 
i Transient elastography (TE) will be conducted at 6-month intervals at all study sites where the Fibroscan® TE device is available. Not required if done within 3 months of visit 
j  DEXA will be conducted at 12-month intervals at all study sites where the DEXA device is available.  Not required if done within 6 months of visit. 
k  Endoscopy will be conducted at all study sites where the device is available to assess for the presence of oesophageal varix/varices. 
l  Ultrasound will be conducted to enhance HCC surveillance.  For all on study (e.g. post-day 0) ultrasounds: unless HCC has already been confirmed by biopsy, a second 
confirmatory image (eg, MRI) should be obtained to confirm if a study endpoint has been met. 
m  Health Outcome Assessments: Data related to non-study related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
n   Pre-titration tolerability assessment, which include a review of AEs and a review of safety laboratory results (eg, chemistry, hematology, and coagulation), must be completed 
by the Investigator before any up-titration can occur as defined in Section 7.4.1.  Lab results obtained within 2 months prior to any up-titration may be used for assessment.   
o  Dose Titration is based on cirrhosis status (see Section 9.7.3)  and Child-Pugh Score (Section 9.7.4).  The initial dose titration of investigational products may occur at the 
Month 3 visit, or any study visit thereafter for subjects on all dosing regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for subjects who are 
classified as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.  For complete 
modified dose titration criteria, refer to Appendix A. 
p  The subject should be instructed to fast overnight (at least 8 hours) prior to each visit.  Fasting is required prior to all study visits, but water is permitted. 
q  Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
r  A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12. 
s Please refer to Section 11.1.2.3 for description of the blood sample to be collected for future analysis.  
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7.1.3. 
Study Duration 
The study is event driven and total duration will be determined by the time required to accrue 
approximately 127 primary endpoint events, estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time of approximately 6 years. 
7.2. 
Number of Subjects 
It is expected that approximately 428 subjects will be randomized in the study to achieve 
127 adjudicated primary endpoint events.   
7.3. 
Planned Dosing Regimen 
Subjects will be randomized to treatment with either OCA or matching placebo in a 1:1 ratio.  
Subjects will be dosed according to their cirrhosis status (as defined in Section 9.7.3) and 
applicable Child-Pugh Score (see Section 9.7.4) as outlined in Table 3.  
Subjects who are non-cirrhotic or classified as Child-Pugh A at screening will receive 5 mg OCA 
or matching placebo once daily for 3 months.  Subjects should titrate to a maximum dose of 10 
mg OCA once daily (or matching placebo) at the Month 3 visit or at any study visit following the 
Month 3 visit based on tolerability of the product and assessment of biochemical response.  Up-
titration should be considered when ALP and/or total bilirubin are >ULN.  A review of safety 
laboratory results (eg, chemistry, hematology, and coagulation) obtained no more than 2 months 
prior to the planned up-titration visit must be completed as part of the product tolerability 
assessment before up-titration can occur (see Section 7.4.1).   
For those subjects that up-titrate to 10 mg, dose may be decreased to 5 mg at any time during the 
study as considered clinically appropriate (eg, tolerability). Subjects may be titrated back up to a 
maximum dose of 10 mg once daily based on tolerability and clinical judgment of the 
Investigator.  A review of safety laboratory results obtained within 2 months of the planned 
up-titration visit date is not required prior to re-challenging a subject up to 10 mg once daily 
dosing, as long as the decrease in dose/dosing frequency was less than 3 months in duration.  
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Table 3: 
Planned Dosing Regimen by Cirrhosis and Child Pugh Score 
 
Scheduled Dosing Regimen 
Standard 
Modifieda 
Non-Cirrhotic/ 
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Starting Dose b  
(Day 0) 
5 mg daily 
5 mg once weekly 
5 mg once weekly 
Titration 1c  
(≥Month 3) 
10 mg daily 
5 mg twice weeklyd 
5 mg twice weeklyd 
Titration 2c  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weeklyd 
10 mg twice weeklyd 
Titration 3c 
(≥6 weeks after Titration 2) 
NA 
5 mg daily 
NA 
a Refer to Appendix A  for additional instructions regarding subjects following the Modified Dosing Regimen. 
b Starting dose based on subject’s cirrhosis status and Child-Pugh score at Screening. 
c Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject 
tolerability, biochemical response, and/or changes in cirrhosis status or Child-Pugh score at any time during the 
study (see Section 7.4). 
d Dosing per the twice weekly schedule must be at least 3 days apart. 
The dosing regimen should be determined as described in Table 4.  Investigators should follow 
the dosing/titration schedule as shown in Table 3. 
Table 4: 
Determination of Dosing Regimen 
Cirrhosis? 
No 
Yes 
Yes 
Yes 
Child-Pugh 
Score 
Any 
A 
B 
C 
Dosing Regimen 
Standard 
Modified for Child-Pugh B 
Modified for Child-Pugh C 
7.4. 
Dose Titration 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 subject’s cirrhosis status (using histology or 
non-histological methods as defined in Section 9.7.3 and Section 9.7.4) or Child-Pugh 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) as well 
as biochemical response (as assessed by reductions in ALP and/or total bilirubin).  In general, 
down-titration will be done in response to tolerability concerns and can occur at any time while 
on-study.  Up-titration will be done per protocol when subjects have no tolerability concerns and 
have not achieved an adequate reduction in ALP and/or total bilirubin to within normal limits, or 
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 for each 
dosing regimen as defined in Section 7.3. 
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Scheduled Dose Titration - The first dose titration for any subject may occur no earlier than 
3 months following initiation of OCA or matching placebo.  Subsequent titrations in dose or 
dosing frequency for subjects following the Modified Dosing Regimens may occur no earlier 
than 6 weeks (via an unscheduled visit or regular visit- see Appendix A) following an 
up-titration. 
Tolerability Dose Titration - Investigators may decrease the dosing frequency or dose for any 
subject at any time during the study, as considered clinically appropriate (eg, tolerability; see 
Section 7.4.1 and Section 7.4.2).   
Dose Titration due to Change in Cirrhosis or Child-Pugh Score - When subjects demonstrate 
a change in cirrhosis status (as assessed per Section 9.7.3) or Child-Pugh Score (Section 9.7.4), 
dosing should be reassessed and the dosing regimen modified appropriately.  Changes to the 
dosing regimen are not mandatory and should be based on clinical judgment as well as change in 
cirrhosis status.  Table 5 provides an overview of the possible changes in dosing regimen due to 
changes in cirrhosis or Child-Pugh 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.    
Table 5: 
Changes in Dosing Regimen Due to Changes in Cirrhosis Status or 
Child-Pugh Score 
Original Status 
New Statusa 
Non-cirrhotic OR  
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Non-cirrhotic or  
Child-Pugh A 
No Change 
10 mg daily  5 mg daily 
5 mg daily No change or 10 mg 
twice weeklyb 
5 mg or 10 mg daily  10 mg 
twice weeklyb 
Child-Pugh B 
5 mg daily  10 mg daily  
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 
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 subject begins dosing with the new dosing regimen, titration should occur as described for that dosing 
regimen in Section 7.3 or Appendix A.  
b Dosing per the twice weekly schedule must be at least 3 days apart. 
Subjects who exhibit development of cirrhosis at any point in the study should be assessed per 
Section 9.7.3.  If the presence of cirrhosis is confirmed and the subject’s Child-Pugh score is 
either B or C, the appropriate modified dosing regimen should be followed.  The dose or 
frequency of investigational product should be down-titrated to the next lowest dosing frequency 
in the appropriate modified dosing regimen unless the subject is currently taking a dose and 
frequency also specified in the modified dosing regimen and the Investigator determines that it is 
clinically appropriate for the subject to continue at that dose (Appendix A). 
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Subjects with pre-existing cirrhosis who demonstrate a change in the Child-Pugh Score from A 
to B or C at any point in the study should also have their dosing modified per the appropriate 
dosing regimen (Appendix A).  
Subjects who demonstrate an improvement in cirrhosis status or in Child-Pugh Score from B to 
A, or from Child-Pugh C to B, may be eligible to transition to the standard dosing regimen or the 
modified dosing for Child-Pugh B, respectively, based on tolerability.  Prior to any dosing 
change, subjects must meet pre-titration assessment requirements for dosing as described in 
Section 7.4.1. 
Child-Pugh Scores will be calculated at all quarterly study visits. All associated visit data 
(including central laboratory results) should be entered into the eCRF in a timely fashion to 
confirm that the subject’s Child Pugh Score has not changed.  If a change in cirrhosis status (as 
defined in Section 9.7.3) and/or Child-Pugh Score is observed independent of a study visit, the 
subject 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. 
Subjects’ dose and dosing frequency may be titrated up or down within the appropriate dosing 
regimen based on the calculated Child-Pugh Scores.  Up-titration should be done per Investigator 
discretion and be guided by the pre-titration tolerability assessments. 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements 
Tolerability of investigational product must be assessed prior to titrating a subject to a higher 
dose.  A review of adverse events and safety laboratory results (eg, chemistry, hematology, and 
coagulation) obtained within 2 months of the up-titration visit must be performed as part of the 
investigational product tolerability assessment, prior to any planned up-titration in study 
medication (eg, Month 3, Month 6).  Safety laboratory results obtained at the Month 1 visit (for 
titration at Month 3) or at the 1 Month Post-Titration Assessment visit (for titration prior to or at 
the subsequent quarterly visit) are acceptable for review purposes; however, 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 subject to a higher 
dose.  
To be eligible for a dose up-titration: 
• Subjects 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.  
• There must be no clinically significant increase (as determined by the investigator) in 
the subject’s liver function tests.  Subjects whose total bilirubin is >2× baseline (and 
>ULN) cannot be up-titrated, and additional unscheduled safety visit procedures, 
outlined in Section 9.7.19, should be implemented, as required. 
7.4.2. 
Safety Criteria for Adjustment or Stopping Doses 
Investigational product may be temporarily decreased (eg, from 10 mg to 5 mg daily, or by 
decreasing dosing frequency) or temporarily or permanently stopped based on tolerability 
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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 that 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 when the needed number of adjudicated events has accrued.  If a subject reaches an 
event, he or she should continue the regular visit schedule and continue taking investigational 
product as long as the Investigator assesses it as safe.  In general, subjects should be strongly 
encouraged to both stay on investigational product and remain in the study until study 
termination.   
7.5. 
Criteria for Study Termination 
The Sponsor 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 DMC, it may be necessary to stop the study before all events have been accrued, and 
when subjects are still active on the study.  In addition, the Sponsor may terminate the study at 
an investigational site at any time (eg, poorly performing sites, as determined by the number of 
subjects 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 subjects for the End of Study Visit.  The window of time for 
scheduling the visit will be based on a final projection of when the requisite 127 adjudicated 
events will have been accrued. 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Population 
This study will be conducted at approximately 170 international study sites with experience in 
treating patients with PBC.  Prospective subjects 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. 
Subject Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with AASLD and EASL practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in low titer 
(<1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies 
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against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase 
complex]). 
• Liver biopsy consistent with PBC. 
2. A mean total bilirubin >ULN and ≤5× ULN and/or a mean ALP >3× ULN  
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking 
UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0. 
5. Contraception:  Female subjects of child-bearing potential must use ≥1 effective method 
of contraception during the study and until 30 days following the last dose of 
investigational product.  Effective methods of contraception are considered to be those 
listed below:   
• Barrier method, ie, (a) condom (male or female) or (b) diaphragm, with spermicide  
• Intrauterine device (IUD)  
• Vasectomy (partner) 
• Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection) 
• Abstinence, if in line with the preferred and usual lifestyle of the subject   
6. Must provide written informed consent and agree to comply with the study protocol 
8.3. 
Subject Exclusion Criteria 
1. History or presence of other concomitant liver diseases including:  
• Hepatitis C virus infection 
• Active hepatitis B infection; however, subjects 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 
• Nonalcoholic steatohepatitis 
• Gilbert’s Syndrome  
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including:  
• History of liver transplant, current placement on a liver transplant list, or current 
MELD score >12.  Subjects who are placed on a transplant list despite a relatively 
early disease stage (for example per regional guidelines) may be eligible as long as 
they do not meet any of the other exclusion criteria. 
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• Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
− Variceal bleed 
− Uncontrolled ascites 
− Encephalopathy  
− Spontaneous bacterial peritonitis  
• Known or suspected hepatocellular carcinoma 
• Prior transjugular intrahepatic portosystemic shunt procedure 
• Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine 
>2 mg/dL (178 μmol/L)  
3. Mean total bilirubin >5× ULN  
4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) 
or ileal resection or plan to undergo either of these procedures. 
5. Other medical conditions that may diminish life expectancy, including known cancers 
(except carcinomas in situ or other stable, relatively benign conditions such as chronic 
lymphatic leukemia). 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test by the central laboratory), or lactating. 
7. Known history of human immunodeficiency virus infection. 
8. Medical conditions that may cause non-hepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months). 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study. 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0. 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components. 
14. UDCA naïve (unless contraindicated) 
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8.4. 
Subject Withdrawal from Investigational Product or Study 
8.4.1. 
Reasons for Mandatory Discontinuation of Investigational Product 
8.4.1.1. 
Severe Drug-Induced Liver Injury 
If a subject develops signs and symptoms of a severe drug-induced liver injury, regardless of 
causality, investigational product should be interrupted until the event has resolved or returned to 
baseline, but the subject should continue with the study visit schedule.  Subjects who develop 
significant drug-induced liver injury which is considered 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, evidence of 
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. 
Severe drug-induced liver injury that is not considered related to investigational product must be 
discussed with the Sponsor before investigational product is reinitiated.  Follow-up procedures 
for subjects resuming treatment, including laboratory evaluations and physical examinations, 
must be performed after a maximum of 2 weeks of re-treatment and may be conducted at a local 
clinic if the subject is unable to return to the site.  Results must be reported immediately to the 
site so the Investigator can determine if the subject is to be allowed to continue treatment.  
Subjects should be encouraged to continue study visits despite stopping investigational product 
for continued study data collection but may withdraw consent at any time. 
All suspected drug-related hepatic injury events will be adjudicated by the Hepatic Safety 
Committee (see Section 13.4). 
8.4.1.2. 
Liver Transplantation 
Subjects must discontinue investigational product after undergoing liver transplantation surgery.  
Subjects should be encouraged to continue study visits, despite stopping investigational product, 
for continued study data collection. 
8.4.2. 
Reasons for Mandatory Interruption of Investigational Product 
Prior to re-starting investigational product after a prolonged interruption, the subject must be 
re-consented and new baseline visit procedures must be performed if the interval from the last 
visit was more than 3 months (+2 weeks) during the first 18 months of the study or more than 
6 months prior (+2 weeks) during the remainder of the study.   
8.4.2.1. 
Pregnancy 
If a female subject becomes pregnant, she must interrupt treatment with investigational product 
immediately, but should continue with the study visit schedule.  As described in Section 12.1.9 
pregnancy is not considered an AE for reporting purposes.  The subject may re-start 
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 12.1.9).  New baseline procedures should include pregnancy testing. 
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8.4.3. 
Other Reasons for Discontinuation of Study or Investigational Product  
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.  With the exception of liver transplant, if a 
subject experiences a suspected or confirmed 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.  Subjects who discontinue investigational product prior to termination of the 
study need to also continue to follow the regular visit schedule through to study closure.  In 
general, subjects should be strongly encouraged to both stay on investigational product and 
remain in the study until study termination.  Early termination procedures should only be 
conducted if the subject withdraws consent (See Section 9.7.18). 
The following events are considered appropriate reasons for a subject to discontinue 
investigational product; however, these subjects are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
• Subject begins treatment with commercially available OCA 
• The Investigator or Sponsor considers that it is advisable or in the best interest of the 
subject. 
• 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 subject 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), liver-related clinical outcomes, and 
drug-related hepatic injury events. 
The Investigator is encouraged to contact the Sponsor prior to discontinuing a subject from 
treatment.  The Investigator must notify the Sponsor study monitor by telephone or email as soon 
as possible if any subject prematurely withdraws from the study.   
8.4.3.1. 
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 
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increases.  Any potentially hepatotoxic medications should be identified and discontinued if 
advisable. 
The Medical Monitor should be contacted, as appropriate. 
8.4.4. 
Withdrawal of Consent 
If the subject 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 subjects 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 subject discontinuation.  This 
information and date must be recorded in the appropriate case report form (CRF).   
8.4.5. 
Lost to Follow-Up 
If a subject fails to return to the clinic for a study visit, and the Investigator ceases to have 
contact with the subject, he or she will be withdrawn from the study. 
A reasonable effort must be made to contact the subject and determine the reason(s) why a 
subject 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 CRF.   
8.4.6. 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by telephone or email as soon as 
possible if any subject prematurely withdraws from the study.  The date when the subject is 
withdrawn and the reason for discontinuation must be recorded in the CRF.  If a subject is “lost 
to follow up” (fails to return for a visit), a reasonable effort should be made to contact the subject 
in order to determine why the subject failed to return.  This information must be documented in 
the CRF.  If a subject is withdrawn from the study early (regardless of the cause), all of the 
EOT/EOS evaluations should be performed at the time of withdrawal, as appropriate (See 
Section 9.7.18, Early Discontinuation and/or Early Termination Procedures).  
9. 
TREATMENT OF SUBJECTS 
9.1. 
Investigational Product Treatment Regimen 
The term investigational product refers to either OCA (provided as part of this clinical study) or 
matching 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 5 mg OCA tablet or one 
10 mg OCA tablet, or matching placebo).   
Investigational product will be taken orally, up to once daily, for the duration of the study.   
All subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1) and 
to take investigational product at approximately the same time of day.  Subjects must be 
instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
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At each study visit where the daily dose of investigational product is administered at the site, all 
assessments, except for the post-dose collection of blood samples for the subset of subjects 
participating in the Month 9 PK assessment, must be completed before administration of 
investigational product. 
9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.1) 
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 CRF, as well as any dose or dose 
regimen changes that occur during the study.  Concomitant medications should be stable prior to 
Day 0.   
Drug Interactions 
Subjects 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 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 Investigator’s Brochure (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 with OCA that may be observed in study subjects. 
PBC-Specific Therapy 
In general, 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 subjects’ 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, subjects 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, subjects should be reminded to keep taking their blinded 
investigational product. 
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9.2.1. 
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.  Subjects who continue with commercial OCA therapy must discontinue study 
medication and are expected to continue through the end of the study (see Section 7.4.2).  The 
study will only terminate at the time when the needed number of adjudicated events has accrued 
or at the discretion of the Sponsor.  Subjects will need to complete EOT procedures but continue 
with regularly scheduled visits until the study is terminated (see Section 9.7.18 Early 
Discontinuation and/or Early Termination Procedures). 
9.3. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Subjects should be instructed to complete a dosing diary to help monitor compliance to the 
prescribed dosing regimen.  Subjects should be instructed to retain all bottles of investigational 
product, even if empty, and to return them to the Investigator at the subsequent visit.  The 
Investigator or designee should perform investigational product accountability and, if applicable, 
follow up with the subject to retrieve any investigational product bottles that have not been 
returned.  
If the Investigator has concerns about a subject’s dosing compliance s/he should discuss this with 
the subject, assess the reasons for noncompliance and the likelihood that the subject will remain 
noncompliant, and notify the Sponsor accordingly.   
9.4. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Allocation to one of 
two treatment groups (OCA or placebo) will occur on a 1:1 ratio across sites and will be 
stratified by UDCA treatment (yes/no) and mean baseline bilirubin categories (>ULN/≤ULN), as 
specified by the central laboratory.  The randomization will be based on a predefined 
randomization code (generated by the Sponsor or designee) using an interactive web response 
system (IWRS), which the Sponsor intends will serve as a computer-based subject registration 
system at Screening and Day 0.  The IWRS will serve as an investigational product inventory 
and management system and may be integrated with the study database.  
The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide subject data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned (refer to Section 9.5.2 below) and 
investigational product dispensing information (ie, bottle number[s]) will be provided. 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects 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 
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blinded treatment assignment is necessary for further medical management of the subject).  If it 
is not reasonable to inform the Medical Monitor in advance of the unblinding, the Investigator 
must promptly document in the subject’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 subject’s treatment will be provided separately to the 
Investigator.  Similarly, if the Medical Monitor breaks the blind for an individual subject for the 
purpose of evaluating an emergent safety issue, the Medical Monitor will document within trial 
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 subjects.  Refer to Section 13.3 for further details regarding DMC access to 
blinded and unblinded data.  The DMC will document details about any unblinded subject data 
reviews in the closed session DMC minutes, which will be made available to the Sponsor only 
after the database is locked and the trial 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 Subject 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 subject data and to identify the site and or Investigator 
within study documents.  This number will be recorded in the CRF. 
9.5.2. 
Subject Numbers 
Subjects 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 trial is prohibited.   
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9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visits should be based on Day 0 (not on the prior visit), eg, Month 3 should ideally occur 
3 calendar months (± 2 weeks) following Day 0.  The visit windows are as follows: 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening Visit 1 interval is 3 to 8 weeks prior to Day 0.  Screening 
Visit 2 interval is 1 to 6 weeks prior to Day 0.  The visit window for 
Screening 2 visits allows for the repeat biochemistry tests to be 
collected at least two weeks after the initial biochemistry sample 
was collected and will ensure ample time to receive lab results.  
The overall Screening interval is up to 56 days, but screening 
procedures should not be performed during the last 7 days of the 
window.  
Day 0 
This is the day of randomization.  On-treatment visit scheduling 
should be calculated from this point going forward. (The first dose 
of investigational product should be taken the next day, on Day 1.) 
Month 1  
+1 week (7 days)  
Titration Visit – Standard Dosing Regimen 
≥Month 3 
Titration Visit 1 – Modified Dosing 
Regimen 
≥Month 3 
Titration Visit 2 – Modified Dosing 
Regimen 
≥6 weeks after Titration Visit 1 
Titration Visit 3 – Modified Dosing 
Regimen (Child-Pugh B ONLY) 
≥6 weeks after Titration Visit 2 
Post-Titration Visit 
1 month (+1week [7 days]) from date of titration or after ≥3 months 
at a decreased dose or frequency   
Month 3 to Month 12 
±2 weeks (14 days)  
Quarterly visits (Months 15 to EOS) 
±2 weeks (14 days) 
EOT 
(When subject discontinues investigational 
product) 
As soon as possible upon study discontinuation and as near as 
possible to last dose taken 
EOS 
(When subject terminates the study) 
The final study visit; EOS will occur concurrent with EOT if a 
subject discontinues study medication at the time the subject’s 
participation in the study ends (eg, withdrawal of consent or study 
termination by the Sponsor); EOS will occur after the EOT if the 
subject discontinues study medication but continues in the study. 
EOS = end of study; EOT = end of treatment  
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk and benefit of the 
study to the subject and will provide him/her with a copy of the written information and 
informed consent form (ICF).  The subject will be given sufficient time to consider the study 
before deciding whether or not to participate.  The subject will be informed that participation is 
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voluntary and that her/his future medical treatment will not be compromised by participation in 
the study and that s/he can withdraw from the study at any time.  The subject must be willing and 
able to provide written informed consent before entering the study.  The Investigator or a 
medically qualified designee is responsible for administering and documenting the written 
informed consent of the subject.  The subject will be given a copy of the written information and 
his/her signed and dated consent form. 
Any change in a subject’s consent status (eg, semi-annual telephone contact or medical record 
review) must be documented in a signed informed consent form or addendum.  The subject will 
be given a signed and dated copy of the consent document. 
9.7.3. 
Assessing Cirrhosis 
9.7.3.1. 
Determination for Dosing Regimen 
To determine which dosing regimen subjects should follow, the presence or absence of cirrhosis 
should be assessed by the Investigator at Screening Visit 1.  Acceptable methods of confirming 
(via medical history) or assessing cirrhosis for purposes of determining dosing is defined as a 
subject 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 (TE) 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  
− elevation in prothrombin time /INR (not due to antithrombotic agent use), or 
− elevated bilirubin (2× ULN) 
Subjects who exhibit no evidence of cirrhosis by the above methods of assessment will be dosed 
using the Standard Dosing Regimen, while those who do exhibit evidence of cirrhosis by one or 
more of the above methods will be dosed using the Modified Dosing Regimen according to their 
Child-Pugh Score calculated in the electronic case report form (eCRF) (see Appendix A, 
Section 7.3, Table 3 and Table 4). 
Cirrhosis status should be reassessed as clinically indicated throughout the study.  Any change in 
cirrhosis status will necessitate re-evaluation of the dosing regimen. 
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9.7.3.2. 
Progression to Cirrhosis 
When a subject identified as non-cirrhotic at baseline per the criteria listed in Section 9.7.3.1 
exhibits any of those same criteria (excluding biopsy results consistent with PBC Stage 4), the 
subject should also be assessed by Fibroscan® TE where available and progression to cirrhosis 
confirmed by biopsy unless not medically indicated.  Sites participating in the paired biopsy sub-
study (see Appendix C) must confirm progression to cirrhosis by biopsy.  All suspected cases of 
progression to cirrhosis should be submitted for adjudication regardless of the availability of 
transient elastography or biopsy results. 
9.7.4. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is calculated and reported within the electronic data 
capture (EDC) system based on data entered into the eCRF adding the scores from the 5 factors 
outlined in Table 6 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 Child-Pugh 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.  It is important to note 
that subjects must have confirmed cirrhosis as assessed by one or more of the above criteria 
(Section 9.7.3) prior to applying the calculated Child-Pugh score for dosing.  Investigators will 
be responsible for determining the appropriate dosing regimen based on both the cirrhosis status 
and the Child-Pugh score (Table 6).  Any change in cirrhosis status or Child-Pugh Score will 
necessitate re-evaluation of the dosing regimen. 
Table 6: 
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) 
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9.7.5. 
Mayo Risk Score 
Mayo Risk Score (MRS) (Dickson 1989) is calculated and reported within the EDC system 
based on data entered into the eCRF.  Calculation of MRS includes investigator assessment of 
peripheral edema and the use of diuretic therapy, which will be assessed during adverse event 
and concomitant medicine review at the scheduled visits and entered into the eCRF, as well as 
total bilirubin, albumin, and prothrombin time results obtained from the central laboratory data. 
9.7.6. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 week to 8 weeks prior to Day 0 to 
determine whether the subject meets all the inclusion criteria and none of the exclusion criteria.  
Screening Visit 1 will occur 3 weeks to 8 weeks prior to Day 0; Screening Visit 2 will occur 
1 week to 6 weeks prior to Day 0, depending on the date that the first serum chemistry sample 
was collected. Subjects who do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects 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.   
Two Screening visits will occur from 1 to 8 weeks prior to Day 0 (as outlined below) allowing 
for the collection of repeated serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values: 
• All subjects will have 2 bilirubin and ALP assessments at least 2 weeks apart. 
• The mean of all available (at least 2; including both scheduled and 
unscheduled) bilirubin and ALP assessments will be used to determine eligibility 
(total bilirubin >ULN and ≤5× ULN and/or an ALP >3× ULN).   
Screening Visit 1 procedures are as follows: 
• The subject is to review and sign the ICF.  Informed consent must be obtained from 
the subject 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  
• Assess for the presence/absence of cirrhosis. 
• Verify inclusion and exclusion criteria for eligibility. 
• Perform a physical examination.  
• Perform assessments for calculation of Child-Pugh Score 
• Perform assessment for calculation of Mayo Risk Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
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• Assess and record any pretreatment-emergent AEs. 
• Record prior (if within 30 days of Screening) and current concomitant medications. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
Screening Visit 2 procedures are as follows: 
• Verify inclusion and exclusion criteria for eligibility. 
• Perform an ultrasound for hepatocellular carcinoma (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 Visit 2, and a 
report/adequate data are available, a pretreatment ultrasound at Screening Visit 2 is 
not required.  If the ultrasound cannot be performed at Screening Visit 2 (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. 
• Assess and record any pretreatment-emergent AEs. 
• Record current concomitant medications. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry tests. 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
• In preparation for the dual-emission X-ray absorptiometry (DEXA) bone density scan 
to be done at Day 0 (selected study sites only), subjects who are taking calcium 
supplements should stop taking them for 48 hours before the scan.  If the subject is 
taking any medications for osteoporosis or osteopenia, s/he should not take them on 
the day of the scan. 
It is acceptable to repeat laboratory evaluations or other assessments or procedures within the 
Screening period (Weeks -8 to -1), as appropriate. 
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9.7.7. 
Day 0 Procedures (Randomization) 
• Review inclusion and exclusion criteria for eligibility. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform transient elastography at all study sites with access to Fibroscan® TE device. 
If TE has been done within 3 months of Day 0 and a report/adequate data are 
available, a pretreatment TE at Day 0 is not required.  If the TE cannot be performed 
on Day 0 (eg, device/technician unavailability, scheduling issues, TE data is needed 
to inform cirrhosis assessment, etc), the procedure may be completed within the 
screening visit window, at Screening Visit 1 (if data is needed for cirrhosis 
assessment) or as close as possible to the Day 0 visit, preferably, after subject 
eligibility has been confirmed. 
• Conduct a DEXA bone density scan (at all study sites where device is available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable.  If DEXA has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment DEXA at Day 0 is not required. If 
the DEXA cannot be performed on Day 0 (eg, device/technician unavailability, 
scheduling issues, etc), the procedure may be completed within the screening visit 
window, as close as possible to the Day 0 visit, preferably, after subject eligibility has 
been confirmed. 
• Perform an esophagogastroduodenoscopy (endoscopy; at study sites, where device is 
available) to assess the presence or absence of oesophageal varix/varices.  If an 
endoscopy has been done within 12 months of Day 0 and a report/adequate data are 
available, a pretreatment endoscopy at Day 0 is not required. If the endoscopy cannot 
be performed on Day 0 (eg, device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening visit window, as close as 
possible to the Day 0 visit, preferably, after subject eligibility has been confirmed. 
− Subsequent endoscopies should be performed annually or per standard of care and 
the Investigator’s clinical judgment throughout the course of the study.  
Endoscopies should also be performed when platelet counts are <150 × 109 /L. 
• Assess and record any pretreatment-emergent AEs. 
• Review and record prior concomitant medications. 
• 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 subject only if s/he meets all inclusion criteria and no exclusion 
criteria. 
• Verify that the subject has fasted for at least 8 hours. 
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− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• 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 tests. 
• Obtain blood samples for:  
− OCA, C4, and fibroblast growth factor-19 (FGF-19) 
− Markers of hepatic fibrosis and/or inflammation (including enhanced liver fibrosis 
[ELF]) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Access the IWRS and dispense investigational product 
• Instruct the subject to begin dosing on the day after the Day 0 visit (ie, on Day 1).  
Instruct the subject to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
Month 1 Procedures 
• Perform a physical examination.  
• Assess and record AEs 
• Review and record concomitant medications. 
• Assess investigational product compliance, perform investigational product 
accountability, and review dosing diary with the subject. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Provide the subject with a dosing diary to document his or her dosing. 
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• In the event it is not feasible for the subject to return to the site for the above 
referenced procedures, the following alternative visit procedures are available to help 
ensure compliance with the Month 1 visit laboratory requirements: 
− At the Day 0 visit, the subject can be provided with the central laboratory 
collection kit and shipping materials associated with the Month 1 visit, and have 
the laboratory specimen collection performed at his or her local doctor’s office or 
designated laboratory collection center.  The subject must also be contacted via 
telephone at the Month 1 visit time point to assess AEs, review concomitant 
medications, and assess investigational product compliance;  
− If all other options for the collection of the Month 1 laboratory samples have been 
exhausted, the use of a local laboratory for the Month 1 samples would be 
accepted for this visit although any laboratory data obtained from a local 
laboratory will not be captured in the eCRF or included in the study analysis.  A 
copy of the local laboratory report would need to be provided to the investigator 
for review and available in the source records.  The subject must also be contacted 
via telephone at the Month 1 visit time point to assess AEs, review concomitant 
medications, and assess investigational product compliance;  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
Month 3 Procedures 
• Perform assessments for calculation of Child-Pugh Score. 
• 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. 
• 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
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− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests.  
• Obtain blood samples for: 
− OCA, C4, and FGF-19 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
Post-Titration Visit Procedures 
• Perform a physical examination.  
• Assess and record AEs. 
• Review and record concomitant medications. 
• Assess investigational product compliance, perform investigational product 
accountability, and review dosing diary with the subject. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Provide the subject with a dosing diary to document his or her dosing. 
• In the event it is not feasible for the subject to return the site for the above referenced 
procedures, the following alternative visit procedures are available, to help ensure 
compliance with the Post-Titration laboratory requirements: 
− At the Up-titration Visit, the subject can be provided with the central laboratory 
collection kit and shipping materials associated with the Post-Titration visit, and 
have the laboratory specimen collection performed at his or her local doctor’s 
office or designated laboratory collection center.  The subject must also be 
contacted via telephone at the Post-Titration Visit time point to assess AEs, 
review concomitant medications, and assess investigational product compliance;  
− If all other options for the collection of the Post-Titration laboratory samples have 
been exhausted, the use of a local laboratory for the Post-Titration samples would 
be accepted for this visit although any laboratory data obtained from a local 
laboratory will not be captured in the eCRF or included in the study analysis.  A 
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copy of the local laboratory report would need to be provided to the investigator 
for review and available in the source records.  The subject must also be contacted 
via telephone at the Post-Titration Visit time point to assess AEs, review 
concomitant medications, and assess investigational product compliance;  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
- 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. 
Month 6 Procedures  
• Perform a physical examination 
• Perform assessment for calculation of Mayo Risk Score. 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.6) 
• Perform TE at all study sites with access to Fibroscan® TE device. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
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• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
• For subjects who will participate in the PK assessment and are taking BAS or 
aluminum hydroxide- or smectite-containing antacids, they should be instructed to 
not take their regular dose on the morning of the study visit.   
9.7.12. 
Month 9 Procedures 
• Perform assessments for calculation of Child-Pugh Score. 
• 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. 
• 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
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• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• PK assessment in participating subjects at select study sites (see Section 9.7.13). 
• In preparation for the DEXA bone density scan to be done at the Month 12 visit 
(selected study sites only), subjects who are taking calcium supplements should stop 
taking them for 48 hours before the scan.  If the subject is taking any medications for 
osteoporosis or osteopenia, s/he should not take them on the day of the scan. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
9.7.13. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic Assessment 
At selected investigational sites, subjects will have the option to consent to participate in an 
additional OCA PK assessment.  PK samples will be used to support further analysis of OCA 
exposure-response in subjects with PBC.  This is optional and subjects may decline to participate 
without affecting their involvement in the rest of the study.  Consent to participate in the 
assessment can be given at any point during study participation prior to the Month 9 visit.  
Subjects who are following the Child-Pugh B and Child-Pugh C modified dosing regimen may 
participate in the PK assessment and will dose in the clinic at this visit even if the previous dose 
was taken less than 3 days prior; however, every attempt should be made to schedule the 
Month 9 PK visit according to the subject’s established dosing schedule. 
Following collection of the Month 9 fasted samples (refer to Section 9.7.12, subjects who are 
participating in the PK assessment will each receive a single dose of investigational product 
(blinded OCA or placebo tablet) with approximately 240 mL of water.  Subjects taking BAS or 
aluminum hydroxide- or smectite-containing antacids should be instructed to stagger their dosing 
of study medication and UDCA, ensuring at least 4 hours between doses of the BAS and/or these 
antacids and the study medication (and UDCA).   
Serial blood samples will be obtained for measurement of OCA and its conjugates prior to 
dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours post dose.  Samples should be collected 
within a window of ±5 minutes of the scheduled sample time.  Subjects should not drink 
additional water for 1 hour after taking the dose of investigational product and will remain fasted 
until the 4-hour sample is collected.  Lunch will be provided following collection of the 4 hour 
PK sample; the lunch will be a meal replacement drink with no other food allowed until after the 
final 6-hour post-dose sample is collected.  Samples will be stored for up to 5 years after the end 
of the study and will be destroyed after 5 years if not analyzed. 
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9.7.14. 
Month 12 Procedures 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Perform assessment for calculation of Mayo Risk Score. 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Quality of Life and Subject questionnaires and (see Section 11.1.2.2 
and Section 12.2.6). 
• Perform TE at all study sites with access to Fibroscan® TE device. 
• Conduct a DEXA bone density scan (at selected study sites, where available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable. 
• Perform an endoscopy (at selected study sites, where available) to assess the presence 
or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
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• Obtain blood samples for: 
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
9.7.15. 
Month 3 and Month 9 Continued Follow-Up Procedures (±2 weeks) 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− NOT to take investigational product on the morning of the next visit, and  
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− 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. 
9.7.16. 
Month 6 Continued Follow-Up Procedures (Semi-annually [±2 weeks]) 
• Perform assessment for calculation of Mayo Risk Score. 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate 
and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.6) 
• Perform TE at all study sites with access to Fibroscan® TE device. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 (refer to Section 7.4). 
• Assess investigational product compliance, perform accountability, and review dosing 
diary with the subject. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− Markers of hepatic fibrosis and/or inflammation (including ELF). 
− Blood sample for future analysis (refer to Section 11.1.2.3). 
• At the semi-annual visit, in preparation for the DEXA bone density scan to be done at 
the annual visit (selected study sites only), subjects who are taking calcium 
supplements should stop taking them for 48 hours before the scan.  If the subject is 
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taking any medications for osteoporosis or osteopenia, s/he should not take them on 
the day of the scan. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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 
9.7.17. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Perform assessment for calculation of Mayo Risk Score. 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform TE at all study sites with access to Fibroscan® TE device. 
• Conduct a DEXA bone density scan (selected study sites); document whether the 
subject stopped taking her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the scan, if applicable. 
• Perform an endoscopy (at study sites, where device is available) to assess the 
presence or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• 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 (refer to Section 7.4). 
• Assess investigational product compliance, perform accountability, and review dosing 
diary with the subject. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product. 
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• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
9.7.18. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent 
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects discontinue treatment with investigational 
product.  The EOT visit and procedures listed below must be performed as close as possible to 
the subject’s last dose of investigational product.  When a subject discontinues investigational 
product but continues with regularly scheduled study visits, the EOS visit will be completed later 
in the study as the subject’s final study visit.  The actual investigational product discontinuation 
scenario (Table 7) will determine the sequence of the EOT and EOS visits and procedures.  In 
some cases, the EOT visit and procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible to the subject’s last dose of 
investigational product.   
When a subject ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (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 
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final assessments on or as near as possible to the final day of dosing.  In some cases, the subject 
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 and EOS procedures in the CRF.  
Table 7: 
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 IP 
Treatment 
Discontinuationb 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
Discontinued 
Semiannual 
contactc 
Telephone 
contact every 6 
months (±2 
weeks) 
Combined Visit, Completed as 
close as possible to last dose IP 
Discontinued 
Record review 
onlyc 
Record review 
only 
Combined visit 
Completed as close as possible 
to last dose IP 
Sponsor 
Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit 
Completed as close as possible 
to last dose IP 
Pregnancy 
Interrupted 
Retained 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
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; IP = investigational product 
a Refer to Section 7.1.2 Schedule of Study Procedures, Table 2 for all procedures and evaluations required at the 
End of Treatment and End of Study Visits.  
b   Includes initiation of commercially available OCA. 
c Outcomes data to be discussed or collected include data related to adjudicated hepatic and cardiovascular event-
related data.  No additional data (e.g. AE, concomitant medication, etc) data will be collected, except as indicated 
in Section 12.1.7. 
Some assessments noted below may be omitted if they have been completed within the 6 months 
(or the timeframe otherwise specified) and so long as safety issues do not warrant repeat testing. 
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Prior to the EOT/EOS Visit: 
If possible to do before the visit, when scheduling the EOT/EOS visit, reiterate dosing 
instructions and advise the subject: 
• If applicable, NOT to take investigational product on the morning of the next visit, 
and  
• To bring the investigational product bottle(s); if applicable, s/he will dose at the 
clinic, 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. 
During the EOT/EOS Visit: 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Perform assessment for calculation of Mayo Risk Score. 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead ECG. 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform TE at all study sites with access to the Fibroscan® TE device (not required at 
EOT/EOS if done within 6 months). 
• Conduct a DEXA bone density scan (selected study sites; not required at EOT/EOS if 
done within 6 months); document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites); not required at 
EOT/EOS if done within 6 months. 
• Assess and record AEs; all ongoing “related” AEs must be followed until stable or 
resolved. 
• Review and record concomitant medications. 
• 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 accountability, and review dosing 
diary with the subject; retrieve used bottles, accordingly, and document returns. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
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− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
9.7.19. 
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.   
In the event of an inexplicable and acute (for example not explained by natural progression of the 
chronic disease) increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
or total bilirubin is observed during the course of the study, refer to Section 8.4.3.1 to confirm 
whether an unscheduled safety visit is required. 
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 5 mg or 10 mg OCA 
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 subject at each visit to provide enough tablets for daily 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. 
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10.3. 
Investigational Product Storage 
The 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 Preparation 
The investigational product will be provided to the distribution center in bulk bottles and 
therefore may be repackaged in unit dose form for administration to subjects before shipping to 
the sites. 
10.5. 
Investigational Product Administration 
Refer to Section 9.1. 
10.6. 
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 subject 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. 
11. 
ASSESSMENT OF EFFICACY  
11.1. 
Assessment of Efficacy  
11.1.1. 
Primary Assessments 
The following primary efficacy assessments will be measured: 
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
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• 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 or greater) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities, unless 
confirmed by biopsy. 
11.1.2. 
Secondary Assessments 
The following secondary efficacy assessments will be measured: 
• Liver-related death 
• Liver biochemistry (see Table 10 for list of analytes to be tested) 
• Progression to cirrhosis as assessed by the presence of clinical, laboratory, or 
radiological evidence of cirrhosis and/or liver stiffness (Fibroscan® TE), confirmed 
by biopsy unless not medically indicated.  
• Histological assessment of disease progression or improvement using paired biopsies 
in a subset of subjects (see Appendix C) 
• Biomarkers, including other markers of hepatic fibrosis and/or inflammation, to be 
tested will include:  IgM, c-reactive protein (CRP), tumor necrosis factor-α (TNF-α), 
FGF-19, cytokeratin-18 (CK-18) and ELF, (and others as determined during the 
course of the study). 
• Data will be collected to inform quality of life and cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Quality of life will be 
assessed by questionnaires (PBC-40, EQ-5D-5L, and FIS) administered annually.  
Resource utilization information will be collected from the Medical and Surgical 
Treatment Procedures and Office Visit Log or other CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician visits (subject reported), 
and use of concomitant medications.  
• Endoscopy will be conducted at selected study sites where the device is available to 
assess for the presence of oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual study assessments or standard 
of care will be collected in the case report form to assess for the development of 
varix/varices. 
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11.1.2.1. Non-Invasive Assessments of Liver Fibrosis 
• Blood samples for measurement of ELF test and other analytes will be collected.  The 
ELF test assesses: hyaluronic acid (HA), procollagen-3 N-terminal peptide (P3NP), 
and a tissue inhibitor of metalloproteinase 1 (TIMP-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.   
11.1.2.2. Other Secondary Assessments 
• OCA (OCA, tauro-OCA, glyco-OCA, total OCA, OCA-glucuronide) and C4 will be 
assayed to determine bioanalytical concentrations.  Additional analyses may include 
other conjugates or metabolites not yet identified.   
• Quality of Life questionnaires. 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 (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 respondent’s self-rate 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). 
− Fatigue Impact Scale (FIS):  The FIS is a validated 40 question questionnaire 
organized into 3 dimensions:  cognitive, physical, and social.  Each dimension has 
5 levels:  no problem, small problem, moderate problem, big problem, and 
extreme problem (Fisk 1994). 
11.1.2.3. Other Exploratory Evaluations 
• A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved 
in PBC will be conducted for subjects and at study sites willing to provide samples at 
Day 0, Month 12, and every other year at the yearly visits thereafter.  RNA 
expression resulting from treatment with OCA will be assessed at indicated 
timepoints during the study.   Subjects will be permitted to decline to provide a blood 
sample for the genetics study, without affecting their involvement in the study.  
IRB/IEC review and approval will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will be stored for up to 1 year 
after the end of the study and destroyed after 1 year if not analyzed. 
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• Blood samples for future analysis of additional analytes, such as PBC autoantibodies 
and other cytokines and interleukins, may be assayed on an exploratory research 
basis.  Blood samples may also be used to assess other disease or investigational 
product characteristics.  Appropriate serum and plasma samples will be collected at 
selected time points during the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their involvement in the study.  IRB/IEC 
review and approval will be required and willing subjects must specifically consent to 
participate in this evaluation.  The samples will be stored for up to 1 year after the end 
of the study and destroyed after 1 year if not analyzed. 
11.1.2.4. Potential Clinical Outcome Events 
The events listed in Section 12.1.5 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 13.4) 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 
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 13.4. 
12. 
ASSESSMENT OF SAFETY 
12.1. 
Adverse Events and Serious Adverse Events 
12.1.1. 
Definitions of Adverse Events 
12.1.1.1. Adverse Event  
An AE is 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) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction. 
Subjects should be questioned in a general way, without leading the subject 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 
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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. 
12.1.1.2. 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-subject 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 subject 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. 
12.1.1.3. Treatment-Emergent Adverse Event  
A treatment-emergent AE (TEAE) is any event not present prior to the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
12.1.2. 
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/serious adverse event (SAE) and the investigational product is 
determined to be “possible” or “probable” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 
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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 subject’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 
A reaction 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 subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
12.1.3. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 9, must be entered on the AE CRF.  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 9: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Causing no limitation of usual activities; the subject may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the subject may experience annoying 
discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the subject may experience intolerable 
discomfort or pain. 
12.1.4. 
Reporting of Adverse Events and Serious Adverse Events 
12.1.4.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
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 subject’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE CRF.  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.  
12.1.4.2. 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 be reported by: 
• E-mail to the SAE email address:  sae@interceptpharma.com 
• Fax using a paper SAE report form:  +1 800 497 8521 
• Telephone:  +1 858 964 1571  
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:   
• Subject 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 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 +1 800 497 8521 or 
emailed to sae@interceptpharma.com as soon as possible.  Redacted medical record source 
documentation will be requested for all SAEs and emergency room visits. 
The Investigator is responsible for submitting information on 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 IECs/IRBs must be retained in the appropriate study file(s).  
As instructed by the Sponsor, Expedited Safety Reports should be retained in the appropriate 
investigative site study files or with the IB. 
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SAEs involving suspected liver-related clinical outcome events will be processed and reported 
by the Sponsor as described in Section 12.1.5.  
12.1.5. 
Suspected Liver-Related Clinical Outcome Events 
Specified liver-related clinical outcome events may, by definition (see Section 12.1.1.2) qualify 
as SAEs.  The Sponsor must be notified of any SAEs within 24 hours of the site becoming aware 
of the event (see Section 12.1.4.2).  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. 
Given that the liver-related 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 liver-related 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 
“study event” on the Adverse Event CRF and will be submitted for adjudication to the Hepatic 
Outcomes Committee as described in Section 13.4. 
The Sponsor will consider the following list of clinical outcome events (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), hepatic encephalopathy (preferred term: hepatic encephalopathy),  spontaneous 
bacterial peritonitis (preferred term: peritonitis bacterial), ascites (preferred term: ascites), and 
histological progression to cirrhosis (preferred term: hepatic cirrhosis). 
12.1.6. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the CRF 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 subject’s AE CRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the Medical Monitor, 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 subject 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. 
12.1.7. 
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 12.1.4.2. 
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All SAEs that occur within 30 days following the cessation of investigational product, 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 12.1.4.2. 
SAEs that occur more than 30 days after a subject has discontinued study medication, and are not 
considered related to investigational product, must still be reported in the EDC system; however, 
these events are not required to be reported within 24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to investigational product, action taken with study 
medication, treatment, outcome, and potential endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event summary, SAE details) may also be required to be 
entered, when requested by the Sponsor. 
12.1.8. 
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 subject 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 subject 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 CRF.  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 subjects 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 CRF. 
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. 
12.1.9. 
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 8.4.2.1) 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 sae@interceptpharma.com or faxed to 
+1 800 497 8521.   The subject and neonate must be followed for outcome information and/or as 
considered appropriate by the Investigator and Sponsor. 
The subject 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 subject must have a negative pregnancy test before restarting investigational product.  If a 
subject’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.  
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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 12.1.4 must also be followed. 
12.2. 
Other Safety Parameters 
12.2.1. 
Medical History/Demographics 
A complete medical history and PBC disease-specific history will be obtained from the subject at 
Screening.  Smoking and alcohol consumption history and current habits will be recorded.  
Demographic characteristics (age, gender, race, and ethnicity) will be recorded. 
12.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the timepoints specified in the Schedule of Study Procedures (Section 7.1.2).  A basic physical 
examination should be performed, including all body systems pertinent to the subject.  Any 
clinically significant abnormality should be reported on the AE CRF page for findings that 
appear after consent, and on the medical history CRF for any finding present prior to consent.  
Information about smoking and alcohol consumption habits will be collected at the same 
(follow-up) timepoints as the physical exam. 
12.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits: height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure.  When taking heart rate, respiratory rate, and blood 
pressure readings, subjects should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
12.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected at the Screening Visit 1, Month 12, and at EOT/EOS.  
The Investigator or designee will review the 12-lead ECG and findings will be recorded in the 
CRF as normal, abnormal but not clinically significant, or abnormal and clinically significant.  
Any clinically significant abnormality on ECGs should be reported on the AE CRF page.  
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 subject’s initials, Subject ID number, 
date, and time. 
12.2.5. 
Dual Emission X-Ray Absorptiometry 
A bone density assessment will be done using the DEXA scan. 
12.2.6. 
Subject Questionnaires 
Information about the subject’s PBC disease history (ie, date of diagnosis, treatment history, 
pruritus history, signs and symptoms, and including smoking history) will be collected during 
Screening.  At subsequent study visits (see Section 7.1.2), subjects will be asked to complete the 
following questionnaires; they may be asked to initial and date to document confirmation of their 
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responses, and the questionnaires should be filed in the subject’s study records.  These may 
require transcription to the CRF by study site staff. 
• 5-D Pruritus Questionnaire:  This is a questionnaire that has been validated in several 
different diseases.  It assesses symptoms in terms of 5 domains: degree, duration, 
direction, disability and distribution (Elman 2010). 
• Pruritus VAS:  A Visual Analogue Scale (VAS) will also be used to assess pruritus in 
individual subjects. 
12.2.7. 
Laboratory Assessments 
Subjects will be instructed to attend each of their study visits (except Screening) in a fasted state, 
and subjects should remain fasted until their blood samples have been collected.  At each visit, 
the Investigator or designee will verify that the subject has fasted for at least 8 hours and record 
fasting status in the source and CRF.  If the subject reports having eaten (water is permitted) 
within 8 hours, the Investigator or designee will document accordingly in the source and CRF 
and remind the subject that fasting is required prior to all study visits. 
Blood samples for serum chemistry and hematology will be collected at every visit as detailed in 
the Schedule of Study Procedures (Section 7.1.2).  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 by the central clinical laboratory in a study specific laboratory 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 subjects 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 10. 
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Table 10: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry  
Albumin, blood urea nitrogen (BUN), 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 very low density 
lipoprotein [VLDL] fractions and triglycerides[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 
Prothrombin time (PT), partial thromboplastin time 
(PTT), international normalized ratio (INR) 
Urinalysis 
pH, specific gravity, total protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, 
albumin, creatine, leucocytes, nitrates, 
albumin/creatine ratio (if positive) 
Biomarkers of Hepatic Fibrosis and/or Inflammation  
IgM, C-reactive protein (CRP), TNF-α, FGF-19, CK-
18, ELF, and others as determined during course of 
study  
Genetics 
DNA including single-nucleotide polymorphisms 
(SNPs) that may be involved in PBC; RNA 
Blood Sample for Future Analysis 
PBC autoantibodies and other cytokines and 
interleukins TBD 
Other 
OCA (parent and conjugates [glyco and tauro], 
OCA-glucuronide) and C4 
The Investigator should manage subjects with clinically significant lipoprotein abnormalities 
using local standard of care procedures as appropriate after assessing the individual subject’s 
total cardiovascular risk profile. 
Urine-based β-hCG pregnancy tests will be performed in female subjects of childbearing 
potential per protocol specified visits.  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 
subject will be followed, as outlined in Section 12.1.9 through pregnancy outcome. 
MELD scores, Child-Pugh score, and MRS will be calculated at screening, and at quarterly 
(MELD and Child-Pugh scores) or semi-annual (MRS) visits based on serum chemistry and 
coagulation. 
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13. 
STATISTICAL METHODS 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
hypothesis tests, will be prepared and approved by the Sponsor and its designees prior to study 
database lock, propensity score determination, and unblinding of the double-blind subject 
treatment assignments. 
13.1. 
Efficacy Analysis 
13.1.1. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
• The Intent-to-Treat (ITT) Population will include all randomized subjects who 
receive any amount of investigational product (OCA or placebo).  The ITT 
Population will be the primary population used for efficacy analyses.  Treatment 
assignment will be based on the randomized treatment. 
• The Safety Population will include all subjects who received any amount of 
investigational product (placebo or OCA).  The Safety Population will be the primary 
population used for safety analyses.  Treatment assignment will be based on the 
treatment actually received. 
• The PK population will include all OCA subjects who have at least one confirmed 
fasted analyzable sample.  Subjects must have been fasting for approximately 8 hours 
prior to the visit and must not have any major protocol deviations that potentially 
affect exposure levels.  The PK population will be used for OCA PK analyses.  
• The Overall Historical Control Population will include subjects from the United 
Kingdom (UK) -PBC Group and Global PBC Study Group databases with 
demonstrated comparability to randomized subjects in this clinical study (747-302) 
with respect to both subject characteristics and disease progression. 
• The UK-PBC Historical Control Population will include subjects from the UK-PBC 
Group databases with demonstrated comparability to randomized subjects in this 
clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
• The Global PBC Historical Control Population will include subjects from the Global 
PBC Study Group database with demonstrated comparability to randomized subjects 
in this clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
13.1.1.1. Comparability of Historical Controls 
Utilization of both historical control/observational databases (UK-PBC and Global PBC Study 
Group), with more than 6000 subjects each, allow for a rigorous subject level meta-analysis.  The 
historical databases include long-term follow up, detailed subject-level information such as 
baseline clinical characteristics, longitudinal liver biochemistry, and long-term outcomes, and 
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span a broad range of subject characteristics that may influence disease (disease state, age, 
gender, and regional differences in standard of care).  Historical controls from both databases 
will be chosen based on the same study inclusion/exclusion criteria where possible. 
13.1.2. 
Determination of Sample Size 
The following assumptions were used in sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.6 at 8 years with a hazard 
ratio of 0.60, and total study duration of 10 years (from first subject enrolled), 
allowing for 4 years subject accrual and 6 years of follow up. 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance. 
• Two interim analyses and one final analysis are planned. 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
13.1.2.1. Sample Size Monitoring 
Conducting a long-term outcomes study given the low disease prevalence, relatively slow 
disease progression, and ethical considerations, which in combination will impact recruitment 
and event rates, is inherently difficult.  As stated in ICH E9, in long-term trials there is an 
opportunity to check the assumptions that underlay the original design and sample size 
calculations.  The power stated above depends on the total number of events.  Thus, the overall 
survival function can be estimated without unblinding. 
Therefore, the aggregate event rate and sample size based on recruitment and retention will be 
evaluated in a blinded manner quarterly.  This evaluation will determine if any increases in 
number of subjects are required in order to obtain a total of 127 adjudicated events for the final 
analysis in the combined groups.  Specifically, the pooled number of events will be available 
during the study in a blinded manner, without any knowledge of the comparative efficacy in the 
treatment groups.  This method for evaluating the sample size does not inflate the type I error 
rate.  Additional subjects may be enrolled as appropriate. 
13.1.3. 
Primary Efficacy Analysis 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
• Liver transplant 
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• MELD score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
• Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities unless 
confirmed by biopsy 
The primary efficacy analysis will compare randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the ITT population.  Only adjudicated events will 
be included in analyses.  The 2 treatment groups will be compared 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 determined based on a 
Cox regression model stratified by randomization strata to estimate the magnitude of the effect. 
13.1.4. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints will compare OCA to placebo on the following: 
• Time to first occurrence of MELD score ≥15 
• Time to liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare randomized OCA to randomized placebo in 
ITT population with respect to the key secondary efficacy endpoints.  Only adjudicated events 
will be included in time-to-event analyses.  The comparison (hypothesis testing) will be 
conducted as specified in Section 13.1.10 in a sequential closed testing gate-keeping procedure, 
provided that the primary efficacy endpoint comparison is statistically significant in favor of the 
OCA treatment group.  If the primary comparison is not statistically significant then comparison 
of the secondary endpoints will be considered as descriptive and exploratory.  This procedure 
controls the study-wise type I error. 
The 2 treatment groups will be compared using the same methodology as specified for the 
primary efficacy analysis (Section 13.1.3). 
Analyses of change from Baseline to end of study in ALP and total bilirubin will be compared 
between treatment groups using analysis of covariance (ANCOVA) with change from Baseline 
as the dependent variable including treatment group and randomization stratification factor as 
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fixed effects and the Baseline values as a covariate.  The same analysis will be carried out using 
percentage change from Baseline as the dependent variable. 
Descriptive statistics of the laboratory values will be summarized by treatment group.  The 
results, change from Baseline, and percentage change from Baseline values as well as estimates 
of least-square means, standard errors, and 95% CIs will be presented by treatment group.  
Estimates of the mean difference between treatment groups, the standard error of the difference, 
and 95% CI of the difference will be presented. 
13.1.5. 
Additional Secondary Efficacy Analyses 
The following time to event secondary efficacy analyses will compare randomized OCA versus 
randomized placebo using the ITT population: 
• Time to each component of the primary efficacy endpoint (except MELD score ≥15 
which is captured above) 
• Time to development of varix/varices 
• Time to liver-related death 
• Time to liver-related death or liver transplant 
• Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls as described below in Section 13.1.8. 
Analyses of changes in liver biochemistry (GGT, ALT, AST, conjugated bilirubin, albumin, and 
INR) will be summarized and analyzed using the same methodology as specified in 
Section 13.1.4 for the key secondary analyses of change in ALP and total bilirubin. 
Progression to cirrhosis will be assessed in the subset of subjects considered non-cirrhotic at 
baseline using available medical history, clinical, and laboratory assessments as well as baseline 
TE, where available.  Specifically, subjects with no clinical, laboratory, or radiological evidence 
of cirrhosis at baseline and/or a TE liver stiffness of <16.9 kPa (Corpechot 2012) will be 
considered non-cirrhotic (See Section 9.7.3.1 ).  Progression to cirrhosis will be assessed by the 
development of clinical, laboratory, or radiological evidence of cirrhosis and/or when liver 
stiffness increases to ≥16.9 kPa during the trial in which case histological progression to 
cirrhosis should be confirmed by biopsy unless not medically indicated. Using this definition for 
progression to cirrhosis, the percentage of non-cirrhotic subjects progressing to cirrhosis during 
the treatment period will be summarized by treatment group and compared using a Cochran–
Mantel–Haenszel test stratified by the randomization stratification factor.  
Analyses for the histological assessment conducted as part of the biopsy sub-study are defined in 
Appendix C). 
Analyses of changes in MELD score, Child-Pugh score, Mayo Risk Score (MRS), IgM, CRP, 
TNF-α, FGF-19, CK-18, C4, and ELF score will be summarized and analyzed using the 
Wilcoxon Rank Sum Test to compare treatment groups.  The median differences and 95% CI of 
the median differences between treatment groups will be constructed using Hodges-Lehmann 
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estimate.  If the median differences between treatments are not symmetrical around the median, 
the Sign Test may be used. 
13.1.5.1. Association of Biochemistry with Clinical Outcomes and Clinical Benefit  
The association between the effect of OCA on ALP and bilirubin and the clinical benefit of OCA 
will be evaluated by estimating the proportion of net treatment effect on the primary composite 
endpoint that is explained by each biochemical marker.  For each biochemical endpoint, this 
proportion will be estimated by applying the partial likelihood function to two Cox models that 
use the same failure time variable, as described in Lin 1997. This analysis will be based on the 
ITT population.  
Based on the association between biochemical changes and clinical outcomes described above, 
clinical benefit of OCA for key subpopulations of interest will be evaluated. This analysis will be 
further described in the SAP. 
13.1.6. 
Exploratory Efficacy Analyses 
13.1.6.1. Responder Analyses 
The percentage of subjects with a decrease in ALP of ≥15% and ≥40% from Baseline will be 
summarized by treatment group.  In addition, the percentage of subjects with ALP ≤ULN will be 
summarized by treatment group. 
The percentage of subjects that meet the criteria of a responder based on each of the definitions 
below will be summarized by treatment group.  The response classification at baseline will also 
be included in the summary:  
• ALP ≤3× ULN and AST ≤2× ULN and total bilirubin ≤ULN (Corpechot 2008) 
• ALP ≤1.5× ULN and AST ≤1.5× ULN and total bilirubin ≤ULN (Corpechot 2011) 
• ALP ≤1.67× ULN and total bilirubin ≤ULN (Momah 2012) 
• Normal bilirubin (values ≤ULN) and normal albumin (values ≥lower limit of normal) 
(Kuiper 2009) 
• ALP ≤1.76× ULN (Kumagi 2010) 
Responder analyses will compare treatment groups using a Cochran–Mantel–Haenszel test 
stratified by the randomization stratification factor.  Missing values will be considered as a 
non-responder.   
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints 
Sufficient data will be collected on resource utilization and quality of life to undertake 
cost-effectiveness analyses that are relevant to the major countries taking part in this study.  
Resource utilization data on hospitalizations, healthcare provider visits, and medications will be 
combined with appropriate national unit costs to calculate a cost per patient per year in the study. 
Quality of life data from patient-reported outcomes measures will be combined with survival 
data to calculate quality adjusted time in the study per patient.  Cost-effectiveness analyses will 
report the incremental cost per major clinical outcome averted, liver-related death averted, 
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life-year gained and quality-adjusted life year gained, including OCA as part of usual care versus 
usual care without OCA.  Analyses will be conducted within the study and using a lifetime 
perspective.  A separate economic analysis plan will be prepared and reported separately from 
this protocol. 
13.1.8. 
Supportive Analysis 
Per the International Conference on Harmonisation (ICH) E10 guidance, “where no obvious 
single optimal external control exists, it may be advisable to study multiple external controls”.  
In order to address the risks associated with the inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare clinical outcomes in the OCA treatment arm to 
historical controls.   
In an attempt to avoid the inherent biases with historical controls and to maintain the integrity of 
this comparison, one can invoke matching methods to optimize comparability and find a 
historical control that is “similar” to a participating subject.  The historical database control 
should be as similar as possible to the study population and should have been exposed to a 
similar standard of care (see Section 5.5.2.3). 
A propensity score can be used to reduce bias through matching, stratification, regression 
adjustment, or some combination.  Propensity scores use information from a pool of patients who 
do not participate in the study (historical controls) to identify what would have happened to 
participating subjects in the absence of the treatment.  By comparing how outcomes differ for 
treated subjects relative to historical controls, it is possible to estimate the effects of the 
treatment. 
Although it might be relatively simple to assign a historical control based on a single observable 
characteristic, in practice, if the matching process is to successfully mitigate potential bias, it has 
to be done considering a full range of covariates across which the treatment and historical 
controls might differ.  Although the results of using matching controls are conditional only on 
the observed covariates, if one has the ability to measure many of the covariates that are believed 
to be related to the treatment assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained.  Both UK-PBC Group and the 
Global PBC Study Group formally collect numerous covariates that could be used for propensity 
score estimation including standard of care, eg, UDCA. 
Historical controls will be chosen based on the same inclusion/exclusion criteria where possible. 
Propensity scores will be estimated using the available covariates that predict receiving the 
treatment.  Only covariates and not outcome variables will be included in the propensity score 
estimation.  Therefore, there is no chance of biasing results in favor of one treatment. 
The covariates and factors collected in the historical databases will be specified in the SAP. 
Propensity scores will be estimated first through a logistic regression model with treatment group 
as the dependent variable and the above covariates/factors as independent variables.  Then the 
stratum boundaries are determined based on the propensity score values for both groups (OCA 
population and control [historical and randomized placebo]) combined or in the OCA population 
or historical control group alone.  Based on recommendations in the literature, quintiles of the 
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estimated propensity score from the combined group will be used to determine the stratum 
boundary cut-offs for the different strata. 
Outcome events collected in the historical database are:  death (liver-related and all-cause), liver 
transplant, hepatocellular carcinoma, and other.  Other is defined as cirrhosis or decompensation 
such as ascites, variceal bleed, and encephalopathy. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare randomized OCA-treated subjects in the ITT population and historical 
controls (Overall Historical Control Population: both the UK-PBC Group and Global PBC Study 
Group databases) on the following outcomes: 
• Time to death (all-cause) 
• Time to liver-related death 
• Time to liver transplant 
• Time to liver transplant or death (all-cause) 
• Time to liver transplant or liver-related death 
• Time to hepatocellular carcinoma 
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 determined based on a Cox regression 
model stratified by randomization strata to estimate the magnitude of the effect. 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
Although the study is designed as a placebo-controlled study, the DMC may recommend changes 
to study conduct based on the pre-specified interim analyses (see Section 13.1.12), including the 
potential use of a revised primary efficacy analysis.  This analysis would compare all subjects in 
the OCA population, to all control subjects (randomized placebo and historical controls) on time 
to liver transplant or death (all-cause), using similar statistical methodology as specified above. 
Notably, the planned primary analysis would not be revised without prior agreement with 
regulatory authorities. 
13.1.9. 
Handling of Dropouts or Missing Data 
Subjects who discontinue investigational product are expected to continue in the study until 
study termination. 
Missing data will be assumed to be missing at random.  In order to determine the effect of 
missing data on the analysis, efficacy endpoints will be analyzed using different methods of 
imputation as described below. 
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13.1.9.1. Time to Event Endpoints 
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 investigational product dosing). 
For analyses of the percentage of subjects with an event, subjects with no data after 
randomization will be considered to have an event. 
All time to event endpoints include only adjudicated events.  Sensitivity analyses may consider 
all events regardless of adjudication.  Events with discrepant adjudication will be analyzed using 
both results. 
13.1.9.2. Quantitative Endpoints 
For efficacy endpoints that utilize an ANCOVA model, observed cases will serve as the primary 
analysis.  Sensitivity analyses to assess the effect of missing data may be conducted where 
missing data is imputed using last observation carried forward. 
Sensitivity analyses of ANCOVA models will also be evaluated using a restricted maximum 
likelihood based mixed-effect repeated measures model where no imputations will be made for 
missing values.   
13.1.9.3. Responder Endpoints 
In an efficacy analysis in which subjects are classified as either a responder or a non-responder 
(binary outcome) based on dichotomizing a continuous variable, any subject who does not 
provide an assessment at the specified time point for the defining of response will be considered 
to be a non-responder.  That is, for the percentage of responders, the subject will be included in 
the denominator and will not contribute to the numerator. 
For sensitivity analyses using only “observed cases,” subjects who do not provide an assessment 
at the specified timepoint for the defining of response will not be included.  That is, for the 
percentage of responders, the subject will not be included in the numerator or the denominator. 
13.1.10. 
Multiple Comparisons/Multiplicity 
The key secondary efficacy endpoints are as follows: 
• Time to MELD score ≥15 
• Time to first occurrence of liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The hypothesis testing of key secondary analyses will compare placebo and OCA and will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of OCA.  If the primary comparison is not statistically significant 
then comparison of the secondary endpoints will be considered as descriptive and exploratory.  
This procedure controls the study-wise type I error.  
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• First (step 1) placebo and OCA will be compared with respect to the primary efficacy 
endpoint.  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• The time to MELD score ≥15 will be compared between placebo and OCA (step 2).  
If the comparison achieves statistical significance at 2-sided 0.05 level in favor of 
OCA group, then 
• The time to liver transplant or death (all-cause) will be compared between placebo 
and OCA (step 3).  If the comparison achieves statistical significance at 2-sided 
0.05 level in favor of OCA group, then 
• Change from Baseline in total bilirubin will be compared between placebo and OCA 
(step 4).  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• Change from Baseline in ALP at the end of study will be compared between placebo 
and OCA (step 5). 
If at any step defined above the comparison is not statistically significant at the 2-sided 
0.05 level then the remaining comparisons in the stated hierarchy will be considered descriptive 
and exploratory.  The study-wise type I error will be maintained with the above closed 
procedure. 
Additional efficacy endpoints will be analyzed; however, hypothesis tests will be applied for 
descriptive and exploratory purposes only.   
13.1.11. 
Examination of Subgroups 
The primary and secondary efficacy endpoints will be analyzed for subject subgroups (eg, age, 
sex, and race) based on the ITT population.  Subgroups will be assessed at baseline and only if 
there are a sufficient number of subjects in each group (eg, >5 subjects per group). 
Baseline subgroups of interest are as follows:  age, age at PBC diagnosis, sex, race, body mass 
index, ALP level, bilirubin level, use of UDCA, years since diagnosis of PBC, and geographic 
region. 
13.1.12. 
Continuous Monitoring and Interim Analyses 
Blinded safety reports including the accrual of events, drop outs and/or loss of patients to 
commercially available OCA will be reviewed by the DMC on a regular basis.  
Two planned interim analyses of the liver-related outcomes will be conducted using the Lan-
DeMets O’Brien-Fleming boundaries (Reboussin 2000).  Both interim analyses will be pre-
specified and will occur after accrual of 50% and 75% of clinical outcome events, respectively.  
The DMC will review the available efficacy data in conjunction with detailed safety data and 
other relevant information to recommend continuation, modification, or cessation (for efficacy or 
futility) of the study beyond each interim analysis.  Modification of the study would not take 
place without prior agreement with regulatory authorities. 
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13.2. 
Safety Analysis 
Safety data, including AEs and clinical laboratory observations, will be summarized by treatment 
group using the Safety Population. 
13.2.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary of Regulatory Activities.  Summary tables of 
treatment-emergent AEs will be provided.  The incidence of TEAEs will be tabulated by system 
organ class and preferred term for each treatment group, and by severity and relationship to 
treatment.  Tables of TEAEs leading to investigational product discontinuation and SAEs will be 
provided. 
13.2.2. 
Clinical Laboratory Evaluations 
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will be 
presented for all study visits.  Changes from pretreatment to each study visit will also be 
summarized by treatment group. 
13.2.3. 
Additional Safety Analysis 
Additional safety assessments include vital signs and ECGs.  Descriptive statistics of the vital 
sign and ECG parameters will be presented by treatment group and study visit, as well as the 
change from pretreatment at each visit. 
13.2.4. 
Cardiovascular Adjudication Committee 
In addition to potential clinical endpoint events, cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study. Adjudicated cardiovascular events include core 
major adverse cardiovascular events (MACE) (cardiovascular death, nonfatal myocardial 
infarction, and nonfatal stroke) and expanded MACE (unstable angina requiring hospitalization, 
transient ischemic attack, peripheral or coronary revascularization procedures, hospitalization for 
congestive heart failure).  Other events potentially related to adverse cardiovascular outcomes 
may be included in the Cardiovascular Adjudication Committee (CAC) Charter for adjudication.  
The adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study (see Section 13.4). 
13.3. 
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. 
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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 subjects.  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 subject treatment information; 
however, the DMC will have access to the database and may unblind individual subject data as 
appropriate.  Summary tables reviewed by the DMC during closed sessions will include an 
overall column containing information regarding all subjects 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, Medical Dictionary for Regulatory Activities (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 subject safety, which alter the 
conduct of this study.  The Investigators will inform the subjects of such actions and the 
protocol, patient information sheet (PIS), and consent will be revised, as appropriate. 
13.4. 
Adjudication Committees 
All suspected liver-related clinical outcomes, 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.   
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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 subject 
treatment or site-specific information.  The assessment of events will be conducted in 
compliance with study-specific procedures, manuals, good clinical practice (GCP), and all other 
applicable regulatory requirements, including the archiving of essential documents.    
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
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 subject’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 CRF.  The CRF 
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 
subject's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
14.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC 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.   
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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the CRF 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 14.2 for more details regarding the audit 
process. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF and/or other subject 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 the Sponsor before he or she can enroll 
any subject 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 subjects to the ethics committee 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 subjects for 
the study.  The protocol must be reapproved by the IRB or 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.  
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, at a minimum annually, and after the study is complete. 
16.2. 
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. 
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16.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated ICF 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 subject. 
16.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential and confidentiality of all subjects will be maintained.  Monitors (eg, 
CRA, Medical Monitor), auditors and inspectors will require access to a subject’s medical notes 
for the purpose of source document verification but the subject’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 subject’s names and identifying information (eg, subject’s 
hospital number, unique subject number).  This list will not be collected by the Sponsor. 
The written information sheet 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 subject 
number/randomization code/subject initials/site number, only. 
When personal data on subjects are stored or processed by computer, the data must be protected 
to prevent their disclosure to unauthorized third parties.  The pertinent sections of the data 
protection laws in which the country is being conducted will be complied with in full. 
The written ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IEC/IRB may require direct access to parts of the hospital 
or study site records relevant to the study, including subject’s medical history. 
17. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the subjects 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 subjects, as applicable. 
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17.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject 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 Medical Monitor. 
17.2. 
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 subject’s safety to be compromised if immediate action is not taken. 
17.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
• Approved ICF (all versions) 
• IRB/EC approvals (of protocol/amendments, subject questionnaires, etc) 
• Form FDA 1572  
• Current medical license 
• Curriculum vitae 
• Laboratory certification and reference ranges 
• Financial disclosure forms 
17.4. 
Ethics Review 
Please see Section 16.1 for the Investigator’s responsibilities regarding ethics review. 
17.5. 
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 subject 
medical files (retained per country specific regulations), completed study subject log and 
confidential subject 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 
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authorization from the Sponsor prior to 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. 
18. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it sponsors consistent 
with the Declaration of Helsinki (Seoul Revision 2008, 
[http://www.wma.net/en/30publications/10policies/b3/index.html, accessed May 22, 2013]).  
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 Study Registries (eg, 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 (when available) 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:  The Sponsor, 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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19. 
LIST OF REFERENCES 
Beuers U, Lindor KD. A major step towards effective treatment evaluation in primary biliary 
cirrhosis. J Hepatol. 2011;55(6):1178-80. 
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and 
long term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871-877. 
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. 
Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: Biochemical response 
to treatment and prediction of long-term outcome. J Hepatol. 2011;55:1361–1367. 
Dickson ER, Grambsch PM, Fleming TR, et al.  Prognosis in primary biliary cirrhosis:  Model 
for decision making.  Hepatology. 1989;10(1):1-7. 
Elman S, Hynan L.S., Gabriel V, and Mayo M.J. The 5-D itch scale: a new measure of pruritus, 
British Journal of Dermatology. 2010;162,587–593. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51:237-267. 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact of fatigue: initial validation of 
the fatigue impact scale. Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
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. 
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. 
Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict 
long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 
2010;105(10):2186-94. 
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Alkaline phosphatase values are a 
surrogate marker in prediction of transplant-free-survival in patients with primary biliary 
cirrhosis - an international, collaborative analysis.  J Hepatol. 2013; 58(Suppl):S388. 
Lin DY, Fleming TR, De Gruttola V.  Estimating the proportion of treatment effect explained by 
a surrogate marker.  Statist Med.  1997;16(13):1515-1527. 
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis: AASLD Practice 
Guidelines. Hepatology. 2009;50(1):291-308. 
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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. 
Momah N, Silveira MG, Jorgensen R, et al. Optimizing biochemical markers as endpoints for 
clinical trials in primary biliary cirrhosis. Liver Int. 2012;32(5):790-795. 
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. 
Reboussin DM, DeMets, DL, Kim KM, et al.  Computations for Group Sequential Boundaries 
Using the Lan-DeMets Spending Function Method.  Controlled Clin Trials.  2000;21(3):190-207. 
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APPENDIX A. MODIFIED DOSING REGIMEN FOR SUBJECTS WITH 
CHILD-PUGH B/C HEPATIC IMPAIRMENT 
Overview of Modified Dosing Regimen for Subjects with Child-Pugh B or C Hepatic 
Impairment 
An overview of the modified dosing regimen for subjects with Child-Pugh Class B or 
Child-Pugh Class C is presented in Figure 2 and Table 11. 
Subjects who are cirrhotic and classified as Child-Pugh Class B or Child-Pugh Class C will 
initiate a modified treatment regimen with 5 mg OCA or matching placebo once weekly for at 
least 3 months.  Subjects classified as Child-Pugh Class B should eventually titrate to a 
maximum dose of 5 mg OCA or matching placebo once daily, based on tolerability and 
biochemical response.  Subjects classified as Child-Pugh Class C should titrate to a maximum 
dose and frequency of 10 mg OCA or matching placebo twice weekly. 
Figure 2: 
Dosing by Cirrhosis Status and Child-Pugh Score 
 
a  Cirrhosis may be assessed by histology or non-histological methods as defined in Section 9.7.3. 
BIW = twice weekly; QW = once weekly 
Table 11: 
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Modified Dosing Regimen 
Child-Pugh B 
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg once weekly 
5 mg once weekly 
Titration 1b  
(≥Month 3) 
5 mg twice weeklyc 
5 mg twice weeklyc 
Titration 2b
(≥6 weeks after Titration 1) 
10 mg twice weeklyc 
10 mg twice weeklyc 
Titration 3b 
(≥6 weeks after Titration 2) 
5 mg daily 
NA 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b  Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject 
tolerability and/or changes in cirrhosis status or Child-Pugh Score at any time during the study. 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
Modified Dosing Regimen for Subjects with Child-Pugh B Hepatic Impairment 
Subjects with cirrhosis and classified as Child-Pugh B at Screening will follow a modified 
dosing schedule receiving 5 mg OCA or matching placebo once weekly as described in Figure 2.  
After a minimum of 3 months dosing once weekly with 5 mg OCA or matching placebo, and 
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following review of the pre-titration laboratory results to assess safety and tolerability, the dosing 
frequency of 5 mg OCA or matching placebo should be increased to twice weekly (at least 3 
days apart).  Subjects who have maintained the twice weekly dosing frequency for a minimum of 
at least 6 weeks, and meet the dose titration criteria, should up-titrate to twice weekly dosing 
with 10 mg OCA or matching placebo.  Subjects with at least 6 weeks of twice weekly dosing at 
10 mg OCA or matching placebo, and meeting dose titration criteria, should up-titrate to the 
maximum allowed dose of 5 mg OCA or matching placebo once daily.  
Investigators may decrease the dosing frequency (back to once or twice weekly) or dose for any 
subject at any time during the study, as considered clinically appropriate (eg, tolerability). 
Modified Dosing Regimen for Subjects with Child-Pugh C Hepatic Impairment 
Subjects with cirrhosis and classified as Child-Pugh C at Screening will follow a modified 
dosing schedule receiving 5 mg OCA or matching placebo once weekly as described in Figure 2.  
After a minimum of 3 months dosing once weekly with 5 mg OCA or matching placebo, and 
following review of the pre-titration laboratory results to assess safety and tolerability, the dosing 
frequency of 5 mg OCA or matching placebo should be increased to twice weekly (at least three 
days apart).  Subjects who have maintained the twice weekly dosing frequency for a minimum of 
at least 6 weeks, and meet the dose titration criteria, should up-titrate to the maximum allowed 
dose of 10 mg OCA or matching placebo twice weekly.   
Investigators may decrease the dosing frequency (back to once weekly) or dose for any subject at 
any time during the study, as considered clinically appropriate (eg, tolerability).   
Dose Titration due to Change in Cirrhosis or Child-Pugh Score 
Subjects on a modified dosing regimen who demonstrate a change in cirrhosis status and/or 
Child-Pugh Score should have their dose of investigational product modified to match their 
current status per the appropriate dosing regimen (see Section 7.4, Table 5); however, changes to 
the dosing regimen are not mandatory and should be based on clinical judgment as well as 
changes in status. Changes in Child-Pugh Score that result from a transient, explainable change 
in laboratory parameters should be documented appropriately, and should not necessarily result 
in a change to the dosing regimen.  Investigators may contact the Medical Monitor at any time to 
discuss potential changes to dosing.   
Possible scenarios for dosing modifications include: 
• Subjects who develop cirrhosis during the course of the trial with a classification of 
Child-Pugh B or C 
• Subjects with pre-existing cirrhosis who demonstrate a change in the Child-Pugh Score 
from A to B or C at any point in the study   
• Improvement in classification of Child-Pugh Score from C to B  
• Improvement in classification of Child-Pugh Score from B to A; these subjects may be 
eligible to transition to the standard dosing regimen 
Subjects may titrate dose and dosing frequency up or down as appropriate, within the appropriate 
dosing regimen.  Up-titration should be done per Investigator discretion and be guided by the 
pre-titration tolerability assessments outlined in Section 7.4.1.  A 1-Month Post-Titration 
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Assessment must be performed any time a subject’s dose or frequency is up-titrated (see 
Section 7.1.2 and Section 9.7.10). 
Unscheduled Titration Visit, Optional Visit 
An unscheduled up-titration visit may be scheduled for as early as 6 weeks after the initial 
titration visit (or subsequent titration visit) occurs for subjects who are following the modified 
dosing regimen.  The visit procedures required for the unscheduled titration visit are outlined 
below.  Subjects who up titrate at an unscheduled visit will continue to follow the regular visit 
schedule for all other study visits.   
For subjects who up titrate at an unscheduled visit the following procedures will be performed: 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Perform the pre-Titration Tolerability Assessment as outlined in Section 7.4.1. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
- 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. 
For subjects who up titrate at an unscheduled visit: The + 1-week window week related to the 
1-Month Post-Titration visit can be extended for up to an additional 5 weeks to allow for the 
post-titration assessment to be performed during one of the subject’s regularly scheduled 
study visits.  If the window is extended past +1 week allowed visit window, at a minimum, a 
telephone safety contact should then be performed 1-month post-titration. 
 
 
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APPENDIX B. ETHICAL CONDUCT ACCORDING TO THE 
DECLARATION OF HELSINKI FOR COUNTRIES 
PARTICIPATING OUTSIDE THE US (DECLARATION 
OF HELSINKI, FORTELEZA, BRAZIL, 2013) 
 
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Copyright 2013 American Medical Association. All rights reserved.
World Medical Association Declaration of Helsinki
Ethical Principles for Medical Research
Involving Human Subjects
World Medical Association
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1. The World Medical Association (WMA) has developed the Dec-
larationofHelsinkiasastatementofethicalprinciplesformedi-
cal research involving human subjects, including research on
identifiable human material and data.
The Declaration is intended to be read as a whole and each of
its constituent paragraphs should be applied with consider-
ation of all other relevant paragraphs.
2. ConsistentwiththemandateoftheWMA,theDeclarationisad-
dressed primarily to physicians. The WMA encourages others
who are involved in medical research involving human subjects
to adopt these principles.
General Principles
3. TheDeclarationofGenevaoftheWMAbindsthephysicianwith
the words, “The health of my patient will be my first consider-
ation,”andtheInternationalCodeofMedicalEthicsdeclaresthat,
“A physician shall act in the patient's best interest when provid-
ing medical care.”
4. It is the duty of the physician to promote and safeguard the
health,well-beingandrightsofpatients,includingthosewhoare
involvedinmedicalresearch.Thephysician'sknowledgeandcon-
science are dedicated to the fulfilment of this duty.
5. Medical progress is based on research that ultimately must in-
clude studies involving human subjects.
6. Theprimarypurposeofmedicalresearchinvolvinghumansub-
jects is to understand the causes, development and effects of
diseasesandimprovepreventive,diagnosticandtherapeuticin-
terventions (methods, procedures and treatments). Even the
bestproveninterventionsmustbeevaluatedcontinuallythrough
research for their safety, effectiveness, efficiency, accessibility
and quality.
7. Medicalresearchissubjecttoethicalstandardsthatpromoteand
ensure respect for all human subjects and protect their health
and rights.
8. Whiletheprimarypurposeofmedicalresearchistogeneratenew
knowledge, this goal can never take precedence over the rights
and interests of individual research subjects.
9. Itisthedutyofphysicianswhoareinvolvedinmedicalresearch
to protect the life, health, dignity, integrity, right to self-
determination,privacy,andconfidentialityofpersonalinforma-
tion of research subjects. The responsibility for the protection
ofresearchsubjectsmustalwaysrestwiththephysicianorother
health care professionals and never with the research subjects,
even though they have given consent.
10. Physiciansmustconsidertheethical,legalandregulatorynorms
andstandardsforresearchinvolvinghumansubjectsintheirown
countries as well as applicable international norms and stan-
dards.Nonationalorinternationalethical,legalorregulatoryre-
quirementshouldreduceoreliminateanyoftheprotectionsfor
research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that mini-
mises possible harm to the environment.
12. Medicalresearchinvolvinghumansubjectsmustbeconducted
onlybyindividualswiththeappropriateethicsandscientificedu-
cation, training and qualifications. Research on patients or
healthyvolunteersrequiresthesupervisionofacompetentand
appropriately qualified physician or other health care profes-
sional.
Clinical Review & Education
Special Communication
jama.com
JAMA
November 27, 2013
Volume 310, Number 20
2191
Copyright 2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by 
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Copyright 2013 American Medical Association. All rights reserved.
13. Groups that are underrepresented in medical research should
be provided appropriate access to participation in research.
14. Physicians who combine medical research with medical care
should involve their patients in research only to the extent that
this is justified by its potential preventive, diagnostic or thera-
peuticvalueandifthephysicianhasgoodreasontobelievethat
participation in the research study will not adversely affect the
health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be en-
sured.
Risks, Burdens and Benefits
16. Inmedicalpracticeandinmedicalresearch,mostinterventions
involve risks and burdens.
Medical research involving human subjects may only be con-
ductediftheimportanceoftheobjectiveoutweighstherisksand
burdens to the research subjects.
17. All medical research involving human subjects must be pre-
ceded by careful assessment of predictable risks and burdens
to the individuals and groups involved in the research in com-
parisonwithforeseeablebenefitstothemandtootherindividu-
als or groups affected by the condition under investigation.
Measurestominimisetherisksmustbeimplemented.Therisks
mustbecontinuouslymonitored,assessedanddocumentedby
the researcher.
18. Physiciansmaynotbeinvolvedinaresearchstudyinvolvinghu-
mansubjectsunlesstheyareconfidentthattheriskshavebeen
adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive proof of definitive outcomes, physi-
cians must assess whether to continue, modify or immediately
stop the study.
Vulnerable Groups and Individuals
19. Somegroupsandindividualsareparticularlyvulnerableandmay
haveanincreasedlikelihoodofbeingwrongedorofincurringad-
ditional harm.
All vulnerable groups and individuals should receive specifi-
cally considered protection.
20. Medical research with a vulnerable group is only justified if the
research is responsive to the health needs or priorities of this
group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to ben-
efit from the knowledge, practices or interventions that result
from the research.
Scientific Requirements and Research Protocols
21. Medicalresearchinvolvinghumansubjectsmustconformtogen-
erally accepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as appropriate, ani-
mal experimentation. The welfare of animals used for research
must be respected.
22. The design and performance of each research study involving
human subjects must be clearly described and justified in a re-
search protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include
information regarding funding, sponsors, institutional affilia-
tions, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compen-
sating subjects who are harmed as a consequence of participa-
tion in the research study.
In clinical trials, the protocol must also describe appropriate ar-
rangements for post-trial provisions.
Research Ethics Committees
23. Theresearchprotocolmustbesubmittedforconsideration,com-
ment, guidance and approval to the concerned research ethics
committee before the study begins. This committee must be
transparent in its functioning, must be independent of the re-
searcher, the sponsor and any other undue influence and must
be duly qualified. It must take into consideration the laws and
regulations of the country or countries in which the research is
to be performed as well as applicable international norms and
standardsbutthesemustnotbeallowedtoreduceoreliminate
anyoftheprotectionsforresearchsubjectssetforthinthisDec-
laration.
The committee must have the right to monitor ongoing stud-
ies.Theresearchermustprovidemonitoringinformationtothe
committee, especially information about any serious adverse
events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of
thestudy,theresearchersmustsubmitafinalreporttothecom-
mittee containing a summary of the study’s findings and con-
clusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of re-
search subjects and the confidentiality of their personal infor-
mation.
Informed Consent
25. Participation by individuals capable of giving informed consent
as subjects in medical research must be voluntary. Although it
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may be appropriate to consult family members or community
leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving
informed consent, each potential subject must be adequately
informed of the aims, methods, sources of funding, any pos-
sible conflicts of interest, institutional affiliations of the re-
searcher,theanticipatedbenefitsandpotentialrisksofthestudy
and the discomfort it may entail, post-study provisions and any
other relevant aspects of the study. The potential subject must
be informed of the right to refuse to participate in the study or
to withdraw consent to participate at any time without repri-
sal. Special attention should be given to the specific informa-
tionneedsofindividualpotentialsubjectsaswellastothemeth-
ods used to deliver the information.
Afterensuringthatthepotentialsubjecthasunderstoodthein-
formation, the physician or another appropriately qualified in-
dividual must then seek the potential subject’s freely-given in-
formed consent, preferably in writing. If the consent cannot be
expressedinwriting,thenon-writtenconsentmustbeformally
documented and witnessed.
Allmedicalresearchsubjectsshouldbegiventheoptionofbeing
informed about the general outcome and results of the study.
27. When seeking informed consent for participation in a research
study the physician must be particularly cautious if the poten-
tial subject is in a dependent relationship with the physician or
mayconsentunderduress.Insuchsituationstheinformedcon-
sentmustbesoughtbyanappropriatelyqualifiedindividualwho
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving in-
formedconsent,thephysicianmustseekinformedconsentfrom
thelegallyauthorisedrepresentative.Theseindividualsmustnot
be included in a research study that has no likelihood of benefit
forthemunlessitisintendedtopromotethehealthofthegroup
represented by the potential subject, the research cannot in-
stead be performed with persons capable of providing in-
formed consent, and the research entails only minimal risk and
minimal burden.
29. When a potential research subject who is deemed incapable of
givinginformedconsentisabletogiveassenttodecisionsabout
participationinresearch,thephysicianmustseekthatassentin
addition to the consent of the legally authorised representa-
tive. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally in-
capable of giving consent, for example, unconscious patients,
may be done only if the physical or mental condition that pre-
ventsgivinginformedconsentisanecessarycharacteristicofthe
research group. In such circumstances the physician must seek
informedconsentfromthelegallyauthorisedrepresentative.If
nosuchrepresentativeisavailableandiftheresearchcannotbe
delayed,thestudymayproceedwithoutinformedconsentpro-
videdthatthespecificreasonsforinvolvingsubjectswithacon-
dition that renders them unable to give informed consent have
beenstatedintheresearchprotocolandthestudyhasbeenap-
provedbyaresearchethicscommittee.Consenttoremaininthe
researchmustbeobtainedassoonaspossiblefromthesubject
or a legally authorised representative.
31. Thephysicianmustfullyinformthepatientwhichaspectsoftheir
care are related to the research. The refusal of a patient to par-
ticipateinastudyorthepatient’sdecisiontowithdrawfromthe
study must never adversely affect the patient-physician rela-
tionship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or
similarrepositories,physiciansmustseekinformedconsentfor
its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracti-
cable to obtain for such research. In such situations the re-
search may be done only after consideration and approval of a
research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new inter-
vention must be tested against those of the best proven inter-
vention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary
to determine the efficacy or safety of an intervention
andthepatientswhoreceiveanyinterventionlesseffectivethan
thebestprovenone,placebo,ornointerventionwillnotbesub-
ject to additional risks of serious or irreversible harm as a result
of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. Inadvanceofaclinicaltrial,sponsors,researchersandhostcoun-
trygovernmentsshouldmakeprovisionsforpost-trialaccessfor
all participants who still need an intervention identified as ben-
eficialinthetrial.Thisinformationmustalsobedisclosedtopar-
ticipants during the informed consent process.
Research Registration and Publication and Dissemination
of Results
35. Every research study involving human subjects must be regis-
teredinapubliclyaccessibledatabasebeforerecruitmentofthe
first subject.
World Medical Association Declaration of Helsinki
Special Communication Clinical Review & Education
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36. Researchers, authors, sponsors, editors and publishers all have
ethical obligations with regard to the publication and dissemi-
nationoftheresultsofresearch.Researchershaveadutytomake
publicly available the results of their research on human sub-
jectsandareaccountableforthecompletenessandaccuracyof
their reports. All parties should adhere to accepted guidelines
for ethical reporting. Negative and inconclusive as well as posi-
tiveresultsmustbepublishedorotherwisemadepubliclyavail-
able. Sources of funding, institutional affiliations and conflicts
of interest must be declared in the publication. Reports of re-
search not in accordance with the principles of this Declaration
should not be accepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven inter-
ventions do not exist or other known interventions have been
ineffective, the physician, after seeking expert advice, with in-
formed consent from the patient or a legally authorised repre-
sentative, may use an unproven intervention if in the physi-
cian's judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should subse-
quently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be re-
corded and, where appropriate, made publicly available.
ARTICLE INFORMATION
Corresponding Author: World Medical
Association, 13, ch. du Levant, CIB - Bâtiment A,
01210 Ferney-Voltaire, France; wma@wma.net.
Published Online: October 19, 2013.
doi:10.1001/jama.2013.281053.
Disclaimer: ©2013 World Medical Association, Inc.
All Rights Reserved. All intellectual property rights
in the Declaration of Helsinki are vested in the
World Medical Association. The WMA has granted
JAMA exclusive rights to publish the
English-language version of the Declaration
through December 31, 2013.
Online-Only Content: Audio podcast is available at
www.jama.com.
Clinical Review & Education Special Communication
World Medical Association Declaration of Helsinki
2194
JAMA
November 27, 2013
Volume 310, Number 20
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APPENDIX C. BIOPSY SUB-STUDY OF PROTOCOL 747-302:  A 
PHASE 4, DOUBLE-BLIND, RANDOMIZED, PLACEBO-
CONTROLLED, MULTICENTER STUDY EVALUATING 
THE EFFECT OF OBETICHOLIC ACID ON CLINICAL 
OUTCOMES IN SUBJECTS WITH PRIMARY BILIARY 
CHOLANGITIS 
The following Protocol Concept is being presented as an Appendix to the current 747-302 
Protocol Version 3.1.  The final Paired Biopsy Sub-Study Protocol will be provided to 
participating sites as Addendum 1 to the 747-302 Protocol. 
Rationale:  The purpose of this sub-study is to assess the effect of OCA versus placebo on the 
histological severity of disease (fibrosis/cirrhosis) in subjects with PBC.  In addition, this sub-
study will explore the relationship between histological changes and clinical, laboratory, and 
non-invasive measures indicative of progression to cirrhosis in patients with PBC. 
Population  
Subjects must meet all Inclusion and Exclusion 
criteria for Protocol 747-302 
Additional Criteria for the Biopsy Sub-Study are: 
Inclusions: 
• 
Must provide written informed consent and agree to comply with the 
requirements of the sub-study protocol 
Exclusions: 
• 
Inability to safely undergo a liver biopsy 
Sample Size 
N= approximately 45 subjects 
Assumes 1-sided test 
80% power to detect a difference in relative risk of progression to cirrhosis at an 
alpha of 0.2 when OCA event rate is 0.23 (50% risk reduction 
80% power to detect a difference in relative risk of progression to cirrhosis at an 
alpha of 0.3 when OCA event rate is 0.28 (~45% risk reduction) 
Study Design / Duration 
Placebo-controlled, randomized, double-blind 
Participation open to all sites participating in the 747-302 protocol (expectation is 
approximately 20 sites globally will participate) 
Placebo, 5-10 mg OCA 
After meeting all eligibility requirements for this sub-study, subjects will follow 
the study procedures as outlined in the main protocol for Study747-302. 
It is expected that subjects will be followed for a minimum of 6 years as in the 
main protocol. 
A baseline biopsy must be performed no later than Day 0 (±7 days) unless biopsy 
was obtained no more than 6 months before Day 1.  
Timing of post-treatment biopsy:  If a subject develops evidence of probable 
progression to cirrhosis as assessed by the indicators listed below, another biopsy 
will be performed at that time; biopsy reports and available clinical, laboratory, 
and radiological assessments will be used as a basis for adjudication by the 
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hepatic adjudication committee to assure that all events of progression to cirrhosis 
meet pre-defined criteria and are consistent across sites. 
A biopsy will be performed at end of study (EOS) on all subjects who have not 
already had a biopsy based on evidence of the clinical, laboratory, or radiological 
indicators of progression during the course of the study. 
Primary objectives 
To evaluate the effect of OCA compared to placebo on the histological severity of 
PBC by assessing the following:  
• 
Progression to cirrhosis  
• 
Improvement in fibrosis/cirrhosis  
Secondary objectives 
To evaluate the effect of OCA compared to placebo on the histological stage of 
PBC 
To demonstrate the relationship between histological changes and clinical, 
laboratory, and non-invasive measurements indicative of progression to cirrhosis 
in subjects with PBC including: 
• 
Transient Elastography (TE) 
• 
Noninvasive scores of liver fibrosis including Enhanced Liver 
Fibrosis (ELF) and aspartate aminotransferase (AST) to platelet ratio 
index (APRI),   
Indicators of Progression 
to Cirrhosis informing the 
timing of biopsy 
Persistent (i.e. 2 consecutive measurements obtained at least 3 months apart) 
elevation in Fibroscan® TE >16.9 kPa 
Presence of any of the following: 
• 
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 total bilirubin >2x ULN 
Biopsies 
Paired biopsies will be read by a central reader 
Adjudication 
Adjudication of progression of cirrhosis will be performed by an independent 
hepatic adjudication committee as per the main protocol.  All available 
documentation of progression including biopsy reports will be made available to 
the adjudicators. 
Statistical Analysis 
For each treatment group, the proportion of subjects with and without biopsy-
assessed cirrhosis at the end of study by baseline biopsy-assessed cirrhosis status 
will be presented in a shift table from Baseline to the end-of-study. 
For the subset of subjects who were non-cirrhotic at Baseline, Kaplan-Meier (KM) 
estimates of the time to cirrhosis (as assessed by biopsy) will be summarized and 
graphed by treatment group. 
For the subset of subjects who were cirrhotic at Baseline, cumulative incidence 
estimates of the time to improvement in fibrosis/cirrhosis (as assessed by biopsy) 
will be summarized and graphed by treatment group. 
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APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 (DATED 29 APR 2015) 
Rationale 
The changes to the Original Version of the protocol, detailed below, modify the dose titration schedule based on observed efficacy and 
tolerability of OCA, address advice provided by regulatory agencies, and clarify questions raised by study site personnel currently 
using Original protocol version 1 dated 03 October 2014. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.  (Note:  Differences are denoted in bold font; Minor 
formatting changes are not listed) 
Section 
Original Text 
Revised Text 
Title Page 
Original:  03 October 2014 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Procedures in 
Case of 
Emergency 
 
Procedures in Case of Emergency 
 
Study Personnel Contact Information 
 
Or if Not 
Available 
Contact:
 MD, 
 & 
 Development, Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
 
Contact:
 MD, Medical Director, Drug Safety, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
Synopsis 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
≤1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 
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Section 
Original Text 
Revised Text 
2 weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
and total bilirubin values (refer to Section 9.7.3).  Subjects who 
meet all inclusion criteria and none of the exclusion criteria will be 
randomized (1:1) to OCA or placebo treatment groups.  The 
randomization will be stratified by ursodeoxycholic acid (UDCA) 
treatment (yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 6 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 6-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
 
2 weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
and total bilirubin values (refer to Section 9.7.3).  Mean values for 
ALP and total bilirubin will be calculated using all available 
screening values.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment (yes/no) and baseline 
bilirubin categories (>upper limit of normal [ULN]/ ≤ ULN). 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 3 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 3-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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Section 
Original Text 
Revised Text 
Synopsis 
Inclusion Criteria 
2.  A mean total  bilirubin >ULN and ≤3× ULN or an ALP 
>5×ULN  
4.  Either is not taking UDCA (UDCA naïve or  no UDCA dose in 
the past 3 months) or has been taking UDCA for at least 12 months 
with an approved, stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
contraception during the study and for 30 days after the end of 
treatment visit. 
 
Inclusion Criteria 
2. A mean total bilirubin >ULN and ≤3× ULN and/or a mean 
ALP >5× ULN 
4.  Either is not taking UDCA (no UDCA dose in the past 
3 months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
Synopsis 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
 
 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
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3. Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
4.  Other medical conditions that may diminish life expectancy to 
<2 years, including known cancers (except carcinomas in situ or 
other stable, relatively benign conditions such as chronic lymphatic 
leukemia) 
5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of screening (pretreatment) QT 
 
3.  Mean total bilirubin >3× ULN 
 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
5.  Deleted text 
Synopsis 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life 
 
 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life (Fatigue 
Impact Score and EQ-5D-
5L) 
 
Synopsis 
Statistical Methods: Other Efficacy Analyses 
• 
Added text 
Statistical Methods: Other Efficacy Analyses 
• 
Development of varix/varices 
4 
List of Abbreviations 
Added text 
 
List of Abbreviations 
EOS 
 end of study 
 
5.4 
As of 31 March 2014, OCA has been evaluated in the clinic in 
18 completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 March 2014, a total of 1023 subjects have 
received at least one dose of OCA and of these, 414 (40%) were 
subjects with PBC.   
As of 31 January 2015, OCA has been evaluated in the clinic in 
20 completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 January 2015, approximately 1650 subjects 
have received at least 1 dose of OCA and of these, 432 were 
subjects with PBC with ≤5 years of OCA treatment.   
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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 up to 4 years.  The LSTE phase of studies 
747-201 and 747-301 are ongoing; the LTSE phase of 
Study 747-202 is complete 
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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is 
complete 
5.5.2.1 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg and 10 mg; both treatment 
groups exhibited clinically meaningful improvements in liver 
biochemistry and were safe and generally well tolerated. 
 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg (titrated to 10 mg after 6 
months based on efficacy and tolerability in the double-blind 
phase and after 3 months in the open-label phase) and 10 mg; 
both treatment groups exhibited clinically meaningful 
improvements in liver biochemistry and were safe and generally 
well tolerated.  Based on these data, the intended commercial 
doses of OCA for the treatment of patients with PBC are 5 mg 
and 10 mg. 
The majority of efficacy results with OCA, in terms of change 
in alkaline phosphatase, was observed by 3 months and the 
time to treatment-emergent pruritus was typically 1 month or 
less in Study 747-301.  As such, Study 747-302 will evaluate the 
effect of OCA on clinical outcomes using the 5 mg OCA dose 
increasing to 10 mg OCA if tolerated. 
 
5.5.2.2. 
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons.   
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons (ie, comparisons to historical and placebo 
controls will be evaluated separately). 
 
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5.6 
Additionally, consistent with nonclinical findings and the 
chemical characteristics of OCA (bile acid and detergent), an 
increase in liver function tests and hepatic AEs, including 
jaundice, were observed in subjects with liver disease at doses 
between 10 mg and 50 mg and in healthy volunteers who were 
treated at doses greater than 100 mg in Phase 1 multiple dose 
studies. 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  The clinical 
significance of these lipid findings remains unclear and is being 
studied further.  Notably, despite the observed decrease, HDL 
levels have generally remained within normal limits in subjects 
treated with OCA. 
• 
Deleted text 
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 subjects with chronic liver disease such as PBC, hepatic 
findings including increased transaminases and bilirubin and 
signs or symptoms of hepatic decompensation such as 
development of jaundice were observed mainly at the highest 
dose of OCA (50mg daily). 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  Notably, in subjects 
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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated 
subjects with the exception of a modest transient and early rise 
after initiation of treatment. 
7.1 
Overall Study Design 
…Subjects will be screened during a ≤1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3)….Following 6 months of treatment with 
investigational product, subjects should be titrated in a blinded 
manner (ie, subjects randomized to OCA will increase their dose to 
10 mg OCA) based on tolerability…. 
Overall Study Design 
…Subjects will be screened during a 1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to Section 9.7.3). 
….Following 3 months of treatment with investigational product, 
subjects should be titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose to 10 mg OCA) based 
on tolerability…. 
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7.1.1 
Study Design Diagram 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
Study Design Diagram 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
7.1.2
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
1st column heading was “Screening Visit  x2) 
 
Visit Window ≤1 to 8 wks … 
Visit window in 2nd column added new text 
Added text 
 
 
 
 
 
 
 
 
 
 
 
 
Footnote a:   All subjects will have two 2 bilirubin assessments at 
least 2 weeks apart including those subjects who qualify based 
on ALP criteria.  For subjects that do not qualify based on 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
Now 2 columns: 1st column now “Screening Visit 1” 
2nd column now Screening Visit 2
3 to 8 wks… 
1 to 6 wks prior to Day 0 
 
Added Procedures: 
Quality of Life Questionnaires (PBC-40, EQ-5D-5L, and 
FIS) g (Day 0, Annually, EOT/EOS) 
Endoscopy I (Day 0, annually, per standard of care) 
Hepatic Ultrasound (Day 0, Annually, EOT/EOS) 
Physical Exam and Assessments for Mayo Risk Score and Child-
Pugh (every 6 months) 
Health Outcome Assessments (All visits) 
Added Dose Titration at M3 
Footnote a All subjects will have the chemistry panel retested 
to ensure subjects have 2 ALP and bilirubin assessments at 
least 2 weeks apart to calculate the mean result for both 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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ALP (ALP >5× ULN), the mean of the two 2 bilirubin 
assessments will be used to determine eligibility (total bilirubin 
>ULN and ≤3× ULN). 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2, and also 2 weeks post dose titration, to assess for AEs 
and concomitant medications and to verify that s/he is dosing as 
directed 
Footnote e:  Medical history at Screening will smoking and alcohol 
consumption history and current habits for both.   
 
Footnote g:  Subject Questionnaires include: Pruritus VAS, 5-D 
Pruritus Scale and Quality of Life questionnaires (See 
Section 11.1.2.2 and Section 12.2.5.1) 
 
 
 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.   
 
 
Footnote i: Added text 
 
 
Footnote j:  Added text 
 
 
 
 
Footnote k:  Added text 
analytes.   The mean of the all screening ALP and bilirubin 
assessments will be used to determine eligibility).  Samples for 
hematology and coagulation will not be collected at Screening 
visit 2. 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2 (± 1 week), and also 2 weeks post dose titration (up or 
down), to assess for AEs and concomitant medications and to 
verify that s/he is dosing as directed.   
Footnote e:  Medical history at Screening and the yearly physical 
exam will include an assessment of smoking and alcohol 
consumption history and current habits for both.   
Footnote g:  The EQ-5D-5L and FIS Quality of Life 
questionnaires are validated for use in multiple languages. If 
a validated translation is not available in the local language 
required for a specific study subject, the data from that 
questionnaire will not be collected.    (See Section 11.1.2.2 and 
Section 12.2.6) 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.  Please refer to Section 9.7.7 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote i: Endoscopy will be conducted at selected study sites 
where the device is available to assess for the presence of 
oesophageal varix/varices.  Please refer to Section 9.7.7 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote j:  Ultrasound will be conducted to enhanced HCC 
surveillance.  If a lesion is found, a second confirmatory 
image (eg, MRI) should be obtained.  Please refer to 
Section 9.7.7 for additional information related to the allowed 
windows at Day 0 for these specific procedures. 
Footnote k:  Child-Pugh Score will be calculated based on 
ascites assessment, hepatic encephalopathy grade, and central 
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Footnote l:  Added text 
 
 
 
Footnote m:  After 6 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 6 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit.  Fasting is required prior to all 
study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at site.  If the blood 
test is also positive, the subject may not be enrolled in the study.  
(Additional testing may be conducted where required, 
regionally). 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
laboratory evaluations per the Child-Pugh scoring system 
noted in the case report form.  Mayo Risk Score will be 
calculated based on central laboratory evaluations, diuretic 
use data, and peripheral edema assessment data captured in 
the CRF.  
Footnote l:  Health Outcome Assessments: Data related to non-
study related medical or surgical treatment procedures that 
the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the 
subject attended should be collected throughout the study. 
Footnote m:  After 3 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 3 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit (except Screening visit 1).  
Fasting is required prior to all study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not 
be enrolled in the study.  (Additional testing may be conducted 
where required, regionally). 
 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
 
7.3 
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 6 month study visit or at 
any study visit thereafter depending on tolerability.   
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 3 month study visit or 
at any study visit thereafter depending on tolerability.   
7.4 
Dose Titration Criteria 
After 6 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
Dose Titration Criteria 
After 3 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
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placebo (in a blinded manner) at the 6-month visit or any study visit 
following the 6-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
placebo (in a blinded manner) at the 3-month visit or any study visit 
following the 3-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
7.4.1 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, her or she should continue the regular 
visit schedule and continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination.  Early termination 
procedures should only be conducted if the subject withdraws 
consent. 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, he or she should continue the regular 
visit schedule and continue taking investigational product as long 
as the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination. 
7.5 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all subjects have 
completed the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the Study/Early Termination Visit. 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all events have been 
accrued, and when subjects are still active on the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the End of Study Visit. 
8.2 
Subject Inclusion Criteria  
2.  A mean total bilirubin >ULN and ≤3× ULN or an ALP >5× 
ULN 
4.  Either is not taking UDCA (UDCA naïve or no UDCA 
dose in the past 3 months) or has been taking UDCA for at 
least 12 months with an approved, stable dose for ≥3 months 
prior to Day 0 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
Subject Inclusion Criteria 
2.  A mean total bilirubin >ULN and ≤3× ULN and/or a mean ALP 
>5× ULN  
4.  Either is not taking UDCA (no UDCA dose in the past 3 
months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
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contraception during the study and for 30 days after the end of 
treatment visit. 
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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
 
 
8.3 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
3.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
4.  Other medical conditions that may diminish life expectancy 
to <2 years, including known cancers (except carcinomas in 
situ or other stable, relatively benign conditions such as chronic 
lymphatic leukemia) 
 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example, per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
3.  Mean total bilirubin >3× ULN 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
 
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5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of Screening (pretreatment) QT 
 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test), or lactating 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
 
5. Deleted text 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test by the central laboratory), or lactating 
 
8.4.1 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test. 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test performed at the central 
laboratory. 
8.4.2 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent. 
 
 
The following events are considered potential appropriate reasons 
for a subject to discontinue investigational product;…  
• 
Withdrawal of Consent 
- 
Added text 
 
 
 
 
 
 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent (See Section 9.7.18 Early 
Discontinuation and/or Early Termination Procedures). 
 
The following events are considered appropriate reasons for a 
subject to discontinue investigational product; … 
• 
Withdrawal of Consent 
- 
Consent may be fully withdrawn 
- 
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 potential adjudicated hepatic and/or 
cardiovascular events 
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The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study.   
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study.   
8.4.3 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study….This information must be documented in the CRF.  
If a subject is withdrawn from the study early (regardless of the 
cause), all of the end of treatment (EOT) evaluations should be 
performed at the time of withdrawal, as appropriate.  
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study….This information must be documented 
in the CRF.  If a subject is withdrawn from the study early 
(regardless of the cause), all of the (EOT/EOS) evaluations should 
be performed at the time of withdrawal, as appropriate (See 
Section 9.7.18 Early Discontinuation and/or Early Termination 
Procedures). 
9.1.1 
Dose Adjustment Beginning at Month 6 
After 6 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 6 visit, or at 
any study visit thereafter.   
Dose Adjustment Beginning at Month 3 
After 3 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 3 visit, or at 
any study visit thereafter.   
9.2 
Concomitant Medications 
Relevant information about all concomitant medications (including 
prescribed, over-the-counter, or herbal preparations) taken prior to 
(ie, within 30 days of Day 0) and during the study must be recorded 
in the source documents and CRF, as well as any dose or dose 
regimen changes that occur during the study.   
Concomitant Medications 
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 CRF, as well as any dose or 
dose regimen changes that occur during the study. 
9.2.1 
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.   
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.  Subjects that discontinue investigational product 
but continue commercial OCA therapy are expected to 
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continue through the end of the study, and the study will only 
terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.  Subjects 
will need to complete EOT procedures but continue with 
regularly scheduled visits until the study is terminated (See 
Section 9.7.18 Early Discontinuation and/or Early Termination 
Procedures). 
9.4 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN), 
as specified by the central laboratory.   
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and mean baseline bilirubin categories 
(>ULN/≤ULN), as specified by the central laboratory.   
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
• 
Added text - New section inserted. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects will be made 
available to the Investigator for emergency use only 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 is necessary for further medical management of the 
subject).  If it is not reasonable to inform the Medical Monitor 
in advance of unblinding the Investigator must promptly 
document in the subject’s source record and should 
subsequently contact the Medical Monitor to explain any 
premature unblinding of treatment assignment (such as 
unblinding which is necessary in order to treat an SAE). 
Procedures for unblinding a subject’s treatment will be 
provided separately to the Investigator.  Similarly, if the 
Medical Monitor breaks the blind for an individual subject for 
the purpose of evaluating an emergent safety issue, the Medical 
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Monitor will document within trial documentation the 
rationale, circumstances, and the person or persons being 
informed about the unblinding. 
The Data and Safety Monitoring Committee (DSMC) will have 
access to the IWRS and will be able to unblind individual 
subjects.  Refer to Section 13.3 for further details regarding 
DSMC access to blinded and unblinded data.  The DSMC will 
document details about any unblinded subject data reviews in 
the closed session DSMC minutes, which will be made available 
to the Sponsor only after the database is locked and the trial is 
unblinded.   Cases of premature unblinding, as noted above, 
will also be reviewed by the DSMC.  
Access to treatment assignments will also be made available 
through the IWRS system to the appropriate named 
individual(s) responsible for reporting SAEs and suspected 
unexpected serious adverse reactions (SUSARs) to the 
Regulatory Authorities. 
9.6 
Restrictions 
No additional restrictions. 
Restrictions 
Participation in another investigation product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the trial is prohibited. 
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9.7.1 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Interval is ≤1 to 8 weeks prior to Day 
0, allowing for 2 Screening 2 visits to 
repeat biochemistry tests, and 
ensuring ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days. 
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (7 days)  
Quarterly visits (Months 
15 – EOT) 
±2 weeks (14 days) 
EOT 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOT = end of treatment 
 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening visit 1 interval is 3 to 8 
weeks prior to Day 0 for screening 
visit 1.  Screening visit 2 interval is 
1 to 6 weeks prior to Day 0.   The 
visit window for Screening 2 visits 
allows for the repeat biochemistry 
tests to be collected at least two 
weeks after the initial biochemistry 
sample was collected, and will 
ensure ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days, but 
screening procedures should not be 
performed during the last 7 days of 
the window.  
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (14 days)  
Quarterly visits 
(Months 15 – EOS) 
±2 weeks (14 days) 
EOT 
(When subject 
discontinues 
investigational 
product) 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOS 
(When subject 
terminates the study) 
The final study visit; EOS will 
occur concurrent with EOT if a 
subject discontinues study 
medication at the time the subject’s 
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participation in the study ends (eg, 
withdrawal of consent or study 
termination by the Sponsor); EOS 
will occur after the EOT if the 
subject discontinues study 
medication but continues in the 
study. 
EOT = end of treatment 
EOS = end of study 
 
9.7.2 
Informed Consent Procedures 
• 
Added text 
Informed Consent Procedures 
Any change in a subject’s consent status (eg, semi-annual 
telephone contact or medical record review) must be 
documented in a signed informed consent form or addendum.  
The subjects will be given a signed and dated copy of the 
consent document. 
9.7.3 
Screening Procedures (≤1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed ≤1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Subjects who 
do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects may be rescreened after 2 months; however, all Screening 
procedures should be repeated and a new 3-digit Screening number 
assigned.  
 
 
 
 
 
• 
All subjects will have 2 bilirubin and ALP 
assessments at least 2 weeks apart including those 
subjects who qualify based on ALP criteria. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Screening 
Visit 1 will occur 3 to 8 weeks prior to Day 0; Screening Visit 2 
will occur 1 to 6 weeks prior to Day 0, depending on the date 
that the first serum chemistry sample was collected. Subjects 
who do not fulfill all eligibility criteria will not be enrolled in the 
study.  Subjects 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 3-digit Screening number 
assigned. 
 
• 
All subjects will have 2 bilirubin and ALP assessments at 
least 2 weeks apart 
 
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• 
For subjects that do not qualify based on ALP alone 
(ALP >5×  
ULN), the mean of the 2 bilirubin assessments will be 
used to determine eligibility (total bilirubin >ULN 
and ≤3× ULN). 
  
 
 
• 
Screening Visit procedures are as follows: 
• 
Record prior (if within 30 days of Day 0) and current 
concomitant medications 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual emission X ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
 
 
• 
Added text 
 
• 
For subjects that do not qualify based on ALP alone (ALP 
>5× ULN), the mean of all available (at least 2; 
including both scheduled and unscheduled) bilirubin 
assessments will be used to determine eligibility (total 
bilirubin >ULN and ≤3× ULN).   
 
 
 
• 
Screening Visit 1 procedures are as follows: 
• 
Record prior (if within 30 days of Screening) and current 
concomitant medications 
• 
Deleted text  
 
• 
Deleted text 
 
 
 
 
 
 
Screening Visit 2 procedures are as follows: 
• 
Verify inclusion and exclusion criteria for eligibility 
• 
Assess and record any pretreatment-emergent AEs 
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• 
Record current concomitant medications 
• 
Verify that the subject has fasted for at least 8 hours 
- 
Record fasting status in the source and CRF 
- 
If the subject reports having eaten within 8 hours, 
document accordingly in the source and CRF and 
remind the subject that fasting is required prior to all 
study visits 
• 
Obtain blood samples for serum chemistry tests 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual-emission X-ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
9.7.4 
Day 0 Procedures (Randomization) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE has 
been done within 3 months of Day 0 and a report/adequate data 
are available, a pretreatment TE at Day 0 is not required.   
 
 
• 
Day 0 Procedures (Randomization) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6.) 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE 
has been done within 6 months of Day 0 and a 
report/adequate data are available, a pretreatment TE at 
Day 0 is not required.  If the TE cannot be performed on 
Day 0 (e.g., device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the 
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• 
 Conduct a DEXA bone density scan (at selected study sites, 
where available); document whether the subject stopped taking 
her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the 
scan, if applicable.  
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
 
 
 
 
 
screening visit window, as close as possible to the Day 0 
visit, after subject eligibility has been confirmed.   
• 
 Conduct a DEXA bone density scan (at selected study 
sites, where available); document whether the subject 
stopped taking her/his calcium supplements for 48 hours 
before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable.  If DEXA 
has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment 
DEXA at Day 0 is not required.  If DEXA cannot be 
performed on Day 0 (e.g., device/technician 
unavailability, scheduling issues, etc), the procedure 
may be completed within the screening visit window, as 
close as possible to the Day 0 visit, after subject 
eligibility has been confirmed. 
• 
Perform an esophagogastroduodenoscopy (endoscopy; 
at selected study sites, where available) to assess the 
presence or absence of oesophageal varix/varices. If an 
endoscopy has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment endoscopy at Day 0 is not required. If the 
endoscopy cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
- 
Subsequent endoscopies should be performed 
annually or per standard of care and the 
Investigator’s clinical judgment throughout 
the course of the study.  Endoscopies should 
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• 
Added text 
 
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
• 
Added text 
 
• 
Record prior (within 30 days of Day 0) and current  
concomitant medications 
also be performed when platelet counts are 
<150 × 109 /L. 
• 
Perform an ultrasound (if equipment is unavailable, 
sites should make every attempt to use available 
community referral sites) for HCC surveillance.  If an 
ultrasound has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment ultrasound at Day 0 is not required. If 
the ultrasound cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
 Review and record prior concomitant medications 
• 
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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9.7.6 
Month 3 Procedures 
• 
Added text 
• 
Added text 
Month 3 Procedures 
• 
Assess for dose titration, if eligible (refer to Section 7.4) 
• 
Obtain blood samples for: 
- 
OCA, C4, and FGF-19 
9.7.7 
 
Month 6 Procedures 
• 
Added text 
 
Month 6 Procedures 
• 
 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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.8 
Month 9 Procedures 
• 
Added text 
Month 9 Procedures 
• 
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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9.7.9 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.9), subjects who are participating in the PK assessment 
will each receive a single dose of investigational product (10 mg 
OCA tablet) with approximately 240 mL of water. 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours postdose.  Subjects should not drink additional water 
for 1 hour after taking the dose of investigational product and will 
remain fasted until the 4 hour sample is collected.  Lunch will be 
provided following collection of the 4 hour PK sample; the lunch 
will be a meal replacement drink. 
 
 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.12), subjects who are participating in the PK 
assessment will each receive a single dose of investigational 
product (blinded OCA or placebo tablet) with approximately 
240 mL of water. 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours post dose.  Samples should be collected within a 
window of ±5 minutes of the scheduled sample time.  Subjects 
should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until the 4 hour 
sample is collected.  Lunch will be provided following collection of 
the 4 hour PK sample; the lunch will be a meal replacement drink.  
Samples will be stored for up to 5 years after the end of the 
study and will be destroyed after 5 years if not analyzed. 
9.7.10 
 
Month 12 Procedures 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Added text 
Month 12 Procedures 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
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o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.11 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
Subjects should come to the study center for a quarterly study 
visit for a clinical laboratory evaluation to collect blood samples 
for calculation of MELD score.  If the subject is not able to 
come to the study center for a visit, home visits may be 
arranged on a per subject basis. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
• 
Deleted text 
• 
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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
9.7.12 
Month 6 Continue Follow-up Procedures (Semi-annually [±2 
weeks]) 
• 
Added text 
Month 6 Continue Follow-up Procedures (Semi-annually [±2 
weeks]) 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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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9.7.13 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Added text  
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
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 physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.14 
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw Consent 
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw from Investigational Product or 
Withdraw Consent  
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
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When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination or 
discontinuation (withdrawal of consent), an EOT visit must be 
performed as near as possible to her/his last dose of investigational 
product and the procedures, listed below, performed.  …  In these 
cases, the data will be recorded as EOT procedures in the CRF.  
 
 
Added table 
 
 
 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects 
discontinue treatment with investigational product.  The EOT 
visit and procedures listed below must be performed as close as 
possible to the subject’s last dose of investigational product.  
When a subject discontinues investigational product but 
continues with regularly scheduled study visits, the EOS visit 
will be completed later in the study as the subject’s final study 
visit.  The actual investigational product discontinuation 
scenario (Table 7) will determine the sequence of the EOT and 
EOS visits and procedures.  In some cases, the EOT visit and 
procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible 
to the subject’s last dose of investigational product.   
When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination 
(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.  ….  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 and EOS procedures in the 
CRF.  
Table 2: 
Early Discontinuation Scenarios 
 
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Investiga
tional 
Product 
Conse
nt 
Study 
Visit 
Status 
EOT 
Visita 
EOS 
Visita 
Early 
Terminati
on 
Discontin
ued 
Withdr
awn 
No 
additi
onal 
visits 
excep
t 
EOT/E
OS 
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
Treatmen
t 
Discontin
uation 
Discontin
ued 
Active 
Regul
ar 
Visit 
Sched
ule 
Comp
lete 
as 
close 
as 
possi
ble to 
last 
dose 
IP 
Comp
lete 
at 
Final 
study 
visit 
Discontin
ued 
Semia
nnual 
contac
tb 
Telep
hone 
conta
ct 
every 
6 
mont
hs (±2 
weeks
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
 
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Some assessments noted below may be omitted if they have been 
completed within the 3 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT Visit: 
During the EOT Visit: 
• 
Subject questionnaires (see Section 12.2.6) 
• 
Conduct a DEXA bone density scan (selected study sites); 
document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for 
osteoporosis or osteopenia on the day of the scan, if applicable 
 
 
• 
Added text 
 
• 
Added text 
 
• 
Added text 
 
a Refer to Section 7.1.2 Schedule of Study Procedures for all procedures 
and evaluations required at the End of Treatment and End of Study Visits. 
b Outcomes data to be discussed or collected include data related to 
adjudicated hepatic and cardiovascular event-related data.  No additional 
data (e.g. AE, concomitant medication, etc) data will be collected, except 
as indicated in Section 12.1.7. 
Some assessments noted below may be omitted if they have been 
completed within the 6 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing 
Prior to the EOT/EOS Visit: 
During the EOT/EOS Visit 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
 Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Subject and Quality of Life  questionnaires (see Section 
11.1.2.2 and Section 12.2.6) 
• 
Perform TE (where available) using the Fibroscan® TE 
device (not required at EOT/EOS if done within 6 months) 
• 
Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
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• 
Added text 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites); not 
required at EOT/EOS if done within 6 months 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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 
 
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.  [Added text]  As appropriate, the Medical 
Monitor should be contacted. 
 
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.   
In the event of an inexplicable and acute (for example not 
explained by natural progression of the chronic disease) 
increase in alanine aminotransferase (ALT) to >3× baseline 
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(and >upper limit of normal [ULN]) or total bilirubin >2× 
baseline (and >ULN), the subject should be followed by repeat 
testing within 48 to 72 hours of the serum chemistry to confirm 
the abnormalities and to determine if they are increasing or 
decreasing. AE information should also be collected.  If 
symptoms persist or repeat testing shows ALT >3× baseline 
(and >ULN) or total bilirubin >2× baseline (and >ULN), 
subjects should be followed until resolution of the abnormality 
and as clinically indicated depending on other laboratory and 
clinical signs and symptoms. 
 
As appropriate, the Medical Monitor should be contacted. 
10.4 
Investigational Product Preparation 
The investigational product will be provided in bulk bottles and 
therefore may be repackaged in unit dose form for administration to 
subjects. 
 
Investigational Product Preparation 
The investigational product will be provided to the distribution 
center in bulk bottles and therefore may be repackaged in unit dose 
form for administration to subjects before shipping to the sites. 
 
11.1.2 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Resource utilization information 
will be collected from CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician 
visits (subject reported), and use of concomitant medications.  
 
 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Quality of life will be assessed by 
questionnaires (PBC-40, EQ-5D-5L, and FIS) 
administered annually.  Resource utilization information will 
be collected from the Medical and Surgical Treatment 
Procedures and Office Visit Log or other CRFs such as 
number, type and duration of hospitalizations, number of 
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• 
Added text 
outpatient physician visits (subject reported), and use of 
concomitant medications.  
• 
Endoscopy will be conducted at selected study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual 
study assessments or standard of care will be collected in 
the case report form to assess for the development of 
varix/varices 
11.1.2.2 
• 
Quality of Life questionnaires.   
• 
Quality of Life questionnaires.  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: 
a. PBC-40: The PBC-40 (Jacoby 2005) 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. 
b. EQ-5D-5L:  The Eq-5D-5L consists of 2 sections – the 
descriptive system and the visual analogue scales (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 
respondent’s self-rate 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). 
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c. 
Fatigue Impact Score (FIS):  The FIS is a validated 40-
question questionnaire organized into 3 dimensions:  
cognitive, physical, and social.  Each dimension has 5 
levels:  no problem, small problem, moderate problem, 
big problem, and extreme problem (Fisk 1994) 
11.1.2.3 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. The samples will be stored for up to 1 year after the 
end of the study and destroyed after 1 year if not analyzed. 
 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their 
involvement in the study.  IRB/IEC review and approval 
will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will 
be stored for up to 1 year after the end of the study and 
destroyed after 1 year if not analyzed. 
 
12.1.1.2 
Serious Adverse Event 
• 
Added text 
Serious Adverse Event 
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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12.1.4.2 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
  
All SAEs (including Potential Clinical Outcome Events that qualify 
as serious) must be reported to the medical monitor immediately 
(ie, within 24 hours) after the Investigator identifies the SAE…. 
 
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 investigational 
new drug (IND) safety reports (SUSARs) that occur during the 
study within the time frames required by each regulatory agency.  
The Investigator is responsible for submitting information on IND 
safety reports received from the Sponsor to her/his local IRB.  
Documentation of the submissions to IRBs and health authorities 
must be retained in the appropriate study file(s). 
 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
All SAEs occurring while subjects are receiving investigational 
product or are on an investigational product holiday (including 
Potential Clinical Outcome Events that qualify as serious) must be 
reported to the medical monitor immediately (ie, within 24 hours) 
after the Investigator identifies the SAE….  
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.  A SAE assessed with a possible, probable, or definite 
causal relationship to the investigational product and 
unexpected according to IB Reference Safety Information 
(RSI), is known as a suspected unexpected serious adverse 
reaction (SUSAR).  The Sponsor will notify the appropriate 
regulatory agencies as well as all participating Investigators of 
investigational new drug (IND) safety reports (SUSARs) that occur 
during the study within the time frames required by each regulatory 
agency.  The Investigator is responsible for submitting information 
on IND safety reports/SUSARs received from the Sponsor or 
Sponsor designee to her/his local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities must be retained in the 
appropriate study file(s). 
 
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12.1.6 
Notification of Post-Study SAEs 
• 
Added text 
 Notification of Post-Study SAEs 
SAEs that occur more than 30 days after a subject has 
discontinued study medication, and are not considered related 
to investigational product, must still be reported in the EDC 
system; however, these events are not required to be reported 
within 24 hours.  At a minimum, the SAE term, event start and 
end date, severity, relationship to investigational product, 
action taken with study medication, treatment, outcome, and 
potential endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event summary, SAE 
details) may also be required to be entered, when requested by 
the Sponsor. 
 
12.1.8 
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments.  
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments. The Sponsor may also 
follow the health of an infant born subsequent to use of 
investigational product. 
 
12.2.2 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page …. 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page for findings that appear after consent, and on the 
medical history CRF for any finding present prior to consent…. 
12.2.5.1 
12.2.5.1  Subject Questionnaires 
 
12.2.6 Subject Questionnaires 
12.2.6/12.2.7 
12.2.6   Laboratory Assessments 
Subjects testing positive for urine drug screen will be excluded 
from the study. 
12.2.7 Laboratory Assessments 
Deleted text 
 
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Table 4  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids, thyroid hormones (T3, 
T4, TSH) 
 
Table 5  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids 
 
12.2.6 
Laboratory Assessments 
• 
Added text 
 
 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly visits based on serum chemistry and coagulation. 
 
12.2.7  Laboratory Assessments 
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. 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly (MELD scores only) and semi-annual visits based on 
serum chemistry and coagulation. 
 
13.1.5 
Additional Secondary Efficacy Analyses 
• 
Added text 
Additional Secondary Efficacy Analyses 
• 
Time to development of varix/varices 
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Section 
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Revised Text 
 
 
13.1.8 
Supportive Analysis 
Although the results of using matching are conditional only on the 
observed covariates, if one has the ability to measure many of the 
covariates that are believed to be related to the treatment 
assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained. 
 
Supportive Analysis 
Although the results of using matching controls are conditional 
only on the observed covariates, if one has the ability to measure 
many of the covariates that are believed to be related to the 
treatment assignment, then one can be fairly confident that 
approximately unbiased estimates for the treatment effect can be 
obtained. 
13.3 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study. In addition, the DSMC statistician 
will evaluate the sample size as described in Section 13.1.2.1. 
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.   
 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study.  
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.  The DSMC will document details about 
any unblinded subject data reviews in the closed session DSMC 
minutes, which will be made available to the Sponsor only after 
the database is locked and the trial is unblinded.   Cases of 
premature unblinding, as noted above, will also be reviewed by 
the DSMC.  
 
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Section 
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Revised Text 
16.2, Ethical 
Conduct of the 
Study 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles 
that have their origin in the Declaration of Helsinki (Seoul 
Revision, 2008) and are consistent with ICH/GCP, applicable 
regulatory requirements and the Sponsor’s policies. 
Ethical Conduct of the Study 
 The study will be performed in accordance with ethical principles 
and are consistent with ICH/GCP, local applicable regulatory 
requirements (in addition to Appendix C) and the Sponsor’s 
policies. 
19 
List of References 
• 
Added text 
List of References 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional 
impact of fatigue: initial validation of the fatigue impact scale. 
Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
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 Dec;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), 1622-1629. 
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. 
 
Appendix C 
• 
Added document 
Ethical Conduct according to the Declaration of Helsinki for 
Countries Participating Outside the US 
 
 
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APPENDIX E.  SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 (DATED 12 NOV 2015) 
Rationale 
The changes to Amendment 1 of the protocol, detailed below, generated specifically for regulatory authority requests, include an 
additional exclusion criteria and changes to text precluding UDCA naïve subjects from entering the study and clarifying information 
showing that OCA may increase the exposure of narrow therapeutic index drugs that are substrates for CYP1A2, thus answering 
questions raised by regulatory authorities. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.1.  (Note:  Revised text in Amendment 1.1 is indicated in 
bold font, and the text deleted from Protocol Amendment 1 is crossed out in the table below. Minor formatting changes are not listed.) 
Section 
Original Text (Amendment 1, 29 April 2015) 
Revised Text (Amendment 1.1, 12 November 2015) 
Title Page 
Original:  03 October 2014 
Amendment 1:  29 APRIL 2015 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Amendment 1.1:  12 November 2015 
Study Personnel 
Contact 
Information 
Mobile:      
 (Pacific time zone) 
Telephone: 
 
Telephone 
 
(deleted) 
Telephone: 
 
(deleted)   
Synopsis, 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
Synopsis, 
Statistical 
Methods:  
Sample Size 
Justification 
• 
5% of the subjects will have never been treated with UDCA; 
95% of the subjects will have been on UDCA for at least 1 
year 
(deleted) 
 
8.3 Subject 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
9.2 Concomitant 
Medications 
(insertion) 
The effect of OCA on drug metabolizing enzymes has been 
evaluated in both in vitro and clinical studies.  The PK profile 
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Section 
Original Text (Amendment 1, 29 April 2015) 
Revised Text (Amendment 1.1, 12 November 2015) 
of caffeine, a sensitive CYP1A2 substrate, 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. 
12.1.4.2 
Reporting of 
Serious Adverse 
Event 
Mobile:      
 (Pacific time zone) 
Telephone: +1 858 964 1571 
(deleted) 
Telephone: 
   
13.1.2 
Determination of 
Sample Size 
5% of the subjects will have never been treated with UDCA; 95% 
of the subjects will have been on UDCA for at least 1 year 
(deleted) 
 
 
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APPENDIX F. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 (DATED 07 SEPTEMBER 2016) 
Rationale 
The changes to Version 3 of the protocol, include dosing adjustments based on Child-Pugh scoring, additional exclusion criteria, 
changes to text precluding UDCA-naïve subjects from entering the study.  
Please note that the Sponsor has renamed protocol “amendments” to “versions”, therefore all future revisions that require a revised 
protocol will have an associated “version” number. The table below includes substantial revisions made to Protocol 747-302 under 
Version 3, which encompass the revisions captured in Protocol Amendment 1.1. Revised text in Version 3 is indicated in bold font, 
and the text deleted from Protocol Amendment 1.1 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 (Amendment 1.1, 
12 November 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology 
...  Mean values for ALP and total bilirubin 
will be calculated using all available 
screening values.  Subjects who meet all 
inclusion criteria and none of the exclusion 
criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The 
randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment 
(yes/no) and baseline bilirubin categories 
(>upper limit of normal [ULN]/ ≤ULN). 
Investigational product (OCA or matched 
placebo) will be taken orally, once daily.  
Investigational product will be initiated at 5 
mg OCA or matched placebo.  After 3 
months of treatment with investigational 
product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched 
placebo, in a blinded manner) at the 3-
month visit or any subsequent study visit 
based on tolerability.  Subjects will be seen 
at quarterly visits for the duration of the 
study. 
...  Investigational product will be taken orally, once daily 
for the majority of subjects; dose and frequency will be 
modified for subjects with cirrhosis (including subjects 
progressing to cirrhosis during the study) and 
classified as Child-Pugh B or C.  The randomization will 
be stratified by ursodeoxycholic acid (UDCA) treatment 
(yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
To incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores, 
to align with the 
recommended dosing 
regimen found in the 
Ocaliva US Package Insert 
for patients with hepatic 
impairment. 
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Synopsis, 
Methodology. 
7.1.1, Study 
Design Diagram, 
Figure 1 
Schematic diagram
 
Updated schematic diagram 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.  Subsequent dose titration(s) for subjects 
classified as Child Pugh B or Child-Pugh C and 
following a modified dosing schedule may occur no 
earlier than 6 weeks after the previous dose titration 
Incorporate updated dosing 
scheme to reflect addition of 
Child-Pugh scoring. 
Synopsis, 
Methodology 
(insertion) 
Dosing frequency will be determined by the presence 
or absence of cirrhosis and, if cirrhosis is present, by 
Child-Pugh Score as described below: 
• 
Non-cirrhotic subjects or subjects classified as 
Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects 
should titrate to a maximum dose of 10-mg OCA once 
daily (or matching placebo) at the Month 3 visit or at 
any study visit following the Month 3 visit based on 
tolerability of the product.    
• 
For those subjects that up-titrate to 10 mg, dosing 
may be decreased to 5 mg at any time during the study 
as considered clinically appropriate (eg, based on 
tolerability). Subjects may be titrated back to a 
maximum dose of 10 mg once daily based on 
tolerability and clinical judgment of the Investigator.    
• 
 Subjects who are cirrhotic and classified as Child-
Pugh Class B or Child-Pugh Class C will initiate a 
modified treatment regimen with 5-mg OCA or 
matching placebo once weekly for at least 3 months.  
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5-mg OCA or 
matching placebo once daily, based on tolerability.  
Subjects classified as Child-Pugh Class C should 
Revised methodology to 
incorporate the changes in 
dosing for subjects based on 
the Child-Pugh Scores. 
 
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titrate to a maximum dose and frequency of 10-mg 
OCA or matching placebo twice weekly, based on 
tolerability. 
Includes New Table: Planned Dosing Regimen by 
Cirrhosis and Child-Pugh Score 
5.1, Overview 
(insertion) 
The United States Food and Drug Administration 
(FDA) has granted accelerated approval for Ocaliva 
for the treatment of PBC.  Ocaliva is not yet approved 
outside the United States for use in any indication. 
Language updated as OCA 
is approved in the US with 
the trade name Ocaliva. 
5.5.2.2, Rationale 
for Modified OCA 
Doses in Patients 
Classified with 
Child-Pugh B or 
Child-Pugh C 
Hepatic 
Impairment 
(Insertion) 
New section: Rationale for Modified OCA Doses in 
Patients Classified with Child-Pugh B or Child-Pugh C 
Hepatic Impairment 
Simulations using a physiologic PK model predicted 
changes in systemic and liver OCA concentrations 
associated with changes in the severity of hepatic 
impairment (Child-Pugh score).  Model simulations 
predicted that for mild (Child-Pugh A), moderate 
(Child-Pugh B), and severe (Child-Pugh C) hepatic 
impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to subjects 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 (Child-Pugh B and C) 
subjects treated with OCA in phase 1 and 2 studies 
experienced plasma OCA exposures >10-fold higher 
than those in healthy subjects, 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.  Collectively, the 
results from these analyses and those from bile acids in 
the literature suggest that the doses of OCA 
administered to hepatically-impaired patients should 
Provide the rationale to 
incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores 
into the protocol. 
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be modestly lower than those for patients with normal 
hepatic function to achieve similar hepatic exposure.   
Per the approved FDA prescribing label, the 
recommended dosing regimen for OCA in subjects 
with moderate and severe hepatic impairment is a 
starting dose of 5-mg OCA once weekly.   Dosage 
adjustments in subjects with moderate (Child-Pugh B) 
or severe (Child-Pugh C) hepatic impairment may be 
made after establishing tolerability at the lower dose 
(full modified dosing regimen is described in 
Appendix A). 
5.6, Summary of 
Known Potential 
Risks with OCA 
(Insertion) 
…These findings were seen more frequently with doses 
above 10 mg OCA.  In addition, cholecystitis, including 
acute cholecystitis, was reported in association with 
treatment with OCA. 
Added two AE terms 
reported in the updated 
Investigator’s Brochure. 
7.1, Overall Study 
Design 
…Investigational product will be initiated 
at 5 mg OCA or matched placebo.   
Following 3 months of treatment with 
investigational product, subjects should be 
titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose 
to 10 mg OCA) based on tolerability 
Investigational product will be taken orally, once daily.  
Subjects who are non-cirrhotic or classified as Child-
Pugh A at Screening will initiate investigational 
product once daily with 5-mg OCA or matching 
placebo. Following 3 months of once daily treatment with 
investigational product, the dose should be titrated to a 
maximum 10 mg OCA or matching placebo once daily, 
based on tolerability (see Section 7.3).  
Subjects with cirrhosis and classified as Child-Pugh 
Class B or Child-Pugh Class C will follow a modified 
dosing regimen, and will initiate investigational 
product once weekly with the 5-mg OCA or matching 
placebo dose.  In addition, these subjects will follow a 
modified titration plan, which is outlined in 
Appendix A.  
Amend the protocol to 
incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores. 
7.1.2, Table 1, 
Schedule of Study 
Procedures – 
Screening to 
Month 12 (Table 1 
of 2), 9.3, 
Safety Contact 
This visit has been deleted. 
Replaced with the 1 Month 
Post-Titration Visit. 
(Insertion) 
Added the following visits: 
• 
Month 1 
• 
1 Month Post-Titration Visit 
Visits were added to 
accommodate the updated 
dosing and titration regimen 
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Treatment 
compliance 
based on subject’s 
Child-Pugh Scores. 
bThe subject should be contacted by 
telephone on a monthly basis in between at-
clinic study visits at Month 1 and Month 2 
(± 1 week), and also 2 weeks post dose 
titration (up or down), to assess for AEs and 
concomitant medications and to verify that 
s/he is dosing as directed. 
cAs soon as possible upon study 
discontinuation and as near as possible to 
last dose taken. 
nSubject to begin dosing on Day 1 
Deleted. 
Result of table being 
updated for the dosing and 
titration regimen based on 
subject’s Child-Pugh Scores. 
(Insertion) 
Added the following study procedures: 
• 
Cirrhosis Status Assessmente 
• 
Assessments for Child-Pugh Scoresg 
• 
Dose Titration: Standard Dosingn,o 
• 
Dose Titration: Modified Dosing n,o 
• 
Dosing Diary 
Study procedures were 
added to accommodate the 
updated dosing/titration 
regimen.  Dosing diary was 
added to improve 
compliance. 
(Insertion) 
Added the following footnotes: 
• 
bSafety 
Post-Titration 
visits 
must 
be 
performed 1 month + 1 week after any up-
titration in dose and/or frequency in subjects 
following modified dosing due to Child-Pugh 
B and Child-Pugh C hepatic impairment.  In 
subjects following the standard dosing 
regimen, the post-titration visit must be 
performed only after the first up-titration to 
10 mg OCA or matching placebo, or after ≥3 
months at a decreased dose or frequency. 
• 
ePresence or absence of cirrhosis should be 
assessed per Section 9.7.3.  Cirrhosis status 
should be repeated as clinically indicated. 
• 
fMayo Risk Score will be calculated based on 
central laboratory evaluations, diuretic use 
Added footnotes provide 
clarity regarding 
assessments and visits based 
on the evaluation of 
Child-Pugh scores.  
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data, and peripheral edema assessment data 
captured in the CRF. 
• 
gChild-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. 
• 
nPre-titration tolerability assessment, which 
include a review of AEs and a review of 
safety laboratory results (eg, chemistry, 
hematology, and coagulation), must be 
completed by the Investigator before any up-
titration 
can 
occur 
as 
defined 
in 
Section 7.4.1.  Lab results obtained within 2 
months prior to any up-titration may be used 
for assessment. 
• 
oDose Titration is based on cirrhosis status 
(Section 9.7.3) 
and 
Child-Pugh 
score 
(Section 7.3).  The initial dose titration of 
investigational product may occur at the 
Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.  Subsequent dose titration(s) for 
subjects who are classified as Child-Pugh B 
or Child-Pugh C and following a modified 
dosing schedule may occur no earlier than 6 
weeks after the previous dose titration.  For 
complete modified dose titration criteria, 
refer to Appendix A. 
• 
pSubjects will be instructed to begin dosing 
on the day after the Day 0 visit (ie, on Day 1) 
and to take investigational product at 
approximately the same time of day.  
Subjects must be instructed to swallow the 
tablet whole; they must not chew, divide, or 
crush the tablet. 
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7.1.2, Table 2, 
Schedule of Study 
Procedures – Year 
2 Through End of 
Study (Table 2 of 
2) 
 
New table- Schedule of Study Procedures – Year 2 
Through End of Study (Table 2 of 2) 
Divided Schedule of Study 
Procedures into 2 tables, 
updated to include visits 
added per updated 
dosing/titration information.   
7.3, Planned 
Dosing Regimen 
7.3 Treatment Assignment 
Subjects will receive either placebo or 5 mg 
OCA and should titrate to 10 mg OCA (in a 
blinded manner) at the 3-month study visit 
or at any study visit thereafter depending on 
tolerability. 
7.3 Planned Dosing Regimen 
Subjects will be randomized to treatment with either 
OCA or matching placebo in a 1:1 ratio.  Subjects will 
be dosed according to their cirrhosis status (as defined 
in Section 9.7.3) and applicable Child-Pugh Score (see 
Section 9.7.4) as outlined in Table 3.  
Subjects who are non-cirrhotic or classified as 
Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects 
should titrate to a maximum dose of 10-mg OCA once 
daily (or matching placebo) at the Month 3 visit or at 
any study visit following the Month 3 visit based on 
tolerability of the product.  A review of safety 
laboratory results (eg, chemistry, hematology, and 
coagulation) obtained no more than 2 months prior to 
the planned up-titration visit must be completed as 
part of the product tolerability assessment before up-
titration can occur (see Section 7.4.1).   
For those subjects that up-titrate to 10 mg, dose may 
be decreased to 5 mg at any time during the study as 
considered clinically appropriate (eg, tolerability). 
Subjects may be titrated back up to a maximum dose 
of 10 mg once daily based on tolerability and clinical 
judgment of the Investigator.  A review of safety 
laboratory results obtained within 2 months of the 
planned up-titration visit date is not required prior to 
re-challenging a subject up to 10 mg once daily dosing, 
as long as the decrease in dose/dosing frequency was 
less than 3 months in duration. 
Section renamed to reflect 
changes in titration and 
dosing for subjects with 
hepatic impairment. 
(Insertion) 
New:  Table 3: Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
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New: Table 4: Determination of Dosing Regimen 
Tables added to clarify 
changes in titration and 
dosing. 
7.4 Dose Titration 
Criteria 
After 3 months of treatment at the 5 mg 
dose, the dose of OCA will be increased to 
the maximum dose of 10 mg OCA or 
matched placebo (in a blinded manner) at 
the 3-month visit or any study visit 
following the 3 month visit based on 
tolerability of investigational product.   
 
For those subjects that increased their dose 
to 10 mg, they may decrease his or her dose 
to 5 mg at any time during the study as 
considered appropriate (eg, tolerability), but 
should be titrated back to 10 mg based on 
tolerability and clinical judgment by the 
Investigator as soon as possible with the 
goal that all subjects remain on the 10-mg 
dose if tolerated 
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 
subject’s cirrhosis status (using histology or 
non-histological methods as defined in Section 9.7.3 
and Section 9.7.4) or Child-Pugh Score.   
Scheduled Dose Titration - The first dose titration for 
any subject may occur no earlier than 3 months 
following initiation of OCA or matching placebo.  
Subsequent titrations in dose or dosing frequency for 
subjects following the Modified Dosing Regimens may 
occur no earlier than 6 weeks (via an unscheduled visit 
or regular visit- see Appendix A) following an 
up-titration. 
Tolerability Dose Titration - Investigators may 
decrease the dosing frequency or dose for any subject at 
any time during the study, as considered clinically 
appropriate (eg, tolerability; see Section 7.4.2).   
Dose Titration due to Change in Cirrhosis or 
Child-Pugh Score - When subjects demonstrate a 
change in cirrhosis status (as assessed per 
Section 9.7.3) or Child-Pugh Score (Section 9.7.4), 
dosing should be reassessed and the dosing regimen 
modified appropriately.  Changes to the dosing 
regimen are not mandatory and should be based on 
clinical judgment as well as change in cirrhosis status.  
Table 5 provides an overview of the possible changes in 
dosing regimen due to changes in cirrhosis or Child-
Pugh 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.  
Entire section revised to 
reflect changes in titration 
and dosing. 
7.4 Dose Titration 
Criteria 
(Insertion) 
New: Table 5:  Changes in Dosing Regimen Due to 
Changes in Cirrhosis Status or Child-Pugh Score 
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7.4 Dose Titration 
Criteria 
(Insertion) 
Subjects who exhibit development of cirrhosis at any 
point in the study should be assessed per Section 9.7.3.  
If the presence of cirrhosis is confirmed and the 
subject’s Child-Pugh score is either B or C, the 
appropriate modified dosing regimen should be 
followed.  The dose or frequency of investigational 
product should be down-titrated to the next lowest 
dosing frequency in the appropriate modified dosing 
regimen unless the subject is currently taking a dose 
and frequency also specified in the modified dosing 
regimen and the investigator determines that it is 
clinically appropriate for the subject to continue at 
that dose (Appendix A). 
Subjects with pre-existing cirrhosis who demonstrate a 
change in the Child-Pugh Score from A to B or C at 
any point in the study should also have their dosing 
modified per the appropriate dosing regimen 
(Appendix A).  
Subjects who demonstrate an improvement in 
cirrhosis status or in Child-Pugh Score from B to A, or 
from Child-Pugh C to B, may be eligible to transition 
to the standard dosing regimen or the modified dosing 
for Child-Pugh B, respectively, based on tolerability.  
Prior to any dosing change, subjects must meet 
pre-titration assessment requirements for dosing as 
described in Section 7.4.1. 
Child-Pugh Scores will be calculated at all quarterly 
study visits. All associated visit data (including central 
laboratory results) should be entered into the eCRF in 
a timely fashion to confirm that the subject’s Child 
Pugh Score has not changed.  If a change in cirrhosis 
status (as defined in Section 9.7.3) and/or Child-Pugh 
Score is observed independent of a study visit, the 
subject 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 and table added to 
provide dosing guidelines to 
investigators. 
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Subjects’ dose and dosing frequency may be titrated 
up or down within the appropriate dosing regimen 
based on the calculated Child-Pugh Scores.  Up-
titration should be done per Investigator discretion 
and be guided by the pre-titration tolerability 
assessments. 
7.4.1, 
Pre-Titration 
Tolerability 
Assessment 
Requirements 
(Insertion) 
7.4.1  Pre-Titration Assessment Requirements 
Tolerability of investigational product must be 
assessed prior to titrating a subject to a higher dose.  A 
review of adverse events and safety laboratory results 
(eg, chemistry, hematology, and coagulation) obtained 
within 2 months of the up-titration visit must be 
performed as part of the investigational product 
tolerability assessment, prior to any planned up-
titration in study medication (eg, Month 3, Month 6).  
Safety laboratory results obtained at the Month 1 visit 
(for titration at Month 3) or at the 1 Month 
Post-Titration Assessment visit (for titration prior to 
or at the subsequent quarterly visit) are acceptable for 
review purposes; however, 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 subject to a higher dose.  
To be eligible for a dose up-titration: 
• 
Subjects 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.  
• 
There must be no clinically significant increase (as 
determined by the investigator) in the subject’s liver 
function tests.  Subjects whose total bilirubin is 
>2× baseline (and >ULN) cannot be up-titrated, and 
additional unscheduled safety visit procedures, 
outlined in Section 9.7.19, should be implemented, as 
required 
Section added to provide 
guidance for assessing 
subject tolerability prior to 
titration. 
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8.4.2, Other 
Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
(Insertion) 
• 
Subject begins treatment with commercially 
available OCA 
… safety concerns and related to study drug 
• 
Consent may be fully withdrawn (in which case the 
subject discontinues both investigational product and 
study visits and procedures) 
…Subjects who undergo a liver transplant during the 
course of the study must discontinue investigational 
product and discontinue the study visit schedule.  
However, these subjects 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. 
Added text as Ocaliva is 
commercially available in 
the US and therefore 
subjects may be 
discontinued if they began 
off-study treatment with 
Ocaliva.   
8.4.2.1, Elevated 
Liver Enzymes 
(Insertion) 
New Section:  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. 
Section added to incorporate 
monitoring of liver test 
results during the study. 
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9.1, 
Investigational 
Product Treatment 
Regimen 
9.1.1 Dose Adjustment Beginning at 
Month 3 
After 3 months of treatment with 
investigational product, the dose of 
investigational product should be increased 
in a blinded manner and based on 
tolerability; this may occur at the Month 3 
visit, or at any study visit thereafter.  
Titration above 10 mg OCA is not 
permitted. 
At each study visit where the daily dose of 
investigational product is administered at the site, all 
assessments, except for the post-dose collection of 
blood samples for the subset of subjects participating 
in the Month 9 PK assessment, must be completed 
before administration of investigational product. 
Section revised to reflect 
changes in titration and 
dosing. 
9.2, Concomitant 
Medications 
Subjects taking bile acid sequestrants 
(BAS) 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). 
 
New sub-heading:   
Drug Interactions 
Subjects 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 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.  
(…) Information related to additional drug-drug 
interaction (DDI) studies is available in the current 
version of the Investigator’s Brochure (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 with OCA that may 
be observed in study subjects. 
Section revised to provide 
additional information on 
drug-drug interactions with 
OCA. 
9.2.1, Prohibited 
Medications 
… the Investigator should be cognizant of 
the possibility of double dosing and 
… the Investigator should be cognizant of the possibility 
of double dosing.  Subjects who continue with 
Ocaliva is commercially 
available in the US and, 
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encourage the discontinuation of open-label 
OCA therapy.  However, if commercial 
OCA therapy remains, then investigational 
product should be discontinued to avoid 
potential double dosing.  Subjects that 
discontinue investigational product but 
continue commercial OCA therapy are 
expected to continue through the end of the 
study, and the … 
commercial OCA therapy must discontinue study 
medication and are expected to continue through the end 
of the study.  … 
therefore, subjects wishing 
to take commercially 
available drug are not 
discouraged, but they must 
discontinue study 
medication. 
9.7.1, Visit 
Windows 
(insertion) 
Added the following visit windows: 
• 
Month 1 (+1 week [7 days]) 
• 
Titration Visit – Standard Dosing Regimen 
(≥Month 3) 
• 
Titration Visit 1 – Modified Dosing Regimen 
(≥Month 3) 
• 
Titration Visit 2 – Modified Dosing Regimen 
(≥6 weeks after Titration Visit 1) 
• 
Titration Visit 3 – Modified Dosing Regimen 
(Child-Pugh B ONLY) (≥6 weeks after 
Titration Visit 2) 
• 
Post-Titration Visit, (+1week [7 days]) from 
date of titration or after ≥3 months at a 
decreased dose or frequency) 
Added visits to 
accommodate the updated 
dosing/titration scheme. 
9.7.3, Assessing 
Cirrhosis 
(Insertion) 
New: 9.7.3. Assessing Cirrhosis 
To determine which dosing regimen subjects should 
follow, the presence or absence of 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 
is defined as a subject 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) 
Added section to assess 
cirrhosis as this assessment 
will determine the 
acceptable dosing regimen 
based on a subject’s 
Child-Pugh score.  
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• 
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  
− 
elevation in prothrombin time /INR (not 
due to antithrombotic agent use), or 
− 
elevated bilirubin (2× ULN) 
Subjects who exhibit no evidence of cirrhosis by the 
above methods of assessment will be dosed using the 
Standard Dosing Regimen, while those who do exhibit 
evidence of cirrhosis by one or more of the above 
methods will be dosed using the Modified Dosing 
Regimen according to their Child-Pugh Score 
calculated in the electronic case report form (eCRF) 
(see Appendix A). 
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, Child-Pugh 
Score 
(Insertion) 
9.7.4. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is 
calculated and reported within the electronic data 
capture (EDC) system based on data entered into the 
eCRF adding the scores from the 5 factors outlined in 
Table 6 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 
Child-Pugh Score includes investigator assessments of 
ascites and hepatic encephalopathy, which may be 
Section added to provide 
Investigators with 
information on the 
Child-Pugh scoring system. 
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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.   
It is important to note that subjects must have 
confirmed cirrhosis as assessed by one or more of the 
above criteria (Section 9.7.3) prior to applying the 
calculated Child-Pugh score for dosing.  Investigators 
will be responsible for determining the appropriate 
dosing regimen based on both the cirrhosis status and 
the Child-Pugh score (Table 6).  Any change in 
cirrhosis status or Child-Pugh Score will necessitate 
re-evaluation of the dosing regimen 
9.7.4, Child-Pugh 
Score 
(Insertion) 
Table 6 (New) Child-Pugh Scoring System 
 
9.7.6, Screening 
Procedures (1 to 8 
Weeks prior to 
Day 0) 
(Insertion) 
The following procedures were added: 
Screening Visit 1 procedures are as follows: 
• 
Provide the subject with a dosing diary to 
document his or her dosing 
• 
Assess for the presence/absence of cirrhosis 
• 
Perform status assessment for calculation of 
Mayo Risk Score 
Screening Visit 2 procedures are as follows: 
• 
Perform an ultrasound for hepatocellular 
carcinoma (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 Visit 2, and a report/adequate data are 
available, a pretreatment ultrasound at Screening 
Visit 2 is not required.  If the ultrasound cannot 
be performed at Screening Visit 2 (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 
Procedures added to assess 
cirrhosis. 
 
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P a ge 1 6 3  
 
C o nfi de ntial a n d Pr o prietar y   
criteri a pri or t o r a n d o miz ati o n.  
9. 7. 7, Da y 0 
Pr oce d ures 
( Ra n d o mizati o n) 
9. 7. 4. 
Da y 0 Pr oce d ures  
• 
P erf or m a n ultras o u n d f or 
he pat ocell ular carci n o ma ( H C C) 
s ur veilla nce (if e q ui p me nt is u na vaila ble, 
… 
• 
P erf or m p h ysical e xa mi nati o n a n d 
o verall stat us assess me nt f or calc ulati o n of 
Ma y o Ris k Sc ore a n d C hil d -P u g h 
Assess me nts.  
 Prese nce/a bse nce of peri p heral e de ma  
 Prese nce ( de gree)/a bse nce of ascites  
 Prese nce ( de gree)/a bse nce of he patic 
e nce p hal o pat h y  
9. 7. 7 : Da y 0 Pr oce d ures ( Ra n d o mizati o n)  
• 
Pr o vi de t he s u bject wit h a d osi n g di ar y t o 
d oc u me nt his or her d osi n g.  
 
U p date d visi t t o 
acc o m m o date t he u p date d 
d osi n g/titrati o n sc he me.  
9. 7. 8, M o nt h 1 
Pr oce d ures  
9. 7. 5 Safet y C o ntact ( M o nt h 1, M o nt h 2, 
a n d 2 W ee ks P ost -Titrati o n [ b y tele p h o ne])  
9. 7. 8  M o nt h 1 Pr oce d ures  
• 
Pr o vi de t he s u bject wit h a d osi n g di ar y t o 
d oc u me nt his or her d osi n g.  
• 
I n t he e ve nt it is n ot fe asi ble f or t he s u bject t o 
ret ur n t o t he site f or t he a b o ve refere nce d pr oce d ures, 
t he f oll o wi n g alter n ati ve visit pr oce d ures are a v ail a ble 
t o hel p e ns ure c o m pli a nce wit h t he M o nt h 1 visit 
re q uire me nts:  
- 
At t he D a y 0 visi t, t he s u bject c a n be pr o vi de d 
wit h t he ce ntr al l a b or at or y c ollecti o n kit a n d s hi p pi n g 
m ateri als ass oci ate d wit h t he M o nt h 1 visit, …  
- 
If all ot her o pti o ns f or t he c ollecti o n of t he M o nt h 
1 l a b or at or y s a m ples h a ve bee n e x h a uste d, t he use of a 
l oc al l a b or at or y f or t he M o nt h 1 s a m ples w o ul d be 
acce pte d f or t his visit alt h o u g h a n y l a b or at or y d at a 
o bt ai ne d fr o m a l oc al l a b or at or y will n ot be c a pt ure d 
i n t he e C R F or i ncl u de d i n t he st u d y a n al ysis.  … 
 
Re vise d secti o n t o i ncl u de 
t he ne w M o nt h 1 visit 
pr oce d ures.   
9. 7. 9, M o nt h 3 
pr oce d ures, 
9. 7. 1 1, M o nt h 6 
(I nserti o n) 
• 
Perf or m assess me nts f or c alc ul ati o n of C hil d -P u g h 
Sc ore  
A d de d pr oce d ure t o 
acc o m m o date t he u p date d 
d osi n g/titrati o n sc he me.  
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Procedures, 
9.7.12, Month 9, 
9.7.14, Month 12 
Procedures  
9.7.9 thru 9.7.17 
(Insertion) 
If up-titration will occur at this visit, complete the pre-
titration visit and visit related assessments as outlined 
to ensure all procedures required for dose titration 
eligibility have been met, including the required review 
of the dose titration laboratory parameters. 
• 
Provide the subject with a dosing diary to 
document his or her dosing 
• 
… review dosing diary with the subject 
Text added to clarify 
procedures required before 
up-titration. 
9.7.10, Post 
Titration Visit 
Procedures 
(Insertion) 
New: 9.7.10. Post Titration Visit Procedures 
• 
Assess and record AEs. 
• 
Review and record concomitant medications. 
• 
Assess investigational product compliance, 
perform investigational product accountability, and 
review dosing diary with the subject. 
• 
Obtain blood samples for serum chemistry, 
hematology, and coagulation tests. 
• 
Provide the subject with a dosing diary to 
document his or her dosing. 
• 
In the event it is not feasible for the subject to 
return the site for the above referenced procedures, 
the following alternative visit procedures are available, 
to help ensure compliance with the Post-Titration visit 
requirements: 
- 
At the Up-titration Visit, the subject can be 
provided with the central laboratory collection kit 
and shipping materials associated with the Post-
Titration visit, and have the laboratory specimen 
collection performed at his or her local doctor’s 
office or designated laboratory collection center.  
The subject must also be contacted via telephone 
at the Post-Titration Visit time point to assess 
Added visit to accommodate 
the updated dosing/titration 
scheme. 
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AEs, review concomitant medications, and assess 
investigational product compliance. 
- 
If all other options for the collection of the 
Post-Titration laboratory samples have been 
exhausted, the use of a local laboratory for the 
Post Titration samples would be accepted for this 
visit although any laboratory data obtained from 
a local laboratory will not be captured in the 
eCRF or included in the study analysis.  A copy of 
the local laboratory report would need to be 
provided to the investigator for review and 
available in the source records.  The subject must 
also be contacted via telephone at the Post-
Titration Visit time point to assess AEs, review 
concomitant medications, and assess 
investigational product compliance. 
• 
Schedule the next visit, reiterate dosing 
instructions, and advise the subject: 
- 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… 
9.7.13, Month 9 
Procedures for 
Subjects 
Participating in 
Pharmacokinetic 
Assessment 
(Insertion) 
…Subjects who are following the Child-Pugh B and 
Child-Pugh C modified dosing regimen may 
participate in the PK assessment and will dose in the 
clinic at this visit even if the previous dose was taken 
less than 3 days prior; however, every attempt should 
be made to schedule the Month 9 PK visit according to 
the subject’s established dosing schedule. 
Clarify that subjects with 
hepatic impairment may 
continue to participate in the 
PK assessment. 
9.7.13, Month 9 
Procedures for 
Subjects 
Participating in 
Pharmacokinetic 
Assessment 
…Lunch will be provided following 
collection of the 4 hour PK sample; the 
lunch will be a meal replacement drink… 
…Lunch will be provided following collection of the 4 
hour PK sample; the lunch will be a meal replacement 
drink with no other food allowed until after the final 6-
hour post dose sample is collected… 
Clarify PK collection 
procedures. 
 
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11.1.2.2, Other 
Secondary 
Assessments 
• 
OCA (and its conjugates) and C4 will 
be assayed 
• 
OCA (OCA, tauro-OCA, glyco-OCA, total OCA, 
OCA-glucuronide) and C4 will be assayed to determine 
bioanalytical concentrations.  Additional analyses may 
include other conjugates or metabolites not yet 
identified. 
Clarify the analytes to be 
measured for the PK 
analyses. 
11.1.2.4, Potential 
Clinical Outcome 
Events 
(Insertion) 
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 13.4. 
Revised to clarify that 
potential clinical outcome 
events meeting the criteria 
of a SUSAR will not be 
reported to regulatory 
authorities expeditiously.  
12.1.4.2 Reporting 
of Serious 
Adverse Event 
In agreeing to the provisions of this 
protocol, the Investigator accepts all legal 
responsibilities for immediate reporting of 
SAEs to the medical monitor. 
All SAEs occurring while subjects are 
receiving investigational product or are on 
an investigational product holiday 
(including Potential Clinical Outcome 
Events that qualify as serious) must be 
reported to the medical monitor 
immediately (ie, within 24 hours) after the 
Investigator identifies the SAE.  SAEs are 
reported by entering the SAE data into the 
electronic data capture (EDC) system.  
Entering the SAE data into the EDC system 
will automatically notify the medical 
monitor of the event.  In the event that the 
EDC system is inaccessible, an SAE may 
be reported by telephone or fax using a 
paper SAE Report form.  If an SAE is 
reported by telephone or fax, an SAE 
Report form must also be completed in the 
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 be reported by: 
• 
E-mail to the SAE email address:  
sae@interceptpharma.com 
• 
Fax using a paper SAE report form:  
+1 800 497 8521 
• 
Telephone:  +1 858 964 1571  
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 
Updated guidance for 
reporting SAEs. 
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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:   
subject number and initials, a description of 
the event, at least one criterion classifying 
the event as serious and the name and title 
of the reporting individual.  Additionally, 
judgment of causality by the Investigator 
must be provided as soon as possible to 
ensure timely reporting to regulatory 
authorities by the Sponsor or designee(s).  
Following the initial report, any additional 
information obtained by the Investigator 
about the SAE must be reported promptly 
to the medical monitor.  Any supporting 
source documentation should be faxed to 
+1 800 497 8521 or emailed to 
sae@interceptpharma.com as soon as 
possible. 
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.  A 
SAE assessed with a possible, probable, or 
definite causal relationship to the 
investigational product and unexpected 
according to IB Reference Safety 
Information (RSI), is known as a suspected 
unexpected serious adverse reaction 
(SUSAR).  The Sponsor will notify the 
appropriate regulatory agencies as well as 
all participating Investigators of 
investigational new drug (IND) safety 
reports (SUSARs) that occur during the 
study within the time frames required by 
following information should be provided at the time of 
the initial report:   
• 
Subject 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 Sponsor will notify the appropriate regulatory 
agencies as well as all participating Investigators of 
investigational new drug (IND) 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 
+1 800 497 8521 or emailed to 
sae@interceptpharma.com as soon as possible.   
The Investigator is responsible for submitting 
information on IND 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 
IECs/IRBs must be retained in the appropriate study 
file(s).  As instructed by the Sponsor, IND 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 12.1.5. 
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each regulatory agency.  The Investigator is 
responsible for submitting information on 
IND safety reports/SUSARs received from 
the Sponsor or Sponsor designee to her/his 
local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities 
must be retained in the appropriate study 
file(s). 
Potential Clinical Outcome Events 
(Appendix A) as well as Anticipated Events 
(Appendix B) will not undergo expeditious 
reporting to regulatory authorities 
Section 12.1.5, 
Suspected Liver-
related Clinical 
Outcome Events 
Clinical Outcome Events (Appendix A) as 
well as Anticipated Events (Appendix B) 
will not undergo expeditous reporting. 
12.1.5 Suspected Liver-Related Clinical Outcome 
Events 
Specified liver-related clinical outcome events may, by 
definition (see Section 12.1.1.2) qualify as SAEs.  The 
Sponsor must be notified of any SAEs within 24 hours 
of the site becoming aware of the event (see 
Section 12.1.4.2).  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. 
Given that the liver-related clinical outcome events 
could also meet the criteria of a SUSAR, please refer to 
Section 11.1.2.4. 
The Sponsor will consider the following list of clinical 
outcome events (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), hepatic encephalopathy (preferred 
Updated section to account 
for events related to hepatic 
impairment. 
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term: hepatic encephalopathy), spontaneous bacterial 
and peritonitis (preferred term: peritonitis bacterial). 
13.2.4, 
Cardiovascular 
Adjudication 
Committee 
13.2.3 
(…) 
In addition to potential clinical endpoint 
events, cardiovascular events will be 
adjudicated.  The adjudication of these 
events will be handled separately from the 
adjudication of events for assessment of the 
primary endpoint in this study and will be 
described separately. 
New Section: Cardiovascular Adjudication Committee 
In addition to potential clinical endpoint events, 
cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately 
from the adjudication of events for assessment of the 
primary endpoint in this study. Adjudicated 
cardiovascular events include core major adverse 
cardiovascular events (MACE) (cardiovascular death, 
nonfatal myocardial infarction, and nonfatal stroke) 
and expanded MACE (unstable angina requiring 
hospitalization, transient ischemic attack, peripheral 
or coronary revascularization procedures, 
hospitalization for congestive heart failure).  Other 
events potentially related to adverse cardiovascular 
outcomes may be included in the Cardiovascular 
Adjudication Committee (CAC) Charter for 
adjudication.  The adjudication of these events will be 
handled separately from the adjudication of events for 
assessment of the primary endpoint in this study (see 
Section 13.4). 
Committee added to assess 
cardiovascular events in 
subjects during the study. 
13.4, Adjudication 
Committee 
All potential endpoint events will be 
reviewed by an adjudication committee 
before inclusion in the any analysis.  The 
adjudication of potential clinical endpoint 
events will include, but is not limited to:  
available hospital reports, histology, 
discharge summaries, and death certificates.  
The assessment of events will be conducted 
in compliance with the protocol, study-
specific procedures, manuals, Good 
Clinical Practice (GCP), and all other 
applicable regulatory requirements, 
including the archiving of essential 
documents.  A separate adjudication 
committee charter will document the entire 
data flow and process from committee 
membership, the reporting of events by the 
All suspected liver-related clinical outcomes, 
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 
Committees added to assess 
liver impairment in subjects 
during the study. 
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study site, reporting of the final assessment, 
supply of source documentation to the 
committee, the review of the events by the 
committee, and the working procedures of 
the committee.  The adjudication committee 
members will be independent hepatologists 
not involved in the study as investigators, 
DSMC members, or consultants.  All 
adjudication committee members will 
remain blinded to treatment group 
throughout the study. 
In addition to potential clinical endpoint 
events, cardiovascular events will also be 
adjudicated.  The adjudication of these 
events will be handled separately from the 
adjudication of events for assessment of the 
primary endpoint in this study and will be 
described separately. 
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 subject treatment or site-
specific information.  The assessment of events will be 
conducted in compliance with study-specific 
procedures, manuals, good clinical practice (GCP), 
and all other applicable regulatory requirements, 
including the archiving of essential documents. 
Appendix A, 
Modified Dosing 
Regimen for 
Subjects with 
Child-Pugh B/C 
Hepatic 
Impairment 
(Insertion) 
New: APPENDIX A. MODIFIED DOSING 
REGIMEN FOR SUBJECTS WITH CHILD-PUGH 
B/C HEPATIC IMPAIRMENT 
Added section to describe 
changes in dosing and 
titration for subjects 
assessed as cirrhotic 
Child-Pugh B or Child-Pugh 
C. 
Appendix B, LIST 
OF STUDY 747-
Was Appendix A 
Now Appendix B  
The hepatic dosing appendix 
became Appendix B  
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302 OUTCOME 
EVENTS 
Appendix C 
LIST OF STUDY 747-302 ANTICIPATED 
EVENTS 
Deleted 
Replaced by Appendix B, 
more comprehensive 
description of the outcome 
events. 
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APPENDIX G. SUMMARY OF CHANGES:  PROTOCOL VERSION 3.1 
(DATED 23 DECEMBER 2016) 
Rationale and Summary of Changes 
Major revisions to Protocol 747-302 include the expansion of the spectrum of stages of PBC 
disease, the addition of progression to cirrhosis as a secondary endpoint, and the addition of two 
interim analyses.   Additional revisions include an increase in subject number and the number of 
required clinical outcome events, a change in the study phase, an update to the nomenclature for 
PBC, and various clarifications within the protocol.   
The following table includes revisions that were made to Protocol Version 3.1 with an associated 
reason or justification for the change.  Rationales (Justifications for Change) that impact multiple 
sections are provided below and referenced in the table with the appropriate rationale number.  
1. The phase of the study has been changed from ‘3b’ to ‘4’ to reflect that this is a post-
marketing study. 
2. The term ‘primary biliary cirrhosis’ has been changed to ‘primary biliary cholangitis’ 
throughout the document to reflect recent changes in nomenclature for PBC. 
3. The increase in number of required events from 121 to 127 is due to the addition of two 
interim analyses (IA), which will allow an independent DMC to recommend 
continuation, modification, or cessation (for efficacy or futility) of the study.  One IA will 
occur at 50% information (after 64 events occur) and one at 75% information (after 
96 events occur).  Inclusion of patients with earlier stage disease will also increase the 
time to event requiring more events in order to keep follow-up to approximately 6 years.   
4. The first year study enrollment rate was lower than projected due to slower-than-
anticipated activation of sites and required a re-estimation of the accrual duration.   Using 
observed accrual rates, the accrual duration was extended by two years.  The follow-up 
period was maintained at 6 years, thereby leading to a total trial duration of 10 years. 
5. ‘Encephalopathy’ has been modified to ‘Hepatic Encephalopathy’ to clarify that the 
relevant clinical outcome enApdpoint should be related to hepatic disease. 
6. Histological confirmation (biopsy) has been added as an acceptable method of 
confirming a diagnosis of Hepatocellular Carcinoma. 
7. Broadening the Spectrum of Disease:  Lowering the minimum allowable baseline ALP 
to 3x ULN and raising the maximum allowable baseline total bilirubin to 5x ULN will 
increase the number of subjects enrolled with early and advanced disease facilitating the 
collection of safety and efficacy data in a population that covers the spectrum of PBC 
disease and overlaps with the subject population in the phase 3 protocol 747-301. 
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8. The titration regimen has been updated to reflect assessment of both tolerability and 
biochemical response prior to up-titration per the USPI and SmPC.   
9. The increase in enrollment from 350 to 428 is due in part to the increased number of 
events, and in part due to the change in the estimated Placebo baseline hazard rate which 
resulted from changing the lower limit of ALP from 5× ULN to 3× ULN in the 
enrollment criteria #2. 
10. Progression to Cirrhosis has been added as a secondary endpoint:  Due to the chronic 
nature of PBC, outcomes require a very long time to accrue to evaluate the impact of 
potential therapies.  Despite the proven prognostic utility of ALP and bilirubin, there is a 
remaining need to evaluate noninvasive assessments of disease progression that can be 
linked to histological progression of the disease.  Therefore, it is important to evaluate 
potential non-invasive markers of fibrosis/cirrhosis and their relationship to clinical 
outcomes as part of 302. 
 
The text deleted from Protocol Version 3 is crossed out while revised text in Version 3.1 is 
indicated in bold font in the table below.  Minor/editorial changes and non-substantial 
changes are not listed individually in the summary table below.  
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Section 
Original Text (Amendment 3, 07 September 
2016) 
Revised Text (Version 3.1, 23 December 2016) 
Justification for Change 
Title Page 
Synopsis, Title of 
Study 
A Phase 3b, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study Evaluating 
the Effect of Obeticholic Acid on Clinical 
Outcomes in Subjects with Primary Biliary 
Cirrhosis 
A Phase 4, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on 
Clinical Outcomes in Subjects with Primary 
Biliary Cholangitis 
 
Rationale 1 and 2  
Study Personnel 
Contact 
Information 
Or if Not Available: 
Contact: 
 MD, PhD, 
Executive Director, Clinical 
Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
 
 
Email: 
 
 (Pacific 
time zone) 
 
 
Or if Not Available: 
Contact: 
 MD, PhD 
Medical Director, Clinical 
Research, 
Intercept Pharmaceuticals, 
Inc. 
Telephone: 
Mobile: 
 
Email: 
 
 (Pacific 
time zone) 
 
Back-up medical monitor 
responsibilities were 
transferred to 
 
Synopsis, Studied 
Period (years) 
 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 and 4   
 
Synopsis, Phase of 
Development  
3b 
4 
Rationale 1 
Synopsis, 
Objectives, 
Primary, 
• 
Encephalopathy (as defined by a West Haven 
score of ≥2) 
• 
Hepatic encephalopathy (as defined by a 
West Haven score of ≥2) 
Rationale 5   
 
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PPD
PPD
PPD
PPD
PPD
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Statistical 
Methods – 
Efficacy Analyses 
Section 6.1 
Primary Objective 
Section 11.1.1 
Primary 
Assessments 
 
Section 13.1.3 
Primary Efficacy 
Analysis 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities unless 
confirmed by biopsy 
 
Rationale 6 
Synopsis, 
Objectives, 
Secondary  
Section 6.2 
Secondary 
Objectives 
 
Insertion 
 
To assess the pharmacokinetics of OCA and its 
conjugates in a subset of subjects 
To assess the effect of OCA compared to 
placebo on progression to cirrhosis 
To characterize the pharmacokinetics of OCA 
and its conjugates in a subset of subjects 
Rationale 6 
 
 
 
Synopsis, 
Methodology: 
Schematic 
Diagram 
 
Section 7.1.1 
Study Design 
Diagram, Figure 1 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.   
 
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability of the product. 
 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability and biochemical response.   
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability and biochemical response of the 
product. 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
Rationale 7 
 
 
 
 
Rationale 8 
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of 5-mg OCA or matching placebo once 
daily, based on tolerability. Subjects 
classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 
10-mg OCA or matching placebo twice 
weekly, based on tolerability. 
 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the titration of 
dose and/or frequency is dependent on subject tolerability, 
and/or changes in cirrhosis status or Child-Pugh Score at any 
time during the study.  
 
of 5-mg OCA or matching placebo once 
daily, based on tolerability and biochemical 
response. Subjects classified as Child-Pugh 
Class C should titrate to a maximum dose 
and frequency of 10-mg OCA or matching 
placebo twice weekly, based on tolerability 
and biochemical response. 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the titration 
of dose and/or frequency is dependent on subject tolerability, 
biochemical response, and/or changes in cirrhosis status or 
Child-Pugh Score at any time during the study. 
Synopsis, Number 
of Subjects 
(planned)  
Approximately 350 subjects 
Approximately 428 subjects 
Rationale 9 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
2.  A mean total bilirubin >ULN and ≤3x ULN 
and/or a mean ALP >5x ULN 
2.  A mean total bilirubin >ULN and ≤5x ULN 
and/or a mean ALP >3x ULN 
Rationale 7 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom 
(male or female) or (b) diaphragm, with 
spermicide; or  
• 
Intrauterine device (IUD); or  
5.  Contraception:  Female subjects of 
childbearing potential must use ≥1 effective 
method of contraception during the study and 
until 30 days following the last dose of 
investigational product.  Effective methods 
of contraception are considered to be those 
listed below:   
• 
Barrier method, ie, (a) condom (male 
or female) or (b) diaphragm, with 
spermicide 
• 
Intrauterine device (IUD)  
Standardizing language across 
protocols; removing double-
barrier terminology 
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• 
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 subject   
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection) 
• 
Abstinence, if in line with the preferred 
and usual lifestyle of the subject   
Synopsis, 
Exclusion Criteria 
Section 8.3 
Subject Exclusion 
Criteria 
 
3.  Mean total bilirubin >3x ULN 
Mean total bilirubin >5x ULN 
Rationale 7 
Synopsis, Criteria 
for Evaluation 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Encephalopathy (as 
defined by a West 
Haven score of ≥2) 
 
• 
Hepatocellular 
carcinoma 
confirmed by 
2 complimentary 
imaging modalities 
 
Secondary Objectives 
 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Hepatic 
encephalopathy (as 
defined by a West 
Haven score of ≥2) 
• 
Hepatocellular 
carcinoma confirmed 
by 2 complimentary 
imaging modalities 
already confirmed by 
biopsy 
Secondary Objectives 
 
Progression to 
cirrhosis 
Clinical, laboratory, 
or radiological 
evidence of cirrhosis 
and/or liver stiffness 
(i.e., Fibroscan® TE) 
confirmed by biopsy 
unless not medically 
indicated 
Rationale 5 
 
 
 
 
 
 
 
 
 
 
Rationale 10 
Synopsis, 
Statistical 
Methods 
Analysis 
Populations 
The following subject populations will be 
evaluated and used for presentation and analysis of 
the data:  Randomized, Intent-to-Treat (ITT), 
Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical 
The following subject populations will be 
evaluated and used for presentation and analysis 
of the data:  Intent-to-Treat (ITT), Safety, PK, 
Overall Historical Control, UKPBC Historical 
Control, and the Global PBS Historical Control.  
Randomized population 
includes patients on OCA who 
withdrew prior to receiving 
drug and this is already 
collected with the safety 
population. 
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Control.  Descriptions of subject populations are 
provided in Section 13.1.1. 
Descriptions of subject populations are provided 
in Section 13.1.1. 
 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Analysis 
The primary efficacy analysis will compare 
randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the 
ITT population.   
The primary efficacy analysis will compare OCA 
to placebo with respect to the primary efficacy 
endpoint using the ITT population.   
 
Synopsis, 
Statistical 
Methods, Key 
Secondary 
Efficacy Analyses 
The key secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
in ITT population with respect to the key 
secondary efficacy endpoints.   
The key secondary efficacy analyses will 
compare OCA to placebo in the ITT population 
with respect to the key secondary efficacy 
endpoints.   
 
Synopsis, 
Statistical 
Methods, Other 
Efficacy Analyses 
 
Section 13.1.5 
Additional 
Secondary 
Efficacy Analyses 
Insertion 
Progression to cirrhosis will be assessed in the 
subset of subjects considered non-cirrhotic at 
baseline using available medical history, 
clinical, and laboratory assessments as well as 
baseline transient elastography (TE), where 
available. Specifically, subjects with no 
clinical, laboratory, or radiological evidence of 
cirrhosis at baseline and/or a TE liver stiffness 
of <16.9 kPa (Corpechot 2012) will be 
considered non cirrhotic.  Progression to 
cirrhosis will be assessed by the development 
of clinical, laboratory, or radiological evidence 
of cirrhosis and/or when liver stiffness 
increases to ≥16.9 kPa during the trial in 
which case histological progression to cirrhosis 
should be confirmed by biopsy unless not 
medically indicated. Using this definition for 
progression to cirrhosis, the percentage of 
non-cirrhotic subjects progressing to cirrhosis 
during the treatment period will be 
summarized by treatment group and 
compared using a Cochran–Mantel–Haenszel 
test stratified by the randomization 
stratification factor. 
Rationale 10 
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Analyses for the histological assessment 
conducted as part of the biopsy sub-study are 
defined in Appendix C. 
 
Synopsis, 
Statistical 
Methods, Safety 
Analyses 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will compare OCA and placebo using the Safety 
Population. 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will be summarized by treatment group for the 
Safety Population. 
 
Clarification of summary 
analyses 
Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
Rationale 3 
Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
 
Section 13.1.2. 
Determination of 
Sample Size 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, placebo 
survival estimate of 0.5 at 8 years 
with a hazard ratio of 0.60, and total 
study duration of 8 years, allowing 
for 2 years accrual and 6 years of 
follow up 
 
• 
Insertion 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, 
placebo survival estimate of 0.6 at 8 
years with a hazard ratio of 0.60, 
and total study duration of 10 years 
(from first subject enrolled), 
allowing for 4 years subject accrual 
and 6 years of follow up 
• 
Two interim analyses and one 
final analysis are planned 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
 
 
Rationale 4 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale 3 
 
 
 
 
 
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In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
 
Section 5.6 
Summary of 
Known Potential 
Risks with OCA 
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).  
Insertion 
An increase in liver enzymes and hepatic AEs, 
including jaundice, were observed in subjects 
with liver disease at OCA doses between 10 mg 
and 50 mg and in healthy subjects who were 
treated at doses ≥100 mg in Phase 1, multiple-
dose studies. 
Refer to the IB for additional information 
regarding the known potential risks with the 
investigational product. 
Language has been updated to 
reflect Sponsor standards 
Section 7.1 
Overall Study 
Design 
This is a Phase 3b, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤3× ULN or ALP 
>5× ULN.   
 
Approximately 350 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 2-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
Investigational product will be taken orally, once 
daily….based on tolerability (see Section 7.3). 
 
 
 
The study will continue until approximately 121 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
This is a Phase 4, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤5× ULN or ALP 
>3× ULN.   
 
Approximately 428 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 4-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
Subjects will be dosed according to their 
cirrhosis status and Child-Pugh Score….based 
on tolerability and biochemical response (see 
Section 7.3)   
 
The study will continue until approximately 127 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
Rationale 1 
 
 
 
 
 
Rationale 9 
 
 
 
 
 
Clarification  
Rationale 7 
 
 
 
Rationale 3 
Section 7.1.2 
Schedule of Study 
Insertions 
 
 
Physical exams have been added at: 
• 
Month 1 
• 
1-Month Post Titration 
Physical Exams have been 
added one month after each 
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Procedures, Table 
1  
 
 
 
 
 
j Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device 
is available.  Similarly, DEXA will be conducted at 
selected study sites where the DEXA device is 
available.    
 
 
Insertion (subsequent footnotes are renumbered 
accordingly) 
 
 
 
 
 
 
 
l Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be obtained to 
confirm if a study endpoint has been met. 
 
 
 
 
o … The initial dose titration of investigational product 
may occur at the Month 3 visit, or any study visit 
thereafter for subjects on all dosing regimens, based 
on tolerability. … 
 
u  A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of these 
samples.  Genetics samples will be collected at Day 0 
and every other year beginning at Month 12. 
• 
Month 6 
Fibroscan® TE has been added at Month 6 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
 
j Transient elastography (TE) will be conducted at 6-
month intervals at all study sites where the 
Fibroscan® TE device is available.   
 
 
 
 
k DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available.  Please refer to Section 9.7.7 for 
additional information related to the allowed 
windows at Day 0 for this procedure. 
 
 
 
 
m Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: unless HCC has already confirmed 
by biopsy, a second confirmatory image (eg, MRI) 
should be obtained to confirm if a study endpoint 
has been met   
 
 
 
p … The initial dose titration of investigational product 
may occur at the Month 3 visit, or any study visit 
thereafter for subjects on all dosing regimens, based 
on tolerability and biochemical response. … 
 
v A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of these 
samples.  Genetics samples will be collected at Day 
0 and every other year beginning at Month 12.  If a 
baseline (e.g. Day 0) genetic sample is not 
obtained, subsequent genetic samples are not 
required to be collected during the course of the 
study. 
 
dose adjustment for added 
safety monitoring. 
 
 
 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments at Day 0 
and Month 12) 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
 
 
Rationale 8 
 
 
 
 
Clarification 
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Section 7.1.2 
Schedule of Study 
Procedures, Table 
2 
Insertions 
 
 
 
 
 
i Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device 
is available.  Similarly, DEXA will be conducted at 
selected study sites where the DEXA device is 
available.  Not required if done within 6 months of 
visit. 
   Insertion (subsequent footnotes are renumbered 
accordingly) 
  
 
j   Endoscopy will be conducted at selected study sites 
where the device is available to assess for the 
presence of oesophageal varix/varices. 
 
k  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be obtained to 
confirm if a study endpoint has been met. 
Fibroscan® TE has been added at Month 6 
continued follow up 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
continued follow up 
 
i Transient elastography (TE) will be conducted at 6-
month intervals at all study sites where the 
Fibroscan® TE device is available. Not required if 
done within 3 months of visit 
 
 
j  DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available.  Not required if done within 6 months 
of visit. 
k   Endoscopy will be conducted at all study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices. 
 
l  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: unless HCC has already been 
confirmed by biopsy, a second confirmatory image 
(eg, MRI) should be obtained to confirm if a study 
endpoint has been met. 
 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
 
 
 
 
 
 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments) 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
Section 7.1.3 
Study Duration 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 
Section 7.2 
Number of 
Subjects 
It is expected that approximately 350 subjects will 
be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
It is expected that approximately 428 subjects 
will be randomized in the study.   
Rationale 9 
 
 
Section 7.3 
Planned Dosing 
Regimen 
Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at 
Subjects should titrate to a maximum dose of 10 
mg OCA once daily (or matching placebo) at the 
Rationale 8 
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the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the 
product.   
 
 
 
Table 3:  Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
Footnotes were re-ordered 
b   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is dependent 
on subject tolerability and/or changes in cirrhosis 
status or Child-Pugh score at any time during the 
study 
Month 3 visit or at any study visit following the 
Month 3 visit based on tolerability of the product 
and assessment of biochemical response.  Up-
titration should be considered if ALP and/or 
total bilirubin >ULN.   
 
Table 3:  Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
 
c   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is 
dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or 
Child-Pugh score at any time during the study 
Section 7.4 Dose 
Titration Criteria 
Insertion 
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) as 
well as biochemical response (as assessed by 
reductions in ALP and/or total bilirubin).  In 
general, down-titration will be done in 
response to tolerability concerns and can occur 
at any time while on-study.  Up-titration will 
be done per protocol when subjects have no 
tolerability concerns and have not achieved an 
adequate reduction in ALP and/or total 
bilirubin to within normal limits, or 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 for each dosing regimen as defined 
in Section 7.3. 
 
Added language to clarify 
titrations (up or down) 
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Section 8.4.1.1 
Severe Drug-
Induced Liver 
Injury 
Insertion 
If a subject develops signs and symptoms of a 
severe drug-induced liver injury, regardless of 
causality, investigational product should be 
interrupted until the event has resolved or 
returned to baseline, but the subject should 
continue with the study visit schedule.  
Subjects who develop significant drug-induced 
liver injury which is considered 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, evidence of 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. 
Severe drug induced-liver injury that is not 
considered related to investigational product 
must be discussed with the Sponsor before 
investigational product is reinitiated.  Follow-
up procedures for subjects resuming 
treatment, including laboratory evaluations 
and physical examinations, must be performed 
after a maximum of 2 weeks of re-treatment 
and may be conducted at a local clinic if the 
subject is unable to return to the site.  Results 
must be reported immediately to the site so the 
Investigator can determine if the subject is to 
be allowed to continue treatment.  Subjects 
should be encouraged to continue study visits 
despite stopping investigational product for 
continued study data collection but may 
withdraw consent at any time. 
Added guidelines for subjects 
who develop severe Drug-
Induced Liver Injury  
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All suspected drug-related hepatic injury 
events will be adjudicated by the Hepatic 
Safety Committee (see Section 13.4). 
Section 8.4.1.2 
Liver 
Transplantation 
Moved from Section 8.4.2 Other Reasons for 
Discontinuation of Study or Investigational 
Product 
8.4.1.2 Liver Transplantation 
Subjects must discontinue investigational 
product after undergoing liver transplantation 
surgery.  Subjects should be encouraged to 
continue study visits, despite stopping 
investigational product, for continued study 
data collection. 
The relocation of this 
statement from within Section 
8.4.2 to 8.4.1.2 clarifies 
directions to discontinue 
subjects who undergo a liver 
transplant from investigational 
product but not study visits 
Section 8.4.2 
Reasons for 
Mandatory 
Interruption of 
Investigational 
Product 
Insertion/Reorganization 
8.4.2 Reasons for Mandatory Interruption of 
Investigational Product 
Prior to re-starting investigational product 
after a prolonged interruption, the subject 
must be re-consented and new baseline visit 
procedures must be performed if the interval 
from the last visit was more than 3 months (+2 
weeks) during the first 18 months of the study 
or more than 6 months prior (+2 weeks) 
during the remainder of the study.   
 
This clarifies what should be 
done when a subject 
experiences a prolonged 
interruption in investigational 
product such as in the event of 
pregnancy  
 
Section 8.4.2.1 
Pregnancy 
Modification of 8.4.1 Reasons for Mandatory 
Discontinuation of Investigational Product 
If a female subject becomes pregnant, she must 
discontinue taking investigational product, but 
should continue with the study visit schedule.  The 
subject must be followed as considered 
appropriate by the Investigator and the medical 
monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an 
AE.  The subject may reinstate investigational 
product after delivery and cessation of 
breastfeeding (if applicable) at the discretion of 
the Investigator.  Subjects whose pregnancy is 
terminated early (planned or unplanned) may be 
8.4.2.1 Pregnancy 
If a female subject becomes pregnant, she must 
interrupt treatment with investigational product 
immediately, but should continue with the study 
visit schedule.  As described in Section 12.1.9 
pregnancy is not considered an AE for reporting 
purposes.  The subject may re-start 
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 12.1.9).  New baseline 
procedures should include pregnancy testing. 
Language simplified and 
aligned with Sponsor 
standards 
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permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotropin (β-
hCG) test performed at the central laboratory. 
Section 8.4.3 
Other Reasons for 
Discontinuation of 
Study of 
Investigational 
Product 
8.4.2 Other Reasons for Discontinuation of Study 
of Investigational Product 
Subjects that discontinue investigational product 
are expected to continue in the study until the end 
of the study, and the study will only terminate at 
the time when the needed number of adjudicated 
events has accrued or at the discretion of the 
Sponsor.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  Subjects who 
choose to discontinue investigational product prior 
to termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.   
The following events are considered appropriate 
reasons for a subject to discontinue investigational 
product; however, these subjects are expected to 
continue in the study until study termination and 
the study will only terminate (or at the discretion 
of the Sponsor): 
− 
Consent may be modified to discontinue 
study visits or semi-annual telephone contact 
but allow continued access to medical 
records to assess for potential adjudicated 
hepatic and/or cardiovascular events. 
Subjects who undergo a liver transplant during the 
course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects should be 
encouraged to consent to the semiannual telephone 
contact and/or continued record review only to 
8.4.3 Other Reasons for Discontinuation of Study 
of Investigational Product 
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.  
With the exception of liver transplant, if a 
subject experiences a suspected or confirmed 
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.  Subjects who 
discontinue investigational product prior to 
termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.   
The following events are considered appropriate 
reasons for a subject to discontinue 
investigational product; however, these subjects 
are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
− 
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), liver-related clinical outcomes, 
and drug-related hepatic injury events. 
The Investigator is encouraged to contact the 
Sponsor prior to discontinuing a subject from 
treatment.   
Discontinuation of 
investigational product 
language updated to clarify the 
process that is to be followed 
after discontinuation and 
instruct subjects to continue 
regular visit schedule. 
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allow for secondary outcome events data to be 
collected. 
 
Section 9.7.3.1 
Determination for 
Dosing Regimen 
Insertion 
To determine which dosing regimen subjects 
should follow, the presence or absence of 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 is defined as a 
subject who has documented evidence or presence 
of one or more of the following cirrhosis 
indicators: 
9.7.3.1 Determination for Dosing Regimen 
To determine which dosing regimen subjects 
should follow, the presence or absence of 
cirrhosis should be assessed by the Investigator at 
Screening Visit 1.  Acceptable methods of 
confirming (via medical history) or assessing 
cirrhosis for purposes of determining dosing is 
defined as a subject who has documented 
evidence or presence of one or more of the 
following cirrhosis indicators: 
Header added to differentiate 
the assessment of cirrhosis for 
determining dosing regimen 
versus progression to cirrhosis 
Section 9.7.3.2 
Progression to 
Cirrhosis 
Insertion 
9.7.3.2 Progression to Cirrhosis  
When a subject identified as non-cirrhotic at 
baseline per the criteria listed in 
Section  9.7.3.1 exhibits any of those same 
criteria (excluding biopsy results consistent 
with PBC Stage 4), the subject should also be 
assessed by Fibroscan® TE where available 
and progression to cirrhosis confirmed by 
biopsy unless not medically indicated.  Sites 
participating in the paired biopsy sub-study 
(see Appendix C) must confirm progression to 
cirrhosis by biopsy.  All suspected cases of 
progression to cirrhosis should be submitted 
for adjudication regardless of the availability 
of transient elastography or biopsy results. 
Provides detail around the 
assessment of Progression to 
Cirrhosis as a secondary 
endpoint 
Section 9.7.6 
Screening 
Procedures 
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments 
will be used to determine eligibility (total 
bilirubin >ULN and ≤3× ULN and/or an ALP 
>5× ULN).   
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments 
will be used to determine eligibility (total 
bilirubin >ULN and ≤5× ULN and/or an ALP 
>3× ULN).   
Reflects new inclusion criteria 
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Section 9.7.7 Day 
0 Procedures 
• 
Perform transient elastography (TE; at 
selected study sites, where available) using 
the Fibroscan® TE device. If TE has been 
done within 6 months of Day 0 and a 
report/adequate data are available, a 
pretreatment TE at Day 0 is not required.   
• 
Perform transient elastography at all study 
sites with access to Fibroscan® TE device. 
If TE has been done within 3 months of Day 
0 and a report/adequate data are available, a 
pretreatment TE at Day 0 is not required.   
Clarifies use of TE and 
modifies the time during 
which an historic TE report 
remains valid 
Section 9.7.8 
Month 1 
Procedures 
 
Section 9.7.10 
Post-titration visit 
Procedures 
Insertion 
 
 
• 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit 
requirements: 
• 
Perform a physical examination.  
 
− 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit 
laboratory requirements: 
Physical examinations 1 
month after initiating dosing 
with investigational product 
will enhance safety 
monitoring 
Returning to the site for 
monthly laboratory 
assessments can present a 
significant burden on subjects, 
thus alternatives are provided 
for collecting lab samples; 
with the addition of the 
physical exam as well the 
requirement for these exams is 
provided in the context of the 
alternatives for laboratory 
specimen collection 
Section 9.7.11 
Month 6 
Procedures 
 
Section 9.7.16 
Month 6 
Continued 
Follow-Up 
Procedures 
Insertion 
• 
Perform a physical examination 
• 
Perform TE at all study sites with access 
to Fibroscan® TE device. 
• 
Perform an ultrasound for HCC 
surveillance (if equipment is unavailable, 
sites should make every attempt to use 
available community referral sites). 
TE assessment has been added 
as biannual assessment at all 
study sites with access to 
Fibroscan® TE device 
 
Hepatic ultrasound should be 
performed biannually per 
AASLD and EASL guidelines 
for subjects with PBC 
Section 11.1.2 
Secondary 
Assessments 
Insertion 
• 
Progression to cirrhosis as assessed by the 
presence of clinical, laboratory, or 
radiological evidence of cirrhosis and/or 
liver stiffness (Fibroscan® TE), confirmed 
by biopsy unless not medically indicated. 
Rationale  
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• 
Histological assessment of disease 
progression or improvement using paired 
biopsies in a subset of subjects (see 
Appendix C) 
Section 11.1.2.4 
Potential Clinical 
Outcome Events 
The events listed in Appendix A will be initially 
assessed by the Investigator to determine if they 
are Potential Clinical Outcome Events.   
The events listed in Section 12.1.5 will be 
initially assessed by the Investigator to determine 
if they are Potential Clinical Outcome Events.   
Appendix referencing clinical 
outcomes events was removed 
due to redundancy 
Section 12.1.4.2 
Reporting of 
Serious Adverse 
Events 
Insertion 
Redacted medical record source 
documentation will be requested for all SAEs 
and emergency room visits. 
 
 
Added sentence regarding 
redacted medical records to 
align with Sponsor safety 
standards 
Section 12.1.5 
Suspected Liver-
Related Clinical 
Outcome Events 
For liver-related clinical outcome events could 
also meet the criteria of a SUSAR, which would 
necessitate unblinding for expedited reporting, 
please refer to Section 11.1.2.4. 
 
 
 
 
 
 
The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy (preferred 
Given that the liver-related 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 liver-related 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 
“study event” on the Adverse Event CRF and 
will be submitted for adjudication to the 
Hepatic Outcomes Committee as described in 
Section 13.4. 
 
The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language 
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term: hepatic encephalopathy),  and spontaneous 
bacterial peritonitis (preferred term: peritonitis 
bacterial). 
 
(preferred term: hepatic encephalopathy),  
spontaneous bacterial peritonitis (preferred term: 
peritonitis bacterial), ascites (preferred term: 
ascites), and histological progression to 
cirrhosis (preferred term: hepatic cirrhosis). 
Section 12.1.7 
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 SAE 
must be reported to the Sponsor immediately (ie, 
within 24 hours). 
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 12.1.4.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language 
Section 12.1.8 
Follow-up of AEs 
and SAEs 
Insertion 
All subjects 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 CRF. 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. 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language 
Section 12.1.9 
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 investigational 
product and the Sponsor must be notified within 
24 hours of the Investigator’s learning of the 
pregnancy by completing the Pregnancy 
Notification Form and faxing or emailing to the 
Sponsor at +1 800 497 8521 or 
sae@interceptpharma.com.  
Safety will be monitored and assessed by 
AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and 
clinical laboratory assessments. The Sponsor may 
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 8.4.2.1) 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 
sae@interceptpharma.com or faxed to 
+1 800 497 8521.   The subject and neonate 
must be followed for outcome information 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language 
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also follow the health of an infant born subsequent 
to use of investigational product. 
The subject may reinstate investigational product 
after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  
Subjects whose pregnancy is terminated early 
(planned or unplanned) may be permitted to 
resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test 
(see Section 8.4.1). 
 
and/or as considered appropriate by the 
Investigator and Sponsor. 
The subject may re-start 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 subject must have a 
negative pregnancy test before restarting 
investigational product.  If a subject’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 12.1.4 must also be followed. 
 
Table 10 List of 
Laboratory 
Analytes 
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Other 
Insertion 
 
 
Deletion 
 
Other 
OCA-glucuronide 
 
Measurements of liver fibrosis 
are captured in a different 
section 
 
OCA-glucuronide was listed 
in the text but missing from 
the table 
Section 13.1.1 
Analysis 
Populations 
• 
The Randomized Population will include all 
randomized subjects 
Deletion 
 
Section 13.1.2.1 
Sample Size 
Monitoring 
9.1.2.1 Sample Size Re-Estimation Plan 
Therefore, starting approximately 2 years after the 
first subject is randomized, the aggregate event 
rate and sample size based on recruitment and 
retention will be evaluated in a blinded manner 
quarterly.  This evaluation will determine if any 
9.1.2.1 Sample Size Monitoring 
Therefore, the aggregate event rate and sample 
size based on recruitment and retention will be 
evaluated in a blinded manner quarterly.  This 
evaluation will determine if any increases in 
number of subjects are required in order to obtain 
 
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increases in number of subjects are required in 
order to obtain a total of 121 adjudicated events 
for the final analysis in the combined groups. 
If after 4 years of accruing subjects, despite 
increases in the number of subjects, it is 
determined that at least an additional 2 years (ie, 
total study duration of at least 10 years) are needed 
to randomize sufficient subjects to achieve a total 
of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label 
OCA.  Previously randomized subjects will 
continue to be treated in a blinded manner with 
either OCA or matching placebo.  If this 
modification is implemented, the alternative 
primary efficacy analysis is specified is Section 
13.1.9. 
Any revised sample size or changes to treatment 
allocation will be justified and documented in a 
protocol amendment and in the CSR. 
a total of 127 adjudicated events for the final 
analysis in the combined groups. 
Deletion 
Section 13.1.5.1 
Association of 
Biochemistry with 
Clinical Outcomes 
and Clinical 
Benefit 
Insertion 
13.1.5.1 Association of Biochemistry with 
Clinical Outcomes and Clinical Benefit  
The association between the effect of OCA on 
ALP and bilirubin and the clinical benefit of 
OCA will be evaluated by estimating the 
proportion of net treatment effect on the 
primary composite endpoint that is explained 
by each biochemical marker.  For each 
biochemical endpoint, this proportion will be 
estimated by applying the partial likelihood 
function to two Cox models that use the same 
failure time variable, as described in Lin 1997. 
This analysis will be based on the ITT 
population.  
Based on the association between biochemical 
changes and clinical outcomes described 
above, clinical benefit of OCA for key 
subpopulations of interest will be evaluated. 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
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This analysis will be further described in the 
SAP. 
13.1.8 Supportive 
Analysis 
Insertion 
Although the study is designed as a placebo-
controlled study, the DMC may recommend 
changes to study conduct based on the pre-
specified interim analyses (see Section 13.1.12), 
including the potential use of a revised 
primary efficacy analysis.  This analysis would 
compare all subjects in the OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant 
or death (all-cause) (see Section 13.1.2.1), using 
similar statistical methodology as specified 
above. 
Notably, the planned primary analysis would 
not be revised without prior agreement with 
regulatory authorities. 
As a placebo-controlled study, 
the alternative primary 
analysis section has been 
removed.   
Upon review of blinded data, 
the DMC may recommend 
changes to study conduct.  
However, such 
recommendations will not be 
implemented unless the 
Sponsor has received 
agreement from regulatory 
authorities. 
Section 13.1.9 
Alternative 
Primary Analysis 
13.1.9 Alternative Primary Analysis 
Based on sample size re-estimations, it may be 
determined that subjects will be enrolled to receive 
open-label OCA from that point forward, and the 
new primary efficacy analysis will become the 
comparison of all subjects in OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant or 
death (all-cause) (see Section 13.1.2.1).  Similar 
statistical methodology as specified above in 
Section 13.1.8 for supportive analyses will be 
utilized. 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare groups.  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 
Deletion 
 
As a placebo-controlled study, 
the alternative primary 
analysis section has been 
removed.   
 Upon review of blinded data, 
the DMC may recommend 
changes to study conduct.  
However, such 
recommendations will not be 
implemented unless the 
Sponsor has received 
agreement from regulatory 
authorities 
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estimated.  The number and percent of subjects 
censored and with events will be presented.  The 
hazard ratio and 95% CI will be determined based 
on a Cox regression model stratified by 
randomization strata to estimate the magnitude of 
the effect. 
 In addition, the outcome events specified above in 
Section 13.1.8 will also be evaluated to compare 
all subjects in OCA population to all control 
subjects (randomized placebo and historical 
controls). 
Sensitivity analyses will be conducted limiting to 
the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC 
Study Group.  To evaluate the robustness of the 
propensity score estimations, additional 
algorithms and factors may be considered. 
 
13.1.12 
Continuous 
Monitoring and 
Interim Analyses 
Insertion 
13.1.12 Continuous Monitoring and Interim 
Analyses  
Blinded safety reports including the accrual of 
events, drop outs and/or loss of patients to 
commercially available OCA will be reviewed 
by the DMC on a regular basis.  
Two planned interim analyses of the liver-
related outcomes will be conducted using the 
Lan-DeMets O’Brien-Fleming boundaries 
(Reboussin 2000).  Both interim analyses will 
be pre-specified and will occur after accrual of 
50% and 75% of clinical outcome events, 
respectively.  
The DMC will review the available efficacy 
data in conjunction with detailed safety data 
and other relevant information to recommend 
continuation, modification, or cessation (for 
efficacy or futility) of the study beyond each 
Explanation of the type of 
review that will be ongoing by 
the DMC during study 
conduct. 
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interim analysis.  Modification of the study 
would not take place without prior agreement 
with regulatory authorities. 
Section 19 List of 
References  
Insertion 
Lin DY, Fleming TR, De Gruttola V.  
Estimating the proportion of treatment effect 
explained by a surrogate marker.  Statistics in 
Medicine.  1997;16(13):1515-1527. 
 
Reboussin DM, DeMets, DL, Kim KM, et al.  
Computations for Group Sequential 
Boundaries Using the Lan-DeMets Spending 
Function Method.  Controlled Clin Trials.  
2000;21(3):190-207. 
Additional relevant references 
were added. 
Appendix B  
List of Study 747-
302 Outcome 
Events 
Several of the specified clinical endpoints will 
also by definition (see 12.1) 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 12.1.4).  
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 
Deleted 
Redundant; Information is 
contained within the protocol 
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Spontaneous bacterial peritonitis 
Ascites 
Hepatocellular carcinoma 
Appendix C 
Biopsy Sub-Study 
of Protocol 
747.302: A Phase 
4, Double-Blind, 
Randomized, 
Placebo-
Controlled, 
Multicenter Study 
Evaluating the 
Effect of 
Obeticholic Acid 
on Clinical 
Outcomes in 
subjects with 
Primary Biliary 
Cholangitis 
Insertion 
See Appendix C 
The purpose of this sub-study 
is to assess the effect of OCA 
versus placebo on the 
histological severity of disease 
(fibrosis/cirrhosis) in subjects 
with PBC.  In addition, this 
sub-study will demonstrate the 
relationship between 
histological changes and 
clinical, laboratory, and non-
invasive measures indicative 
of progression to cirrhosis in 
patients with PBC. 
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1. 
TITLE PAGE 
 
Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cholangitis 
 
THE COBALT STUDY 
Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) 
 
Version 4:  10 May 2017 
 
EudraCT Number:  2014-005012-42 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA  92121 
USA 
 
TEL: +1 858 250 6398 
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 747-302.  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 747-302 and in accordance 
with Good Clinical Practice (CPMP/ICH/135/95), 21CFR Part 312 and all applicable regulatory 
requirements. 
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: 
 (Pacific time zone) 
Telephone: 
  
Email: 
 
SAE Fax: 
+1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product: 
Obeticholic Acid (OCA) 
Name of Active Ingredient: 
Obeticholic acid (OCA); 6α-ethyl-chenodeoxycholic acid; (6-ECDCA); INT-747 
Title of Study:  
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Effect of 
Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary Cholangitis 
Investigators and/or Study Center(s):  
Approximately 170 investigational study sites, globally. 
Studied Period (Years):  
The study is event driven and total duration will be determined by the 
time required to accrue approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects are expected to have a 
minimum follow-up time of approximately 6 years. 
Phase of Development:   
Phase 4 
 
 
Objectives: 
Primary  
To assess the effect of OCA compared to placebo, in conjunction with established local standard of care, on 
clinical outcomes in subjects with primary biliary cholangitis (PBC) as measured by time to first occurrence of 
any of the following adjudicated events, derived as a composite event endpoint:  
• 
Death (all-cause) 
• 
Liver transplant 
• 
Model of end stage liver disease (MELD) score ≥15 
• 
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 (confirmed by diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of 
at least twice in a month) 
Secondary  
To assess the effect of OCA compared to placebo on time to first occurrence of each individual component of 
the primary endpoint as listed above.  
To assess the effect of OCA compared to placebo on time to occurrence of liver-related death. 
To assess the effect of OCA compared to placebo on progression to cirrhosis.  
To assess the effect of OCA compared to placebo on time to occurrence of hepatocellular carcinoma (HCC). 
To assess the effect of OCA compared to placebo on disease progression via the following: 
• 
Liver biochemistry  
• 
Markers of inflammation and fibrosis 
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To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To characterize the pharmacokinetics (PK) of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource utilization, and 
quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
Methodology: 
This Phase 4, double-blind, randomized, placebo-controlled, multicenter study will evaluate the effect of OCA 
on clinical outcomes in subjects with PBC.  Subjects will be screened twice during a 1- to 8-week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples (at least 2 weeks 
apart) to confirm pretreatment alkaline phosphatase (ALP) and total bilirubin values (refer to Section 9.7.6). 
Investigational product will be taken orally, once daily for the majority of subjects; dose and frequency will be 
modified for subjects with cirrhosis (including subjects progressing to cirrhosis during the study) and classified 
as Child-Pugh B or C.  The randomization will be stratified by ursodeoxycholic acid (UDCA) treatment (yes/no) 
and baseline bilirubin categories (> upper limit of normal [ULN]/ ≤ULN).  A minimum of 30% of subjects will 
have elevated bilirubin (>ULN) at Screening. 
Schematic Diagram Study 747-302:  
 
 
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for subjects on all dosing 
regimens, based on tolerability and biochemical response (up-titration should be considered when ALP and/or total bilirubin are >ULN).  
Subsequent dose titration(s) for subjects classified as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur 
no earlier than 6 weeks after the previous dose titration. 
 
Dosing frequency will be determined by the presence or absence of cirrhosis and, if cirrhosis is present, by 
Child-Pugh Score as described below: 
• 
Noncirrhotic subjects or subjects classified as Child-Pugh A at screening will receive 5-mg OCA 
or matching placebo once daily for 3 months.  Subjects should titrate to a maximum dose of 10-mg 
OCA once daily (or matching placebo) at the Month 3 visit or at any study visit following the 
Month 3 visit based on tolerability and biochemical response of the product.    
• 
For those subjects that up-titrate to 10 mg, dosing may be decreased to 5 mg at any time during the 
study as considered clinically appropriate (eg, based on tolerability). Subjects may be titrated back 
to a maximum dose of 10 mg once daily based on tolerability and clinical judgment of the 
Investigator.    
• 
Subjects who are cirrhotic and classified as Child-Pugh Class B or Child-Pugh Class C will initiate 
a modified treatment regimen with 5-mg OCA or matching placebo once weekly for at least 
3 months.  Subjects classified as Child-Pugh Class B should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once daily, based on tolerability and biochemical response.  
Subjects classified as Child-Pugh Class C should titrate to a maximum dose and frequency of 
10-mg OCA or matching placebo twice weekly, based on tolerability and biochemical response. 
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Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Planned Dosing Regimen 
Standard 
Modified 
Noncirrhotic/ 
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
5 mg once weekly 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weekly 
5 mg twice weekly 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weekly 
10 mg twice weekly 
Titration 3b 
(≥6 weeks after Titration 2) 
NA 
5 mg daily 
NA 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or Child-Pugh Score at any time during the study. 
Number of Subjects (Planned):  
Approximately 428 subjects are planned to be enrolled in the study.  In the event additional subjects are needed 
for the enrollment in the biopsy substudy (N = 45 subjects, as defined in Addendum 2), subjects who agree to 
participate in the substudy may be added to the target subject enrollment number currently planned.   
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver 
Diseases [AASLD] and the European Association for the Study of the Liver [EASL] practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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 
2. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN 
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past ≥3 months) or has been taking UDCA for at 
least 12 months with a stable dose for ≥3 months prior to Day 0 
5. Contraception:  Female subjects of childbearing potential must use ≥1 effective method of 
contraception during the study and until 30 days following the last dose of investigational product.  
Effective methods of contraception are considered to be those listed below: 
• 
Barrier method, ie, (a) condom (male or female) or (b) diaphragm, with spermicide 
• 
Intrauterine device (IUD) 
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection) 
• 
Abstinence, if in line with the preferred and usual lifestyle of the subject   
6. Must provide written informed consent and agree to comply with the study protocol 
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Exclusion Criteria 
1. History or presence of other concomitant liver diseases including: 
• 
Hepatitis C virus infection 
• 
Active hepatitis B infection; however, subjects 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 
• 
Nonalcoholic steatohepatitis 
• 
Gilbert's Syndrome 
2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including: 
• 
History of liver transplant, current placement on a liver transplant list, or current MELD score >12.  
Subjects who are placed on a transplant list despite a relatively early disease stage (for example per 
regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria 
• 
Cirrhosis with complications, including history (within the past 12 months) or presence of: 
− 
Variceal bleed 
− 
Uncontrolled ascites  
− 
Encephalopathy  
− 
Spontaneous bacterial peritonitis 
• 
Known or suspected HCC 
• 
Prior transjugular intrahepatic portosystemic shunt procedure 
• 
Hepatorenal syndrome (type I or II) or Screening (Visit 1 or 2) serum creatinine >2 mg/dL 
(178 μmol/L) 
3. Mean total bilirubin >5x ULN  
4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal 
resection or plan to undergo either of these procedures 
5. Other medical conditions that may diminish life expectancy, including known cancers (except 
carcinomas in situ or other stable, relatively benign conditions such as chronic lymphatic leukemia) 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed 
by a positive serum pregnancy test), or lactating 
7. Known history of human immunodeficiency virus infection 
8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 
3 months) 
9. Other clinically significant medical conditions that are not well controlled or for which medication 
needs are anticipated to change during the study 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 
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-month 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. History of known or suspected clinically significant hypersensitivity to OCA or any of its components 
14. UDCA naïve (unless contraindicated) 
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Investigational Product, Dosage and Mode of Administration:  
OCA (5 mg or 10 mg tablets) 
Reference Therapy, Dosage and Mode of Administration:  
Placebo (matching tablets) 
Duration of Treatment:  
It is expected that subjects will be followed up for a minimum of 6 years.  The study is event driven and total 
duration of treatment will be determined by the time to accrue 127 total primary endpoint events. 
Criteria for Evaluation: 
Primary Objectives 
Assessments 
Clinical outcomes 
• 
Death (all-cause) 
• 
Liver transplant 
• 
MELD score ≥15 
• 
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 (confirmed by 
diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic-resistant ascites requiring 
therapeutic paracentesis at a frequency of at least twice in a 
month) 
Secondary Objectives 
 
Individual components of the 
primary endpoint 
As listed above and including liver-related death 
Progression to cirrhosis 
Clinical, laboratory, or radiological evidence of cirrhosis and/or liver 
stiffness (ie, Fibroscan® transient elastography [TE]) confirmed by 
biopsy unless not medically indicated 
HCC 
Confirmed by 2 complimentary imaging modalities unless confirmed by 
biopsy 
Change in baseline liver 
biochemistry 
Liver biochemistry (see Table 11 for list of analytes to be tested)  
Inflammation and fibrosis 
IgM, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), 
fibroblast growth factor-19 (FGF-19), cytokeratin-18 (CK-18), enhanced 
liver fibrosis (ELF), and Fibroscan® TE 
Clinical outcomes compared to 
historical controls 
Similar endpoints as used for the primary objective where available 
including liver transplant and death 
PK 
OCA and its conjugates 
Health outcomes and economics 
research 
Including the following: 
Cost-effectiveness and resource utilization 
Quality of life (Fatigue Impact Score and EQ-5D-5L)  
Safety and tolerability 
Including the following: 
Treatment-emergent adverse events 
Clinical laboratory values 
 
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Statistical Methods: 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the data: Intent-to-
Treat (ITT), Per Protocol (PP), Safety, PK, Overall Historical Control, UK-PBC Historical Control, and the 
Global PBC Historical Control.  Descriptions of subject populations are provided in Section 13.1.1. 
Efficacy Analyses 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the time to first occurrence of one of the following:  
• 
Death (all-cause) 
• 
Liver transplant 
• 
Model of end stage liver disease (MELD) score ≥15 
• 
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 (confirmed by diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of 
at least twice in a month) 
All events will be adjudicated by an independent committee. 
Primary Efficacy Analysis 
The primary efficacy analysis will compare OCA to placebo with respect to the primary efficacy endpoint using 
the ITT population.  The 2 treatment groups will be compared 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 its 95% CI will be determined based 
on a Cox regression model stratified by randomization strata to estimate the magnitude of the effect.  The same 
analyses for primary efficacy endpoints will be performed for PP population as a sensitivity analysis.   
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints are as follows: 
• 
Time to first occurrence of MELD score ≥15 
• 
Time to liver transplant or death (all-cause) 
• 
Change from Baseline in total bilirubin at end of study 
• 
Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare OCA to placebo in the ITT population with respect to the key 
secondary efficacy endpoints.  Only adjudicated events will be included in time-to-event analyses.  The 
comparison (hypothesis testing) will be conducted in a sequential closed testing gate-keeping procedure (in the 
order in which the key secondary endpoints are stated above), provided that the primary efficacy endpoint 
comparison is statistically significant in favor of the OCA treatment group.  If the primary comparison is not 
statistically significant then comparison of the secondary endpoints will be considered as descriptive and 
exploratory.  The same analyses for key secondary efficacy endpoints will be performed for PP population as a 
sensitivity analysis. 
Additional Secondary Efficacy Analyses 
The following time-to-event secondary efficacy analyses will compare OCA versus placebo using the ITT 
population: 
• 
Time to each component of the primary efficacy endpoint (except MELD score ≥15 which is 
captured above) 
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• 
Time to development of varix/varices 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
• 
Time to liver-related death 
• 
Time to liver-related death or liver transplant 
• 
Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these secondary 
efficacy analyses.  Similar endpoints, where available, will be analyzed to compare OCA to historical controls. 
Progression to cirrhosis will be assessed in the subset of subjects considered noncirrhotic at Baseline using 
available medical history, clinical, and laboratory assessments as well as Baseline TE where available.  
Specifically, subjects with no clinical, laboratory, or radiological evidence of cirrhosis at Baseline and/or a TE 
liver stiffness of <16.9 kPa (Corpechot 2012) will be considered noncirrhotic.  Progression to cirrhosis will be 
assessed by the development of clinical, laboratory, or radiological evidence of cirrhosis and/or when liver 
stiffness increases to ≥16.9 kPa during the study in which case histological progression to cirrhosis should be 
confirmed by biopsy unless not medically indicated.  Using this definition for progression to cirrhosis, the 
percentage of noncirrhotic subjects progressing to cirrhosis during the treatment period will be summarized by 
treatment group and compared using a Cochran–Mantel–Haenszel test stratified by the randomization 
stratification factor. 
For those subjects enrolled in the biopsy substudy (defined in Addendum 2) progression to cirrhosis identified 
by the above criteria and improvement in fibrosis/cirrhosis will be confirmed by paired biopsy.  Analyses for the 
histological assessment conducted as part of the biopsy substudy are defined in Addendum 2.  
Further details on efficacy, health outcomes, and PK analyses are specified in Section 13. 
Safety Analyses 
Safety data, including AEs, vitals, electrocardiogram, and clinical laboratory results will be summarized by 
treatment group for the Safety Population. 
Sample Size Justification 
The target population is subjects who are at higher risk of liver-related clinical complications.  Eligible subjects 
will have a diagnosis of PBC with bilirubin levels >ULN and ≤5x ULN and/or ALP >3x ULN.  The following 
assumptions were used in sample size calculations:  
• 
Exponential survival curves, placebo survival estimate of 0.6 at 8 years with a hazard ratio of 0.60, 
and total study duration of 10 years (from first subject enrolled), allowing for 4 years of subject 
accrual and 6 years of follow-up 
• 
Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• 
The 2 groups will be compared using a 2-sided log rank test at the 5% level of significance. 
• 
Two interim analyses and one final analysis are planned.  The first interim analysis will be 
performed when 50% of the target events are accrued and the second interim will be performed 
when 75% of the target events are accrued. 
• 
A dropout rate of 10% is assumed.  
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 127 events (both 
groups combined) will provide 80% power to demonstrate a statistically significant difference between OCA 
and placebo on time to liver-related outcomes, including all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 428 subjects 
will be enrolled to attain 127 events. 
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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 .............................19 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Overview of Primary Biliary Cholangitis and Obeticholic Acid ................................22 
5.2. 
Mechanism of Action of Obeticholic Acid .................................................................22 
5.3. 
Nonclinical Experience with Obeticholic Acid ..........................................................23 
5.4. 
Clinical Experience with Obeticholic Acid ................................................................23 
5.5. 
Rationale for Study Design and Dose for Investigational Product .............................24 
5.5.1. 
Rationale for Study Design .........................................................................................24 
5.5.2. 
Rationale for Dose ......................................................................................................25 
5.5.2.1. 
Rationale for OCA Dose .............................................................................................25 
5.5.2.2. 
Rationale for Modified OCA Doses in Patients Classified with Child-Pugh B 
or Child-Pugh C Hepatic Impairment .........................................................................25 
5.5.2.3. 
Rationale for Control Groups .....................................................................................26 
5.6. 
Summary of Known Potential Risks with OCA .........................................................26 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................27 
6.1. 
Primary Objective .......................................................................................................27 
6.2. 
Secondary Objectives .................................................................................................27 
7. 
INVESTIGATIONAL PLAN .....................................................................................28 
7.1. 
Overall Study Design ..................................................................................................28 
7.1.1. 
Study Design Diagram ................................................................................................29 
7.1.2. 
Schedule of Study Procedures ....................................................................................30 
7.1.3. 
Study Duration ............................................................................................................36 
7.2. 
Number of Subjects ....................................................................................................36 
7.3. 
Planned Dosing Regimen ...........................................................................................36 
7.4. 
Dose Titration Criteria ................................................................................................37 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements .................................................39 
7.5. 
Criteria for Study Termination ...................................................................................39 
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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................40 
8.1. 
Subject Population ......................................................................................................40 
8.2. 
Subject Inclusion Criteria ...........................................................................................40 
8.3. 
Subject Exclusion Criteria ..........................................................................................41 
8.4. 
Dose Adjustment, Interruption, and Withdrawal from Investigational 
Product or Study .........................................................................................................42 
8.4.1. 
Reasons for Additional Monitoring or Mandatory Interruption of 
Investigational Product ...............................................................................................42 
8.4.1.1. 
Reasons for Additional Monitoring Related to Liver Chemistries .............................42 
8.4.1.2. 
Reasons for Investigational Product Interruption Related to Elevated Liver 
Chemistries .................................................................................................................43 
8.4.1.3. 
Pregnancy ...................................................................................................................44 
8.4.2. 
Reasons for Mandatory Discontinuation of Investigational Product ..........................44 
8.4.2.1. 
Liver Transplantation ..................................................................................................44 
8.4.3. 
Other Reasons for Discontinuation of Study or Investigational Product ...................44 
8.4.4. 
Withdrawal of Consent ...............................................................................................45 
8.4.5. 
Lost to Follow-Up .......................................................................................................45 
8.4.6. 
Subject Discontinuation Notification .........................................................................45 
9. 
TREATMENT OF SUBJECTS ..................................................................................46 
9.1. 
Investigational Product Treatment Regimen ..............................................................46 
9.2. 
Concomitant Medications ...........................................................................................46 
9.2.1. 
Prohibited Medications ...............................................................................................47 
9.3. 
Treatment Compliance ................................................................................................47 
9.4. 
Randomization and Blinding ......................................................................................48 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures ...................................48 
9.5. 
Assignment of Site and Subject Numbers ..................................................................49 
9.5.1. 
Site Numbers ..............................................................................................................49 
9.5.2. 
Subject Numbers .........................................................................................................49 
9.6. 
Restrictions .................................................................................................................49 
9.7. 
Visit Procedures ..........................................................................................................49 
9.7.1. 
Visit Windows ............................................................................................................49 
9.7.2. 
Informed Consent Procedures .....................................................................................50 
9.7.3. 
Assessing Cirrhosis .....................................................................................................50 
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9.7.3.1. 
Determination for Dosing Regimen ............................................................................50 
9.7.3.2. 
Progression to Cirrhosis ..............................................................................................51 
9.7.4. 
Child-Pugh Score ........................................................................................................51 
9.7.5. 
Mayo Risk Score .........................................................................................................52 
9.7.6. 
Screening Procedures (1 to 8 Weeks prior to Day 0) .................................................52 
9.7.7. 
Day 0 Procedures (Randomization) ............................................................................54 
9.7.8. 
Month 1 Procedures ....................................................................................................56 
9.7.9. 
Month 3 Procedures ....................................................................................................57 
9.7.10. 
1-Month Post-Titration Visit Procedures ....................................................................58 
9.7.11. 
Month 6 Procedures ....................................................................................................59 
9.7.12. 
Month 9 Procedures ....................................................................................................60 
9.7.13. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment .................................................................................................................61 
9.7.14. 
Month 12 Procedures ..................................................................................................61 
9.7.15. 
Month 3 and Month 9 Continued Follow-Up Procedures (±2 weeks) .......................63 
9.7.16. 
Month 6 Continued Follow-Up Procedures (Semi-annually [±2 weeks]) ..................64 
9.7.17. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) .........................65 
9.7.18. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent ..................................66 
9.7.19. 
Unscheduled Safety Visit ...........................................................................................69 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............69 
10.1. 
Investigational Product ...............................................................................................69 
10.2. 
Investigational Product Packaging and Labeling .......................................................69 
10.3. 
Investigational Product Storage ..................................................................................70 
10.4. 
Investigational Product Preparation ............................................................................70 
10.5. 
Investigational Product Administration ......................................................................70 
10.6. 
Investigational Product Accountability and Disposal .................................................70 
11. 
ASSESSMENT OF EFFICACY ................................................................................70 
11.1. 
Assessment of Efficacy ...............................................................................................70 
11.1.1. 
Primary Assessments ..................................................................................................70 
11.1.2. 
Secondary Assessments ..............................................................................................71 
11.1.2.1. 
Noninvasive Assessments of Liver Fibrosis ...............................................................72 
11.1.2.2. 
Other Secondary Assessments ....................................................................................72 
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11.1.2.3. 
Other Exploratory Evaluations ...................................................................................72 
11.1.2.4. 
Potential Clinical Outcome Events .............................................................................73 
12. 
ASSESSMENT OF SAFETY .....................................................................................73 
12.1. 
Adverse Events and Serious Adverse Events .............................................................73 
12.1.1. 
Definitions of Adverse Events ....................................................................................73 
12.1.1.1. 
Adverse Event .............................................................................................................73 
12.1.1.2. 
Serious Adverse Event ................................................................................................74 
12.1.1.3. 
Treatment-Emergent Adverse Event ..........................................................................74 
12.1.2. 
Relationship to Investigational Product ......................................................................74 
12.1.3. 
Relationship of Adverse Events to Liver Biopsy .......................................................75 
12.1.4. 
Recording Adverse Event Severity .............................................................................75 
12.1.5. 
Reporting of Adverse Events and Serious Adverse Events ........................................76 
12.1.5.1. 
Reporting of Adverse Events ......................................................................................76 
12.1.5.2. 
Reporting of Serious Adverse Events .........................................................................76 
12.1.6. 
Suspected Liver-Related Clinical Outcome Events ....................................................77 
12.1.7. 
Additional Investigator Responsibilities for SAEs .....................................................78 
12.1.8. 
Notification of Post-Treatment SAEs for Subjects Who Continue in the 
Study ...........................................................................................................................78 
12.1.9. 
Notification of Poststudy SAEs ..................................................................................78 
12.1.10. 
Follow-Up of AEs and SAEs ......................................................................................78 
12.1.11. 
Pregnancy and Follow-Up ..........................................................................................79 
12.2. 
Other Safety Parameters .............................................................................................79 
12.2.1. 
Medical History/Demographics ..................................................................................79 
12.2.2. 
Physical Examination .................................................................................................79 
12.2.3. 
Vital Signs ..................................................................................................................79 
12.2.4. 
Electrocardiogram .......................................................................................................80 
12.2.5. 
Dual Emission X-Ray Absorptiometry .......................................................................80 
12.2.6. 
Subject Questionnaires ...............................................................................................80 
12.2.7. 
Laboratory Assessments .............................................................................................80 
13. 
STATISTICAL METHODS .......................................................................................82 
13.1. 
Efficacy Analysis ........................................................................................................82 
13.1.1. 
Analysis Populations ..................................................................................................82 
13.1.1.1. 
Comparability of Historical Controls .........................................................................83 
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13.1.2. 
Determination of Sample Size ....................................................................................83 
13.1.2.1. 
Sample Size Monitoring .............................................................................................83 
13.1.3. 
Primary Efficacy Analysis ..........................................................................................84 
13.1.4. 
Key Secondary Efficacy Analyses ..............................................................................84 
13.1.5. 
Additional Secondary Efficacy Analyses ...................................................................85 
13.1.5.1. 
Association of Biochemistry with Clinical Outcomes and Clinical Benefit ..............86 
13.1.6. 
Exploratory Efficacy Analyses ...................................................................................86 
13.1.6.1. 
Responder Analyses ....................................................................................................86 
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints ................................................87 
13.1.8. 
Supportive Analysis ....................................................................................................87 
13.1.9. 
Handling of Dropouts or Missing Data ......................................................................89 
13.1.9.1. 
Time to Event Endpoints ............................................................................................89 
13.1.9.2. 
Quantitative Endpoints ...............................................................................................89 
13.1.9.3. 
Responder Endpoints ..................................................................................................90 
13.1.10. 
Multiple Comparisons/Multiplicity ............................................................................90 
13.1.11. 
Examination of Subgroups .........................................................................................91 
13.1.12. 
Continuous Monitoring and Interim Analyses ...........................................................91 
13.2. 
Safety Analysis ...........................................................................................................92 
13.2.1. 
Adverse Events ...........................................................................................................92 
13.2.2. 
Clinical Laboratory Evaluations .................................................................................92 
13.2.3. 
Additional Safety Analysis .........................................................................................92 
13.2.4. 
Cardiovascular Adjudication Committee ...................................................................92 
13.3. 
Data Monitoring Committee .......................................................................................92 
13.4. 
Adjudication Committees ...........................................................................................93 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................94 
14.1. 
Study Monitoring ........................................................................................................94 
14.2. 
Audits and Inspections ................................................................................................94 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................95 
16. 
ETHICS ......................................................................................................................95 
16.1. 
Ethics Review .............................................................................................................95 
16.2. 
Ethical Conduct of the Study ......................................................................................95 
16.3. 
Written Informed Consent ..........................................................................................96 
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16.4. 
Subject Confidentiality and Data Protection ..............................................................96 
17. 
INVESTIGATOR OBLIGATIONS ...........................................................................96 
17.1. 
AE Reporting ..............................................................................................................97 
17.2. 
Protocol Deviations ....................................................................................................97 
17.3. 
Regulatory Documentation .........................................................................................97 
17.4. 
Ethics Review .............................................................................................................97 
17.5. 
Archiving and Record Retention ................................................................................97 
18. 
PUBLICATION POLICY ..........................................................................................98 
19. 
LIST OF REFERENCES ..........................................................................................100 
APPENDIX A.  MODIFIED DOSING REGIMEN FOR SUBJECTS WITH CHILD-
PUGH B/C HEPATIC IMPAIRMENT ....................................................................102 
APPENDIX B.  ETHICAL CONDUCT ACCORDING TO THE DECLARATION OF 
HELSINKI FOR COUNTRIES PARTICIPATING OUTSIDE THE US 
(DECLARATION OF HELSINKI, FORTELEZA, BRAZIL, 2013) ......................105 
APPENDIX C.  REFERENCE LABORATORY VALUES FROM CENTRAL 
LABORATORIES ....................................................................................................110 
APPENDIX D.  SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 
(DATED 29 APR 2015) ...........................................................................................112 
APPENDIX E.  SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 
(DATED 12 NOV 2015) ..........................................................................................149 
APPENDIX F.  SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 TO 
VERSION 3 (DATED 07 SEP 2016) .......................................................................151 
APPENDIX G.  SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO 
PROTOCOL VERSION 3.1 (DATED 23 DEC 2016) .............................................181 
APPENDIX H.  SUMMARY OF CHANGES:  PROTOCOL VERSION 3.1 TO 
PROTOCOL VERSION 4 (DATED 10 MAY 2017) ..............................................208 
APPENDIX I.  SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO 
PROTOCOL VERSION 4 (DATED 10 MAY 2017) ..............................................236 
 
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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) .......................30 
Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) ............33 
Table 3: 
Planned Dosing Regimen by Cirrhosis and Child Pugh Score ...................................37 
Table 4: 
Determination of Dosing Regimen .............................................................................37 
Table 5: 
Changes in Dosing Regimen Due to Changes in Cirrhosis Status or 
Child-Pugh Score ........................................................................................................38 
Table 6: 
Child-Pugh Scoring System ........................................................................................52 
Table 7: 
Early Discontinuation Scenarios .................................................................................67 
Table 8: 
Relationship of Adverse Events to Investigational Product .......................................75 
Table 9: 
Relationship of Adverse Events to Liver Biopsy .......................................................75 
Table 10:  Severity of Adverse Events ........................................................................................76 
Table 11:  List of Laboratory Analytes to be Tested ...................................................................81 
Table 12:  Planned Dosing Regimen by Cirrhosis and Child-Pugh Score ................................102 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram Study 747-302 ............................................................................29 
Figure 2: 
Dosing by Cirrhosis Status and Child-Pugh Score ...................................................102 
  
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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 
APRI 
aspartate aminotransferase to platelet ratio index 
AST 
aspartate aminotransferase 
β-hCG 
beta human chorionic gonadotropin 
BAS 
bile acid sequestrants 
CAC 
Cardiovascular Adjudication Committee 
CDCA 
chenodeoxycholic acid 
CI 
confidence interval 
CK-18 
cytokeratin-18 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
C-reactive protein 
DEXA 
dual-emission X-ray absorptiometry 
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 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
FIS 
Fatigue Impact Scale 
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 
Investigator’s 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 
LDL 
low-density lipoprotein 
LTSE 
long-term safety extension 
MACE 
major adverse cardiovascular events 
MELD 
model of end stage liver disease  
MRS 
Mayo Risk Score 
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cholangitis (also known as primary biliary 
cirrhosis) 
PIS 
patient information sheet 
PK 
pharmacokinetic 
PP 
per protocol 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
SUSAR 
suspected unexpected serious adverse reaction 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
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Abbreviation or Specialist Term 
Explanation 
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 Primary Biliary Cholangitis and Obeticholic Acid 
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 United States (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.   
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), 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 (Pellicciari 2002).  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. 
Mechanism of Action of Obeticholic Acid 
OCA is a 6α-ethyl derivative of the naturally occurring primary human bile acid CDCA, which is 
the endogenous ligand for FXR.  FXR is a ligand-dependent transcription factor that is part of 
the nuclear receptor superfamily.  FXR regulates a wide variety of target genes involved in the 
control of bile acid, lipid, and glucose homeostasis and in the regulation of immune responses. 
OCA’s potent FXR agonist effects are believed to account for the predominant efficacy of the 
investigational product.  Some of the pharmacological properties of OCA and other FXR 
agonists that have been elucidated in animal models of chronic liver disease relevant to the 
treatment of PBC include the following: 
• Improvement in hepatic choleresis with reduced inflammation and necrosis  
• Prevention and reversal of hepatic fibrosis 
The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and 
anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury 
and improved liver function in a cholestatic liver disease such as PBC. 
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5.3. 
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. 
5.4. 
Clinical Experience with Obeticholic Acid 
As of 31 Jan 2017, approximately 2186 subjects1 have received at least 1 dose of OCA.  Of 
these, 844 were healthy volunteers, 525 subjects had PBC, 686 subjects had NASH, 41 subjects 
had diabetes mellitus/nonalcoholic fatty liver disease, 33 subjects had alcoholic cirrhosis/portal 
hypertension, and 52 subjects had primary sclerosing cholangitis, and 5 subjects 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.  
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. 
To date, the efficacy and safety of OCA in PBC has been evaluated in 2 placebo-controlled, 
double-blind, Phase 2 studies (747-201 and 747-202), and 1 placebo-controlled, double-blind 
Phase 3 study (747-301).  Following the double-blind phase, subjects in all 3 studies were 
eligible to continue with treatment in a long-term safety extension (LTSE) phase for up to 
5 years in Study 747-201, up to 1 year in Study 747-202, and up to 5 years in Study 747-301. 
Study 747-201 (59 subjects) 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 subjects) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in subjects 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. 
                                                 
1 Includes estimated numbers from ongoing blinded studies. 
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Study 747-301 (216 subjects) was a Phase 3, double-blind, placebo-controlled, parallel group 
study followed by an LTSE using OCA in subjects with PBC.  The primary endpoint for 
Study 747-301 was a composite endpoint based on the proportion of subjects reaching specific 
criteria for ALP and bilirubin (ALP <1.67× 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 <1.67× 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 10 mg OCA 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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is complete. 
5.5. 
Rationale for Study Design and Dose for Investigational Product 
5.5.1. 
Rationale for Study Design 
OCA is a modified bile acid and FXR agonist that is derived from the primary human bile acid 
chenodeoxycholic acid.  The key mechanisms of action of OCA, including its choleretic, anti-
inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in 
attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. 
PBC is characterized by biochemical increases in ALP and GGT enzymes with or without 
elevations of hepatocellular transaminases and bilirubin (Lindor 2009).  Both the American 
Association for the Study of Liver Diseases (AASLD) (Lindor 2009) and the European 
Association for the Study of the Liver (EASL) (EASL 2009) guidelines base the biochemical 
component of PBC diagnosis on elevations of ALP.  In addition, a growing literature supports 
the use of biochemical endpoints, specifically serum ALP alone or with other parameters such as 
bilirubin, to manage subjects, test the efficacy of novel therapies in clinical studies, and gauge 
the risk of long-term adverse clinical outcomes in subjects with PBC (Beuers 2011, 
Momah 2012).  Data from the Global PBC Study Group (Lammers 2013), which has built a 
database tracking biochemical status and clinical outcomes in several thousand PBC subjects, 
provides evidence for the use of the composite biochemical endpoint of ALP and bilirubin as an 
acceptable surrogate endpoint. 
Study 747-301, a Phase 3 double-blind study, evaluated the safety and efficacy of OCA at doses 
of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability) and 10 mg and used 
a composite biochemical endpoint of ALP and bilirubin as a surrogate endpoint.  In this study, 
both treatment groups exhibited clinically meaningful improvements in liver biochemistry and 
were safe and generally well-tolerated.  As a result, starting subjects on 5 mg OCA and titrating 
to 10 mg based on tolerability and clinical response appears to be an appropriate dosing strategy 
in subjects with PBC.  
Study 747-302 is a clinical outcomes study, supportive of Phase 3 Study 747-301 which was 
based on a surrogate biochemical endpoint, designed to confirm the clinical benefit of OCA 
treatment in patients with PBC.  A retrospective observational database (Global PBC Study 
Group [Lammers 2013]) of patients with PBC allowed for a rigorous patient-level meta-analysis 
and provided an opportunity for a robust assessment of ALP and bilirubin as viable surrogate 
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biochemical parameters and a comprehensive understanding of the natural history of the PBC 
disease process.  Data from the Global PBC Study Group was also utilized to inform the design 
of the confirmatory outcomes study. 
5.5.2. 
Rationale for Dose 
5.5.2.1. 
Rationale for OCA Dose 
The safety and tolerability of multiple doses of OCA have been established in subjects with PBC 
at doses up to 50 mg.  As demonstrated in the Phase 2 PBC studies (Studies 747-201 and 
747-202), OCA significantly reduced serum ALP levels at doses of 10 mg, 25 mg, and 50 mg, 
but with an increase in the incidence and severity of pruritus at higher dose levels.  The Phase 3 
PBC study (Study 747-301) subsequently evaluated the safety and efficacy of OCA at lower 
doses of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability in the double-
blind phase and after 3 months in the open-label phase) and 10 mg; both treatment groups 
exhibited clinically meaningful improvements in liver biochemistry and were safe and generally 
well tolerated.  Study 747-301 demonstrated that titration of OCA from a starting dose of 5 mg to 
10 mg improved tolerance to pruritus relative to 10 mg (56% versus 69% of subjects who 
experienced pruritus) and minimized dropouts due to pruritus.  Based on these data, the approved 
dosing regimens for OCA for the treatment of patients with PBC are 5 mg and 10 mg. 
The majority of efficacy results with OCA, in terms of change in alkaline phosphatase, was 
observed by 3 months and the time to treatment-emergent pruritus was typically 1 month or less 
in Study 747-301.  Study 747-302 will evaluate the effect of OCA on clinical outcomes using the 
5 mg OCA dose for at least 3 months, increasing to 10 mg OCA, if tolerated. 
5.5.2.2. 
Rationale for Modified OCA Doses in Patients Classified with Child-Pugh B or 
Child-Pugh C Hepatic Impairment 
Simulations using a physiologic PK model predicted changes in systemic and liver OCA 
concentrations associated with changes in the severity of hepatic impairment (Child-Pugh Score).  
Model simulations predicted that for mild (Child-Pugh A), moderate (Child-Pugh B), and severe 
(Child-Pugh C) hepatic impairment, total OCA plasma concentrations increase 1.4-, 8.0-, and 
13-fold relative to subjects 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 (Child-Pugh B and C) subjects treated 
with OCA in Phase 1 and 2 studies experienced plasma OCA exposures >10-fold higher than 
those in healthy subjects, 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.  Collectively, the results from these analyses suggest that the doses of OCA 
administered to hepatically-impaired patients should be modestly lower than those for patients 
with normal hepatic function to achieve similar hepatic exposure.   
Per the approved FDA prescribing label, the recommended dosing regimen for OCA in subjects 
with moderate and severe hepatic impairment is a starting dose of 5-mg OCA once weekly.  
Dosage adjustments in subjects with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic 
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impairment may be made after establishing tolerability at the lower dose (full modified dosing 
regimen is described in Appendix A).   
5.5.2.3. 
Rationale for Control Groups  
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 a standard of care 
effect.  Notably, accounting for the standard of care effect is critical when designing an 
outcome-based study conducted globally when there are regional differences in the treatment of 
subjects with PBC. 
Historical Control Group 
The available robust historical PBC observational datasets (UK-PBC and Global PBC Study 
Group) will also be leveraged to provide further comparative evaluation of the clinical benefit of 
OCA.  Each database includes >6000 patients with long-term follow-up. 
Comparison of OCA treatment to the historical controls may provide utility in addressing 
potential bias or confounds associated with the placebo arm.  For example, bias associated with 
the potential addition of commercial OCA and/or differences in long-term standard of care 
between the treatment arms including ancillary treatments and diagnostics. 
Therefore, further evaluation of the effect of OCA will compare OCA treatment versus historical 
controls, and will be supportive to placebo comparisons (ie, comparisons to historical and 
placebo controls will be evaluated separately). 
5.6. 
Summary of Known Potential Risks with OCA 
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, but with a much 
lower frequency than that observed in subjects 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 subjects 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 (HDL) and an increase in low density lipoprotein (LDL).  Notably, in 
subjects 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, 
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decreases in total cholesterol were observed in subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated subjects with the exception of a 
modest transient and early rise after initiation of treatment.   
Refer to the Investigator’s Brochure (IB) for additional information regarding the known 
potential risks with the investigational product. 
6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care on clinical outcomes in subjects with PBC as measured by time to first occurrence of any 
of the following adjudicated events, derived as a composite event endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
6.2. 
Secondary Objectives 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above. 
To assess the effect of OCA compared to placebo on time to occurrence of liver-related death.  
To assess the effect of OCA compared to placebo on progression to cirrhosis.  
To assess the effect of OCA compared to placebo on time to occurrence of HCC. 
To assess the effect of OCA compared to placebo on disease progression via the following: 
• Liver biochemistry 
• Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To characterize the PK of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 4, double-blind, randomized, placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with bilirubin levels of >ULN and ≤5x ULN and/or ALP 
>3x ULN.  Subjects enrolled will be at higher risk of liver-related clinical complications. 
Approximately 428 subjects meeting all enrollment criteria will be recruited into the study over 
an approximate 4-year period, randomly allocated to treatment with either OCA or matching 
placebo in a 1:1 ratio (Figure 1).  Subjects will be screened during a 1- to 8-week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples 
(at least 2 weeks apart) to confirm pretreatment ALP and total bilirubin values (refer to 
Section 9.7.6).  Randomization will be stratified by UDCA treatment (yes/no) and baseline 
bilirubin categories (>ULN/≤ULN).  A minimum of 30% of subjects will have elevated bilirubin 
(>ULN) at Screening.  In addition to the placebo control arm, multiple historical control groups 
(concurrent and retrospective) will be used.   
Subjects will be dosed according to their cirrhosis status and Child-Pugh Score. Subjects who are 
noncirrhotic or classified as Child-Pugh A at Screening will initiate investigational product once 
daily with 5-mg OCA or matching placebo.  Following 3 months of once daily treatment with 
investigational product, the dose should be titrated to a maximum 10 mg OCA or matching 
placebo once daily, based on tolerability and biochemical response (see Section 7.3).  
Subjects with cirrhosis (see Section 9.7.3) and classified as Child-Pugh Class B or Child-Pugh 
Class C will follow a modified dosing regimen, and will initiate investigational product once 
weekly with the 5-mg OCA or matching placebo dose.  In addition, these subjects will follow a 
modified titration plan, which is outlined in Appendix A. 
It is anticipated that subjects will be followed for a minimum of approximately 6 years.  The 
study will continue until approximately 127 adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor (eg, based on advisement by the Data 
Monitoring Committee; DMC) terminates the study. 
This study will be conducted at approximately 170 international study sites with experience in 
treating subjects with PBC.  Prospective subjects will be identified primarily from the hospital 
and/or physician’s database of subjects with PBC, or may be referred from other physicians.  
Subjects may self-refer to an Investigator if they become aware of the study through local, 
national, or international PBC subject societies, forums, and networks. 
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7.1.1. 
Study Design Diagram 
Figure 1: 
Schematic Diagram Study 747-302 
 
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for 
subjects on all dosing regimens, based on tolerability and biochemical response (Up-titration should be considered 
when ALP and/or total bilirubin are >ULN).  Subsequent dose titration(s) for subjects classified as Child-Pugh B or 
Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose 
titration. 
 
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) 
 
Screening Visits 
Day 0 
M 1 
M 3 
1-Month 
Post-Titration 
Visitb 
M 6 
M 9 
M 12 
1 
2a 
Visit Windows (+/-)c 
3 to 8 wk 
prior to 
Day 0 
1 to 6 wk 
prior to 
Day 0 
 
+1 
wk 
±2 
wk 
±1 wk 
±2 wk 
±2 
wk 
±2 wk 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical/PBC Historyd  
X 
 
 
 
 
 
 
 
 
Cirrhosis Status Assessmente 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
Physical Exam  
X 
 
 
X 
 
X 
X 
 
Xd 
Assessments for Mayo Risk Scoref 
X 
 
 
 
 
 
X 
 
X 
Assessments for Child-Pugh Scoreg 
X 
 
 
 
X 
 
X 
X 
X 
Vital Signs (including weight) 
Xh 
 
X 
 
X 
 
X 
X 
Xh 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
X 
Subject Questionnaires (5-D Pruritus Scale and 
Pruritus VAS) 
 
 
X 
 
 
 
X 
 
X 
Quality of Life Questionnaires (PBC-40, 
EQ-5D-5L, and FIS)i 
 
 
X 
 
 
 
 
 
X 
Fibroscan® TEj 
 
 
X 
 
 
 
X 
 
X 
DEXAk 
 
 
X 
 
 
 
 
 
X 
Endoscopyl 
 
 
X 
 
 
 
 
 
X 
Hepatic Ultrasoundm 
 
X 
 
 
 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health Outcome Assessmentsn 
 
 
X 
 
X 
 
X 
X 
X 
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Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) (Continued) 
 
Screening Visits 
Day 0 
M 1 
M 3 
1-Month 
Post-Titration 
Visitb 
M 6 
M 9 
M 12 
1 
2a 
Visit Windows (+/-)c 
3 to 8 wk 
prior to 
Day 0 
1 to 6 wk 
prior to 
Day 0 
 
+1 
wk 
±2 
wk 
±1 wk 
±2 wk 
±2 
wk 
±2 wk 
Randomization/Treatment Assigned 
 
 
X 
 
 
 
 
 
 
Dose Titration: Standard Dosingo,p 
 
 
 
 
X 
 
X (if applicable) 
Dose Titration: Modified Dosing (if applicable)o,p 
 
 
 
 
X 
 
X 
X 
X  
Dispense Investigational Productq 
 
 
X 
 
X 
 
X 
X 
X 
IP Accountability/Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
Dosing Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSr 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
X 
Urine-based β-hCG Pregnancy Tests 
X 
 
X 
 
 
 
 
 
 
Chemistry/Hematology/Coagulation 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
OCA, C4, and FGF-19 (plasma)  
 
 
X 
 
X 
 
X 
Xt 
X 
Markers of Hepatic Fibrosis and/or Inflammationu 
 
 
X 
 
 
 
X 
 
X 
Geneticsv 
 
 
X 
 
 
 
 
 
X 
Blood Sample for Future Analysisw 
 
 
X 
 
 
 
X 
 
X 
AE = adverse event; ALP = alkaline phosphatase; β-hCG = beta human chorionic gonadotropin; DEXA = dual-emission X-ray absorptiometry; eCRF = electronic case report 
form; EOS= End of Study; EOT = End of Treatment; FGF-19 = fibroblast growth factor-19; FIS = Fatigue Impact Scale; IP = Investigational Product; M = month, TE = transient 
elastography; VAS = Visual Analogue Scale; wk = week 
a All subjects will have the chemistry panel retested to ensure subjects have at least two ALP and bilirubin assessments at least 2 weeks apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and bilirubin assessments will be used to determine eligibility. Refer to Section 9.7.6 for guidance on when an additional ALP or 
bilirubin sample may be needed to confirm eligibility. Samples for hematology and coagulation will not be collected at Screening Visit 2. 
b Post-Titration visits must be performed 1 month (+ 1 week) after any up-titration in dose and/or frequency in subjects following modified dosing due to Child-Pugh B and Child-
Pugh C hepatic impairment.  In subjects following the standard dosing regimen, the post-titration visit must be performed only after the first up-titration to 10 mg OCA or 
matching placebo, or after ≥3 months at a decreased dose or frequency. 
c Visits should be based on Day 0 (not on the prior visit) with the exception of the Post-Titration Visit, which is based on the date of titration. 
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d Medical history at Screening and the yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both. 
e Presence or absence of cirrhosis should be assessed per Section 9.7.3.  Cirrhosis status should be repeated as clinically indicated. 
f Mayo Risk Score will be calculated based on central laboratory evaluations, diuretic use data, and peripheral edema assessment data captured in the eCRF. 
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 Height will be collected at this visit. 
i The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2 and Section 12.2.6). 
j Transient elastography (TE) will be conducted at 6-month intervals at all study sites where the Fibroscan® TE device is available.  Please refer to Section 9.7.7 for additional 
information related to the allowed windows at Day 0 for this procedure. 
k DEXA will be conducted at 12-month intervals at all study sites where the DEXA device is available.  Please refer to Section 9.7.7 for additional information related to the 
allowed windows at Day 0 for this procedure. 
l Endoscopy will be conducted at all study sites where the device is available to assess for the presence of oesophageal varix/varices.  Please refer to Section 9.7.7 for additional 
information related to the allowed window at Day 0 for this specific procedure.  
m 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.   
n Health Outcome Assessments: Data related to nonstudy related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
o Pre-titration tolerability assessment, which include a review of AEs and a review of safety laboratory results (eg, chemistry, hematology, and coagulation), must be completed 
by the Investigator before any up-titration can occur as defined in Section 7.4.1.  Lab results obtained within 2 months prior to any up-titration may be used for assessment.  
p Dose Titration is based on cirrhosis status (Section 9.7.3) and Child-Pugh Score (Section 9.7.4).  The initial dose titration of investigational product may occur at the Month 3 
visit, or any study visit thereafter for subjects on all dosing regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for subjects who are classified 
as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.  For complete modified dose 
titration criteria, refer to Appendix A. 
q Subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1) and to take investigational product at approximately the same time of day.  Subjects 
must be instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
r The subject 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. 
s Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry.  If positive, a confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not be enrolled in the study.  (Additional testing may be conducted where required, regionally). 
t Only OCA PK samples will be collected at Month 9 at select study sites in a subset of subjects.  Please refer to Section 9.7.13 for the PK sampling schedule. 
u Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
v A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12.  If a Baseline (eg, Day 0) genetic sample is not obtained, subsequent genetic samples are not required to be collected during the course of the study. 
w Please refer to Section 11.1.2.3 for description of the blood sample to be collected for future analysis. 
 
 
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Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) 
 
Year 2 Through End of Study 
 
M 3 
continued follow-up 
1-Month Post-
Titration Visita 
(if applicable) 
M 6 
continued follow-up 
M 9 
continued follow-up 
M 12 
continued follow-up 
EOT/ 
EOSb 
Visit Windows (+/-)c 
±2 wk 
+1 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
Physical Examd 
 
X 
 
 
X 
X 
Assessment for Mayo Risk Scoree 
 
 
X 
 
X 
X 
Assessments for Child-Pugh Scoresf 
X 
 
X 
X 
X 
X 
Vital Signs (including weight) 
 
 
X 
 
Xg 
Xg 
12-Lead Electrocardiogram 
 
 
 
 
X 
X 
Subject Questionnaires (5-D Pruritus 
Scale and Pruritus VAS) 
 
 
X 
 
X 
X 
Quality of Life Questionnaires (PBC-40, 
EQ-5D-5L, and FIS)h 
 
 
 
 
X 
X 
Fibroscan®TEi 
 
 
X 
 
X 
X 
DEXAj 
 
 
 
 
X 
X 
Endoscopyk 
 
 
 
 
X 
 
Hepatic Ultrasoundl 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
Health Outcome Assessmentsm 
X 
 
X 
X 
X 
X 
Dose Titration (if applicable)n,o 
X 
 
X 
X 
X 
 
Dispense Investigational Product 
X 
 
X 
X 
X 
 
IP Accountability/Compliance 
X 
X 
X 
X 
X 
X 
Dosing Diary 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSp 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
X 
X 
Chemistry/Hematology/Coagulation 
X 
X 
X 
X 
X 
X 
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Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) (Continued) 
 
Year 2 Through End of Study 
 
M 3 
continued follow-up 
1-Month Post-
Titration Visita 
(if applicable) 
M 6 
continued follow-up 
M 9 
continued follow-up 
M 12 
continued follow-up 
EOT/ 
EOSb 
Visit Windows (+/-)c 
±2 wk 
+1 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
OCA, C4, and FGF-19 (plasma) 
 
 
 
 
X 
X 
Markers of Hepatic Fibrosis and/or 
Inflammationq 
 
 
X 
 
X 
X 
Geneticsr 
 
 
 
 
X 
 
Blood Sample for Future Analysiss 
 
 
X 
 
X 
X 
AE = adverse event; β-hCG = beta human chorionic gonadotropin; DEXA = dual-emission X-ray absorptiometry; EOS= End of Study; EOT = End of Treatment; 
FGF-19 = fibroblast growth factor-19; FIS = Fatigue Impact Scale; IP = Investigational Product; M = month, TE = transient elastography; VAS = Visual Analogue Scale; 
wk = week 
a  In subjects following the standard dosing regimen, the post-titration visit must be performed only after the first up-titration to 10 mg OCA or matching placebo, or after 
≥3 months at a decreased dose or frequency.  Post-titration visits must be performed 1 month ± 1 week after any up-titration in dose and/or frequency in subjects following 
modified dosing due to Child-Pugh B and Child-Pugh C hepatic impairment.   
b  
As soon as possible upon study discontinuation and as near as possible to last dose taken. 
c Visits should be based on Day 0 (not on the prior visit) with the exception of the Post-Titration Visit, which is based on the date of titration. 
d The yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both. 
e Mayo Risk Score will be calculated based on central laboratory evaluations, diuretic use data, and peripheral edema assessment data captured in the CRF. 
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 case report form. 
g Height will be collected at this visit. 
h  The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2 and Section 12.2.6). 
i Transient elastography (TE) will be conducted at 6-month intervals at all study sites where the Fibroscan® TE device is available. 
j  DEXA will be conducted at 12-month intervals at all study sites where the DEXA device is available. 
k  Endoscopy will be conducted at all study sites where the device is available to assess for the presence of oesophageal varix/varices. 
l  Ultrasound will be conducted to enhance HCC surveillance.  For all on study (eg, postday 0) ultrasounds: unless HCC has already been confirmed by biopsy, a second 
confirmatory image (eg, MRI) should be obtained to confirm suspected HCC. 
m  
Health Outcome Assessments: Data related to nonstudy related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
n   
Pre-titration tolerability assessment, which include a review of AEs and a review of safety laboratory results (eg, chemistry, hematology, and coagulation), must be completed 
by the Investigator before any up-titration can occur as defined in Section 7.4.1.  Lab results obtained within 2 months prior to any up-titration may be used for assessment.   
o  Dose Titration is based on cirrhosis status (see Section 9.7.3)  and Child-Pugh Score (Section 9.7.4).  The initial dose titration of investigational products may occur at the Month 
3 visit, or any study visit thereafter for subjects on all dosing regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for subjects who are 
classified as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.  For complete modified 
dose titration criteria, refer to Appendix A. 
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p  The subject should be instructed to fast overnight (at least 8 hours) prior to each visit.  Fasting is required prior to all study visits, but water is permitted. 
q  Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
r  A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12. 
s Please refer to Section 11.1.2.3 for description of the blood sample to be collected for future analysis.  
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7.1.3. 
Study Duration 
The study is event driven and total duration will be determined by the time required to accrue 
approximately 127 primary endpoint events, estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time of approximately 6 years. 
7.2. 
Number of Subjects 
It is expected that approximately 428 subjects will be randomized in the study to achieve 
127 adjudicated primary endpoint events.  In the event additional subjects are needed to 
complete enrollment in the biopsy substudy (N = 45 subjects, as defined in Addendum 2), 
subjects who agree to participate in the substudy may be added to the target subject enrollment 
number currently planned.  
7.3. 
Planned Dosing Regimen 
Subjects will be randomized to treatment with either OCA or matching placebo in a 1:1 ratio.  
Subjects will be dosed according to their cirrhosis status (as defined in Section 9.7.3) and 
applicable Child-Pugh Score (see Section 9.7.4) as outlined in Table 3.  
Subjects who are noncirrhotic or classified as Child-Pugh A at screening will receive 5 mg OCA 
or matching placebo once daily for 3 months.  Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the product and assessment of biochemical response.  
Up-titration should be considered when ALP and/or total bilirubin are >ULN.  A review of safety 
laboratory results (eg, chemistry, hematology, and coagulation) obtained no more than 2 months 
prior to the planned up-titration visit must be completed as part of the product tolerability 
assessment before up-titration can occur (see Section 7.4.1).   
For those subjects that up-titrate to 10 mg, dose may be decreased to 5 mg at any time during the 
study as considered clinically appropriate (eg, tolerability). Subjects may be titrated back up to a 
maximum dose of 10 mg once daily based on tolerability and clinical judgment of the 
Investigator.  A review of safety laboratory results obtained within 2 months of the planned 
up-titration visit date is not required prior to re-challenging a subject up to 10 mg once daily 
dosing, as long as the decrease in dose/dosing frequency was less than 3 months in duration.  
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Table 3: 
Planned Dosing Regimen by Cirrhosis and Child Pugh Score 
 
Scheduled Dosing Regimen 
Standard 
Modifieda 
Noncirrhotic/ 
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Starting Dose b  
(Day 0) 
5 mg daily 
5 mg once weekly 
5 mg once weekly 
Titration 1c  
(≥Month 3) 
10 mg daily 
5 mg twice weeklyd 
5 mg twice weeklyd 
Titration 2c  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weeklyd 
10 mg twice weeklyd 
Titration 3c 
(≥6 weeks after Titration 2) 
NA 
5 mg daily 
NA 
a Refer to Appendix A  for additional instructions regarding subjects following the Modified Dosing Regimen. 
b Starting dose based on subject’s cirrhosis status and Child-Pugh score at Screening. 
c Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject tolerability, 
biochemical response, and/or changes in cirrhosis status or Child-Pugh score at any time during the study (see Section 7.4). 
d Dosing per the twice weekly schedule must be at least 3 days apart. 
The dosing regimen should be determined as described in Table 4.  Investigators should follow 
the dosing/titration schedule as shown in Table 3. 
Table 4: 
Determination of Dosing Regimen 
Cirrhosis? 
No 
Yes 
Yes 
Yes 
Child-Pugh Score 
Any 
A 
B 
C 
Dosing Regimen 
Standard 
Modified for Child-Pugh B 
Modified for Child-Pugh C 
7.4. 
Dose Titration 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 subject’s cirrhosis status (using histology or 
non-histological methods as defined in Section 9.7.3 and Section 9.7.4) or Child-Pugh 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) as well 
as biochemical response (as assessed by reductions in ALP and/or total bilirubin).  In general, 
down-titration will be done in response to tolerability concerns and can occur at any time while 
on-study.  Up-titration will be done per protocol when subjects have no tolerability concerns and 
have not achieved an adequate reduction in ALP and/or total bilirubin to within normal limits, or 
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 for each 
dosing regimen as defined in Section 7.3. 
Scheduled Dose Titration - The first dose titration for any subject may occur no earlier than 
3 months following initiation of OCA or matching placebo.  Subsequent titrations in dose or 
dosing frequency for subjects following the Modified Dosing Regimens may occur no earlier 
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than 6 weeks (via an unscheduled visit or regular visit- see Appendix A) following an 
up-titration. 
Tolerability Dose Titration - Investigators may decrease the dosing frequency or dose for any 
subject at any time during the study, as considered clinically appropriate (eg, tolerability; see 
Section 7.4.1).   
Dose Titration due to Change in Cirrhosis or Child-Pugh Score - When subjects demonstrate 
a change in cirrhosis status (as assessed per Section 9.7.3) or Child-Pugh Score (Section 9.7.4), 
dosing should be reassessed and the dosing regimen modified appropriately.  Changes to the 
dosing regimen are not mandatory and should be based on clinical judgment as well as change in 
cirrhosis status.  Table 5 provides an overview of the possible changes in dosing regimen due to 
changes in cirrhosis or Child-Pugh 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, biochemical response, and clinical judgment.  
Table 5: 
Changes in Dosing Regimen Due to Changes in Cirrhosis Status or 
Child-Pugh Score 
Original Status 
New Statusa 
Noncirrhotic OR 
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Noncirrhotic or  
Child-Pugh A 
No Change 
10 mg daily  5 mg daily 
5 mg daily No change or 10 mg 
twice weeklyb 
5 mg or 10 mg daily  10 mg 
twice weeklyb 
Child-Pugh B 
5 mg daily  10 mg daily 
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 
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 subject begins dosing with the new dosing regimen, titration should occur as described for that dosing regimen in 
Section 7.3 or Appendix A.  
b Dosing per the twice weekly schedule must be at least 3 days apart. 
Subjects who exhibit development of cirrhosis at any point in the study should be assessed per 
Section 9.7.3.  If the presence of cirrhosis is confirmed and the subject’s Child-Pugh score is 
either B or C, the appropriate modified dosing regimen should be followed.  The dose or 
frequency of investigational product should be down-titrated to the next lowest dosing frequency 
in the appropriate modified dosing regimen unless the subject is currently taking a dose and 
frequency also specified in the modified dosing regimen and the Investigator determines that it is 
clinically appropriate for the subject to continue at that dose (Appendix A). 
Subjects with pre-existing cirrhosis who demonstrate a change in the Child-Pugh Score from A 
to B or C at any point in the study should also have their dosing modified per the appropriate 
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dosing regimen. Changes in Child-Pugh Score that result from a transient, explainable change in 
laboratory parameters should be documented appropriately and should not necessarily result in a 
change to the dosing regimen (Appendix A).  
Subjects who demonstrate an improvement in cirrhosis status or in Child-Pugh Score from B to 
A, or from Child-Pugh C to B, may be eligible to transition to the standard dosing regimen or the 
modified dosing for Child-Pugh B, respectively, based on tolerability.  Prior to any dosing 
change, subjects must meet pre-titration assessment requirements for dosing as described in 
Section 7.4.1. 
Child-Pugh Scores will be calculated at all quarterly study visits. All associated visit data 
(including central laboratory results) should be entered into the eCRF in a timely fashion to 
confirm that the subject’s Child Pugh Score has not changed.  If a change in cirrhosis status (as 
defined in Section 9.7.3) and/or Child-Pugh Score is observed independent of a study visit, the 
subject 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. 
Subjects’ dose and dosing frequency may be titrated up or down within the appropriate dosing 
regimen based on the calculated Child-Pugh Scores.  Up-titration should be done per Investigator 
discretion and be guided by the pre-titration tolerability assessments. 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements 
Tolerability of investigational product must be assessed prior to titrating a subject to a higher 
dose.  A review of adverse events and safety laboratory results (eg, chemistry, hematology, and 
coagulation) obtained within 2 months of the up-titration visit must be performed as part of the 
investigational product tolerability assessment, prior to any planned up-titration in study 
medication (eg, Month 3, Month 6).  Safety laboratory results obtained at the Month 1 visit (for 
titration at Month 3) or at the 1 Month Post-Titration Assessment visit (for titration prior to or at 
the subsequent quarterly visit) are acceptable for review purposes; however, 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 subject to a higher 
dose.  
To be eligible for a dose up-titration: 
• Subjects 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.  
• There must be no clinically significant increase (as determined by the Investigator) in 
the subject’s liver function tests.  
7.5. 
Criteria for Study Termination 
The Sponsor 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 DMC, it may be necessary to stop the study before all events have been accrued, and 
when subjects are still active on the study.  In addition, the Sponsor may terminate the study at 
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an investigational site at any time (eg, poorly performing sites, as determined by the number of 
subjects 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 subjects for the End of Study Visit.  The window of time for 
scheduling the visit will be based on a final projection of when the requisite 127 adjudicated 
events will have been accrued. 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Population 
This study will be conducted at approximately 170 international study sites with experience in 
treating patients with PBC.  Prospective subjects 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. 
Subject Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with AASLD and EASL practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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. 
2. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN  
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking 
UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0. 
5. Contraception:  Female subjects of child-bearing potential must use ≥1 effective method 
of contraception during the study and until 30 days following the last dose of 
investigational product.  Effective methods of contraception are considered to be those 
listed below:   
• Barrier method, ie, (a) condom (male or female) or (b) diaphragm, with spermicide  
• Intrauterine device (IUD)  
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• Vasectomy (partner) 
• Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection) 
• Abstinence, if in line with the preferred and usual lifestyle of the subject   
6. Must provide written informed consent and agree to comply with the study protocol 
8.3. 
Subject Exclusion Criteria 
1. History or presence of other concomitant liver diseases including:  
• Hepatitis C virus infection 
• Active hepatitis B infection; however, subjects 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 
• Nonalcoholic steatohepatitis 
• Gilbert’s Syndrome  
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including:  
• History of liver transplant, current placement on a liver transplant list, or current 
MELD score >12.  Subjects who are placed on a transplant list despite a relatively 
early disease stage (for example per regional guidelines) may be eligible as long as 
they do not meet any of the other exclusion criteria. 
• Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
− Variceal bleed 
− Uncontrolled ascites 
− Encephalopathy  
− Spontaneous bacterial peritonitis  
• Known or suspected hepatocellular carcinoma 
• Prior transjugular intrahepatic portosystemic shunt procedure 
• Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine 
>2 mg/dL (178 μmol/L)  
3. Mean total bilirubin >5x ULN  
4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) 
or ileal resection or plan to undergo either of these procedures. 
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5. Other medical conditions that may diminish life expectancy, including known cancers 
(except carcinomas in situ or other stable, relatively benign conditions such as chronic 
lymphatic leukemia). 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test by the central laboratory), or lactating. 
7. Known history of human immunodeficiency virus infection. 
8. Medical conditions that may cause non-hepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months). 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study. 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0. 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components.  
14. UDCA naïve (unless contraindicated) 
8.4. 
Dose Adjustment, Interruption, and Withdrawal from 
Investigational Product or Study 
Investigational product may be temporarily decreased (eg, from 10 mg to 5 mg daily, or by 
decreasing dosing frequency) or temporarily or permanently stopped based on tolerability 
concerns.  The dose of investigational product should be adjusted back to the maintenance dose 
in a blinded manner once the issues relating to the lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated events has accrued.  If a subject reaches an 
outcome event, he or she should continue the regular visit schedule and continue taking 
investigational product as long as the subject has not met any of the criteria for mandatory 
interruption of investigational product outlined in Section 8.4.1, and the Investigator assesses it 
as safe.  In general, subjects should be strongly encouraged to both stay on investigational 
product and remain in the study until study termination.   
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  
Subjects 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.  Subjects with 
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persistent elevations (eg, additional lab testing per Investigator discretion) should be closely 
monitored.  Concomitant elevations in total bilirubin or international normalized ratio (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 >3x baseline (and >ULN) 
• Total bilirubin >2x 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 AE information should also be collected 
and the subject 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 >3x baseline (and >ULN) or total 
bilirubin >2x baseline (and >ULN), subjects 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 study medication and no other cause for the 
elevation is identified, it may be assumed that the elevations were due to disease progression and 
the subject 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. 
If at any time a subject 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.  
Subjects who develop evidence of severe drug-induced liver injury, which is suspected to be 
causally related to the investigational product should be discontinued from investigational 
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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 subjects 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 subject to continue treatment.  In the event the investigational product is 
required to be discontinued, subjects should be encouraged to continue study visits for continued 
data collection but may withdraw consent at any time.  
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 13.4). 
8.4.1.3. 
Pregnancy 
If a female subject becomes pregnant, she must interrupt treatment with investigational product 
immediately, but should continue with the study visit schedule.  As described in Section 12.1.11 
pregnancy is not considered an AE for reporting purposes.  The subject may re-start 
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 12.1.11. 
8.4.2. 
Reasons for Mandatory Discontinuation of Investigational Product 
8.4.2.1. 
Liver Transplantation 
Subjects who undergo a liver transplant during the course of the study must discontinue 
investigational product and discontinue the study visit schedule.  However, these subjects 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 subject to discontinue 
investigational product; however, these subjects are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
• Subject begins treatment with commercially available OCA 
• The Investigator or Sponsor considers that it is advisable or in the best interest of the 
subject. 
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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 subject 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 outcomes. 
−  Early termination procedures should be conducted if the subject withdraws 
consent (See Section 9.7.18). 
The Investigator is encouraged to contact the Sponsor prior to discontinuing a subject from 
treatment.  The Investigator must notify the Sponsor study monitor by telephone or email as soon 
as possible if any subject prematurely withdraws from the study.   
8.4.4. 
Withdrawal of Consent 
If the subject 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 subjects 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 subject discontinuation.  This 
information and date must be recorded in the appropriate case report form (CRF).   
8.4.5. 
Lost to Follow-Up 
If a subject fails to return to the clinic for a study visit, and the Investigator ceases to have 
contact with the subject, he or she will be withdrawn from the study. 
A reasonable effort must be made to contact the subject and determine the reason(s) why a 
subject 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 CRF.   
8.4.6. 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by telephone or email as soon as 
possible if any subject prematurely withdraws from the study.  The date when the subject is 
withdrawn and the reason for discontinuation must be recorded in the CRF.  If a subject is “lost 
to follow up” (fails to return for a visit), a reasonable effort should be made to contact the subject 
in order to determine why the subject failed to return.  This information must be documented in 
the CRF.  If a subject is withdrawn from the study early (regardless of the cause), all of the 
EOT/EOS evaluations should be performed at the time of withdrawal, as appropriate (See 
Section 9.7.18, Early Discontinuation and/or Early Termination Procedures).  
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Investigational Product Treatment Regimen 
The term investigational product refers to either OCA (provided as part of this clinical study) or 
matching 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 5 mg OCA tablet or one 
10 mg OCA tablet, or matching placebo).   
Investigational product will be taken orally, up to once daily, for the duration of the study.   
All subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1) and 
to take investigational product at approximately the same time of day.  Subjects must be 
instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
At each study visit where the daily dose of investigational product is administered at the site, all 
assessments, except for the post-dose collection of blood samples for the subset of subjects 
participating in the Month 9 PK assessment, must be completed before administration of 
investigational product. 
9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.1) 
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 CRF, as well as any dose or dose 
regimen changes that occur during the study.  Concomitant medications should be stable prior to 
Day 0.   
Drug Interactions 
Subjects 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 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. 
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Information related to additional drug-drug interaction (DDI) studies is available in the current 
version of the Investigator’s Brochure (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 with OCA that may be observed in study subjects. 
PBC-Specific Therapy 
In general, 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 subjects’ 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, subjects 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, subjects should be reminded to keep taking their blinded 
investigational product. 
9.2.1. 
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.  Subjects who continue with commercial OCA therapy must discontinue study 
medication and are expected to continue through the end of the study (see Section 9.7.18).  The 
study will only terminate at the time when the needed number of adjudicated events has accrued 
or at the discretion of the Sponsor.  Subjects will need to complete EOT procedures but continue 
with regularly scheduled visits until the study is terminated (see Section 9.7.18 Early 
Discontinuation and/or Early Termination Procedures). 
9.3. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Subjects should be instructed to complete a dosing diary to help monitor compliance to the 
prescribed dosing regimen.  Subjects should be instructed to retain all bottles of investigational 
product, even if empty, and to return them to the Investigator at the subsequent visit.  The 
Investigator or designee should perform investigational product accountability and, if applicable, 
follow up with the subject to retrieve any investigational product bottles that have not been 
returned.  
If the Investigator has concerns about a subject’s dosing compliance s/he should discuss this with 
the subject, assess the reasons for noncompliance and the likelihood that the subject will remain 
noncompliant, and notify the Sponsor accordingly.   
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9.4. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Allocation to one of 
two treatment groups (OCA or placebo) will occur on a 1:1 ratio across sites and will be 
stratified by UDCA treatment (yes/no) and mean baseline bilirubin categories (>ULN/≤ULN), as 
specified by the central laboratory.  The randomization will be based on a predefined 
randomization code (generated by the Sponsor or designee) using an interactive web response 
system (IWRS), which the Sponsor intends will serve as a computer-based subject registration 
system at Screening and Day 0.  The IWRS will serve as an investigational product inventory 
and management system and may be integrated with the study database.  
The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide subject data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned (refer to Section 9.5.2 below) and 
investigational product dispensing information (ie, bottle number[s]) will be provided. 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects 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 subject).  If it 
is not reasonable to inform the Medical Monitor in advance of the unblinding, the Investigator 
must promptly document in the subject’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 subject’s treatment will be provided separately to the 
Investigator.  Similarly, if the Medical Monitor breaks the blind for an individual subject for the 
purpose of evaluating an emergent safety issue, the Medical Monitor will document within trial 
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 subjects.  Refer to Section 13.3 for further details regarding DMC access to 
blinded and unblinded data.  The DMC will document details about any unblinded subject data 
reviews in the closed session DMC minutes, which will be made available to the Sponsor only 
after the database is locked and the trial 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. 
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9.5. 
Assignment of Site and Subject 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 subject data and to identify the site and or Investigator 
within study documents.  This number will be recorded in the CRF. 
9.5.2. 
Subject Numbers 
Subjects 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 trial is prohibited.   
9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visits should be based on Day 0 (not on the prior visit), eg, Month 3 should ideally occur 
3 calendar months (± 2 weeks) following Day 0.  The visit windows are as follows: 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening Visit 1 interval is 3 to 8 weeks prior to Day 0.  Screening 
Visit 2 interval is 1 to 6 weeks prior to Day 0.  The visit window for 
Screening 2 visits allows for the repeat biochemistry tests to be 
collected at least two weeks after the initial biochemistry sample 
was collected and will ensure ample time to receive lab results.  
The overall Screening interval is up to 56 days, but screening 
procedures should not be performed during the last 7 days of the 
window.  
See Section 9.7.6 for scenario specific visit windows that may be 
applicable at Screening.  
Day 0 
This is the day of randomization.  On-treatment visit scheduling 
should be calculated from this point going forward. (The first dose 
of investigational product should be taken the next day, on Day 1.) 
Month 1  
+1 week (7 days)  
Titration Visit – Standard Dosing Regimen 
≥Month 3 
Titration Visit 1 – Modified Dosing 
Regimen 
≥Month 3 
Titration Visit 2 – Modified Dosing 
Regimen 
≥6 weeks after Titration Visit 1 
Titration Visit 3 – Modified Dosing 
Regimen (Child-Pugh B ONLY) 
≥6 weeks after Titration Visit 2 
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Visit or Procedure 
Visit Window and/or Interval 
Post-Titration Visit 
1 month (+1week [7 days]) from date of titration or after ≥3 months 
at a decreased dose or frequency   
Month 3 to Month 12 
±2 weeks (14 days)  
Quarterly visits (Months 15 to EOS) 
±2 weeks (14 days) 
EOT 
(When subject discontinues investigational 
product) 
As soon as possible upon study discontinuation and as near as 
possible to last dose taken 
EOS 
(When subject terminates the study) 
The final study visit; EOS will occur concurrent with EOT if a 
subject discontinues study medication at the time the subject’s 
participation in the study ends (eg, withdrawal of consent or study 
termination by the Sponsor); EOS will occur after the EOT if the 
subject discontinues study medication but continues in the study. 
EOS = end of study; EOT = end of treatment  
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk and benefit of / study 
to the subject and will provide him/her with a copy of the written information and informed 
consent form (ICF).  The subject will be given sufficient time to consider the study before 
deciding whether or not to participate.  The subject 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 s/he can withdraw from the study at any time.  The subject must be willing and 
able to provide written informed consent before entering the study.  The Investigator or a 
medically qualified designee is responsible for administering and documenting the written 
informed consent of the subject.  The subject will be given a copy of the written information and 
his/her signed and dated consent form. 
Any change in a subject’s consent status (eg, semi-annual telephone contact or medical record 
review) must be documented in a signed informed consent form or addendum.  The subject will 
be given a signed and dated copy of the consent document. 
9.7.3. 
Assessing Cirrhosis 
9.7.3.1. 
Determination for Dosing Regimen 
To determine which dosing regimen subjects should follow, the presence or absence of cirrhosis 
should be assessed by the Investigator at Screening Visit 1.  Acceptable methods of confirming 
(via medical history) or assessing cirrhosis for purposes of determining dosing is defined as a 
subject who has documented evidence or presence of one or more of the following cirrhosis 
indicators: 
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• Biopsy results consistent with PBC Stage 4 (Ludwig 1978)   
• TE 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  
− elevation in prothrombin time /INR (not due to antithrombotic agent use), or 
− elevated bilirubin (2× ULN) 
Subjects who exhibit no evidence of cirrhosis by the above methods of assessment will be dosed 
using the Standard Dosing Regimen, while those who do exhibit evidence of cirrhosis by one or 
more of the above methods will be dosed using the Modified Dosing Regimen according to their 
Child-Pugh Score calculated in the electronic case report form (eCRF) (see Appendix A, 
Section 7.3, Table 3 and Table 4). 
Cirrhosis status should be reassessed as clinically indicated throughout the study.  Any change in 
cirrhosis status will necessitate re-evaluation of the dosing regimen. 
9.7.3.2. 
Progression to Cirrhosis 
When a subject identified as noncirrhotic at Baseline per the criteria listed in Section 9.7.3.1 
exhibits any signs or symptoms associated with progression to cirrhosis, as defined by the same 
criteria, the subject should also be assessed by Fibroscan® TE where available and progression 
to cirrhosis confirmed by biopsy (centrally read) unless not medically indicated.  Laboratory 
samples needed to obtain noninvasive scores of liver fibrosis (ELF, and aspartate 
aminotransferase to platelet ratio index [APRI]) will also be collected when a subject develops 
evidence of progression to cirrhosis. 
Full instructions concerning the sample collection methods, processing, labeling, and shipping 
will be provided by the Sponsor in a study-specific histology manual.  Collection supplies will be 
provided by the central laboratory. 
Sites participating in the paired biopsy substudy must confirm progression to cirrhosis by biopsy 
as per the information outlined in protocol Addendum 2. 
All suspected cases of progression to cirrhosis should be submitted for adjudication regardless of 
the availability of transient elastography or biopsy results. 
9.7.4. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is calculated and reported within the electronic data 
capture (EDC) system based on data entered into the eCRF adding the scores from the 5 factors 
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outlined in Table 6 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 Child-Pugh 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.  It is important to note 
that subjects must have confirmed cirrhosis as assessed by one or more of the above criteria 
(Section 9.7.3) prior to applying the calculated Child-Pugh score for dosing.  Investigators will 
be responsible for determining the appropriate dosing regimen based on both the cirrhosis status 
and the Child-Pugh score (Table 6).  Any change in cirrhosis status or Child-Pugh Score will 
necessitate re-evaluation of the dosing regimen. 
Table 6: 
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) 
9.7.5. 
Mayo Risk Score 
Mayo Risk Score (MRS) (Dickson 1989) is calculated and reported within the EDC system 
based on data entered into the eCRF.  Calculation of MRS includes investigator assessment of 
peripheral edema and the use of diuretic therapy, which will be assessed during adverse event 
and concomitant medicine review at the scheduled visits and entered into the eCRF, as well as 
total bilirubin, albumin, and prothrombin time results obtained from the central laboratory data. 
9.7.6. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 week to 8 weeks prior to Day 0 to 
determine whether the subject meets all the inclusion criteria and none of the exclusion criteria.  
Screening Visit 1 will occur 3 weeks to 8 weeks prior to Day 0; Screening Visit 2 will occur 
1 week to 6 weeks prior to Day 0, depending on the date that the first serum chemistry sample 
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was collected. Subjects who do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects 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.   
Collection of 2 serum chemistry samples (collected at least 2 weeks apart) during Screening is 
required for confirmation of the pretreatment serum chemistry values, including the ALP and 
total bilirubin used to determine eligibility: 
• All subjects will have 2 bilirubin and ALP assessments at least 2 weeks apart. 
• When the 2 bilirubin or ALP assessments collected at Screening Visit 1 and 
Screening Visit 2 differ by ≥30%, a third sample must be collected at an unscheduled 
visit as a confirmatory sample to include in the mean result(s) that will be used to 
determine eligibility.  
• The mean of all available (at least 2; including both scheduled and 
unscheduled) bilirubin and ALP assessments will be used to determine eligibility 
(total bilirubin >ULN and ≤5x ULN and/or an ALP >3x ULN).   
Screening Visit 1 procedures are as follows: 
• The subject is to review and sign the ICF.  Informed consent must be obtained from 
the subject 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  
• Assess for the presence/absence of cirrhosis. 
• Verify inclusion and exclusion criteria for eligibility. 
• Perform a physical examination.  
• Perform assessments for calculation of Child-Pugh Score 
• Perform assessment for calculation of Mayo Risk Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Assess and record any pretreatment-emergent AEs. 
• Record prior (if within 30 days of Screening) and current concomitant medications. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
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• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
Screening Visit 2 procedures are as follows: 
• Verify inclusion and exclusion criteria for eligibility. 
• 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 Visit 2, and a report/adequate data are 
available, a pretreatment ultrasound at Screening Visit 2 is not required.  If the 
ultrasound cannot be performed at Screening Visit 2 (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. 
• Assess and record any pretreatment-emergent AEs. 
• Record current concomitant medications. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry tests. 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
• In preparation for the dual-emission X-ray absorptiometry (DEXA) bone density scan 
to be done at Day 0 (at all study sites where the device is available), subjects who are 
taking calcium supplements should stop taking them for 48 hours before the scan.  If 
the subject is taking any medications for osteoporosis or osteopenia, s/he should not 
take them on the day of the scan. 
It is acceptable to repeat laboratory evaluations or other assessments or procedures within the 
Screening period (Weeks -8 to -1), as appropriate.  In the event that the 2 screening bilirubin or 
ALP assessments differ by ≥30%, and a third confirmatory sample is required to be collected, the 
Screening Visit window may be extended up to 3 additional weeks. 
9.7.7. 
Day 0 Procedures (Randomization) 
• Review inclusion and exclusion criteria for eligibility. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
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• Perform TE at all study sites with access to Fibroscan® TE device.  If TE has been 
done within 3 months of Day 0 and a report/adequate data are available, a 
pretreatment TE at Day 0 is not required.  If the TE cannot be performed on Day 0 
(eg, device/technician unavailability, scheduling issues, TE data is needed to inform 
cirrhosis assessment, etc), the procedure may be completed within the screening visit 
window, at Screening Visit 1 (if data is needed for cirrhosis assessment) or as close as 
possible to the Day 0 visit, preferably, after subject eligibility has been confirmed. 
• Conduct a DEXA bone density scan (at all study sites where the device is available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable.  If DEXA has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment DEXA at Day 0 is not required. If 
the DEXA cannot be performed on Day 0 (eg, device/technician unavailability, 
scheduling issues, etc), the procedure may be completed within the screening visit 
window, as close as possible to the Day 0 visit, preferably, after subject eligibility has 
been confirmed. 
• Perform an esophagogastroduodenoscopy (endoscopy; at study sites, where the 
device is available) to assess the presence or absence of oesophageal varix/varices.  If 
an endoscopy has been done within 12 months of Day 0 and a report/adequate data 
are available, a pretreatment endoscopy at Day 0 is not required. If the endoscopy 
cannot be performed on Day 0 (eg, device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the screening visit window, as 
close as possible to the Day 0 visit, preferably, after subject eligibility has been 
confirmed. 
− Subsequent endoscopies should be performed annually or per standard of care and 
the Investigator’s clinical judgment throughout the course of the study.  
Endoscopies should also be performed when platelet counts are <150 × 109 /L. 
• Assess and record any pretreatment-emergent AEs. 
• Review and record prior concomitant medications. 
• Review and record any nonstudy 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 subject only if s/he meets all inclusion criteria and no exclusion 
criteria. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
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• Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and fibroblast growth factor-19 (FGF-19) 
− Markers of hepatic fibrosis and/or inflammation (including enhanced liver fibrosis 
[ELF]) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Access the IWRS and dispense investigational product 
• Instruct the subject to begin dosing on the day after the Day 0 visit (ie, on Day 1).  
Instruct the subject to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
Month 1 Procedures 
• Perform a physical examination.  
• Assess and record AEs 
• Review and record concomitant medications. 
• Assess investigational product compliance, perform investigational product 
accountability, and review dosing diary with the subject. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Provide the subject with a dosing diary to document his or her dosing. 
• In the event it is not feasible for the subject to return to the site for the above 
referenced procedures, the following alternative visit procedures are available to help 
ensure compliance with the Month 1 visit laboratory requirements: 
− At the Day 0 visit, the subject can be provided with the central laboratory 
collection kit and shipping materials associated with the Month 1 visit, and have 
the laboratory specimen collection performed at his or her local doctor’s office or 
designated laboratory collection center.  The subject must also be contacted via 
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telephone at the Month 1 visit time point to assess AEs, review concomitant 
medications, and assess investigational product compliance;  
− If all other options for the collection of the Month 1 laboratory samples have been 
exhausted, the use of a local laboratory for the Month 1 samples would be 
accepted for this visit although any laboratory data obtained from a local 
laboratory will not be captured in the eCRF or included in the study analysis.  A 
copy of the local laboratory report would need to be provided to the investigator 
for review and available in the source records.  The subject must also be contacted 
via telephone at the Month 1 visit time point to assess AEs, review concomitant 
medications, and assess investigational product compliance;  
− A physical examination should be performed at the Month 3 visit if an onsite 
Month 1 visit was not performed. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
Month 3 Procedures 
• Perform assessments for calculation of Child-Pugh Score. 
• 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. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests.  
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• Obtain blood samples for: 
− OCA, C4, and FGF-19 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
1-Month Post-Titration Visit Procedures 
• Perform a physical examination.  
• Assess and record AEs. 
• Review and record concomitant medications. 
• Assess investigational product compliance, perform investigational product 
accountability, and review dosing diary with the subject. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Provide the subject with a dosing diary to document his or her dosing. 
• In the event it is not feasible for the subject to return the site for the above referenced 
procedures, the following alternative visit procedures are available, to help ensure 
compliance with the Post-Titration laboratory requirements: 
− At the Up-titration Visit, the subject can be provided with the central laboratory 
collection kit and shipping materials associated with the Post-Titration visit, and 
have the laboratory specimen collection performed at his or her local doctor’s 
office or designated laboratory collection center.  The subject must also be 
contacted via telephone at the Post-Titration Visit time point to assess AEs, 
review concomitant medications, and assess investigational product compliance;  
− If all other options for the collection of the Post-Titration laboratory samples have 
been exhausted, the use of a local laboratory for the Post-Titration samples would 
be accepted for this visit although any laboratory data obtained from a local 
laboratory will not be captured in the eCRF or included in the study analysis.  A 
copy of the local laboratory report would need to be provided to the investigator 
for review and available in the source records.  The subject must also be contacted 
via telephone at the Post-Titration Visit time point to assess AEs, review 
concomitant medications, and assess investigational product compliance;  
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− A physical examination should be performed at the next scheduled visit if an 
onsite post-titration visit was not performed 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
- 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. 
Month 6 Procedures  
• Perform a physical examination. 
• Perform assessment for calculation of Mayo Risk Score. 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.6) 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
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• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
• For subjects who will participate in the PK assessment and are taking BAS or 
aluminum hydroxide- or smectite-containing antacids, they should be instructed to 
not take their regular dose on the morning of the study visit.   
9.7.12. 
Month 9 Procedures 
• Perform assessments for calculation of Child-Pugh Score. 
• 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. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
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• PK assessment in participating subjects at select study sites (see Section 9.7.13). 
• In preparation for the DEXA bone density scan to be done at the Month 12 visit (at all 
study sites where the device is available), subjects who are taking calcium 
supplements should stop taking them for 48 hours before the scan.  If the subject is 
taking any medications for osteoporosis or osteopenia, s/he should not take them on 
the day of the scan. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
9.7.13. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic Assessment 
At selected investigational sites, subjects will have the option to consent to participate in an 
additional OCA PK assessment.  PK samples will be used to support further analysis of OCA 
exposure-response in subjects with PBC.  This is optional and subjects may decline to participate 
without affecting their involvement in the rest of the study.  Consent to participate in the 
assessment can be given at any point during study participation prior to the Month 9 visit.  
Subjects who are following the Child-Pugh B and Child-Pugh C modified dosing regimen may 
participate in the PK assessment and will dose in the clinic at this visit even if the previous dose 
was taken less than 3 days prior; however, every attempt should be made to schedule the 
Month 9 PK visit according to the subject’s established dosing schedule. 
Following collection of the Month 9 fasted samples (refer to Section 9.7.12, subjects who are 
participating in the PK assessment will each receive a single dose of investigational product 
(blinded OCA or placebo tablet) with approximately 240 mL of water.  Subjects taking BAS or 
aluminum hydroxide- or smectite-containing antacids should be instructed to stagger their dosing 
of study medication and UDCA, ensuring at least 4 hours between doses of the BAS and/or these 
antacids and the study medication (and UDCA).   
Serial blood samples will be obtained for measurement of OCA and its conjugates prior to 
dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours post dose.  Samples should be collected 
within a window of ±5 minutes of the scheduled sample time.  Subjects should not drink 
additional water for 1 hour after taking the dose of investigational product and will remain fasted 
until the 4-hour sample is collected.  Lunch will be provided following collection of the 4 hour 
PK sample; the lunch will be a meal replacement drink with no other food allowed until after the 
final 6-hour post-dose sample is collected.  Samples will be stored for up to 5 years after the end 
of the study and will be destroyed after 5 years if not analyzed. 
9.7.14. 
Month 12 Procedures 
• Perform a physical examination (including smoking and alcohol consumption habits). 
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• Perform assessment for calculation of Mayo Risk Score. 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Quality of Life and Subject questionnaires and (see Section 11.1.2.2 
and Section 12.2.6). 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
• Conduct a DEXA bone density scan (at all study sites, where the device is available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable. 
• Perform an endoscopy (at all study sites, where device is available) to assess the 
presence or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for: 
− OCA, C4, and FGF-19 
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− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
9.7.15. 
Month 3 and Month 9 Continued Follow-Up Procedures (±2 weeks) 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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 
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− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.16. 
Month 6 Continued Follow-Up Procedures (Semi-annually [±2 weeks]) 
• Perform assessment for calculation of Mayo Risk Score. 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate 
and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.6) 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Review and record any nonstudy 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 (refer to Section 7.4). 
• Assess investigational product compliance, perform accountability, and review dosing 
diary with the subject. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− Markers of hepatic fibrosis and/or inflammation (including ELF). 
− Blood sample for future analysis (refer to Section 11.1.2.3). 
• At the semi-annual visit, in preparation for the DEXA bone density scan to be done at 
the annual visit (at all study sites where the device is available), subjects who are 
taking calcium supplements should stop taking them for 48 hours before the scan.  If 
the subject is taking any medications for osteoporosis or osteopenia, s/he should not 
take them on the day of the scan. 
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• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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 
9.7.17. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Perform assessment for calculation of Mayo Risk Score. 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
• Conduct a DEXA bone density scan (at all study sites where the device is available); 
document whether the subject stopped taking her/his calcium supplements for 
48 hours before the scan and medications for osteoporosis or osteopenia on the day of 
the scan, if applicable. 
• Perform an endoscopy (at all study sites, where device is available) to assess the 
presence or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Review and record any nonstudy 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 (refer to Section 7.4). 
• Assess investigational product compliance, perform accountability, and review dosing 
diary with the subject. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product. 
• Verify that the subject has fasted for at least 8 hours. 
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− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
9.7.18. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent 
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects discontinue treatment with investigational 
product.  The EOT visit and procedures listed below must be performed as close as possible to 
the subject’s last dose of investigational product.  When a subject discontinues investigational 
product but continues with regularly scheduled study visits, the EOS visit will be completed later 
in the study as the subject’s final study visit.  The actual investigational product discontinuation 
scenario (Table 7) will determine the sequence of the EOT and EOS visits and procedures.  In 
some cases, the EOT visit and procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible to the subject’s last dose of 
investigational product.   
When a subject ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (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 subject 
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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 and EOS procedures in the CRF.  
Table 7: 
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 IP 
Treatment 
Discontinuationb 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
Discontinued 
Semiannual 
contactc 
Telephone 
contact every 6 
months (±2 
weeks) 
Combined Visit, Completed as 
close as possible to last dose IP 
Discontinued 
Record review 
onlyc 
Record review 
only 
Combined visit 
Completed as close as possible 
to last dose IP 
Sponsor 
Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit 
Completed as close as possible 
to last dose IP 
Pregnancy 
Interrupted 
Retained 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
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; IP = investigational product 
a Refer to Section 7.1.2 Schedule of Study Procedures, Table 2 for all procedures and evaluations required at the 
End of Treatment and End of Study Visits.  
b   Includes initiation of commercially available OCA. 
c Outcomes data to be discussed or collected include data related to adjudicated hepatic and cardiovascular event-
related data.  No additional data (e.g. AE, concomitant medication, etc) data will be collected, except as indicated 
in Section 12.1.8. 
Some assessments noted below may be omitted if they have been completed within the 6 months 
(or the timeframe otherwise specified) and so long as safety issues do not warrant repeat testing. 
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Prior to the EOT/EOS Visit: 
If possible to do before the visit, when scheduling the EOT/EOS visit, reiterate dosing 
instructions and advise the subject: 
• If applicable, NOT to take investigational product on the morning of the next visit, 
and  
• To bring the investigational product bottle(s); if applicable, s/he will dose at the 
clinic, 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. 
During the EOT/EOS Visit: 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Perform assessment for calculation of Mayo Risk Score. 
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead ECG. 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.6). 
• Perform TE at all study sites with access to the Fibroscan® TE device (not required at 
EOT/EOS if done within 6 months). 
• Conduct a DEXA bone density scan (at all study sites where the device is available; 
not required at EOT/EOS if done within 6 months); document whether the subject 
stopped taking her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the scan, if applicable. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites); not required at 
EOT/EOS if done within 6 months. 
• Assess and record AEs; all ongoing “related” AEs must be followed until stable or 
resolved. 
• Review and record concomitant medications. 
• Review and record any nonstudy 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 accountability, and review dosing 
diary with the subject; retrieve used bottles, accordingly, and document returns. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
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− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Blood sample for future analysis (refer to Section 11.1.2.3)  
9.7.19. 
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.   
In the event of an inexplicable and acute (for example not explained by natural progression of the 
chronic disease) increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
or total bilirubin is observed during the course of the study, refer to Section 8.4.1.1 to confirm 
whether an unscheduled safety visit is required. 
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 5 mg or 10 mg OCA 
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 subject at each visit to provide enough tablets for daily 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. 
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10.3. 
Investigational Product Storage 
All OCA tablet strengths provided to clinical trial sites in support of clinical study 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 Preparation 
The investigational product will be provided to the distribution center in bulk bottles and 
therefore may be repackaged in unit dose form for administration to subjects before shipping to 
the sites. 
10.5. 
Investigational Product Administration 
Refer to Section 9.1. 
10.6. 
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 subject 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. 
11. 
ASSESSMENT OF EFFICACY  
11.1. 
Assessment of Efficacy  
11.1.1. 
Primary Assessments 
The following primary efficacy assessments will be measured: 
• Death (all-cause) 
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• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• 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 or greater) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
11.1.2. 
Secondary Assessments 
The following secondary efficacy assessments will be measured: 
• Individual components of the primary endpoint 
• Liver-related death 
• Progression to cirrhosis as assessed by the presence of clinical, laboratory, or 
radiological evidence of cirrhosis and/or liver stiffness (Fibroscan® TE), confirmed 
by biopsy unless not medically indicated.  
− Histological assessment of disease progression or improvement using paired 
biopsies in a subset of subjects (defined in Addendum 2). 
• HCC confirmed by 2 complimentary imaging modalities, unless confirmed by biopsy. 
• Liver biochemistry (see Table 11 for list of analytes to be tested) 
• Biomarkers, including other markers of hepatic fibrosis and/or inflammation, to be 
tested will include:  IgM, c-reactive protein (CRP), tumor necrosis factor-α (TNF-α), 
FGF-19, cytokeratin-18 (CK-18) ELF, and Fibroscan (and others as determined 
during the course of the study). 
• Clinical outcomes, including individual component of the primary endpoint (where 
available), liver transplant, and death will be compared to historical controls. 
• PK of OCA and its conjugates. 
• Data will be collected to inform quality of life and cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Quality of life will be 
assessed by questionnaires (PBC-40, EQ-5D-5L, and FIS) administered annually.  
Resource utilization information will be collected from the Medical and Surgical 
Treatment Procedures and Office Visit Log or other CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician visits (subject reported), 
and use of concomitant medications.  
• Endoscopy will be conducted at all study sites where the device is available to assess 
for the presence of oesophageal varix/varices at baseline.  Throughout the study, any 
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endoscopy performed as part of the annual study assessments or standard of care will 
be collected in the case report form to assess for the development of varix/varices. 
11.1.2.1. Noninvasive Assessments of Liver Fibrosis 
• Blood samples for measurement of ELF test and other analytes will be collected.  The 
ELF test assesses: hyaluronic acid (HA), procollagen-3 N-terminal peptide (P3NP), 
and a tissue inhibitor of metalloproteinase 1 (TIMP-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.   
11.1.2.2. Other Secondary Assessments 
• OCA (OCA, tauro-OCA, glyco-OCA, total OCA, OCA-glucuronide) and C4 will be 
assayed to determine bioanalytical concentrations.  Additional analyses may include 
other conjugates or metabolites not yet identified.   
• Quality of Life questionnaires. 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 (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 respondent’s self-rate 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). 
− Fatigue Impact Scale (FIS):  The FIS is a validated 40 question questionnaire 
organized into 3 dimensions:  cognitive, physical, and social.  Each dimension has 
5 levels:  no problem, small problem, moderate problem, big problem, and 
extreme problem (Fisk 1994). 
11.1.2.3. Other Exploratory Evaluations 
• A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved 
in PBC will be conducted for subjects and at study sites willing to provide samples at 
Day 0, Month 12, and every other year at the yearly visits thereafter.  RNA 
expression resulting from treatment with OCA will be assessed at indicated 
timepoints during the study.   Subjects will be permitted to decline to provide a blood 
sample for the genetics study, without affecting their involvement in the study.  
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IRB/IEC review and approval will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will be stored for up to 1 year 
after the end of the study and destroyed after 1 year if not analyzed. 
• Blood samples for future analysis of additional analytes, such as PBC autoantibodies 
and other cytokines and interleukins, may be assayed on an exploratory research 
basis.  Blood samples may also be used to assess other disease or investigational 
product characteristics.  Appropriate serum and plasma samples will be collected at 
selected time points during the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their involvement in the study.  IRB/IEC 
review and approval will be required and willing subjects must specifically consent to 
participate in this evaluation.  The samples will be stored for up to 1 year after the end 
of the study and destroyed after 1 year if not analyzed. 
11.1.2.4. Potential Clinical Outcome Events 
The events listed in Section 12.1.6 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 13.4) 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 suspected 
unexpected serious adverse reaction (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 13.4. 
12. 
ASSESSMENT OF SAFETY 
12.1. 
Adverse Events and Serious Adverse Events 
12.1.1. 
Definitions of Adverse Events 
12.1.1.1. Adverse Event  
An AE is 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) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction. 
Subjects should be questioned in a general way, without leading the subject or asking about the 
occurrence of any specific symptom.  The Investigator should attempt to establish a diagnosis of 
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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. 
12.1.1.2. 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-subject 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 subject 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. 
12.1.1.3. Treatment-Emergent Adverse Event  
A treatment-emergent AE (TEAE) is any event not present prior to the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
12.1.2. 
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/serious adverse event (SAE) and the investigational product is 
determined to be “possible” or “probable” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 
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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 subject’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 
A reaction 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 subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
12.1.3. 
Relationship of Adverse Events to Liver Biopsy 
The Investigator will document her/his opinion of the relationship of an AE to liver biopsy using 
the criteria outlined in Table 9.  
Table 9: 
Relationship of Adverse Events to Liver Biopsy 
Relationship 
Description 
Related 
A reaction that follows a reasonable temporal sequence from the liver biopsy; that follows 
a known or expected response pattern to the liver biopsy. 
Not Related 
Any event that does not meet the above criteria. 
12.1.4. 
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 CRF.  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 subject may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the subject may experience annoying 
discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the subject may experience intolerable 
discomfort or pain. 
12.1.5. 
Reporting of Adverse Events and Serious Adverse Events 
12.1.5.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
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 subject’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE CRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product.  
12.1.5.2. 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 be reported by: 
• E-mail to the SAE email address:  sae@interceptpharma.com 
• Fax using a paper SAE report form:  +1 800 497 8521 
If an SAE is reported by email 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:   
• Subject 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 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 +1 800 497 8521 or 
emailed to sae@interceptpharma.com as soon as possible.  Redacted medical record source 
documentation will be requested for all SAEs and emergency room visits. 
The Investigator is responsible for submitting information on 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 IECs/IRBs must be retained in the appropriate study file(s).  
As instructed by the Sponsor, 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 12.1.6.  
12.1.6. 
Suspected Liver-Related Clinical Outcome Events 
Specified liver-related clinical outcome events may, by definition qualify as SAEs (see 
Section 12.1.1.2).  The Sponsor must be notified of any SAEs within 24 hours of the site 
becoming aware of the event (see Section 12.1.5.2).  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. 
Given that the liver-related clinical outcome events may also meet the criteria of a SUSAR, but 
are considered in aggregate as part of the primary endpoint and the DMC reviews of all safety 
and efficacy data at least quarterly, the Sponsor will not expeditiously report suspected 
liver-related 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 “study event” on the AE 
CRF and will be submitted for adjudication to the Hepatic Outcomes Committee as described in 
Section 13.4. 
The Sponsor will consider the following list of clinical outcome events (MedDRA preferred 
terms) to be disease related and exempt from expeditious regulatory reporting, but will continue 
to report them in a nonexpeditious 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 or oesophageal varices haemorrhage), hepatic encephalopathy (preferred term: 
hepatic encephalopathy),  spontaneous bacterial peritonitis (preferred term: peritonitis bacterial), 
ascites (preferred term: ascites), and histological or clinical progression to cirrhosis (preferred 
term: hepatic cirrhosis). 
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12.1.7. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the CRF 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 subject’s AE CRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the Medical Monitor, 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 subject 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. 
12.1.8. 
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 12.1.5.2. 
SAEs that occur in subjects 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 12.1.5.2.  
12.1.9. 
Notification of Poststudy 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 12.1.5.2. 
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 12.1.5.2. 
12.1.10. 
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 subject 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 subject 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 CRF.  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 subjects 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 CRF. 
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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. 
12.1.11. 
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 sae@interceptpharma.com or faxed to 
+1 800 497 8521.   The subject and neonate must be followed for outcome information and/or as 
considered appropriate by the Investigator and Sponsor. 
The subject 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 subject must have a negative pregnancy test before restarting investigational product.  If a 
subject’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 12.1.5 must also be followed. 
12.2. 
Other Safety Parameters 
12.2.1. 
Medical History/Demographics 
A complete medical history and PBC disease-specific history will be obtained from the subject at 
Screening.  Smoking and alcohol consumption history and current habits will be recorded.  
Demographic characteristics (age, gender, race, and ethnicity) will be recorded. 
12.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the timepoints specified in the Schedule of Study Procedures (Section 7.1.2).  A basic physical 
examination should be performed, including all body systems pertinent to the subject.  Any 
clinically significant abnormality should be reported on the AE CRF page for findings that 
appear after consent, and on the medical history CRF for any finding present prior to consent.  
Information about smoking and alcohol consumption habits will be collected at the same 
(follow-up) timepoints as the physical exam. 
12.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits: height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure.  When taking heart rate, respiratory rate, and blood 
pressure readings, subjects should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
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12.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected at the Screening Visit 1, Month 12, and at EOT/EOS.  
The Investigator or designee will review the 12-lead ECG and findings will be recorded in the 
CRF as normal, abnormal but not clinically significant, or abnormal and clinically significant.  
Any clinically significant abnormality on ECGs should be reported on the AE CRF page.  
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 subject’s initials, Subject ID number, 
date, and time. 
12.2.5. 
Dual Emission X-Ray Absorptiometry 
A bone density assessment will be done using the DEXA scan. 
12.2.6. 
Subject Questionnaires 
Information about the subject’s PBC disease history (ie, date of diagnosis, treatment history, 
pruritus history, signs and symptoms, and including smoking history) will be collected during 
Screening.  At subsequent study visits (see Section 7.1.2), subjects will be asked to complete the 
following questionnaires; they may be asked to initial and date to document confirmation of their 
responses, and the questionnaires should be filed in the subject’s study records.  These may 
require transcription to the CRF by study site staff. 
• 5-D Pruritus Questionnaire:  This is a questionnaire that has been validated in several 
different diseases.  It assesses symptoms in terms of 5 domains: degree, duration, 
direction, disability and distribution (Elman 2010). 
• Pruritus VAS:  A Visual Analogue Scale (VAS) will also be used to assess pruritus in 
individual subjects. 
12.2.7. 
Laboratory Assessments 
Subjects will be instructed to attend each of their study visits (except Screening) in a fasted state, 
and subjects should remain fasted until their blood samples have been collected.  At each visit, 
the Investigator or designee will verify that the subject has fasted for at least 8 hours and record 
fasting status in the source and CRF.  If the subject reports having eaten (water is permitted) 
within 8 hours, the Investigator or designee will document accordingly in the source and CRF 
and remind the subject that fasting is required prior to all study visits. 
Blood samples for serum chemistry and hematology will be collected at every visit as detailed in 
the Schedule of Study Procedures (Section 7.1.2).  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 by the central clinical laboratory in a study specific laboratory 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 subjects 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 
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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, and the normal reference ranges 
for liver biochemistries are shown in Appendix C. 
Table 11: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry  
Albumin, blood urea nitrogen (BUN), 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 very low density 
lipoprotein [VLDL] fractions and triglycerides[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 
Prothrombin time (PT), partial thromboplastin time 
(PTT), international normalized ratio (INR) 
Urinalysis 
pH, specific gravity, total protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, 
albumin, creatine, leucocytes, nitrates, 
albumin/creatine ratio (if positive) 
Biomarkers of Hepatic Fibrosis and/or Inflammation  
IgM, C-reactive protein (CRP), TNF-α, FGF-19, CK-
18, ELF, and others as determined during course of 
study  
Genetics 
DNA including single-nucleotide polymorphisms 
(SNPs) that may be involved in PBC; RNA 
Blood Sample for Future Analysis 
PBC autoantibodies and other cytokines and 
interleukins TBD 
Other 
OCA (parent and conjugates [glyco and tauro], 
OCA-glucuronide) and C4 
The Investigator should manage subjects with clinically significant lipoprotein abnormalities 
using local standard of care procedures as appropriate after assessing the individual subject’s 
total cardiovascular risk profile. 
Urine-based β-hCG pregnancy tests will be performed in female subjects of childbearing 
potential per protocol specified visits.  If a urine pregnancy test is positive, a serum pregnancy 
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test must be performed to confirm the result.  If positive, the Sponsor must be notified and the 
subject will be followed, as outlined in Section 12.1.11 through pregnancy outcome. 
MELD scores, Child-Pugh score, and MRS will be calculated at screening, and at quarterly 
(MELD and Child-Pugh scores) or semi-annual (MRS) visits based on serum chemistry and 
coagulation. 
13. 
STATISTICAL METHODS 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
hypothesis tests, will be prepared and approved by the Sponsor and its designees prior to the first 
interim analysis, propensity score determination, and unblinding of the double-blind subject 
treatment assignments. 
13.1. 
Efficacy Analysis 
13.1.1. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
• The Intent-to-Treat (ITT) Population will include all randomized subjects who 
receive any amount of investigational product (OCA or placebo).  The ITT 
Population will be the primary population used for efficacy analyses.  Treatment 
assignment will be based on the randomized treatment. 
• The Per Protocol (PP) Population will include all ITT subjects who do not have any 
major protocol violations that potentially affect the efficacy conclusion.  Treatment 
assignment will be based on the randomized treatment. 
• The Safety Population will include all subjects who received any amount of 
investigational product (placebo or OCA).  The Safety Population will be the primary 
population used for safety analyses.  Treatment assignment will be based on the 
treatment actually received. 
• The PK Population will include all OCA subjects who have at least one confirmed 
fasted analyzable sample.  Subjects must have been fasting for approximately 8 hours 
prior to the visit and must not have any major protocol deviations that potentially 
affect exposure levels.  The PK population will be used for OCA PK analyses.  
• The Overall Historical Control Population will include subjects from the United 
Kingdom (UK) -PBC Group and Global PBC Study Group databases with 
demonstrated comparability to randomized subjects in this clinical study (747-302) 
with respect to both subject characteristics and disease progression. 
• The UK-PBC Historical Control Population will include subjects from the UK-PBC 
Group databases with demonstrated comparability to randomized subjects in this 
clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
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• The Global PBC Historical Control Population will include subjects from the Global 
PBC Study Group database with demonstrated comparability to randomized subjects 
in this clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
13.1.1.1. Comparability of Historical Controls 
Utilization of both historical control/observational databases (UK-PBC and Global PBC Study 
Group), with more than 6000 subjects each, allow for a rigorous subject level meta-analysis.  The 
historical databases include long-term follow up, detailed subject-level information such as 
baseline clinical characteristics, longitudinal liver biochemistry, and long-term outcomes, and 
span a broad range of subject characteristics that may influence disease (disease state, age, 
gender, and regional differences in standard of care).  Historical controls from both databases 
will be chosen based on the same study inclusion/exclusion criteria.  Propensity score matching 
method will be utilized to select historical controls that match the treated subjects using available 
covariates. The adequacy of matching will be assessed by statistical methods described under 
Section 13.1.8.  
13.1.2. 
Determination of Sample Size 
The target population is subjects who are at higher risk of liver-related clinical complications. 
Eligible subjects will have a diagnosis of PBC with bilirubin levels >ULN and ≤5x ULN and/or 
ALP >3× ULN.  The following assumptions were used in sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.6 at 8 years with a hazard 
ratio of 0.60, and total study duration of 10 years (from first subject enrolled), 
allowing for 4 years of subject accrual and 6 years of follow up. 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance. 
• Two interim analyses and one final analysis are planned.  The first interim analysis 
will be performed when 50% of the target events are accrued and the second interim 
will be performed when 75% of the target events are accrued.  
• A dropout rate of 10% is assumed 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
13.1.2.1. Sample Size Monitoring 
Conducting a long-term outcomes study given the low disease prevalence, relatively slow 
disease progression, and ethical considerations, which in combination will impact recruitment 
and event rates, is inherently difficult.  As stated in ICH E9, in long-term trials there is an 
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opportunity to check the assumptions that underlay the original design and sample size 
calculations.  The power stated above depends on the total number of events.  Thus, the overall 
survival function can be estimated without unblinding. 
Therefore, the aggregate event rate and sample size based on recruitment and retention will be 
evaluated in a blinded manner quarterly.  This evaluation will determine if any increases in 
number of subjects are required in order to obtain a total of 127 adjudicated events for the final 
analysis in the combined groups.  Specifically, the pooled number of events will be available 
during the study in a blinded manner, without any knowledge of the comparative efficacy in the 
treatment groups.  This method for evaluating the sample size does not inflate the type I error 
rate.  Additional subjects may be enrolled as appropriate. 
13.1.3. 
Primary Efficacy Analysis 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
• Liver transplant 
• MELD score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
The primary efficacy analysis will compare OCA to placebo with respect to the primary efficacy 
endpoint using the ITT population.  Only adjudicated events will be included in analyses.  The 
2 treatment groups will be compared 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 determined based on a Cox regression model stratified by 
randomization strata to estimate the magnitude of the effect.  The same analyses for primary 
efficacy endpoints will be performed for PP population as a sensitivity analysis.  
13.1.4. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints will compare OCA to placebo on the following: 
• Time to first occurrence of MELD score ≥15 
• Time to liver transplant or death (all-cause) 
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• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare OCA to placebo in the ITT population with 
respect to the key secondary efficacy endpoints.  Only adjudicated events will be included in 
time-to-event analyses.  The comparison (hypothesis testing) will be conducted as specified in 
Section 13.1.10 in a sequential closed testing gate-keeping procedure, provided that the primary 
efficacy endpoint comparison is statistically significant in favor of the OCA treatment group.  If 
the primary comparison is not statistically significant then comparison of the secondary 
endpoints will be considered as descriptive and exploratory.  This procedure controls the study-
wise type I error. 
The 2 treatment groups will be compared using the same methodology as specified for the 
primary efficacy analysis (Section 13.1.3).  The same analyses for key secondary efficacy 
endpoints will be performed for PP population as a sensitivity analysis. 
Analyses of change from Baseline to end of study in ALP and total bilirubin will be compared 
between treatment groups using analysis of covariance (ANCOVA) with change from Baseline 
as the dependent variable including treatment group and randomization stratification factor as 
fixed effects and the Baseline values as a covariate.  The same analysis will be carried out using 
percentage change from Baseline as the dependent variable. 
Descriptive statistics of the laboratory values will be summarized by treatment group.  The 
results, change from Baseline, and percentage change from Baseline values as well as estimates 
of least-square means, standard errors, and 95% CIs will be presented by treatment group.  
Estimates of the mean difference between treatment groups, the standard error of the difference, 
and 95% CI of the difference will be presented.  
13.1.5. 
Additional Secondary Efficacy Analyses 
The following time-to-event secondary efficacy analyses will compare OCA versus placebo 
using the ITT population: 
• Time to each component of the primary efficacy endpoint (except MELD score ≥15 
which is captured above) 
• Time to development of varix/varices 
• Progression to cirrhosis 
• Time to occurrence of HCC 
• Time to liver-related death 
• Time to liver-related death or liver transplant 
• Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls as described below in Section 13.1.8. 
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Analyses of changes in liver biochemistry (GGT, ALT, AST, conjugated bilirubin, albumin, and 
INR) will be summarized and analyzed using the same methodology as specified in 
Section 13.1.4 for the key secondary analyses of change in ALP and total bilirubin. 
Progression to cirrhosis will be assessed in the subset of subjects considered noncirrhotic at 
Baseline using available medical history, clinical, and laboratory assessments as well as baseline 
TE, where available.  Specifically, subjects with no clinical, laboratory, or radiological evidence 
of cirrhosis at baseline and/or a TE liver stiffness of <16.9 kPa (Corpechot 2012) will be 
considered noncirrhotic (See Section 9.7.3.1).  Progression to cirrhosis will be assessed by the 
development of clinical, laboratory, or radiological evidence of cirrhosis and/or when liver 
stiffness increases to ≥16.9 kPa during the study in which case histological progression to 
cirrhosis should be confirmed by biopsy unless not medically indicated. Using this definition for 
progression to cirrhosis, the percentage of noncirrhotic subjects progressing to cirrhosis during 
the treatment period will be summarized by treatment group and compared using a Cochran–
Mantel–Haenszel test stratified by the randomization stratification factor.  
For those subjects enrolled in the biopsy substudy (defined in Addendum 2) progression to 
cirrhosis identified by the above criteria and improvement in fibrosis/cirrhosis will be confirmed 
by paired biopsy.  Analyses for the histological assessment conducted as part of the biopsy 
substudy are defined in Addendum 2). 
Analyses of changes in MELD score, Child-Pugh score, MRS, IgM, CRP, TNF-α, FGF-19, 
CK-18, C4, and ELF score will be summarized and analyzed using the Wilcoxon Rank Sum Test 
to compare treatment groups.  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. 
13.1.5.1. Association of Biochemistry with Clinical Outcomes and Clinical Benefit  
The association between biochemistry including ALP and bilirubin with clinical outcomes will 
be assessed and the clinical benefit of OCA using biochemistry as a surrogate endpoint will be 
evaluated.  Detailed analysis will be described in the SAP.  
Based on the association between biochemical changes and clinical outcomes described above, 
clinical benefit of OCA using biochemistry as a surrogate endpoint for key subpopulations of 
interest will be evaluated. This analysis will be further described in the SAP. 
13.1.6. 
Exploratory Efficacy Analyses 
13.1.6.1. Responder Analyses 
The percentage of subjects with a decrease in ALP of ≥15% and ≥40% from Baseline will be 
summarized by treatment group.  In addition, the percentage of subjects with ALP ≤ULN will be 
summarized by treatment group. 
The percentage of subjects that meet the criteria of a responder based on each of the definitions 
below will be summarized by treatment group.  The response classification at baseline will also 
be included in the summary:  
• ALP ≤3x ULN and AST ≤2x ULN and total bilirubin ≤ULN (Corpechot 2008) 
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• ALP ≤1.5x ULN and AST ≤1.5x ULN and total bilirubin ≤ULN (Corpechot 2011) 
• ALP ≤1.67x ULN and total bilirubin ≤ULN (Momah 2012) 
• Normal bilirubin (values ≤ULN) and normal albumin (values ≥lower limit of normal) 
(Kuiper 2009) 
• ALP ≤1.76x ULN (Kumagi 2010) 
Responder analyses will compare treatment groups using a Cochran–Mantel–Haenszel test 
stratified by the randomization stratification factor.  Missing values will be considered as a 
non-responder.   
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints 
Sufficient data will be collected on resource utilization and quality of life to undertake 
cost-effectiveness analyses that are relevant to the major countries taking part in this study.  
Resource utilization data on hospitalizations, healthcare provider visits, and medications will be 
combined with appropriate national unit costs to calculate a cost per patient per year in the study. 
Quality of life data from patient-reported outcomes measures will be combined with survival 
data to calculate quality adjusted time in the study per patient.  Cost-effectiveness analyses will 
report the incremental cost per major clinical outcome averted, liver-related death averted, 
life-year gained and quality-adjusted life year gained, including OCA as part of usual care versus 
usual care without OCA.  Analyses will be conducted within the study and using a lifetime 
perspective.  A separate economic analysis plan will be prepared and reported separately from 
this protocol. 
13.1.8. 
Supportive Analysis 
Per the International Conference on Harmonisation (ICH) E10 guidance, “where no obvious 
single optimal external control exists, it may be advisable to study multiple external controls”.  
In order to address the risks associated with the inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare clinical outcomes in the OCA treatment arm to 
historical controls, which serves as an external control for supportive analysis.   
In an attempt to avoid the inherent biases with historical controls and to maintain the integrity of 
this comparison, one can invoke matching methods to optimize comparability and find a 
historical control that is “similar” to a participating subject.  The historical database control 
should be as similar as possible to the study population and should have been exposed to a 
similar standard of care (see Section 5.5.2.3). 
A propensity score can be used to reduce bias through matching, stratification, regression 
adjustment, or some combination.  Propensity scores use information from a pool of patients who 
do not participate in the study (historical controls) to identify what would have happened to 
participating subjects in the absence of the treatment.  By comparing how outcomes differ for 
treated subjects relative to historical controls, it is possible to estimate the effects of the treatment 
between the treated subjects and the matched natural history subjects. 
A full range of covariates across which the treatment and historical controls might differ will be 
considered to mitigate potential bias. Although the results of using matching controls are 
conditional only on the observed covariates, if one has the ability to measure many of the 
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covariates that are believed to be related to the treatment assignment, then one can be fairly 
confident that approximately unbiased estimates for the treatment effect can be obtained.  Both 
UK-PBC Group and the Global PBC Study Group formally collect numerous covariates that 
could be used for propensity score estimation including standard of care, eg, UDCA. 
Historical controls will be chosen based on the same inclusion/exclusion criteria where possible. 
Propensity scores will be estimated using the available covariates that predict receiving the 
treatment.  Only covariates and not outcome variables will be included in the propensity score 
estimation, to avoid biased results that are in favor of one treatment.  
The covariates and factors collected in the historical databases will be specified in the SAP. 
Propensity scores will be estimated first through a logistic regression model with treatment group 
as the dependent variable and the above covariates/factors as independent variables.  Then the 
stratum boundaries are determined based on the propensity score values for both groups (OCA 
population and control [historical and randomized placebo]) combined or in the OCA population 
or historical control group alone.  Based on recommendations in the literature, quintiles of the 
estimated propensity score from the combined group will be used to determine the stratum 
boundary cut-offs for the different strata.  
The baseline characteristics between treated and natural history subjects in the matched dataset 
will be summarized and presented in a tabular format.  Statistical methods such as Wilcoxon 
Rank-Sum test will be used to assess the balance for baseline covariates.  The standardized 
difference and variance ratios for these covariates will also be calculated.  In addition, box plots 
of propensity scores for treated and natural history subjects will be separately presented, to 
further assess the adequacy of matching.  
A third-party statistician(s) will perform the propensity score modeling and matching.  This 
third-party statistician(s) will be separate and independent from the statistician(s) who will assess 
the success of matching and perform efficacy analyses.  Outcome events collected in the 
historical database are:  death (liver-related and all-cause), liver transplant, HCC, and other.  
Other is defined as cirrhosis or decompensation such as ascites, variceal bleed, and 
encephalopathy. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare randomized OCA-treated subjects in the ITT population and historical 
controls (Overall Historical Control Population: both the UK-PBC Group and Global PBC Study 
Group databases) on the following outcomes: 
• Time to death (all-cause) 
• Time to liver-related death 
• Time to liver transplant 
• Time to liver transplant or death (all-cause) 
• Time to liver transplant or liver-related death 
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 
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will be presented.  The hazard ratio and 95% CI will be determined based on a Cox regression 
model stratified by randomization strata to estimate the magnitude of the effect. 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
Although the study is designed as a placebo-controlled study, the DMC may recommend changes 
to study conduct based on the pre-specified interim analyses (see Section 13.1.12), including the 
potential use of a revised primary efficacy analysis.  This analysis would compare all subjects in 
the OCA population, to all control subjects (randomized placebo and historical controls) on time 
to liver transplant or death (all-cause), using similar statistical methodology as specified above. 
Notably, the planned primary analysis would not be revised without prior agreement with 
regulatory authorities. 
13.1.9. 
Handling of Dropouts or Missing Data 
Subjects who discontinue investigational product are expected to continue in the study until 
study termination. 
Missing data will be assumed to be missing at random.  In order to determine the effect of 
missing data on the analysis, efficacy endpoints will be analyzed using different methods of 
imputation as described below. In addition, the same analyses for primary and key secondary 
endpoints based on ITT and PP populations will be performed to assess robustness of analysis 
results.  During the conduct of the study, the DMC may recommend refining the missing data 
strategy to better address the observed pattern of missing data, based on blinded monitoring of 
the data. 
13.1.9.1. Time to Event Endpoints 
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 investigational product dosing). 
For analyses of the percentage of subjects with an event, subjects with no data after 
randomization will be considered to have an event. 
All time to event endpoints include only adjudicated events.  Sensitivity analyses may consider 
all events regardless of adjudication.  Events with discrepant adjudication will be analyzed using 
both results. 
13.1.9.2. Quantitative Endpoints 
For efficacy endpoints that utilize an ANCOVA model, observed cases will serve as the primary 
analysis.  Sensitivity analyses to assess the effect of missing data may be conducted where 
missing data is imputed using last observation carried forward. 
Sensitivity analyses of ANCOVA models will also be evaluated using a restricted maximum 
likelihood based mixed-effect repeated measures model where no imputations will be made for 
missing values.   
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13.1.9.3. Responder Endpoints 
In an efficacy analysis in which subjects are classified as either a responder or a non-responder 
(binary outcome) based on dichotomizing a continuous variable, any subject who does not 
provide an assessment at the specified time point for the defining of response will be considered 
to be a non-responder.  That is, for the percentage of responders, the subject will be included in 
the denominator and will not contribute to the numerator. 
For sensitivity analyses using only “observed cases,” subjects who do not provide an assessment 
at the specified timepoint for the defining of response will not be included.  That is, for the 
percentage of responders, the subject will not be included in the numerator or the denominator. 
13.1.10. 
Multiple Comparisons/Multiplicity 
The key secondary efficacy endpoints are as follows: 
• Time to MELD score ≥15 
• Time to first occurrence of liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The hypothesis testing of key secondary analyses will compare placebo and OCA and will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of OCA.  If the primary comparison is not statistically significant 
then comparison of the secondary endpoints will be considered as descriptive and exploratory.  
This procedure controls the study-wise type I error.  
• First (step 1) placebo and OCA will be compared with respect to the primary efficacy 
endpoint.  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• The time to MELD score ≥15 will be compared between placebo and OCA (step 2).  
If the comparison achieves statistical significance at 2-sided 0.05 level in favor of 
OCA group, then 
• The time to liver transplant or death (all-cause) will be compared between placebo 
and OCA (step 3).  If the comparison achieves statistical significance at 2-sided 
0.05 level in favor of OCA group, then 
• Change from Baseline in total bilirubin will be compared between placebo and OCA 
(step 4).  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• Change from Baseline in ALP at the end of study will be compared between placebo 
and OCA (step 5). 
If at any step defined above the comparison is not statistically significant at the 2-sided 
0.05 level then the remaining comparisons in the stated hierarchy will be considered descriptive 
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and exploratory.  The study-wise type I error will be maintained with the above closed 
procedure. 
Additional efficacy endpoints will be analyzed; however, hypothesis tests will be applied for 
descriptive and exploratory purposes only.  
13.1.11. 
Examination of Subgroups 
The primary and secondary efficacy endpoints will be analyzed for subject subgroups based on 
the ITT population.  Subgroups will be assessed at Baseline and only if there are a sufficient 
number of subjects in each group (eg, >5 subjects per group). 
Baseline subgroups of interest are as follows:  age, age at PBC diagnosis, sex, race, body mass 
index, ALP level, bilirubin level, use of UDCA, years since diagnosis of PBC, and geographic 
region. 
The primary efficacy endpoint will also be assessed across the spectrum of PBC disease stage as 
defined by Rotterdam criteria (Kuiper 2009)  
• Early (normal albumin and normal bilirubin) 
• Moderate (abnormal albumin or abnormal bilirubin) 
• Advanced (abnormal albumin and abnormal bilirubin) 
The primary efficacy endpoint will also be assessed for the following clinically relevant 
subpopulations. 
• Monotherapy in patients who are intolerant or non-responsive to UDCA  
• Elderly patients 
Assuming a strong correlation between biochemistry and clinical outcomes using the total study 
population (Section 13.1.5.1) is observed, we will further assess the biochemical improvement in 
relevant subpopulations as applicable (eg, Rotterdam disease severity and monotherapy) and 
estimate the reduction in risk of clinical outcomes associated with the biochemical improvement. 
Additional details regarding statistical methods and subgroup definitions will be provided in the 
SAP. 
13.1.12. 
Continuous Monitoring and Interim Analyses 
Blinded safety reports including the accrual of events, drop outs, and/or loss of subjects to 
commercially available OCA will be reviewed by the DMC on a regular basis.  
Two planned interim analyses of the liver-related outcomes will be conducted using the Lan-
DeMets O’Brien-Fleming boundaries (Reboussin 2000).  Both interim analyses will be pre-
specified and will occur after accrual of 50% (64 events) and 75% (96 events) of clinical 
outcome events, respectively.  
The DMC will review the available efficacy data in conjunction with detailed safety data and 
other relevant information to recommend continuation, modification, or cessation (for efficacy) 
of the study beyond each interim analysis.  Modification of the study would not take place 
without prior agreement with regulatory authorities. 
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13.2. 
Safety Analysis 
Safety data, including AEs and clinical laboratory observations, will be summarized by treatment 
group using the Safety Population. 
13.2.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary of Regulatory Activities.  Summary tables of 
treatment-emergent AEs will be provided.  The incidence of TEAEs will be tabulated by system 
organ class and preferred term for each treatment group, and by severity and relationship to 
treatment.  Tables of TEAEs leading to investigational product discontinuation and SAEs will be 
provided. 
13.2.2. 
Clinical Laboratory Evaluations 
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will be 
presented for all study visits.  Changes from pretreatment to each study visit will also be 
summarized by treatment group. 
13.2.3. 
Additional Safety Analysis 
Additional safety assessments include vital signs and ECGs.  Descriptive statistics of the vital 
sign and ECG parameters will be presented by treatment group and study visit, as well as the 
change from pretreatment at each visit. 
13.2.4. 
Cardiovascular Adjudication Committee 
In addition to potential clinical endpoint events, cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study. Adjudicated cardiovascular events include core 
MACE (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) and expanded 
MACE (unstable angina requiring hospitalization, transient ischemic attack, peripheral or 
coronary revascularization procedures, hospitalization for congestive heart failure).  Other events 
potentially related to adverse cardiovascular outcomes may be included in the Cardiovascular 
Adjudication Committee (CAC) Charter for adjudication.  The adjudication of these events will 
be handled separately from the adjudication of events for assessment of the primary endpoint in 
this study (see Section 13.4). 
13.3. 
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 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. 
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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 subjects.  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 subject treatment information; 
however, the DMC will have access to the database and may unblind individual subject data as 
appropriate.  Summary tables reviewed by the DMC during closed sessions will include an 
overall column containing information regarding all subjects 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, Medical Dictionary for Regulatory Activities (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 subject safety, which alter the 
conduct of this study.  The Investigators will inform the subjects of such actions and the 
protocol, patient information sheet (PIS), and consent will be revised, as appropriate. 
13.4. 
Adjudication Committees 
All suspected liver-related clinical outcomes, 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.   
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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 subject 
treatment or site-specific information.  The assessment of events will be conducted in 
compliance with study-specific procedures, manuals, good clinical practice (GCP), and all other 
applicable regulatory requirements, including the archiving of essential documents.    
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
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 subject’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 CRF.  The CRF 
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 
subject's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
14.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC 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.   
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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the CRF 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 14.2 for more details regarding the audit 
process. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF and/or other subject 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 the Sponsor before he or she can enroll 
any subject 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 subjects to the ethics committee 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 subjects for 
the study.  The protocol must be reapproved by the IRB or 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.  
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, at a minimum annually, and after the study is complete. 
16.2. 
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. 
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16.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated ICF 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 subject. 
16.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential and confidentiality of all subjects will be maintained.  Monitors (eg, 
CRA, Medical Monitor), auditors and inspectors will require access to a subject’s medical notes 
for the purpose of source document verification but the subject’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 subject’s names and identifying information (eg, subject’s 
hospital number, unique subject number).  This list will not be collected by the Sponsor. 
The written information sheet 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 subject 
number/randomization code/subject initials/site number, only. 
When personal data on subjects are stored or processed by computer, the data must be protected 
to prevent their disclosure to unauthorized third parties.  The pertinent sections of the data 
protection laws in which the country is being conducted will be complied with in full. 
The written ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IEC/IRB may require direct access to parts of the hospital 
or study site records relevant to the study, including subject’s medical history. 
17. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the subjects 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 subjects, as applicable. 
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17.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject 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 Medical Monitor. 
17.2. 
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 subject’s safety to be compromised if immediate action is not taken. 
17.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
• Approved ICF (all versions) 
• IRB/EC approvals (of protocol/amendments, subject questionnaires, etc) 
• Form FDA 1572  
• Current medical license 
• Curriculum vitae 
• Laboratory certification and reference ranges 
• Financial disclosure forms 
17.4. 
Ethics Review 
Please see Section 16.1 for the Investigator’s responsibilities regarding ethics review. 
17.5. 
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 subject 
medical files (retained per country specific regulations), completed study subject log and 
confidential subject 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 
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authorization from the Sponsor prior to 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. 
18. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it sponsors consistent 
with the Declaration of Helsinki (Seoul Revision 2008, 
[http://www.wma.net/en/30publications/10policies/b3/index.html, accessed May 22, 2013]).  
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 Study Registries (eg, 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 (when available) 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:  The Sponsor, 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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19. 
LIST OF REFERENCES 
Beuers U, Gershwin M, Gish R, et al. Changing nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Digestive and Liver Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin M, Gish R, et al. Changing nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Gastroenterology. 2015b;149(6):1627-9. 
Beuers U, Gershwin M, Gish R, et al. Changing nomenclature for PBC: From 'cirrhosis' to 
'cholangitis'. Hepatology. 2015c;62(5):1620-2. 
Beuers U, Lindor KD. A major step towards effective treatment evaluation in primary biliary 
cirrhosis. J Hepatol. 2011;55(6):1178-80. 
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and 
long term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871-877. 
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. 
Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: Biochemical response 
to treatment and prediction of long-term outcome. J Hepatol. 2011;55:1361–1367. 
Dickson ER, Grambsch PM, Fleming TR, et al.  Prognosis in primary biliary cirrhosis:  Model 
for decision making.  Hepatology. 1989;10(1):1-7. 
Elman S, Hynan L.S., Gabriel V, and Mayo M.J. The 5-D itch scale: a new measure of pruritus, 
British Journal of Dermatology. 2010;162,587–593. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51:237-267. 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact of fatigue: initial validation of 
the fatigue impact scale. Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
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. 
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. 
Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict 
long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 
2010;105(10):2186-94. 
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Lammers WJ, van Buuren HR, Hirschfield GM, et al. Alkaline phosphatase values are a 
surrogate marker in prediction of transplant-free-survival in patients with primary biliary 
cirrhosis - an international, collaborative analysis.  J Hepatol. 2013; 58(Suppl):S388. 
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. 
Momah N, Silveira MG, Jorgensen R, et al. Optimizing biochemical markers as endpoints for 
clinical trials in primary biliary cirrhosis. Liver Int. 2012;32(5):790-795. 
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. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-3572. 
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. 
Reboussin DM, DeMets, DL, Kim KM, et al.  Computations for Group Sequential Boundaries 
Using the Lan-DeMets Spending Function Method.  Controlled Clin Trials.  2000;21(3):190-207. 
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APPENDIX A. MODIFIED DOSING REGIMEN FOR SUBJECTS WITH 
CHILD-PUGH B/C HEPATIC IMPAIRMENT 
Overview of Modified Dosing Regimen for Subjects with Child-Pugh B or C Hepatic 
Impairment 
An overview of the modified dosing regimen for subjects with Child-Pugh Class B or 
Child-Pugh Class C is presented in Figure 2 and Table 12. 
Subjects who are cirrhotic and classified as Child-Pugh Class B or Child-Pugh Class C will 
initiate a modified treatment regimen with 5 mg OCA or matching placebo once weekly for at 
least 3 months.  Subjects classified as Child-Pugh Class B should eventually titrate to a 
maximum dose of 5 mg OCA or matching placebo once daily, based on tolerability and 
biochemical response.  Subjects classified as Child-Pugh Class C should titrate to a maximum 
dose and frequency of 10 mg OCA or matching placebo twice weekly. 
Figure 2: 
Dosing by Cirrhosis Status and Child-Pugh Score 
 
a  Cirrhosis may be assessed by histology or non-histological methods as defined in Section 9.7.3. 
BIW = twice weekly; QW = once weekly 
Table 12: 
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Modified Dosing Regimen 
Child-Pugh B 
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg once weekly 
5 mg once weekly 
Titration 1b  
(≥Month 3) 
5 mg twice weeklyc 
5 mg twice weeklyc 
Titration 2b  
(≥6 weeks after Titration 1) 
10 mg twice weeklyc 
10 mg twice weeklyc 
Titration 3b 
(≥6 weeks after Titration 2) 
5 mg daily 
NA 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject 
tolerability and/or changes in cirrhosis status or Child-Pugh Score at any time during the study. 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
Modified Dosing Regimen for Subjects with Child-Pugh B Hepatic Impairment 
Subjects with cirrhosis and classified as Child-Pugh B at Screening will follow a modified 
dosing schedule receiving 5 mg OCA or matching placebo once weekly as described in Figure 2.  
After a minimum of 3 months dosing once weekly with 5 mg OCA or matching placebo, and 
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following review of the pre-titration laboratory results to assess safety and tolerability, the dosing 
frequency of 5 mg OCA or matching placebo should be increased to twice weekly (at least 
3 days apart).  Subjects who have maintained the twice weekly dosing frequency for a minimum 
of at least 6 weeks, and meet the dose titration criteria, should up-titrate to twice weekly dosing 
with 10 mg OCA or matching placebo.  Subjects with at least 6 weeks of twice weekly dosing at 
10 mg OCA or matching placebo, and meeting dose titration criteria, should up-titrate to the 
maximum allowed dose of 5 mg OCA or matching placebo once daily.  
Investigators may decrease the dosing frequency (back to once or twice weekly) or dose for any 
subject at any time during the study, as considered clinically appropriate (eg, tolerability). 
Modified Dosing Regimen for Subjects with Child-Pugh C Hepatic Impairment 
Subjects with cirrhosis and classified as Child-Pugh C at Screening will follow a modified 
dosing schedule receiving 5 mg OCA or matching placebo once weekly as described in Figure 2.  
After a minimum of 3 months dosing once weekly with 5 mg OCA or matching placebo, and 
following review of the pre-titration laboratory results to assess safety and tolerability, the dosing 
frequency of 5 mg OCA or matching placebo should be increased to twice weekly (at least three 
days apart).  Subjects who have maintained the twice weekly dosing frequency for a minimum of 
at least 6 weeks, and meet the dose titration criteria, should up-titrate to the maximum allowed 
dose of 10 mg OCA or matching placebo twice weekly.   
Investigators may decrease the dosing frequency (back to once weekly) or dose for any subject at 
any time during the study, as considered clinically appropriate (eg, tolerability).   
Dose Titration due to Change in Cirrhosis or Child-Pugh Score 
Subjects on a modified dosing regimen who demonstrate a change in cirrhosis status and/or 
Child-Pugh Score should have their dose of investigational product modified to match their 
current status per the appropriate dosing regimen (see Section 7.4, Table 5); however, changes to 
the dosing regimen are not mandatory and should be based on clinical judgment as well as 
changes in status. Changes in Child-Pugh Score that result from a transient, explainable change 
in laboratory parameters should be documented appropriately, and should not necessarily result 
in a change to the dosing regimen.  Investigators may contact the Medical Monitor at any time to 
discuss potential changes to dosing.   
Possible scenarios for dosing modifications include: 
• Subjects who develop cirrhosis during the course of the trial with a classification of 
Child-Pugh B or C 
• Subjects with pre-existing cirrhosis who demonstrate a change in the Child-Pugh 
Score from A to B or C at any point in the study   
• Improvement in classification of Child-Pugh Score from C to B  
• Improvement in classification of Child-Pugh Score from B to A; these subjects may 
be eligible to transition to the standard dosing regimen 
Subjects may titrate dose and dosing frequency up or down as appropriate, within the appropriate 
dosing regimen.  Up-titration should be done per Investigator discretion and be guided by the 
pre-titration tolerability assessments outlined in Section 7.4.1.  A 1-Month Post-Titration 
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Assessment must be performed any time a subject’s dose or frequency is up-titrated (see 
Section 7.1.2 and Section 9.7.10). 
Unscheduled Titration Visit, Optional Visit 
An unscheduled up-titration visit may be scheduled for as early as 6 weeks after the initial 
titration visit (or subsequent titration visit) occurs for subjects who are following the modified 
dosing regimen.  The visit procedures required for the unscheduled titration visit are outlined 
below.  Subjects who up titrate at an unscheduled visit will continue to follow the regular visit 
schedule for all other study visits.   
For subjects who up titrate at an unscheduled visit the following procedures will be performed: 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Perform the pre-Titration Tolerability Assessment as outlined in Section 7.4.1. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
- 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. 
For subjects who up titrate at an unscheduled visit: The + 1-week window week related to the 
1-Month Post-Titration visit can be extended for up to an additional 5 weeks to allow for the 
post-titration assessment to be performed during one of the subject’s regularly scheduled study 
visits.  If the window is extended past +1 week allowed visit window, at a minimum, a telephone 
safety contact should then be performed 1-month post-titration. 
 
 
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APPENDIX B. ETHICAL CONDUCT ACCORDING TO THE 
DECLARATION OF HELSINKI FOR COUNTRIES 
PARTICIPATING OUTSIDE THE US (DECLARATION 
OF HELSINKI, FORTELEZA, BRAZIL, 2013) 
 
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Copyright 2013 American Medical Association. All rights reserved.
World Medical Asociation Declaration of Helsinki
Ethical Principles for Medical Research
Involving Human Subjects
World Medical Asociation
Adopted by the 18th WMA General Asembly, Helsinki, Finland, June 1964, and amended by the:
29th WMA General Asembly, Tokyo, Japan, October 1975
35th WMA General Asembly, Venice, Italy, October 1983
41st WMA General Asembly, Hong Kong, September 1989
48th WMA General Asembly, Somerset West, Republic of South Africa, October 196
52nd WMA General Asembly, Edinburgh, Scotland, October 20
53rd WMA General Asembly, Washington, DC, USA, October 202 (Note of Clarification aded)
5th WMA General Asembly, Tokyo, Japan, October 204 (Note of Clarification aded)
59th WMA General Asembly, Seoul, Republic of Korea, October 208
64th WMA General Asembly, Fortaleza, Brazil, October 2013
Preamble
1. The World Medical Asociation (WMA) has developed the Dec-
larationofHelsinkiasastatementofethicalprinciplesformedi-
cal research involving human subjects, including research on
identifiable human material and data.
The Declaration is intended to be read as a whole and each of
its constituent paragraphs should be aplied with consider-
ation of al other relevant paragraphs.
2. ConsistentwiththemandateoftheWMA,theDeclarationisad-
dresed primarily to physicians. The WMA encourages others
who are involved in medical research involving human subjects
to adopt these principles.
General Principles
3. TheDeclarationofGenevaoftheWMAbindsthephysicianwith
the words, “The health of my patient wil be my first consider-
ation,”andtheInternationalCodeofMedicalEthicsdeclaresthat,
“A physician shal act in the patient's best interest when provid-
ing medical care.”
4. It is the duty of the physician to promote and safeguard the
health,wel-beingandrightsofpatients,includingthosewhoare
involvedinmedicalresearch.Thephysician'sknowledgeandcon-
science are dedicated to the fulfilment of this duty.
5. Medical progres is based on research that ultimately must in-
clude studies involving human subjects.
6. Theprimarypurposeofmedicalresearchinvolvinghumansub-
jects is to understand the causes, development and efects of
diseasesandimprovepreventive,diagnosticandtherapeuticin-
terventions (methods, procedures and treatments). Even the
bestproveninterventionsmustbeevaluatedcontinualythrough
research for their safety, efectivenes, eficiency, acesibility
and quality.
7. Medicalresearchissubjecttoethicalstandardsthatpromoteand
ensure respect for al human subjects and protect their health
and rights.
8. Whiletheprimarypurposeofmedicalresearchistogeneratenew
knowledge, this goal can never take precedence over the rights
and interests of individual research subjects.
9. Itisthedutyofphysicianswhoareinvolvedinmedicalresearch
to protect the life, health, dignity, integrity, right to self-
determination,privacy,andconfidentialityofpersonalinforma-
tion of research subjects. The responsibility for the protection
ofresearchsubjectsmustalwaysrestwiththephysicianorother
health care profesionals and never with the research subjects,
even though they have given consent.
10. Physiciansmustconsidertheethical,legalandregulatorynorms
andstandardsforresearchinvolvinghumansubjectsintheirown
countries as wel as aplicable international norms and stan-
dards.Nonationalorinternationalethical,legalorregulatoryre-
quirementshouldreduceoreliminateanyoftheprotectionsfor
research subjects set forth in this Declaration.
1. Medical research should be conducted in a maner that mini-
mises posible harm to the environment.
12. Medicalresearchinvolvinghumansubjectsmustbeconducted
onlybyindividualswiththeapropriateethicsandscientificedu-
cation, training and qualifications. Research on patients or
healthyvoluntersrequiresthesupervisionofacompetentand
apropriately qualified physician or other health care profes-
sional.
Clinical Review & Education
Special Comunication
jama.com
JAMA
November 27, 2013
Volume 310, Number 20
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Copyright 2013 American Medical Association. All rights reserved.
13. Groups that are underepresented in medical research should
be provided apropriate aces to participation in research.
14. Physicians who combine medical research with medical care
should involve their patients in research only to the extent that
this is justified by its potential preventive, diagnostic or thera-
peuticvalueandifthephysicianhasgodreasontobelievethat
participation in the research study wil not adversely afect the
health of the patients who serve as research subjects.
15. Apropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be en-
sured.
Risks, Burdens and Benefits
16. Inmedicalpracticeandinmedicalresearch,mostinterventions
involve risks and burdens.
Medical research involving human subjects may only be con-
ductediftheimportanceoftheobjectiveoutweighstherisksand
burdens to the research subjects.
17. Al medical research involving human subjects must be pre-
ceded by careful asesment of predictable risks and burdens
to the individuals and groups involved in the research in com-
parisonwithforeseablebenefitstothemandtootherindividu-
als or groups afected by the condition under investigation.
Measurestominimisetherisksmustbeimplemented.Therisks
mustbecontinuouslymonitored,asesedanddocumentedby
the researcher.
18. Physiciansmaynotbeinvolved
inaresearchstudyinvolvinghu-
mansubjectsunlestheyareconfidentthattheriskshaveben
adequately asesed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive prof of definitive outcomes, physi-
cians must ases whether to continue, modify or imediately
stop the study.
Vulnerable Groups and Individuals
19. Somegroupsandindividualsareparticularlyvulnerableandmay
haveanincreasedlikelihodofbeingwrongedorofincuringad-
ditional harm.
Al vulnerable groups and individuals should receive specifi-
caly considered protection.
20. Medical research with a vulnerable group is only justified if the
research is responsive to the health neds or priorities of this
group and the research canot be caried out in a non-
vulnerable group. In adition, this group should stand to ben-
efit from the knowledge, practices or interventions that result
from the research.
Scientific Requirements and Research Protocols
21. Medicalresearchinvolvinghumansubjectsmustconformtogen-
eraly acepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as apropriate, ani-
mal experimentation. The welfare of animals used for research
must be respected.
2. The design and performance of each research study involving
human subjects must be clearly described and justified in a re-
search protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have ben adresed. The protocol should include
information regarding funding, sponsors, institutional afilia-
tions, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compen-
sating subjects who are harmed as a consequence of participa-
tion in the research study.
In clinical trials, the protocol must also describe apropriate ar-
rangements for post-trial provisions.
Research Ethics Comites
23. Theresearchprotocolmustbesubmitedforconsideration,com-
ment, guidance and aproval to the concerned research ethics
comite before the study begins. This comite must be
transparent in its functioning, must be independent of the re-
searcher, the sponsor and any other undue influence and must
be duly qualified. It must take into consideration the laws and
regulations of the country or countries in which the research is
to be performed as wel as aplicable international norms and
standardsbutthesemustnotbealowedtoreduceoreliminate
anyoftheprotectionsforresearchsubjectssetforthinthisDec-
laration.
The comite must have the right to monitor ongoing stud-
ies.Theresearchermustprovidemonitoringinformationtothe
comite, especialy information about any serious adverse
events. No amendment to the protocol may be made without
consideration and aproval by the comite. After the end of
thestudy,theresearchersmustsubmitafinalreporttothecom-
mite containing a sumary of the study’s findings and con-
clusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of re-
search subjects and the confidentiality of their personal infor-
mation.
Informed Consent
25. Participation by individuals capable of giving informed consent
as subjects in medical research must be voluntary. Although it
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may be apropriate to consult family members or comunity
leaders, no individual capable of giving informed consent may
be enroled in a research study unles he or she frely agres.
26. In medical research involving human subjects capable of giving
informed consent, each potential subject must be adequately
informed of the aims, methods, sources of funding, any pos-
sible conflicts of interest, institutional afiliations of the re-
searcher,theanticipatedbenefitsandpotentialrisksofthestudy
and the discomfort it may entail, post-study provisions and any
other relevant aspects of the study. The potential subject must
be informed of the right to refuse to participate in the study or
to withdraw consent to participate at any time without repri-
sal. Special atention should be given to the specific informa-
tionnedsofindividualpotentialsubjectsaswelastothemeth-
ods used to deliver the information.
Afterensuringthatthepotentialsubjecthasunderstodthein-
formation, the physician or another apropriately qualified in-
dividual must then sek the potential subject’s frely-given in-
formed consent, preferably in writing. If the consent canot be
expresedinwriting,thenon-writenconsentmustbeformaly
documented and witnesed.
Almedicalresearchsubjectsshouldbegiventheoptionofbeing
informed about the general outcome and results of the study.
27. When seking informed consent for participation in a research
study the physician must be particularly cautious if the poten-
tial subject is in a dependent relationship with the physician or
mayconsentunderdures.Insuchsituationstheinformedcon-
sentmustbesoughtbyanapropriatelyqualifiedindividualwho
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving in-
formedconsent,thephysicianmustsekinformedconsentfrom
thelegalyauthorisedrepresentative.Theseindividualsmustnot
be included in a research study that has no likelihod of benefit
forthemunlesitisintendedtopromotethehealthofthegroup
represented by the potential subject, the research canot in-
stead be performed with persons capable of providing in-
formed consent, and the research entails only minimal risk and
minimal burden.
29. When a potential research subject who is demed incapable of
givinginformedconsentisabletogiveasenttodecisionsabout
participationinresearch,thephysicianmustsekthatasentin
adition to the consent of the legaly authorised representa-
tive. The potential subject’s disent should be respected.
30. Research involving subjects who are physicaly or mentaly in-
capable of giving consent, for example, unconscious patients,
may be done only if the physical or mental condition that pre-
ventsgivinginformedconsentisanecesarycharacteristicofthe
research group. In such circumstances the physician must sek
informedconsentfromthelegalyauthorisedrepresentative.If
nosuchrepresentativeisavailableandiftheresearchcanotbe
delayed,thestudymayprocedwithoutinformedconsentpro-
videdthatthespecificreasonsforinvolvingsubjectswithacon-
dition that renders them unable to give informed consent have
benstatedintheresearchprotocolandthestudyhasbenap-
provedbyaresearchethicscomite.Consenttoremaininthe
researchmustbeobtainedassonasposiblefromthesubject
or a legaly authorised representative.
31. Thephysicianmustfulyinformthepatientwhichaspectsoftheir
care are related to the research. The refusal of a patient to par-
ticipateinastudyorthepatient’sdecisiontowithdrawfromthe
study must never adversely afect the patient-physician rela-
tionship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or
similarrepositories,physiciansmustsekinformedconsentfor
its colection, storage and/or reuse. There may be exceptional
situations where consent would be imposible or impracti-
cable to obtain for such research. In such situations the re-
search may be done only after consideration and aproval of a
research ethics comite.
Use of Placebo
3. The benefits, risks, burdens and efectivenes of a new inter-
vention must be tested against those of the best proven inter-
vention(s), except in the folowing circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is aceptable; or
Where for compeling and scientificaly sound methodological
reasons the use of any intervention les efective than the best
proven one, the use of placebo, or no intervention is necesary
to determine the eficacy or safety of an intervention
andthepatientswhoreceiveanyinterventionlesefectivethan
thebestprovenone,placebo,ornointerventionwilnotbesub-
ject to aditional risks of serious or ireversible harm as a result
of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. Inadvanceofaclinicaltrial,sponsors,researchersandhostcoun-
trygovernmentsshouldmakeprovisionsforpost-trialacesfor
al participants who stil ned an intervention identified as ben-
eficialinthetrial.Thisinformationmustalsobedisclosedtopar-
ticipants during the informed consent proces.
Research Registration and Publication and Disemination
of Results
35. Every research study involving human subjects must be regis-
teredinapubliclyacesibledatabasebeforerecruitmentofthe
first subject.
World Medical Asociation Declaration of Helsinki
Special Comunication
Clinical Review & Education
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36. Researchers, authors, sponsors, editors and publishers al have
ethical obligations with regard to the publication and disemi-
nationoftheresultsofresearch.Researchershaveadutytomake
publicly available the results of their research on human sub-
jectsandareacountableforthecompletenesandacuracyof
their reports. Al parties should adhere to acepted guidelines
for ethical reporting. Negative and inconclusive as wel as posi-
tiveresultsmustbepublishedorotherwisemadepubliclyavail-
able. Sources of funding, institutional afiliations and conflicts
of interest must be declared in the publication. Reports of re-
search not in acordance with the principles of this Declaration
should not be acepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven inter-
ventions do not exist or other known interventions have ben
inefective, the physician, after seking expert advice, with in-
formed consent from the patient or a legaly authorised repre-
sentative, may use an unproven intervention if in the physi-
cian's judgement it ofers hope of saving life, re-establishing
health or aleviating sufering. This intervention should subse-
quently be made the object of research, designed to evaluate
its safety and eficacy. In al cases, new information must be re-
corded and, where apropriate, made publicly available.
ARTICLE INFORMATION
Coresponding Author:
World Medical
Asociation, 13, ch. du Levant, CIB - Bâtiment A,
01210 Ferney-Voltaire, France; wma@wma.net.
Published Online:
October 19, 2013.
doi:10.101/jama.2013.281053.
Disclaimer:
©2013 World Medical Asociation, Inc.
Al Rights Reserved. Al intelectual property rights
in the Declaration of Helsinki are vested in the
World Medical Asociation. The WMA has granted
JAMA
exclusive rights to publish the
English-language version of the Declaration
through December 31, 2013.
Online-Only Content:
Audio podcast is available at
w.jama.com.
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2194
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APPENDIX C. REFERENCE LABORATORY VALUES FROM CENTRAL LABORATORIES 
Covance Central Laboratories (Indianapolis, Indiana, US [for North America and Latin America regions]; Geneva, Switzerland [for 
Europe]; and Singapore [for Asia-Pacific region]) will serve as the central labs for analysis or specimen management for the analytes 
listed in the Table 11 of Protocol 747-302 Version 4.  The following in text table provides the Covance Laboratory reference ranges 
for the pertinent liver biochemistries analyzed by Covance.  These reference ranges are sex and/or age specific, and can change during 
the course of the clinical trial; therefore, investigative sites should always refer to the reference ranges available on the Covance issued 
laboratory reports. 
 
Covance Indianapolis 
Covance Geneva and Covance Singapore 
Analyte 
Sex 
Agea 
Reference Range 
Agea 
Reference Range 
Albumin 
Both 
18Y – 69Y 
SI Units: 33-49 g/L 
Conventional Units: 3.3-4.9 g/dL 
18Y – 69Y 
33-49 g/L 
69Y-80Y 
SI Units: 33-46 g/L 
Conventional Units: 3.3-4.6 g/dL 
69Y-80Y 
33-46 g/L 
80Y-150Y 
SI Units: 30-46 g/L 
Conventional Units: 3.0-4.6 g/dL 
80Y-150Y 
30-46 g/L 
ALP 
Female 
18Y - 50Y 
31-106 U/L 
18Y - 50Y 
31-106 U/L 
50Y - 60Y 
35-123 U/L 
50Y - 60Y 
35-123 U/L 
60Y - 70Y 
35-123 U/L 
60Y - 70Y 
35-123 U/L 
70Y - 80Y 
35-123 U/L 
70Y - 80Y 
35-123 U/L 
80Y - 90Y 
35–135 U/L 
80Y - 90Y 
35–135 U/L 
90Y – 150Y 
35-140 U/L 
90Y – 150Y 
35-140 U/L 
ALP 
Male 
18Y - 50Y 
31-129 U/L 
18Y - 50Y 
31-129 U/L 
50Y - 60Y 
35-131 U/L 
50Y - 60Y 
35-131 U/L 
60Y - 70Y 
35-125 U/L 
60Y - 70Y 
35-125 U/L 
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Covance Indianapolis 
Covance Geneva and Covance Singapore 
Analyte 
Sex 
Agea 
Reference Range 
Agea 
Reference Range 
70Y - 80Y 
35-130 U/L 
70Y - 80Y 
35-130 U/L 
80Y - 90Y 
35–125 U/L 
80Y - 90Y 
35–125 U/L 
90Y – 150Y 
35-125 U/L 
90Y – 150Y 
35-125 U/L 
ALT 
Female 
18Y – 69Y 
6-34 U/L 
18Y – 69Y 
6-34 U/L 
69Y – 150Y 
6-32 U/L 
69Y – 150Y 
6-32 U/L 
ALT 
Male 
18Y – 69Y 
6-43 U/L 
18Y – 69Y 
6-43 U/L 
69Y – 150Y 
6-35 U/L 
69Y – 150Y 
6-35 U/L 
AST 
Female 
18Y – 59Y 
9-34 U/L 
18Y – 59Y 
9-34 U/L 
59Y – 150Y 
9-34 U/L 
59Y – 150Y 
9-34 U/L 
AST 
Male 
18Y – 59Y 
11-36 U/L 
18Y – 59Y 
11-36 U/L 
59Y – 150Y 
11-36 U/L 
59Y – 150Y 
11-36 U/L 
Direct 
Bilirubin 
Both 
18Y – 150Y 
SI Units: 2-7 umol/L 
Conventional Units: 0.1-0.4 mg/dL 
18Y – 150Y 
2-7 umol/L 
Indirect 
Bilirubin 
Both 
0Y – 150Y 
SI Units: 0-21 umol/L 
Conventional Units: 0.0-1.2 mg/dL 
0Y – 150Y 
0-21 umol/L 
Total 
Bilirubin 
Both 
18Y – 150Y 
SI Units: 3-21 umol/L 
Conventional Units: 0.2-1.2 mg/dL 
18Y – 150Y 
3-21 umol/L 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; Y = years; SI=International System of Units 
a The unstated word “to” is implied by the “dash” appearing in age specific reference ranges. A range such as “0-59 years” and “59-150 years” means: “0 up to 
but not including 59 years” and “59 up to but not including 150 years”. 
Source: Covance Laboratory Services Manual Version 5.0.0. Dates vary by region: 10 Nov 2016 (North America), 22 Nov 2016 (Europe and Singapore) 
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APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 (DATED 29 APR 2015) 
Rationale 
The changes to the Original Version of the protocol, detailed below, modify the dose titration schedule based on observed efficacy and 
tolerability of OCA, address advice provided by regulatory agencies, and clarify questions raised by study site personnel currently 
using Original protocol version 1 dated 03 October 2014. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.  (Note:  Differences are denoted in bold font; Minor 
formatting changes are not listed) 
Section 
Original Text 
Revised Text 
Title Page 
Original:  03 October 2014 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Procedures in 
Case of 
Emergency 
 
Procedures in Case of Emergency 
 
Study Personnel Contact Information 
 
Or if Not 
Available 
Contact:
 MD, 
 & 
 Development, Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
 
Contact:
 MD, Medical Director, Drug Safety, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
Synopsis 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
≤1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 
2 weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 
2 weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
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Revised Text 
and total bilirubin values (refer to Section 9.7.3).  Subjects who 
meet all inclusion criteria and none of the exclusion criteria will be 
randomized (1:1) to OCA or placebo treatment groups.  The 
randomization will be stratified by ursodeoxycholic acid (UDCA) 
treatment (yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 6 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 6-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
 
and total bilirubin values (refer to Section 9.7.3).  Mean values for 
ALP and total bilirubin will be calculated using all available 
screening values.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment (yes/no) and baseline 
bilirubin categories (>upper limit of normal [ULN]/ ≤ ULN). 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 3 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 3-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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Section 
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Revised Text 
Synopsis 
Inclusion Criteria 
2.  A mean total  bilirubin >ULN and ≤3× ULN or an ALP 
>5×ULN  
4.  Either is not taking UDCA (UDCA naïve or  no UDCA dose in 
the past 3 months) or has been taking UDCA for at least 12 months 
with an approved, stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
contraception during the study and for 30 days after the end of 
treatment visit. 
 
Inclusion Criteria 
2. A mean total bilirubin >ULN and ≤3× ULN and/or a mean 
ALP >5× ULN 
4.  Either is not taking UDCA (no UDCA dose in the past 
3 months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
Synopsis 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
 
 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
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3. Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
4.  Other medical conditions that may diminish life expectancy to 
<2 years, including known cancers (except carcinomas in situ or 
other stable, relatively benign conditions such as chronic lymphatic 
leukemia) 
5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of screening (pretreatment) QT 
 
3.  Mean total bilirubin >3× ULN 
 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
5.  Deleted text 
Synopsis 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life 
 
 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life (Fatigue 
Impact Score and EQ-5D-
5L) 
 
Synopsis 
Statistical Methods: Other Efficacy Analyses 
• 
Added text 
Statistical Methods: Other Efficacy Analyses 
• 
Development of varix/varices 
4 
List of Abbreviations 
Added text 
 
List of Abbreviations 
EOS 
 end of study 
 
5.4 
As of 31 March 2014, OCA has been evaluated in the clinic in 
18 completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 March 2014, a total of 1023 subjects have 
received at least one dose of OCA and of these, 414 (40%) were 
subjects with PBC.   
As of 31 January 2015, OCA has been evaluated in the clinic in 
20 completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 January 2015, approximately 1650 subjects 
have received at least 1 dose of OCA and of these, 432 were 
subjects with PBC with ≤5 years of OCA treatment.   
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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 up to 4 years.  The LSTE phase of studies 
747-201 and 747-301 are ongoing; the LTSE phase of 
Study 747-202 is complete 
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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is 
complete 
5.5.2.1 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg and 10 mg; both treatment 
groups exhibited clinically meaningful improvements in liver 
biochemistry and were safe and generally well tolerated. 
 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg (titrated to 10 mg after 6 
months based on efficacy and tolerability in the double-blind 
phase and after 3 months in the open-label phase) and 10 mg; 
both treatment groups exhibited clinically meaningful 
improvements in liver biochemistry and were safe and generally 
well tolerated.  Based on these data, the intended commercial 
doses of OCA for the treatment of patients with PBC are 5 mg 
and 10 mg. 
The majority of efficacy results with OCA, in terms of change 
in alkaline phosphatase, was observed by 3 months and the 
time to treatment-emergent pruritus was typically 1 month or 
less in Study 747-301.  As such, Study 747-302 will evaluate the 
effect of OCA on clinical outcomes using the 5 mg OCA dose 
increasing to 10 mg OCA if tolerated. 
 
5.5.2.2. 
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons.   
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons (ie, comparisons to historical and placebo 
controls will be evaluated separately). 
 
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5.6 
Additionally, consistent with nonclinical findings and the 
chemical characteristics of OCA (bile acid and detergent), an 
increase in liver function tests and hepatic AEs, including 
jaundice, were observed in subjects with liver disease at doses 
between 10 mg and 50 mg and in healthy volunteers who were 
treated at doses greater than 100 mg in Phase 1 multiple dose 
studies. 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  The clinical 
significance of these lipid findings remains unclear and is being 
studied further.  Notably, despite the observed decrease, HDL 
levels have generally remained within normal limits in subjects 
treated with OCA. 
• 
Deleted text 
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 subjects with chronic liver disease such as PBC, hepatic 
findings including increased transaminases and bilirubin and 
signs or symptoms of hepatic decompensation such as 
development of jaundice were observed mainly at the highest 
dose of OCA (50mg daily). 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  Notably, in subjects 
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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated 
subjects with the exception of a modest transient and early rise 
after initiation of treatment.
7.1 
Overall Study Design 
…Subjects will be screened during a ≤1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3)….Following 6 months of treatment with 
investigational product, subjects should be titrated in a blinded 
manner (ie, subjects randomized to OCA will increase their dose to 
10 mg OCA) based on tolerability…. 
Overall Study Design 
…Subjects will be screened during a 1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to Section 9.7.3). 
….Following 3 months of treatment with investigational product, 
subjects should be titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose to 10 mg OCA) based 
on tolerability…. 
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7.1.1 
Study Design Diagram 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
Study Design Diagram 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
7.1.2 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
1st column heading was “Screening Visit  x2) 
 
Visit Window ≤1 to 8 wks … 
Visit window in 2nd column added new text 
Added text 
 
 
 
 
 
 
 
 
 
 
 
 
Footnote a:   All subjects will have two 2 bilirubin assessments at 
least 2 weeks apart including those subjects who qualify based 
on ALP criteria.  For subjects that do not qualify based on 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
Now 2 columns: 1st column now “Screening Visit 1” 
2nd column now Screening Visit 2 
3 to 8 wks… 
1 to 6 wks prior to Day 0 
 
Added Procedures: 
Quality of Life Questionnaires (PBC-40, EQ-5D-5L, and 
FIS) g  (Day 0, Annually, EOT/EOS) 
Endoscopy I (Day 0, annually, per standard of care) 
Hepatic Ultrasound (Day 0, Annually, EOT/EOS) 
Physical Exam and Assessments for Mayo Risk Score and Child-
Pugh (every 6 months) 
Health Outcome Assessments (All visits) 
Added Dose Titration at M3 
Footnote a All subjects will have the chemistry panel retested 
to ensure subjects have 2 ALP and bilirubin assessments at 
least 2 weeks apart to calculate the mean result for both 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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ALP (ALP >5× ULN), the mean of the two 2 bilirubin 
assessments will be used to determine eligibility (total bilirubin 
>ULN and ≤3× ULN). 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2, and also 2 weeks post dose titration, to assess for AEs 
and concomitant medications and to verify that s/he is dosing as 
directed 
Footnote e:  Medical history at Screening will smoking and alcohol 
consumption history and current habits for both.   
 
Footnote g:  Subject Questionnaires include: Pruritus VAS, 5-D 
Pruritus Scale and Quality of Life questionnaires (See 
Section 11.1.2.2 and Section 12.2.5.1) 
 
 
 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.   
 
 
Footnote i: Added text 
 
 
Footnote j:  Added text 
 
 
 
 
Footnote k:  Added text 
analytes.   The mean of the all screening ALP and bilirubin 
assessments will be used to determine eligibility).  Samples for 
hematology and coagulation will not be collected at Screening 
visit 2. 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2 (± 1 week), and also 2 weeks post dose titration (up or 
down), to assess for AEs and concomitant medications and to 
verify that s/he is dosing as directed.   
Footnote e:  Medical history at Screening and the yearly physical 
exam will include an assessment of smoking and alcohol 
consumption history and current habits for both.   
Footnote g:  The EQ-5D-5L and FIS Quality of Life 
questionnaires are validated for use in multiple languages. If 
a validated translation is not available in the local language 
required for a specific study subject, the data from that 
questionnaire will not be collected.    (See Section 11.1.2.2 and 
Section 12.2.6) 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.  Please refer to Section 9.7.7 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote i: Endoscopy will be conducted at selected study sites 
where the device is available to assess for the presence of 
oesophageal varix/varices.  Please refer to Section 9.7.7 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote j:  Ultrasound will be conducted to enhanced HCC 
surveillance.  If a lesion is found, a second confirmatory 
image (eg, MRI) should be obtained.  Please refer to 
Section 9.7.7 for additional information related to the allowed 
windows at Day 0 for these specific procedures. 
Footnote k:  Child-Pugh Score will be calculated based on 
ascites assessment, hepatic encephalopathy grade, and central 
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Footnote l:  Added text 
 
 
 
Footnote m:  After 6 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 6 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit.  Fasting is required prior to all 
study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at site.  If the blood 
test is also positive, the subject may not be enrolled in the study.  
(Additional testing may be conducted where required, 
regionally). 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
laboratory evaluations per the Child-Pugh scoring system 
noted in the case report form.  Mayo Risk Score will be 
calculated based on central laboratory evaluations, diuretic 
use data, and peripheral edema assessment data captured in 
the CRF.  
Footnote l:  Health Outcome Assessments: Data related to non-
study related medical or surgical treatment procedures that 
the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the 
subject attended should be collected throughout the study. 
Footnote m:  After 3 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 3 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit (except Screening visit 1).  
Fasting is required prior to all study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not 
be enrolled in the study.  (Additional testing may be conducted 
where required, regionally). 
 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
 
7.3 
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 6 month study visit or at 
any study visit thereafter depending on tolerability.   
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 3 month study visit or 
at any study visit thereafter depending on tolerability.   
7.4 
Dose Titration Criteria 
After 6 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
Dose Titration Criteria 
After 3 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
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placebo (in a blinded manner) at the 6-month visit or any study visit 
following the 6-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
placebo (in a blinded manner) at the 3-month visit or any study visit 
following the 3-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
7.4.1 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, her or she should continue the regular 
visit schedule and continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination.  Early termination 
procedures should only be conducted if the subject withdraws 
consent. 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, he or she should continue the regular 
visit schedule and continue taking investigational product as long 
as the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination. 
7.5 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all subjects have 
completed the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the Study/Early Termination Visit. 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all events have been 
accrued, and when subjects are still active on the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the End of Study Visit. 
8.2 
Subject Inclusion Criteria  
2.  A mean total bilirubin >ULN and ≤3× ULN or an ALP >5× 
ULN 
4.  Either is not taking UDCA (UDCA naïve or no UDCA 
dose in the past 3 months) or has been taking UDCA for at 
least 12 months with an approved, stable dose for ≥3 months 
prior to Day 0 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
Subject Inclusion Criteria 
2.  A mean total bilirubin >ULN and ≤3× ULN and/or a mean ALP 
>5× ULN  
4.  Either is not taking UDCA (no UDCA dose in the past 
3 months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
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contraception during the study and for 30 days after the end of 
treatment visit. 
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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
 
 
8.3 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
3.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
4.  Other medical conditions that may diminish life expectancy 
to <2 years, including known cancers (except carcinomas in 
situ or other stable, relatively benign conditions such as chronic 
lymphatic leukemia) 
 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example, per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
3.  Mean total bilirubin >3× ULN 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
 
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5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of Screening (pretreatment) QT 
 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test), or lactating 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
 
5. Deleted text 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test by the central laboratory), or lactating 
 
8.4.1 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test. 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test performed at the central 
laboratory. 
8.4.2 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent. 
 
 
The following events are considered potential appropriate reasons 
for a subject to discontinue investigational product;…  
• 
Withdrawal of Consent 
- 
Added text 
 
 
 
 
 
 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent (See Section 9.7.18 Early 
Discontinuation and/or Early Termination Procedures). 
 
The following events are considered appropriate reasons for a 
subject to discontinue investigational product; … 
• 
Withdrawal of Consent 
- 
Consent may be fully withdrawn 
- 
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 potential adjudicated hepatic and/or 
cardiovascular events 
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The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study.   
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study.   
8.4.3 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study….This information must be documented in the CRF.  
If a subject is withdrawn from the study early (regardless of the 
cause), all of the end of treatment (EOT) evaluations should be 
performed at the time of withdrawal, as appropriate.  
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study….This information must be documented 
in the CRF.  If a subject is withdrawn from the study early 
(regardless of the cause), all of the (EOT/EOS) evaluations should 
be performed at the time of withdrawal, as appropriate (See 
Section 9.7.18 Early Discontinuation and/or Early Termination 
Procedures). 
9.1.1 
Dose Adjustment Beginning at Month 6 
After 6 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 6 visit, or at 
any study visit thereafter.   
Dose Adjustment Beginning at Month 3 
After 3 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 3 visit, or at 
any study visit thereafter.   
9.2 
Concomitant Medications 
Relevant information about all concomitant medications (including 
prescribed, over-the-counter, or herbal preparations) taken prior to 
(ie, within 30 days of Day 0) and during the study must be recorded 
in the source documents and CRF, as well as any dose or dose 
regimen changes that occur during the study.   
Concomitant Medications 
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 CRF, as well as any dose or 
dose regimen changes that occur during the study. 
9.2.1 
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.   
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.  Subjects that discontinue investigational product 
but continue commercial OCA therapy are expected to 
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continue through the end of the study, and the study will only 
terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.  Subjects 
will need to complete EOT procedures but continue with 
regularly scheduled visits until the study is terminated (See 
Section 9.7.18 Early Discontinuation and/or Early Termination 
Procedures). 
 
9.4 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN), 
as specified by the central laboratory.   
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and mean baseline bilirubin categories 
(>ULN/≤ULN), as specified by the central laboratory.   
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
• 
Added text - New section inserted. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects will be made 
available to the Investigator for emergency use only 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 is necessary for further medical management of the 
subject).  If it is not reasonable to inform the Medical Monitor 
in advance of unblinding the Investigator must promptly 
document in the subject’s source record and should 
subsequently contact the Medical Monitor to explain any 
premature unblinding of treatment assignment (such as 
unblinding which is necessary in order to treat an SAE). 
Procedures for unblinding a subject’s treatment will be 
provided separately to the Investigator.  Similarly, if the 
Medical Monitor breaks the blind for an individual subject for 
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the purpose of evaluating an emergent safety issue, the Medical 
Monitor will document within trial documentation the 
rationale, circumstances, and the person or persons being 
informed about the unblinding. 
The Data and Safety Monitoring Committee (DSMC) will have 
access to the IWRS and will be able to unblind individual 
subjects.  Refer to Section 13.3 for further details regarding 
DSMC access to blinded and unblinded data.  The DSMC will 
document details about any unblinded subject data reviews in 
the closed session DSMC minutes, which will be made available 
to the Sponsor only after the database is locked and the trial is 
unblinded.   Cases of premature unblinding, as noted above, 
will also be reviewed by the DSMC.  
Access to treatment assignments will also be made available 
through the IWRS system to the appropriate named 
individual(s) responsible for reporting SAEs and suspected 
unexpected serious adverse reactions (SUSARs) to the 
Regulatory Authorities. 
9.6 
Restrictions 
No additional restrictions. 
Restrictions 
Participation in another investigation product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the trial is prohibited. 
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9.7.1 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Interval is ≤1 to 8 weeks prior to 
Day 0, allowing for 2 Screening 2 
visits to repeat biochemistry tests, 
and ensuring ample time to receive 
lab results.  The overall Screening 
interval is up to 56 days. 
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (7 days)  
Quarterly visits (Months 
15 – EOT) 
±2 weeks (14 days) 
EOT 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOT = end of treatment 
 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening visit 1 interval is 3 to 8 
weeks prior to Day 0 for screening 
visit 1.  Screening visit 2 interval is 
1 to 6 weeks prior to Day 0.   The 
visit window for Screening 2 visits 
allows for the repeat biochemistry 
tests to be collected at least two 
weeks after the initial biochemistry 
sample was collected, and will 
ensure ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days, but 
screening procedures should not be 
performed during the last 7 days of 
the window.  
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (14 days)  
Quarterly visits 
(Months 15 – EOS) 
±2 weeks (14 days) 
EOT 
(When subject 
discontinues 
investigational 
product) 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOS 
(When subject 
terminates the study) 
The final study visit; EOS will 
occur concurrent with EOT if a 
subject discontinues study 
medication at the time the subject’s 
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participation in the study ends (eg, 
withdrawal of consent or study 
termination by the Sponsor); EOS 
will occur after the EOT if the 
subject discontinues study 
medication but continues in the 
study. 
EOT = end of treatment 
EOS = end of study 
 
9.7.2 
Informed Consent Procedures 
• 
Added text 
Informed Consent Procedures 
Any change in a subject’s consent status (eg, semi-annual 
telephone contact or medical record review) must be 
documented in a signed informed consent form or addendum.  
The subjects will be given a signed and dated copy of the 
consent document. 
9.7.3 
Screening Procedures (≤1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed ≤1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Subjects who 
do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects may be rescreened after 2 months; however, all Screening 
procedures should be repeated and a new 3-digit Screening number 
assigned.  
 
 
 
 
 
• 
All subjects will have 2 bilirubin and ALP 
assessments at least 2 weeks apart including those 
subjects who qualify based on ALP criteria. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Screening 
Visit 1 will occur 3 to 8 weeks prior to Day 0; Screening Visit 2 
will occur 1 to 6 weeks prior to Day 0, depending on the date 
that the first serum chemistry sample was collected. Subjects 
who do not fulfill all eligibility criteria will not be enrolled in the 
study.  Subjects 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 3-digit Screening number 
assigned. 
 
• 
All subjects will have 2 bilirubin and ALP assessments at 
least 2 weeks apart 
 
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• 
For subjects that do not qualify based on ALP alone 
(ALP >5×  
ULN), the mean of the 2 bilirubin assessments will be 
used to determine eligibility (total bilirubin >ULN 
and ≤3× ULN). 
  
 
 
• 
Screening Visit procedures are as follows: 
• 
Record prior (if within 30 days of Day 0) and current 
concomitant medications 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual emission X ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
 
 
• 
Added text 
 
• 
For subjects that do not qualify based on ALP alone (ALP 
>5× ULN), the mean of all available (at least 2; 
including both scheduled and unscheduled) bilirubin 
assessments will be used to determine eligibility (total 
bilirubin >ULN and ≤3× ULN).   
 
 
 
• 
Screening Visit 1 procedures are as follows: 
• 
Record prior (if within 30 days of Screening) and current 
concomitant medications 
• 
Deleted text  
 
• 
Deleted text 
 
 
 
 
 
 
Screening Visit 2 procedures are as follows: 
• 
Verify inclusion and exclusion criteria for eligibility 
• 
Assess and record any pretreatment-emergent AEs 
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• 
Record current concomitant medications 
• 
Verify that the subject has fasted for at least 8 hours 
- 
Record fasting status in the source and CRF 
- 
If the subject reports having eaten within 8 hours, 
document accordingly in the source and CRF and 
remind the subject that fasting is required prior to all 
study visits 
• 
Obtain blood samples for serum chemistry tests 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual-emission X-ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
9.7.4 
Day 0 Procedures (Randomization) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE has 
been done within 3 months of Day 0 and a report/adequate data 
are available, a pretreatment TE at Day 0 is not required.   
 
 
• 
Day 0 Procedures (Randomization) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6.) 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE 
has been done within 6 months of Day 0 and a 
report/adequate data are available, a pretreatment TE at 
Day 0 is not required.  If the TE cannot be performed on 
Day 0 (e.g., device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the 
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• 
 Conduct a DEXA bone density scan (at selected study sites, 
where available); document whether the subject stopped taking 
her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the 
scan, if applicable.  
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
 
 
 
 
 
screening visit window, as close as possible to the Day 0 
visit, after subject eligibility has been confirmed.   
• 
 Conduct a DEXA bone density scan (at selected study 
sites, where available); document whether the subject 
stopped taking her/his calcium supplements for 48 hours 
before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable.  If DEXA 
has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment 
DEXA at Day 0 is not required.  If DEXA cannot be 
performed on Day 0 (e.g., device/technician 
unavailability, scheduling issues, etc), the procedure 
may be completed within the screening visit window, as 
close as possible to the Day 0 visit, after subject 
eligibility has been confirmed. 
• 
Perform an esophagogastroduodenoscopy (endoscopy; 
at selected study sites, where available) to assess the 
presence or absence of oesophageal varix/varices. If an 
endoscopy has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment endoscopy at Day 0 is not required. If the 
endoscopy cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
- 
Subsequent endoscopies should be performed 
annually or per standard of care and the 
Investigator’s clinical judgment throughout 
the course of the study.  Endoscopies should 
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• 
Added text 
 
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
• 
Added text 
 
• 
Record prior (within 30 days of Day 0) and current  
concomitant medications 
also be performed when platelet counts are 
<150 × 109 /L. 
• 
Perform an ultrasound (if equipment is unavailable, 
sites should make every attempt to use available 
community referral sites) for HCC surveillance.  If an 
ultrasound has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment ultrasound at Day 0 is not required. If 
the ultrasound cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
 Review and record prior concomitant medications 
• 
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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9.7.6 
Month 3 Procedures 
• 
Added text 
• 
Added text 
Month 3 Procedures 
• 
Assess for dose titration, if eligible (refer to Section 7.4) 
• 
Obtain blood samples for: 
- 
OCA, C4, and FGF-19 
9.7.7 
 
Month 6 Procedures 
• 
Added text 
 
Month 6 Procedures 
• 
 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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.8 
Month 9 Procedures 
• 
Added text 
Month 9 Procedures 
• 
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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9.7.9 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.9), subjects who are participating in the PK assessment 
will each receive a single dose of investigational product (10 mg 
OCA tablet) with approximately 240 mL of water. 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours postdose.  Subjects should not drink additional water 
for 1 hour after taking the dose of investigational product and will 
remain fasted until the 4 hour sample is collected.  Lunch will be 
provided following collection of the 4 hour PK sample; the lunch 
will be a meal replacement drink. 
 
 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.12), subjects who are participating in the PK 
assessment will each receive a single dose of investigational 
product (blinded OCA or placebo tablet) with approximately 
240 mL of water. 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours post dose.  Samples should be collected within a 
window of ±5 minutes of the scheduled sample time.  Subjects 
should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until the 4 hour 
sample is collected.  Lunch will be provided following collection of 
the 4 hour PK sample; the lunch will be a meal replacement drink.  
Samples will be stored for up to 5 years after the end of the 
study and will be destroyed after 5 years if not analyzed. 
9.7.10 
 
Month 12 Procedures 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Added text 
Month 12 Procedures 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
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o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.11 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
Subjects should come to the study center for a quarterly study 
visit for a clinical laboratory evaluation to collect blood samples 
for calculation of MELD score.  If the subject is not able to 
come to the study center for a visit, home visits may be 
arranged on a per subject basis. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
• 
Deleted text 
• 
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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
9.7.12 
Month 6 Continue Follow-up Procedures (Semi-annually 
[±2 weeks]) 
• 
Added text 
Month 6 Continue Follow-up Procedures (Semi-annually 
[±2 weeks]) 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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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9.7.13 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Added text  
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
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 physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.14 
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw Consent 
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw from Investigational Product or 
Withdraw Consent  
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
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When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination or 
discontinuation (withdrawal of consent), an EOT visit must be 
performed as near as possible to her/his last dose of investigational 
product and the procedures, listed below, performed.  …  In these 
cases, the data will be recorded as EOT procedures in the CRF.  
 
 
Added table 
 
 
 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects 
discontinue treatment with investigational product.  The EOT 
visit and procedures listed below must be performed as close as 
possible to the subject’s last dose of investigational product.  
When a subject discontinues investigational product but 
continues with regularly scheduled study visits, the EOS visit 
will be completed later in the study as the subject’s final study 
visit.  The actual investigational product discontinuation 
scenario (Table 7) will determine the sequence of the EOT and 
EOS visits and procedures.  In some cases, the EOT visit and 
procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible 
to the subject’s last dose of investigational product.   
When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination 
(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.  ….  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 and EOS procedures in the 
CRF.  
Table 2: 
Early Discontinuation Scenarios 
 
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Investiga
tional 
Product 
Conse
nt 
Study 
Visit 
Status
EOT 
Visita 
EOS 
Visita 
Early 
Terminati
on 
Discontin
ued 
Withdr
awn 
No 
additi
onal 
visits 
excep
t 
EOT/E
OS 
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
Treatmen
t 
Discontin
uation 
Discontin
ued 
Active 
Regul
ar 
Visit 
Sched
ule 
Comp
lete 
as 
close 
as 
possi
ble to 
last 
dose 
IP 
Comp
lete 
at 
Final 
study 
visit 
Discontin
ued 
Semia
nnual 
contac
tb 
Telep
hone 
conta
ct 
every 
6 
mont
hs (±2 
weeks
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
 
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Some assessments noted below may be omitted if they have been 
completed within the 3 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT Visit: 
During the EOT Visit: 
• 
Subject questionnaires (see Section 12.2.6) 
• 
Conduct a DEXA bone density scan (selected study sites); 
document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for 
osteoporosis or osteopenia on the day of the scan, if applicable 
 
 
• 
Added text 
 
• 
Added text 
 
• 
Added text 
 
a Refer to Section 7.1.2 Schedule of Study Procedures for all procedures 
and evaluations required at the End of Treatment and End of Study Visits. 
b Outcomes data to be discussed or collected include data related to 
adjudicated hepatic and cardiovascular event-related data.  No additional 
data (e.g. AE, concomitant medication, etc) data will be collected, except 
as indicated in Section 12.1.7. 
Some assessments noted below may be omitted if they have been 
completed within the 6 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing 
Prior to the EOT/EOS Visit: 
During the EOT/EOS Visit 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
 Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Subject and Quality of Life  questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform TE (where available) using the Fibroscan® TE 
device (not required at EOT/EOS if done within 6 months) 
• 
Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
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• 
Added text 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites); not 
required at EOT/EOS if done within 6 months 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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 
 
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.  [Added text]  As appropriate, the Medical 
Monitor should be contacted. 
 
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.   
In the event of an inexplicable and acute (for example not 
explained by natural progression of the chronic disease) 
increase in alanine aminotransferase (ALT) to >3× baseline 
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(and >upper limit of normal [ULN]) or total bilirubin >2× 
baseline (and >ULN), the subject should be followed by repeat 
testing within 48 to 72 hours of the serum chemistry to confirm 
the abnormalities and to determine if they are increasing or 
decreasing. AE information should also be collected.  If 
symptoms persist or repeat testing shows ALT >3× baseline 
(and >ULN) or total bilirubin >2× baseline (and >ULN), 
subjects should be followed until resolution of the abnormality 
and as clinically indicated depending on other laboratory and 
clinical signs and symptoms. 
 
As appropriate, the Medical Monitor should be contacted. 
10.4 
Investigational Product Preparation 
The investigational product will be provided in bulk bottles and 
therefore may be repackaged in unit dose form for administration to 
subjects. 
 
Investigational Product Preparation 
The investigational product will be provided to the distribution 
center in bulk bottles and therefore may be repackaged in unit dose 
form for administration to subjects before shipping to the sites. 
 
11.1.2 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Resource utilization information 
will be collected from CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician 
visits (subject reported), and use of concomitant medications. 
 
 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Quality of life will be assessed by 
questionnaires (PBC-40, EQ-5D-5L, and FIS) 
administered annually.  Resource utilization information will 
be collected from the Medical and Surgical Treatment 
Procedures and Office Visit Log or other CRFs such as 
number, type and duration of hospitalizations, number of 
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• 
Added text 
outpatient physician visits (subject reported), and use of 
concomitant medications.  
• 
Endoscopy will be conducted at selected study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual 
study assessments or standard of care will be collected in 
the case report form to assess for the development of 
varix/varices 
11.1.2.2 
• 
Quality of Life questionnaires.   
• 
Quality of Life questionnaires.  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: 
a. PBC-40: The PBC-40 (Jacoby 2005) 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. 
b. EQ-5D-5L:  The Eq-5D-5L consists of 2 sections – the 
descriptive system and the visual analogue scales (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 
respondent’s self-rate 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). 
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c. 
Fatigue Impact Score (FIS):  The FIS is a validated 
40-question questionnaire organized into 3 dimensions:  
cognitive, physical, and social.  Each dimension has 5 
levels:  no problem, small problem, moderate problem, 
big problem, and extreme problem (Fisk 1994) 
11.1.2.3 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. The samples will be stored for up to 1 year after the 
end of the study and destroyed after 1 year if not analyzed. 
 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their 
involvement in the study.  IRB/IEC review and approval 
will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will 
be stored for up to 1 year after the end of the study and 
destroyed after 1 year if not analyzed. 
 
12.1.1.2 
Serious Adverse Event 
• 
Added text 
Serious Adverse Event 
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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12.1.4.2 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
  
All SAEs (including Potential Clinical Outcome Events that qualify 
as serious) must be reported to the medical monitor immediately 
(ie, within 24 hours) after the Investigator identifies the SAE…. 
 
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 investigational 
new drug (IND) safety reports (SUSARs) that occur during the 
study within the time frames required by each regulatory agency.  
The Investigator is responsible for submitting information on IND 
safety reports received from the Sponsor to her/his local IRB.  
Documentation of the submissions to IRBs and health authorities 
must be retained in the appropriate study file(s). 
 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
All SAEs occurring while subjects are receiving investigational 
product or are on an investigational product holiday (including 
Potential Clinical Outcome Events that qualify as serious) must be 
reported to the medical monitor immediately (ie, within 24 hours) 
after the Investigator identifies the SAE….  
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.  A SAE assessed with a possible, probable, or definite 
causal relationship to the investigational product and 
unexpected according to IB Reference Safety Information 
(RSI), is known as a suspected unexpected serious adverse 
reaction (SUSAR).  The Sponsor will notify the appropriate 
regulatory agencies as well as all participating Investigators of 
investigational new drug (IND) safety reports (SUSARs) that occur 
during the study within the time frames required by each regulatory 
agency.  The Investigator is responsible for submitting information 
on IND safety reports/SUSARs received from the Sponsor or 
Sponsor designee to her/his local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities must be retained in the 
appropriate study file(s). 
 
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12.1.6 
Notification of Post-Study SAEs 
• 
Added text 
 Notification of Post-Study SAEs 
SAEs that occur more than 30 days after a subject has 
discontinued study medication, and are not considered related 
to investigational product, must still be reported in the EDC 
system; however, these events are not required to be reported 
within 24 hours.  At a minimum, the SAE term, event start and 
end date, severity, relationship to investigational product, 
action taken with study medication, treatment, outcome, and 
potential endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event summary, SAE 
details) may also be required to be entered, when requested by 
the Sponsor. 
 
12.1.8 
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments.  
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments. The Sponsor may also 
follow the health of an infant born subsequent to use of 
investigational product. 
 
12.2.2 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page …. 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page for findings that appear after consent, and on the 
medical history CRF for any finding present prior to consent…. 
12.2.5.1 
12.2.5.1  Subject Questionnaires 
 
12.2.6 Subject Questionnaires 
12.2.6/12.2.7 
12.2.6   Laboratory Assessments 
Subjects testing positive for urine drug screen will be excluded 
from the study. 
12.2.7 Laboratory Assessments 
Deleted text 
 
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Table 4  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids, thyroid hormones (T3, 
T4, TSH) 
 
 
Table 5  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids 
 
12.2.6 
Laboratory Assessments 
• 
Added text 
 
 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly visits based on serum chemistry and coagulation. 
 
12.2.7  Laboratory Assessments 
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. 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly (MELD scores only) and semi-annual visits based on 
serum chemistry and coagulation. 
 
13.1.5 
Additional Secondary Efficacy Analyses 
• 
Added text 
Additional Secondary Efficacy Analyses 
• 
Time to development of varix/varices 
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13.1.8 
Supportive Analysis 
Although the results of using matching are conditional only on the 
observed covariates, if one has the ability to measure many of the 
covariates that are believed to be related to the treatment 
assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained. 
 
Supportive Analysis 
Although the results of using matching controls are conditional 
only on the observed covariates, if one has the ability to measure 
many of the covariates that are believed to be related to the 
treatment assignment, then one can be fairly confident that 
approximately unbiased estimates for the treatment effect can be 
obtained. 
13.3 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study. In addition, the DSMC statistician 
will evaluate the sample size as described in Section 13.1.2.1. 
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.   
 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study.  
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.  The DSMC will document details about 
any unblinded subject data reviews in the closed session DSMC 
minutes, which will be made available to the Sponsor only after 
the database is locked and the trial is unblinded.   Cases of 
premature unblinding, as noted above, will also be reviewed by 
the DSMC.  
 
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16.2, Ethical 
Conduct of the 
Study 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles 
that have their origin in the Declaration of Helsinki (Seoul 
Revision, 2008) and are consistent with ICH/GCP, applicable 
regulatory requirements and the Sponsor’s policies. 
Ethical Conduct of the Study 
 The study will be performed in accordance with ethical principles 
and are consistent with ICH/GCP, local applicable regulatory 
requirements (in addition to Appendix C) and the Sponsor’s 
policies. 
19 
List of References 
• 
Added text 
List of References 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional 
impact of fatigue: initial validation of the fatigue impact scale. 
Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
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 Dec;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), 1622-1629. 
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. 
 
Appendix C 
• 
Added document 
Ethical Conduct according to the Declaration of Helsinki for 
Countries Participating Outside the US 
 
 
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APPENDIX E.  SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 (DATED 12 NOV 2015) 
Rationale 
The changes to Amendment 1 of the protocol, detailed below, generated specifically for regulatory authority requests, include an 
additional exclusion criteria and changes to text precluding UDCA naïve subjects from entering the study and clarifying information 
showing that OCA may increase the exposure of narrow therapeutic index drugs that are substrates for CYP1A2, thus answering 
questions raised by regulatory authorities. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.1.  (Note:  Revised text in Amendment 1.1 is indicated in 
bold font, and the text deleted from Protocol Amendment 1 is crossed out in the table below. Minor formatting changes are not listed.) 
Section 
Original Text (Amendment 1, 29 April 2015) 
Revised Text (Amendment 1.1, 12 November 2015) 
Title Page 
Original:  03 October 2014 
Amendment 1:  29 APRIL 2015 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Amendment 1.1:  12 November 2015 
Study Personnel 
Contact 
Information 
Mobile:      
 (Pacific time zone) 
Telephone: 
 
Telephone 
 
(deleted) 
Telephone: 
 
(deleted)   
Synopsis, 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
Synopsis, 
Statistical 
Methods:  
Sample Size 
Justification 
• 
5% of the subjects will have never been treated with UDCA; 
95% of the subjects will have been on UDCA for at least 1 
year 
(deleted) 
 
8.3 Subject 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
9.2 Concomitant 
Medications 
(insertion) 
The effect of OCA on drug metabolizing enzymes has been 
evaluated in both in vitro and clinical studies.  The PK profile 
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Revised Text (Amendment 1.1, 12 November 2015) 
of caffeine, a sensitive CYP1A2 substrate, 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. 
12.1.4.2 
Reporting of 
Serious Adverse 
Event 
Mobile:      
 (Pacific time zone) 
Telephone: +1 858 964 1571 
(deleted) 
Telephone: 
   
13.1.2 
Determination of 
Sample Size 
5% of the subjects will have never been treated with UDCA; 95% 
of the subjects will have been on UDCA for at least 1 year 
(deleted) 
 
 
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APPENDIX F. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 TO VERSION 3 
(DATED 07 SEP 2016) 
Rationale 
The changes to Version 3 of the protocol, include dosing adjustments based on Child-Pugh scoring, additional exclusion criteria, 
changes to text precluding UDCA-naïve subjects from entering the study.  
Please note that the Sponsor has renamed protocol “amendments” to “versions”, therefore all future revisions that require a revised 
protocol will have an associated “version” number. The table below includes substantial revisions made to Protocol 747-302 under 
Version 3, which encompass the revisions captured in Protocol Amendment 1.1. Revised text in Version 3 is indicated in bold font, 
and the text deleted from Protocol Amendment 1.1 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 (Amendment 1.1, 
12 November 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology 
...  Mean values for ALP and total bilirubin 
will be calculated using all available 
screening values.  Subjects who meet all 
inclusion criteria and none of the exclusion 
criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The 
randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment 
(yes/no) and baseline bilirubin categories 
(>upper limit of normal [ULN]/ ≤ULN). 
Investigational product (OCA or matched 
placebo) will be taken orally, once daily.  
Investigational product will be initiated at 5 
mg OCA or matched placebo.  After 3 
months of treatment with investigational 
product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched 
placebo, in a blinded manner) at the 3-
month visit or any subsequent study visit 
based on tolerability.  Subjects will be seen 
at quarterly visits for the duration of the 
study. 
...  Investigational product will be taken orally, once daily 
for the majority of subjects; dose and frequency will be 
modified for subjects with cirrhosis (including subjects 
progressing to cirrhosis during the study) and 
classified as Child-Pugh B or C.  The randomization will 
be stratified by ursodeoxycholic acid (UDCA) treatment 
(yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
To incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores, 
to align with the 
recommended dosing 
regimen found in the 
Ocaliva US Package Insert 
for patients with hepatic 
impairment. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology. 
7.1.1, Study 
Design Diagram, 
Figure 1 
Schematic diagram
 
Updated schematic diagram 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.  Subsequent dose titration(s) for subjects 
classified as Child Pugh B or Child-Pugh C and 
following a modified dosing schedule may occur no 
earlier than 6 weeks after the previous dose titration 
Incorporate updated dosing 
scheme to reflect addition of 
Child-Pugh scoring. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology 
(insertion) 
Dosing frequency will be determined by the presence 
or absence of cirrhosis and, if cirrhosis is present, by 
Child-Pugh Score as described below: 
• 
Non-cirrhotic subjects or subjects classified as 
Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects 
should titrate to a maximum dose of 10-mg OCA once 
daily (or matching placebo) at the Month 3 visit or at 
any study visit following the Month 3 visit based on 
tolerability of the product.    
• 
For those subjects that up-titrate to 10 mg, dosing 
may be decreased to 5 mg at any time during the study 
as considered clinically appropriate (eg, based on 
tolerability). Subjects may be titrated back to a 
maximum dose of 10 mg once daily based on 
tolerability and clinical judgment of the Investigator.    
• 
 Subjects who are cirrhotic and classified as Child-
Pugh Class B or Child-Pugh Class C will initiate a 
modified treatment regimen with 5-mg OCA or 
matching placebo once weekly for at least 3 months.  
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5-mg OCA or 
matching placebo once daily, based on tolerability.  
Subjects classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 10-mg 
OCA or matching placebo twice weekly, based on 
tolerability. 
Includes New Table: Planned Dosing Regimen by 
Cirrhosis and Child-Pugh Score 
Revised methodology to 
incorporate the changes in 
dosing for subjects based on 
the Child-Pugh Scores. 
 
5.1, Overview 
(insertion) 
The United States Food and Drug Administration 
(FDA) has granted accelerated approval for Ocaliva 
for the treatment of PBC.  Ocaliva is not yet approved 
outside the United States for use in any indication. 
Language updated as OCA 
is approved in the US with 
the trade name Ocaliva. 
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5.5.2.2, Rationale 
for Modified OCA 
Doses in Patients 
Classified with 
Child-Pugh B or 
Child-Pugh C 
Hepatic 
Impairment 
(Insertion) 
New section: Rationale for Modified OCA Doses in 
Patients Classified with Child-Pugh B or Child-Pugh C 
Hepatic Impairment 
Simulations using a physiologic PK model predicted 
changes in systemic and liver OCA concentrations 
associated with changes in the severity of hepatic 
impairment (Child-Pugh score).  Model simulations 
predicted that for mild (Child-Pugh A), moderate 
(Child-Pugh B), and severe (Child-Pugh C) hepatic 
impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to subjects 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 (Child-Pugh B and C) 
subjects treated with OCA in phase 1 and 2 studies 
experienced plasma OCA exposures >10-fold higher 
than those in healthy subjects, 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.  Collectively, the 
results from these analyses and those from bile acids in 
the literature suggest that the doses of OCA 
administered to hepatically-impaired patients should 
be modestly lower than those for patients with normal 
hepatic function to achieve similar hepatic exposure.   
Per the approved FDA prescribing label, the 
recommended dosing regimen for OCA in subjects 
with moderate and severe hepatic impairment is a 
starting dose of 5-mg OCA once weekly.   Dosage 
adjustments in subjects with moderate (Child-Pugh B) 
or severe (Child-Pugh C) hepatic impairment may be 
made after establishing tolerability at the lower dose 
Provide the rationale to 
incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores 
into the protocol. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
(full modified dosing regimen is described in 
Appendix A). 
5.6, Summary of 
Known Potential 
Risks with OCA 
(Insertion) 
…These findings were seen more frequently with doses 
above 10 mg OCA.  In addition, cholecystitis, including 
acute cholecystitis, was reported in association with 
treatment with OCA. 
Added two AE terms 
reported in the updated 
Investigator’s Brochure. 
7.1, Overall Study 
Design 
…Investigational product will be initiated 
at 5 mg OCA or matched placebo.   
Following 3 months of treatment with 
investigational product, subjects should be 
titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose 
to 10 mg OCA) based on tolerability 
Investigational product will be taken orally, once daily.  
Subjects who are non-cirrhotic or classified as Child-
Pugh A at Screening will initiate investigational 
product once daily with 5-mg OCA or matching 
placebo. Following 3 months of once daily treatment with 
investigational product, the dose should be titrated to a 
maximum 10 mg OCA or matching placebo once daily, 
based on tolerability (see Section 7.3).  
Subjects with cirrhosis and classified as Child-Pugh 
Class B or Child-Pugh Class C will follow a modified 
dosing regimen, and will initiate investigational 
product once weekly with the 5-mg OCA or matching 
placebo dose.  In addition, these subjects will follow a 
modified titration plan, which is outlined in 
Appendix A.  
Amend the protocol to 
incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores. 
7.1.2, Table 1, 
Schedule of Study 
Procedures – 
Screening to 
Month 12 (Table 1 
of 2), 9.3, 
Treatment 
compliance 
Safety Contact 
This visit has been deleted. 
Replaced with the 1 Month 
Post-Titration Visit. 
(Insertion) 
Added the following visits: 
• 
Month 1 
• 
1 Month Post-Titration Visit 
Visits were added to 
accommodate the updated 
dosing and titration regimen 
based on subject’s 
Child-Pugh Scores. 
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Justification for Change 
bThe subject should be contacted by 
telephone on a monthly basis in between at-
clinic study visits at Month 1 and Month 2 
(± 1 week), and also 2 weeks post dose 
titration (up or down), to assess for AEs and 
concomitant medications and to verify that 
s/he is dosing as directed. 
cAs soon as possible upon study 
discontinuation and as near as possible to 
last dose taken. 
nSubject to begin dosing on Day 1 
Deleted. 
Result of table being 
updated for the dosing and 
titration regimen based on 
subject’s Child-Pugh Scores. 
(Insertion) 
Added the following study procedures: 
• 
Cirrhosis Status Assessmente 
• 
Assessments for Child-Pugh Scoresg 
• 
Dose Titration: Standard Dosingn,o 
• 
Dose Titration: Modified Dosing n,o 
• 
Dosing Diary 
Study procedures were 
added to accommodate the 
updated dosing/titration 
regimen.  Dosing diary was 
added to improve 
compliance. 
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(Insertion) 
Added the following footnotes: 
• 
bSafety 
Post-Titration 
visits 
must 
be 
performed 1 month + 1 week after any up-
titration in dose and/or frequency in subjects 
following modified dosing due to Child-Pugh 
B and Child-Pugh C hepatic impairment.  In 
subjects following the standard dosing 
regimen, the post-titration visit must be 
performed only after the first up-titration to 
10 mg OCA or matching placebo, or after ≥3 
months at a decreased dose or frequency. 
• 
ePresence or absence of cirrhosis should be 
assessed per Section 9.7.3.  Cirrhosis status 
should be repeated as clinically indicated. 
• 
fMayo Risk Score will be calculated based on 
central laboratory evaluations, diuretic use 
data, and peripheral edema assessment data 
captured in the CRF. 
• 
gChild-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. 
• 
nPre-titration tolerability assessment, which 
include a review of AEs and a review of 
safety laboratory results (eg, chemistry, 
hematology, and coagulation), must be 
completed by the Investigator before any up-
titration 
can 
occur 
as 
defined 
in 
Section 7.4.1.  Lab results obtained within 2 
months prior to any up-titration may be used 
for assessment. 
• 
oDose Titration is based on cirrhosis status 
(Section 9.7.3) 
and 
Child-Pugh 
score 
(Section 7.3).  The initial dose titration of 
investigational product may occur at the 
Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.  Subsequent dose titration(s) for 
Added footnotes provide 
clarity regarding 
assessments and visits based 
on the evaluation of 
Child-Pugh scores.  
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Justification for Change 
subjects who are classified as Child-Pugh B 
or Child-Pugh C and following a modified 
dosing schedule may occur no earlier than 6 
weeks after the previous dose titration.  For 
complete modified dose titration criteria, 
refer to Appendix A. 
• 
pSubjects will be instructed to begin dosing 
on the day after the Day 0 visit (ie, on Day 1) 
and to take investigational product at 
approximately the same time of day.  
Subjects must be instructed to swallow the 
tablet whole; they must not chew, divide, or 
crush the tablet. 
7.1.2, Table 2, 
Schedule of Study 
Procedures – Year 
2 Through End of 
Study (Table 2 of 
2) 
 
New table- Schedule of Study Procedures – Year 2 
Through End of Study (Table 2 of 2) 
Divided Schedule of Study 
Procedures into 2 tables, 
updated to include visits 
added per updated 
dosing/titration information.  
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Justification for Change 
7.3, Planned 
Dosing Regimen 
7.3 Treatment Assignment 
Subjects will receive either placebo or 5 mg 
OCA and should titrate to 10 mg OCA (in a 
blinded manner) at the 3-month study visit 
or at any study visit thereafter depending on 
tolerability. 
7.3 Planned Dosing Regimen 
Subjects will be randomized to treatment with either 
OCA or matching placebo in a 1:1 ratio.  Subjects will 
be dosed according to their cirrhosis status (as defined 
in Section 9.7.3) and applicable Child-Pugh Score (see 
Section 9.7.4) as outlined in Table 3.  
Subjects who are non-cirrhotic or classified as 
Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects 
should titrate to a maximum dose of 10-mg OCA once 
daily (or matching placebo) at the Month 3 visit or at 
any study visit following the Month 3 visit based on 
tolerability of the product.  A review of safety 
laboratory results (eg, chemistry, hematology, and 
coagulation) obtained no more than 2 months prior to 
the planned up-titration visit must be completed as 
part of the product tolerability assessment before up-
titration can occur (see Section 7.4.1).   
For those subjects that up-titrate to 10 mg, dose may 
be decreased to 5 mg at any time during the study as 
considered clinically appropriate (eg, tolerability). 
Subjects may be titrated back up to a maximum dose 
of 10 mg once daily based on tolerability and clinical 
judgment of the Investigator.  A review of safety 
laboratory results obtained within 2 months of the 
planned up-titration visit date is not required prior to 
re-challenging a subject up to 10 mg once daily dosing, 
as long as the decrease in dose/dosing frequency was 
less than 3 months in duration. 
Section renamed to reflect 
changes in titration and 
dosing for subjects with 
hepatic impairment. 
(Insertion) 
New:  Table 3: Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
Tables added to clarify 
changes in titration and 
dosing. 
New: Table 4: Determination of Dosing Regimen 
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Justification for Change 
7.4 Dose Titration 
Criteria 
After 3 months of treatment at the 5 mg 
dose, the dose of OCA will be increased to 
the maximum dose of 10 mg OCA or 
matched placebo (in a blinded manner) at 
the 3-month visit or any study visit 
following the 3 month visit based on 
tolerability of investigational product.   
 
For those subjects that increased their dose 
to 10 mg, they may decrease his or her dose 
to 5 mg at any time during the study as 
considered appropriate (eg, tolerability), but 
should be titrated back to 10 mg based on 
tolerability and clinical judgment by the 
Investigator as soon as possible with the 
goal that all subjects remain on the 10-mg 
dose if tolerated 
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 
subject’s cirrhosis status (using histology or 
non-histological methods as defined in Section 9.7.3 
and Section 9.7.4) or Child-Pugh Score.   
Scheduled Dose Titration - The first dose titration for 
any subject may occur no earlier than 3 months 
following initiation of OCA or matching placebo.  
Subsequent titrations in dose or dosing frequency for 
subjects following the Modified Dosing Regimens may 
occur no earlier than 6 weeks (via an unscheduled visit 
or regular visit- see Appendix A) following an 
up-titration. 
Tolerability Dose Titration - Investigators may 
decrease the dosing frequency or dose for any subject at 
any time during the study, as considered clinically 
appropriate (eg, tolerability; see Section 7.4.2).   
Dose Titration due to Change in Cirrhosis or 
Child-Pugh Score - When subjects demonstrate a 
change in cirrhosis status (as assessed per 
Section 9.7.3) or Child-Pugh Score (Section 9.7.4), 
dosing should be reassessed and the dosing regimen 
modified appropriately.  Changes to the dosing 
regimen are not mandatory and should be based on 
clinical judgment as well as change in cirrhosis status.  
Table 5 provides an overview of the possible changes in 
dosing regimen due to changes in cirrhosis or Child-
Pugh 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.  
Entire section revised to 
reflect changes in titration 
and dosing. 
7.4 Dose Titration 
Criteria 
(Insertion) 
New: Table 5:  Changes in Dosing Regimen Due to 
Changes in Cirrhosis Status or Child-Pugh Score 
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7.4 Dose Titration 
Criteria 
(Insertion) 
Subjects who exhibit development of cirrhosis at any 
point in the study should be assessed per Section 9.7.3.  
If the presence of cirrhosis is confirmed and the 
subject’s Child-Pugh score is either B or C, the 
appropriate modified dosing regimen should be 
followed.  The dose or frequency of investigational 
product should be down-titrated to the next lowest 
dosing frequency in the appropriate modified dosing 
regimen unless the subject is currently taking a dose 
and frequency also specified in the modified dosing 
regimen and the investigator determines that it is 
clinically appropriate for the subject to continue at 
that dose (Appendix A). 
Subjects with pre-existing cirrhosis who demonstrate a 
change in the Child-Pugh Score from A to B or C at 
any point in the study should also have their dosing 
modified per the appropriate dosing regimen 
(Appendix A).  
Subjects who demonstrate an improvement in 
cirrhosis status or in Child-Pugh Score from B to A, or 
from Child-Pugh C to B, may be eligible to transition 
to the standard dosing regimen or the modified dosing 
for Child-Pugh B, respectively, based on tolerability.  
Prior to any dosing change, subjects must meet 
pre-titration assessment requirements for dosing as 
described in Section 7.4.1. 
Child-Pugh Scores will be calculated at all quarterly 
study visits. All associated visit data (including central 
laboratory results) should be entered into the eCRF in 
a timely fashion to confirm that the subject’s Child 
Pugh Score has not changed.  If a change in cirrhosis 
status (as defined in Section 9.7.3) and/or Child-Pugh 
Score is observed independent of a study visit, the 
subject 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 and table added to 
provide dosing guidelines to 
investigators. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Subjects’ dose and dosing frequency may be titrated 
up or down within the appropriate dosing regimen 
based on the calculated Child-Pugh Scores.  Up-
titration should be done per Investigator discretion 
and be guided by the pre-titration tolerability 
assessments. 
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7.4.1, 
Pre-Titration 
Tolerability 
Assessment 
Requirements 
(Insertion) 
7.4.1  Pre-Titration Assessment Requirements 
Tolerability of investigational product must be 
assessed prior to titrating a subject to a higher dose.  A 
review of adverse events and safety laboratory results 
(eg, chemistry, hematology, and coagulation) obtained 
within 2 months of the up-titration visit must be 
performed as part of the investigational product 
tolerability assessment, prior to any planned up-
titration in study medication (eg, Month 3, Month 6).  
Safety laboratory results obtained at the Month 1 visit 
(for titration at Month 3) or at the 1 Month 
Post-Titration Assessment visit (for titration prior to 
or at the subsequent quarterly visit) are acceptable for 
review purposes; however, 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 subject to a higher dose.  
To be eligible for a dose up-titration: 
• 
Subjects 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.  
• 
There must be no clinically significant increase (as 
determined by the investigator) in the subject’s liver 
function tests.  Subjects whose total bilirubin is 
>2× baseline (and >ULN) cannot be up-titrated, and 
additional unscheduled safety visit procedures, 
outlined in Section 9.7.19, should be implemented, as 
required 
Section added to provide 
guidance for assessing 
subject tolerability prior to 
titration. 
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8.4.2, Other 
Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
(Insertion) 
• 
Subject begins treatment with commercially 
available OCA 
… safety concerns and related to study drug 
• 
Consent may be fully withdrawn (in which case the 
subject discontinues both investigational product and 
study visits and procedures) 
…Subjects who undergo a liver transplant during the 
course of the study must discontinue investigational 
product and discontinue the study visit schedule.  
However, these subjects 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. 
Added text as Ocaliva is 
commercially available in 
the US and therefore 
subjects may be 
discontinued if they began 
off-study treatment with 
Ocaliva.   
8.4.2.1, Elevated 
Liver Enzymes 
(Insertion) 
New Section:  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. 
Section added to incorporate 
monitoring of liver test 
results during the study. 
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9.1, 
Investigational 
Product Treatment 
Regimen 
9.1.1 Dose Adjustment Beginning at 
Month 3 
After 3 months of treatment with 
investigational product, the dose of 
investigational product should be increased 
in a blinded manner and based on 
tolerability; this may occur at the Month 3 
visit, or at any study visit thereafter.  
Titration above 10 mg OCA is not 
permitted. 
At each study visit where the daily dose of 
investigational product is administered at the site, all 
assessments, except for the post-dose collection of 
blood samples for the subset of subjects participating 
in the Month 9 PK assessment, must be completed 
before administration of investigational product. 
Section revised to reflect 
changes in titration and 
dosing. 
9.2, Concomitant 
Medications 
Subjects taking bile acid sequestrants 
(BAS) 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). 
 
New sub-heading:   
Drug Interactions 
Subjects 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 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.  
(…) Information related to additional drug-drug 
interaction (DDI) studies is available in the current 
version of the Investigator’s Brochure (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 with OCA that may 
be observed in study subjects. 
Section revised to provide 
additional information on 
drug-drug interactions with 
OCA. 
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9.2.1, Prohibited 
Medications 
… the Investigator should be cognizant of 
the possibility of double dosing and 
encourage the discontinuation of open-label 
OCA therapy.  However, if commercial 
OCA therapy remains, then investigational 
product should be discontinued to avoid 
potential double dosing.  Subjects that 
discontinue investigational product but 
continue commercial OCA therapy are 
expected to continue through the end of the 
study, and the … 
… the Investigator should be cognizant of the possibility 
of double dosing.  Subjects who continue with 
commercial OCA therapy must discontinue study 
medication and are expected to continue through the end 
of the study.  … 
Ocaliva is commercially 
available in the US and, 
therefore, subjects wishing 
to take commercially 
available drug are not 
discouraged, but they must 
discontinue study 
medication. 
9.7.1, Visit 
Windows 
(insertion) 
Added the following visit windows: 
• 
Month 1 (+1 week [7 days]) 
• 
Titration Visit – Standard Dosing Regimen 
(≥Month 3) 
• 
Titration Visit 1 – Modified Dosing Regimen 
(≥Month 3) 
• 
Titration Visit 2 – Modified Dosing Regimen 
(≥6 weeks after Titration Visit 1) 
• 
Titration Visit 3 – Modified Dosing Regimen 
(Child-Pugh B ONLY) (≥6 weeks after 
Titration Visit 2) 
• 
Post-Titration Visit, (+1week [7 days]) from 
date of titration or after ≥3 months at a 
decreased dose or frequency) 
Added visits to 
accommodate the updated 
dosing/titration scheme. 
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9.7.3, Assessing 
Cirrhosis 
(Insertion) 
New: 9.7.3. Assessing Cirrhosis 
To determine which dosing regimen subjects should 
follow, the presence or absence of 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 
is defined as a subject 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  
− 
elevation in prothrombin time /INR (not 
due to antithrombotic agent use), or 
− 
elevated bilirubin (2× ULN) 
Subjects who exhibit no evidence of cirrhosis by the 
above methods of assessment will be dosed using the 
Standard Dosing Regimen, while those who do exhibit 
evidence of cirrhosis by one or more of the above 
methods will be dosed using the Modified Dosing 
Regimen according to their Child-Pugh Score 
calculated in the electronic case report form (eCRF) 
(see Appendix A). 
Cirrhosis status should be reassessed as clinically 
indicated throughout the study.  Any change in 
Added section to assess 
cirrhosis as this assessment 
will determine the 
acceptable dosing regimen 
based on a subject’s 
Child-Pugh score.  
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cirrhosis status will necessitate re-evaluation of the 
dosing regimen. 
9.7.4, Child-Pugh 
Score 
(Insertion) 
9.7.4. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is 
calculated and reported within the electronic data 
capture (EDC) system based on data entered into the 
eCRF adding the scores from the 5 factors outlined in 
Table 6 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 
Child-Pugh 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.   
It is important to note that subjects must have 
confirmed cirrhosis as assessed by one or more of the 
above criteria (Section 9.7.3) prior to applying the 
calculated Child-Pugh score for dosing.  Investigators 
will be responsible for determining the appropriate 
dosing regimen based on both the cirrhosis status and 
the Child-Pugh score (Table 6).  Any change in 
cirrhosis status or Child-Pugh Score will necessitate 
re-evaluation of the dosing regimen 
Section added to provide 
Investigators with 
information on the 
Child-Pugh scoring system. 
9.7.4, Child-Pugh 
Score 
(Insertion) 
Table 6 (New) Child-Pugh Scoring System 
 
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9.7.6, Screening 
Procedures (1 to 8 
Weeks prior to 
Day 0) 
(Insertion) 
The following procedures were added: 
Screening Visit 1 procedures are as follows: 
• 
Provide the subject with a dosing diary to 
document his or her dosing 
• 
Assess for the presence/absence of cirrhosis 
• 
Perform status assessment for calculation of 
Mayo Risk Score 
Screening Visit 2 procedures are as follows: 
• 
Perform an ultrasound for hepatocellular 
carcinoma (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 Visit 2, and a report/adequate data are 
available, a pretreatment ultrasound at Screening 
Visit 2 is not required.  If the ultrasound cannot 
be performed at Screening Visit 2 (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. 
Procedures added to assess 
cirrhosis. 
 
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9.7.7, Day 0 
Procedures 
(Randomization) 
9.7.4. 
Day 0 Procedures 
• 
Perform an ultrasound for 
hepatocellular carcinoma (HCC) 
surveillance (if equipment is unavailable, 
… 
• 
Perform physical examination and 
overall status assessment for calculation of 
Mayo Risk Score and Child-Pugh 
Assessments. 
 ̀
Presence/absence of peripheral edema 
 ̀
Presence (degree)/absence of ascites 
 ̀
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.7: Day 0 Procedures (Randomization) 
• 
Provide the subject with a dosing diary to 
document his or her dosing. 
 
Updated visit to 
accommodate the updated 
dosing/titration scheme. 
9.7.8, Month 1 
Procedures 
9.7.5 Safety Contact (Month 1, Month 2, 
and 2 Weeks Post-Titration [by telephone]) 
9.7.8 Month 1 Procedures 
• 
Provide the subject with a dosing diary to 
document his or her dosing. 
• 
In the event it is not feasible for the subject to 
return to the site for the above referenced procedures, 
the following alternative visit procedures are available 
to help ensure compliance with the Month 1 visit 
requirements: 
- 
At the Day 0 visit, the subject can be provided 
with the central laboratory collection kit and shipping 
materials associated with the Month 1 visit, … 
- 
If all other options for the collection of the Month 
1 laboratory samples have been exhausted, the use of a 
local laboratory for the Month 1 samples would be 
accepted for this visit although any laboratory data 
obtained from a local laboratory will not be captured 
in the eCRF or included in the study analysis.  … 
 
Revised section to include 
the new Month 1 visit 
procedures.  
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9.7.9, Month 3 
procedures, 
9.7.11, Month 6 
Procedures, 
9.7.12, Month 9, 
9.7.14, Month 12 
Procedures  
(Insertion) 
• 
Perform assessments for calculation of Child-Pugh 
Score 
Added procedure to 
accommodate the updated 
dosing/titration scheme. 
9.7.9 thru 9.7.17 
(Insertion) 
If up-titration will occur at this visit, complete the pre-
titration visit and visit related assessments as outlined 
to ensure all procedures required for dose titration 
eligibility have been met, including the required review 
of the dose titration laboratory parameters. 
• 
Provide the subject with a dosing diary to 
document his or her dosing 
• 
… review dosing diary with the subject 
Text added to clarify 
procedures required before 
up-titration. 
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9.7.10, Post 
Titration Visit 
Procedures 
(Insertion) 
New: 9.7.10. Post Titration Visit Procedures 
• 
Assess and record AEs. 
• 
Review and record concomitant medications. 
• 
Assess investigational product compliance, 
perform investigational product accountability, and 
review dosing diary with the subject. 
• 
Obtain blood samples for serum chemistry, 
hematology, and coagulation tests. 
• 
Provide the subject with a dosing diary to 
document his or her dosing. 
• 
In the event it is not feasible for the subject to 
return the site for the above referenced procedures, 
the following alternative visit procedures are available, 
to help ensure compliance with the Post-Titration visit 
requirements: 
- 
At the Up-titration Visit, the subject can be 
provided with the central laboratory collection kit 
and shipping materials associated with the Post-
Titration visit, and have the laboratory specimen 
collection performed at his or her local doctor’s 
office or designated laboratory collection center.  
The subject must also be contacted via telephone 
at the Post-Titration Visit time point to assess 
AEs, review concomitant medications, and assess 
investigational product compliance. 
- 
If all other options for the collection of the 
Post-Titration laboratory samples have been 
exhausted, the use of a local laboratory for the 
Post Titration samples would be accepted for this 
visit although any laboratory data obtained from 
a local laboratory will not be captured in the 
eCRF or included in the study analysis.  A copy of 
the local laboratory report would need to be 
provided to the investigator for review and 
available in the source records.  The subject must 
also be contacted via telephone at the Post-
Titration Visit time point to assess AEs, review 
Added visit to accommodate 
the updated dosing/titration 
scheme. 
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concomitant medications, and assess 
investigational product compliance. 
• 
Schedule the next visit, reiterate dosing 
instructions, and advise the subject: 
- 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… 
9.7.13, Month 9 
Procedures for 
Subjects 
Participating in 
Pharmacokinetic 
Assessment 
(Insertion) 
…Subjects who are following the Child-Pugh B and 
Child-Pugh C modified dosing regimen may 
participate in the PK assessment and will dose in the 
clinic at this visit even if the previous dose was taken 
less than 3 days prior; however, every attempt should 
be made to schedule the Month 9 PK visit according to 
the subject’s established dosing schedule. 
Clarify that subjects with 
hepatic impairment may 
continue to participate in the 
PK assessment. 
9.7.13, Month 9 
Procedures for 
Subjects 
Participating in 
Pharmacokinetic 
Assessment 
…Lunch will be provided following 
collection of the 4 hour PK sample; the 
lunch will be a meal replacement drink… 
…Lunch will be provided following collection of the 
4 hour PK sample; the lunch will be a meal replacement 
drink with no other food allowed until after the final 
6-hour post dose sample is collected… 
Clarify PK collection 
procedures. 
 
11.1.2.2, Other 
Secondary 
Assessments 
• 
OCA (and its conjugates) and C4 will 
be assayed 
• 
OCA (OCA, tauro-OCA, glyco-OCA, total OCA, 
OCA-glucuronide) and C4 will be assayed to determine 
bioanalytical concentrations.  Additional analyses may 
include other conjugates or metabolites not yet 
identified. 
Clarify the analytes to be 
measured for the PK 
analyses. 
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11.1.2.4, Potential 
Clinical Outcome 
Events 
(Insertion) 
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 13.4. 
Revised to clarify that 
potential clinical outcome 
events meeting the criteria 
of a SUSAR will not be 
reported to regulatory 
authorities expeditiously.  
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12.1.4.2 Reporting 
of Serious 
Adverse Event 
In agreeing to the provisions of this 
protocol, the Investigator accepts all legal 
responsibilities for immediate reporting of 
SAEs to the medical monitor. 
All SAEs occurring while subjects are 
receiving investigational product or are on 
an investigational product holiday 
(including Potential Clinical Outcome 
Events that qualify as serious) must be 
reported to the medical monitor 
immediately (ie, within 24 hours) after the 
Investigator identifies the SAE.  SAEs are 
reported by entering the SAE data into the 
electronic data capture (EDC) system.  
Entering the SAE data into the EDC system 
will automatically notify the medical 
monitor of the event.  In the event that the 
EDC system is inaccessible, an SAE may 
be reported by telephone or fax using a 
paper SAE Report form.  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:   
subject number and initials, a description of 
the event, at least one criterion classifying 
the event as serious and the name and title 
of the reporting individual.  Additionally, 
judgment of causality by the Investigator 
must be provided as soon as possible to 
ensure timely reporting to regulatory 
authorities by the Sponsor or designee(s).  
Following the initial report, any additional 
information obtained by the Investigator 
about the SAE must be reported promptly 
to the medical monitor.  Any supporting 
source documentation should be faxed to 
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 be reported by: 
• 
E-mail to the SAE email address:  
sae@interceptpharma.com 
• 
Fax using a paper SAE report form:  
+1 800 497 8521 
• 
Telephone:  +1 858 964 1571  
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:   
• 
Subject 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 Sponsor will notify the appropriate regulatory 
agencies as well as all participating Investigators of 
investigational new drug (IND) 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 
Updated guidance for 
reporting SAEs. 
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+1 800 497 8521 or emailed to 
sae@interceptpharma.com as soon as 
possible. 
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.  A 
SAE assessed with a possible, probable, or 
definite causal relationship to the 
investigational product and unexpected 
according to IB Reference Safety 
Information (RSI), is known as a suspected 
unexpected serious adverse reaction 
(SUSAR).  The Sponsor will notify the 
appropriate regulatory agencies as well as 
all participating Investigators of 
investigational new drug (IND) safety 
reports (SUSARs) that occur during the 
study within the time frames required by 
each regulatory agency.  The Investigator is 
responsible for submitting information on 
IND safety reports/SUSARs received from 
the Sponsor or Sponsor designee to her/his 
local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities 
must be retained in the appropriate study 
file(s). 
Potential Clinical Outcome Events 
(Appendix A) as well as Anticipated Events 
(Appendix B) will not undergo expeditious 
reporting to regulatory authorities 
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 
+1 800 497 8521 or emailed to 
sae@interceptpharma.com as soon as possible.   
The Investigator is responsible for submitting 
information on IND 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 
IECs/IRBs must be retained in the appropriate study 
file(s).  As instructed by the Sponsor, IND 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 12.1.5. 
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Section 12.1.5, 
Suspected Liver-
related Clinical 
Outcome Events 
Clinical Outcome Events (Appendix A) as 
well as Anticipated Events (Appendix B) 
will not undergo expeditous reporting. 
12.1.5 Suspected Liver-Related Clinical Outcome 
Events 
Specified liver-related clinical outcome events may, by 
definition (see Section 12.1.1.2) qualify as SAEs.  The 
Sponsor must be notified of any SAEs within 24 hours 
of the site becoming aware of the event (see 
Section 12.1.4.2).  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. 
Given that the liver-related clinical outcome events 
could also meet the criteria of a SUSAR, please refer to 
Section 11.1.2.4. 
The Sponsor will consider the following list of clinical 
outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy), spontaneous bacterial 
and peritonitis (preferred term: peritonitis bacterial). 
Updated section to account 
for events related to hepatic 
impairment. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
13.2.4, 
Cardiovascular 
Adjudication 
Committee 
13.2.3 
(…) 
In addition to potential clinical endpoint 
events, cardiovascular events will be 
adjudicated.  The adjudication of these 
events will be handled separately from the 
adjudication of events for assessment of the 
primary endpoint in this study and will be 
described separately. 
New Section: Cardiovascular Adjudication Committee 
In addition to potential clinical endpoint events, 
cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately 
from the adjudication of events for assessment of the 
primary endpoint in this study. Adjudicated 
cardiovascular events include core major adverse 
cardiovascular events (MACE) (cardiovascular death, 
nonfatal myocardial infarction, and nonfatal stroke) 
and expanded MACE (unstable angina requiring 
hospitalization, transient ischemic attack, peripheral 
or coronary revascularization procedures, 
hospitalization for congestive heart failure).  Other 
events potentially related to adverse cardiovascular 
outcomes may be included in the Cardiovascular 
Adjudication Committee (CAC) Charter for 
adjudication.  The adjudication of these events will be 
handled separately from the adjudication of events for 
assessment of the primary endpoint in this study (see 
Section 13.4). 
Committee added to assess 
cardiovascular events in 
subjects during the study. 
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13.4, Adjudication 
Committee 
All potential endpoint events will be 
reviewed by an adjudication committee 
before inclusion in the any analysis.  The 
adjudication of potential clinical endpoint 
events will include, but is not limited to:  
available hospital reports, histology, 
discharge summaries, and death certificates.  
The assessment of events will be conducted 
in compliance with the protocol, study-
specific procedures, manuals, Good 
Clinical Practice (GCP), and all other 
applicable regulatory requirements, 
including the archiving of essential 
documents.  A separate adjudication 
committee charter will document the entire 
data flow and process from committee 
membership, the reporting of events by the 
study site, reporting of the final assessment, 
supply of source documentation to the 
committee, the review of the events by the 
committee, and the working procedures of 
the committee.  The adjudication committee 
members will be independent hepatologists 
not involved in the study as investigators, 
DSMC members, or consultants.  All 
adjudication committee members will 
remain blinded to treatment group 
throughout the study. 
In addition to potential clinical endpoint 
events, cardiovascular events will also be 
adjudicated.  The adjudication of these 
events will be handled separately from the 
adjudication of events for assessment of the 
primary endpoint in this study and will be 
described separately. 
All suspected liver-related clinical outcomes, 
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 subject treatment or site-
specific information.  The assessment of events will be 
conducted in compliance with study-specific 
Committees added to assess 
liver impairment in subjects 
during the study. 
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Justification for Change 
procedures, manuals, good clinical practice (GCP), 
and all other applicable regulatory requirements, 
including the archiving of essential documents. 
Appendix A, 
Modified Dosing 
Regimen for 
Subjects with 
Child-Pugh B/C 
Hepatic 
Impairment 
(Insertion) 
New: APPENDIX A. MODIFIED DOSING 
REGIMEN FOR SUBJECTS WITH CHILD-PUGH 
B/C HEPATIC IMPAIRMENT 
Added section to describe 
changes in dosing and 
titration for subjects 
assessed as cirrhotic 
Child-Pugh B or 
Child-Pugh C. 
Appendix B, LIST 
OF STUDY 747-
302 OUTCOME 
EVENTS 
Was Appendix A 
Now Appendix B  
The hepatic dosing appendix 
became Appendix B  
Appendix C 
LIST OF STUDY 747-302 ANTICIPATED 
EVENTS 
Deleted 
Replaced by Appendix B, 
more comprehensive 
description of the outcome 
events. 
 
 
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APPENDIX G. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO PROTOCOL VERSION 3.1 
(DATED 23 DEC 2016) 
Please note that Protocol 747-302 Version 3.1 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.  This 
summary of changes is provided for completeness.  A full accounting of the changes from Protocol Version 3 to Protocol 
Version 4 is provided in Appendix I. 
Rationale and Summary of Changes 
Major revisions to Protocol 747-302 include the expansion of the spectrum of stages of PBC disease, the addition of progression to 
cirrhosis as a secondary endpoint, and the addition of two interim analyses.   Additional revisions include an increase in subject 
number and the number of required clinical outcome events, a change in the study phase, an update to the nomenclature for PBC, and 
various clarifications within the protocol.   
The following table includes revisions that were made to Protocol Version 3.1 with an associated reason or justification for the 
change.  Rationales (Justifications for Change) that impact multiple sections are provided below and referenced in the table with the 
appropriate rationale number.  
1. The phase of the study has been changed from ‘3b’ to ‘4’ to reflect that this is a post-marketing study. 
2. The term ‘primary biliary cirrhosis’ has been changed to ‘primary biliary cholangitis’ throughout the document to reflect 
recent changes in nomenclature for PBC. 
3. The increase in number of required events from 121 to 127 is due to the addition of two interim analyses (IA), which will 
allow an independent DMC to recommend continuation, modification, or cessation (for efficacy or futility) of the study.  One 
IA will occur at 50% information (after 64 events occur) and one at 75% information (after 96 events occur).  Inclusion of 
patients with earlier stage disease will also increase the time to event requiring more events in order to keep follow-up to 
approximately 6 years.   
4. The first-year study enrollment rate was lower than projected due to slower-than-anticipated activation of sites and required a 
re-estimation of the accrual duration.   Using observed accrual rates, the accrual duration was extended by two years.  The 
follow-up period was maintained at 6 years, thereby leading to a total trial duration of 10 years. 
5. ‘Encephalopathy’ has been modified to ‘Hepatic Encephalopathy’ to clarify that the relevant clinical outcome endpoint should 
be related to hepatic disease. 
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6. Histological confirmation (biopsy) has been added as an acceptable method of confirming a diagnosis of Hepatocellular 
Carcinoma. 
7. Broadening the Spectrum of Disease:  Lowering the minimum allowable baseline ALP to 3x ULN and raising the maximum 
allowable baseline total bilirubin to 5x ULN will increase the number of subjects enrolled with early and advanced disease 
facilitating the collection of safety and efficacy data in a population that covers the spectrum of PBC disease and overlaps with 
the subject population in the phase 3 protocol 747-301. 
8. The titration regimen has been updated to reflect assessment of both tolerability and biochemical response prior to up-titration 
per the USPI and SmPC.   
9. The increase in enrollment from 350 to 428 is due in part to the increased number of events, and in part due to the change in 
the estimated Placebo baseline hazard rate which resulted from changing the lower limit of ALP from 5× ULN to 3× ULN in 
the enrollment criteria #2. 
10. Progression to Cirrhosis has been added as a secondary endpoint:  Due to the chronic nature of PBC, outcomes require a very 
long time to accrue to evaluate the impact of potential therapies.  Despite the proven prognostic utility of ALP and bilirubin, 
there is a remaining need to evaluate noninvasive assessments of disease progression that can be linked to histological 
progression of the disease.  Therefore, it is important to evaluate potential non-invasive markers of fibrosis/cirrhosis and their 
relationship to clinical outcomes as part of 302. 
The text deleted from Protocol Version 3 is crossed out while revised text in Version 3.1 is indicated in bold font in the table below.  
Minor/editorial changes and non-substantial changes are not listed individually in the summary table below.  
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Section 
Original Text (Amendment 3, 
07 September 2016) 
Revised Text (Version 3.1, 23 December 2016) 
Justification for Change 
Title Page 
Synopsis, Title of 
Study 
A Phase 3b, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study Evaluating 
the Effect of Obeticholic Acid on Clinical 
Outcomes in Subjects with Primary Biliary 
Cirrhosis 
A Phase 4, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on 
Clinical Outcomes in Subjects with Primary 
Biliary Cholangitis 
 
Rationale 1 and 2  
Study Personnel 
Contact 
Information 
Or if Not Available: 
Contact: 
 MD, PhD, 
Executive Director, Clinical 
Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
 
 
Email: 
 
 (Pacific 
time zone) 
 
 
Or if Not Available: 
Contact: 
 MD, PhD 
Medical Director, Clinical 
Research, 
Intercept Pharmaceuticals, 
Inc. 
Telephone: 
Mobile: 
 
Email: 
 
 (Pacific 
time zone) 
 
Back-up medical monitor 
responsibilities were 
transferred to 
 
Synopsis, Studied 
Period (years) 
 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 and 4   
 
Synopsis, Phase of 
Development  
3b 
4 
Rationale 1 
Synopsis, 
Objectives, 
Primary, 
Statistical 
• 
Encephalopathy (as defined by a West Haven 
score of ≥2) 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities 
• 
Hepatic encephalopathy (as defined by a 
West Haven score of ≥2) 
Rationale 5   
 
 
Rationale 6 
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PPD
PPD
PPD
PPD
PPD
PPD
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Methods – 
Efficacy Analyses 
Section 6.1 
Primary Objective 
Section 11.1.1 
Primary 
Assessments 
 
Section 13.1.3 
Primary Efficacy 
Analysis 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities unless 
confirmed by biopsy 
Synopsis, 
Objectives, 
Secondary  
Section 6.2 
Secondary 
Objectives 
 
Insertion 
 
To assess the pharmacokinetics of OCA and its 
conjugates in a subset of subjects 
To assess the effect of OCA compared to 
placebo on progression to cirrhosis 
To characterize the pharmacokinetics of OCA 
and its conjugates in a subset of subjects 
Rationale 6 
 
 
 
Synopsis, 
Methodology: 
Schematic 
Diagram 
 
Section 7.1.1 
Study Design 
Diagram, Figure 1 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.   
 
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability of the product. 
 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability and biochemical response.   
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability and biochemical response of the 
product. 
Rationale 7 
 
 
 
 
Rationale 8 
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• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability. Subjects 
classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 
10-mg OCA or matching placebo twice 
weekly, based on tolerability. 
 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the titration of 
dose and/or frequency is dependent on subject tolerability, 
and/or changes in cirrhosis status or Child-Pugh Score at any 
time during the study.  
 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability and biochemical 
response. Subjects classified as Child-Pugh 
Class C should titrate to a maximum dose 
and frequency of 10-mg OCA or matching 
placebo twice weekly, based on tolerability 
and biochemical response. 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the titration 
of dose and/or frequency is dependent on subject tolerability, 
biochemical response, and/or changes in cirrhosis status or 
Child-Pugh Score at any time during the study. 
Synopsis, Number 
of Subjects 
(planned)  
Approximately 350 subjects 
Approximately 428 subjects 
Rationale 9 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
2.  A mean total bilirubin >ULN and ≤3x ULN 
and/or a mean ALP >5x ULN 
2.  A mean total bilirubin >ULN and ≤5x ULN 
and/or a mean ALP >3x ULN 
Rationale 7 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
5.  Contraception:  Female subjects 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:   
5.  Contraception:  Female subjects of 
childbearing potential must use ≥1 effective 
method of contraception during the study and 
until 30 days following the last dose of 
investigational product.  Effective methods 
of contraception are considered to be those 
listed below:   
Standardizing language across 
protocols; removing double-
barrier terminology 
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• 
Double barrier method, ie, (a) condom 
(male or female) or (b) diaphragm, with 
spermicide; or  
• 
Intrauterine device (IUD); 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 subject   
• 
Barrier method, ie, (a) condom (male 
or female) or (b) diaphragm, with 
spermicide 
• 
Intrauterine device (IUD)  
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection) 
• 
Abstinence, if in line with the preferred 
and usual lifestyle of the subject   
Synopsis, 
Exclusion Criteria 
Section 8.3 
Subject Exclusion 
Criteria 
 
3.  Mean total bilirubin >3x ULN 
Mean total bilirubin >5x ULN 
Rationale 7 
Synopsis, Criteria 
for Evaluation 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Encephalopathy (as 
defined by a West 
Haven score of ≥2) 
 
• 
Hepatocellular 
carcinoma 
confirmed by 
2 complimentary 
imaging modalities 
 
Secondary Objectives 
 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Hepatic 
encephalopathy (as 
defined by a West 
Haven score of ≥2) 
• 
Hepatocellular 
carcinoma confirmed 
by 2 complimentary 
imaging modalities 
already confirmed by 
biopsy 
Secondary Objectives 
 
Rationale 5 
 
 
 
 
 
 
 
 
 
 
Rationale 10 
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Progression to 
cirrhosis 
Clinical, laboratory, 
or radiological 
evidence of cirrhosis 
and/or liver stiffness 
(i.e., Fibroscan® TE) 
confirmed by biopsy 
unless not medically 
indicated 
Synopsis, 
Statistical 
Methods 
Analysis 
Populations 
 
The following subject populations will be 
evaluated and used for presentation and analysis of 
the data:  Randomized, Intent-to-Treat (ITT), 
Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical 
Control.  Descriptions of subject populations are 
provided in Section 13.1.1. 
The following subject populations will be 
evaluated and used for presentation and analysis 
of the data:  Intent-to-Treat (ITT), Safety, PK, 
Overall Historical Control, UKPBC Historical 
Control, and the Global PBS Historical Control.  
Descriptions of subject populations are provided 
in Section 13.1.1. 
 
Randomized population 
includes patients on OCA who 
withdrew prior to receiving 
drug and this is already 
collected with the safety 
population. 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Analysis 
The primary efficacy analysis will compare 
randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the 
ITT population.   
The primary efficacy analysis will compare OCA 
to placebo with respect to the primary efficacy 
endpoint using the ITT population.   
 
Synopsis, 
Statistical 
Methods, Key 
Secondary 
Efficacy Analyses 
The key secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
in ITT population with respect to the key 
secondary efficacy endpoints.   
The key secondary efficacy analyses will 
compare OCA to placebo in the ITT population 
with respect to the key secondary efficacy 
endpoints.   
 
Synopsis, 
Statistical 
Methods, Other 
Efficacy Analyses 
 
Section 13.1.5 
Additional 
Insertion 
Progression to cirrhosis will be assessed in the 
subset of subjects considered non-cirrhotic at 
baseline using available medical history, 
clinical, and laboratory assessments as well as 
baseline transient elastography (TE), where 
available. Specifically, subjects with no 
clinical, laboratory, or radiological evidence of 
cirrhosis at baseline and/or a TE liver stiffness 
of <16.9 kPa (Corpechot 2012) will be 
Rationale 10 
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Secondary 
Efficacy Analyses 
considered non cirrhotic.  Progression to 
cirrhosis will be assessed by the development 
of clinical, laboratory, or radiological evidence 
of cirrhosis and/or when liver stiffness 
increases to ≥16.9 kPa during the trial in 
which case histological progression to cirrhosis 
should be confirmed by biopsy unless not 
medically indicated. Using this definition for 
progression to cirrhosis, the percentage of 
non-cirrhotic subjects progressing to cirrhosis 
during the treatment period will be 
summarized by treatment group and 
compared using a Cochran–Mantel–Haenszel 
test stratified by the randomization 
stratification factor. 
Analyses for the histological assessment 
conducted as part of the biopsy sub-study are 
defined in Appendix C. 
 
Synopsis, 
Statistical 
Methods, Safety 
Analyses 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will compare OCA and placebo using the Safety 
Population. 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will be summarized by treatment group for the 
Safety Population. 
 
Clarification of summary 
analyses 
Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
Rationale 3 
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Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
 
Section 13.1.2. 
Determination of 
Sample Size 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, placebo 
survival estimate of 0.5 at 8 years 
with a hazard ratio of 0.60, and total 
study duration of 8 years, allowing 
for 2 years accrual and 6 years of 
follow up 
 
• 
Insertion 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, 
placebo survival estimate of 0.6 at 8 
years with a hazard ratio of 0.60, 
and total study duration of 10 years 
(from first subject enrolled), 
allowing for 4 years subject accrual 
and 6 years of follow up 
• 
Two interim analyses and one 
final analysis are planned 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
 
 
 
Rationale 4 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale 3 
 
 
 
 
 
 
Section 5.6 
Summary of 
Known Potential 
Risks with OCA 
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).  
An increase in liver enzymes and hepatic AEs, 
including jaundice, were observed in subjects 
with liver disease at OCA doses between 10 mg 
and 50 mg and in healthy subjects who were 
treated at doses ≥100 mg in Phase 1, multiple-
dose studies. 
Language has been updated to 
reflect Sponsor standards 
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Insertion 
Refer to the IB for additional information 
regarding the known potential risks with the 
investigational product. 
Section 7.1 
Overall Study 
Design 
This is a Phase 3b, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤3× ULN or ALP 
>5× ULN.   
 
Approximately 350 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 2-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
Investigational product will be taken orally, once 
daily….based on tolerability (see Section 7.3). 
 
 
 
The study will continue until approximately 121 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
This is a Phase 4, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤5× ULN or ALP 
>3× ULN.   
 
Approximately 428 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 4-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
Subjects will be dosed according to their 
cirrhosis status and Child-Pugh Score….based 
on tolerability and biochemical response (see 
Section 7.3)   
 
The study will continue until approximately 127 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
Rationale 1 
 
 
 
 
 
Rationale 9 
 
 
 
 
 
Clarification  
Rationale 7 
 
 
 
Rationale 3 
Section 7.1.2 
Schedule of Study 
Procedures, Table 
1  
Insertions 
 
 
 
 
 
 
Physical exams have been added at: 
• 
Month 1 
• 
1-Month Post Titration 
• 
Month 6 
Fibroscan® TE has been added at Month 6 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring. 
 
 
 
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j Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device 
is available.  Similarly, DEXA will be conducted at 
selected study sites where the DEXA device is 
available.    
 
 
Insertion (subsequent footnotes are renumbered 
accordingly) 
 
 
 
 
 
 
 
l Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be obtained to 
confirm if a study endpoint has been met. 
 
 
 
 
o … The initial dose titration of investigational product 
may occur at the Month 3 visit, or any study visit 
thereafter for subjects on all dosing regimens, based 
on tolerability. … 
 
u  A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of these 
samples.  Genetics samples will be collected at Day 0 
and every other year beginning at Month 12. 
 
j Transient elastography (TE) will be conducted at 6-
month intervals at all study sites where the 
Fibroscan® TE device is available.   
 
 
 
 
k DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available.  Please refer to Section 9.7.7 for 
additional information related to the allowed 
windows at Day 0 for this procedure. 
 
 
 
 
m Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: unless HCC has already confirmed 
by biopsy, a second confirmatory image (eg, MRI) 
should be obtained to confirm if a study endpoint 
has been met   
 
 
 
p … The initial dose titration of investigational product 
may occur at the Month 3 visit, or any study visit 
thereafter for subjects on all dosing regimens, based 
on tolerability and biochemical response. … 
 
v A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of these 
samples.  Genetics samples will be collected at Day 
0 and every other year beginning at Month 12.  If a 
baseline (e.g. Day 0) genetic sample is not 
obtained, subsequent genetic samples are not 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments at Day 0 
and Month 12) 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
 
 
Rationale 8 
 
 
 
 
Clarification 
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required to be collected during the course of the 
study. 
 
Section 7.1.2 
Schedule of Study 
Procedures, Table 
2 
Insertions 
 
 
 
 
 
i Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device 
is available.  Similarly, DEXA will be conducted at 
selected study sites where the DEXA device is 
available.  Not required if done within 6 months of 
visit. 
   Insertion (subsequent footnotes are renumbered 
accordingly) 
  
 
j   Endoscopy will be conducted at selected study sites 
where the device is available to assess for the 
presence of oesophageal varix/varices. 
 
k  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be obtained to 
confirm if a study endpoint has been met. 
Fibroscan® TE has been added at Month 6 
continued follow up 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
continued follow up 
 
i Transient elastography (TE) will be conducted at 6-
month intervals at all study sites where the 
Fibroscan® TE device is available. Not required if 
done within 3 months of visit 
 
 
j  DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available.  Not required if done within 6 months 
of visit. 
k   Endoscopy will be conducted at all study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices. 
 
l  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: unless HCC has already been 
confirmed by biopsy, a second confirmatory image 
(eg, MRI) should be obtained to confirm if a study 
endpoint has been met. 
 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
 
 
 
 
 
 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments) 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
Section 7.1.3 
Study Duration 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
Rationale 3 
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are expected to have a minimum follow-up time of 
approximately 6 years. 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Section 7.2 
Number of 
Subjects 
It is expected that approximately 350 subjects will 
be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
It is expected that approximately 428 subjects 
will be randomized in the study.   
Rationale 9 
 
 
Section 7.3 
Planned Dosing 
Regimen 
Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at 
the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the 
product.   
 
 
 
Table 3:  Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
Footnotes were re-ordered 
b   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is dependent 
on subject tolerability and/or changes in cirrhosis 
status or Child-Pugh score at any time during the 
study 
Subjects should titrate to a maximum dose of 10 
mg OCA once daily (or matching placebo) at the 
Month 3 visit or at any study visit following the 
Month 3 visit based on tolerability of the product 
and assessment of biochemical response.  Up-
titration should be considered if ALP and/or 
total bilirubin >ULN.   
 
Table 3:  Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
 
c   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is 
dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or 
Child-Pugh score at any time during the study 
Rationale 8 
Section 7.4 Dose 
Titration Criteria 
Insertion 
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) as 
well as biochemical response (as assessed by 
reductions in ALP and/or total bilirubin).  In 
general, down-titration will be done in 
response to tolerability concerns and can occur 
at any time while on-study.  Up-titration will 
be done per protocol when subjects have no 
tolerability concerns and have not achieved an 
adequate reduction in ALP and/or total 
Added language to clarify 
titrations (up or down) 
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bilirubin to within normal limits, or 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 for each dosing regimen as defined 
in Section 7.3. 
 
Section 8.4.1.1 
Severe Drug-
Induced Liver 
Injury 
Insertion 
If a subject develops signs and symptoms of a 
severe drug-induced liver injury, regardless of 
causality, investigational product should be 
interrupted until the event has resolved or 
returned to baseline, but the subject should 
continue with the study visit schedule.  
Subjects who develop significant drug-induced 
liver injury which is considered 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, evidence of 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. 
Severe drug induced-liver injury that is not 
considered related to investigational product 
must be discussed with the Sponsor before 
investigational product is reinitiated.  Follow-
up procedures for subjects resuming 
treatment, including laboratory evaluations 
and physical examinations, must be performed 
Added guidelines for subjects 
who develop severe Drug-
Induced Liver Injury  
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after a maximum of 2 weeks of re-treatment 
and may be conducted at a local clinic if the 
subject is unable to return to the site.  Results 
must be reported immediately to the site so the 
Investigator can determine if the subject is to 
be allowed to continue treatment.  Subjects 
should be encouraged to continue study visits 
despite stopping investigational product for 
continued study data collection but may 
withdraw consent at any time. 
All suspected drug-related hepatic injury 
events will be adjudicated by the Hepatic 
Safety Committee (see Section 13.4). 
Section 8.4.1.2 
Liver 
Transplantation 
Moved from Section 8.4.2 Other Reasons for 
Discontinuation of Study or Investigational 
Product 
8.4.1.2 Liver Transplantation 
Subjects must discontinue investigational 
product after undergoing liver transplantation 
surgery.  Subjects should be encouraged to 
continue study visits, despite stopping 
investigational product, for continued study 
data collection. 
The relocation of this 
statement from within 
Section 8.4.2 to 8.4.1.2 
clarifies directions to 
discontinue subjects who 
undergo a liver transplant 
from investigational product 
but not study visits 
Section 8.4.2 
Reasons for 
Mandatory 
Interruption of 
Investigational 
Product 
Insertion/Reorganization 
8.4.2 Reasons for Mandatory Interruption of 
Investigational Product 
Prior to re-starting investigational product 
after a prolonged interruption, the subject 
must be re-consented and new baseline visit 
procedures must be performed if the interval 
from the last visit was more than 3 months 
(+2 weeks) during the first 18 months of the 
study or more than 6 months prior (+2 weeks) 
during the remainder of the study.   
 
This clarifies what should be 
done when a subject 
experiences a prolonged 
interruption in investigational 
product such as in the event of 
pregnancy  
 
Section 8.4.2.1 
Pregnancy 
Modification of 8.4.1 Reasons for Mandatory 
Discontinuation of Investigational Product 
8.4.2.1 Pregnancy 
If a female subject becomes pregnant, she must 
interrupt treatment with investigational product 
Language simplified and 
aligned with Sponsor 
standards 
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If a female subject becomes pregnant, she must 
discontinue taking investigational product, but 
should continue with the study visit schedule.  The 
subject must be followed as considered 
appropriate by the Investigator and the medical 
monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an 
AE.  The subject may reinstate investigational 
product after delivery and cessation of 
breastfeeding (if applicable) at the discretion of 
the Investigator.  Subjects whose pregnancy is 
terminated early (planned or unplanned) may be 
permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotropin (β-
hCG) test performed at the central laboratory. 
immediately, but should continue with the study 
visit schedule.  As described in Section 12.1.9 
pregnancy is not considered an AE for reporting 
purposes.  The subject may re-start 
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 12.1.9).  New baseline 
procedures should include pregnancy testing. 
Section 8.4.3 
Other Reasons for 
Discontinuation of 
Study of 
Investigational 
Product 
8.4.2 Other Reasons for Discontinuation of Study 
of Investigational Product 
Subjects that discontinue investigational product 
are expected to continue in the study until the end 
of the study, and the study will only terminate at 
the time when the needed number of adjudicated 
events has accrued or at the discretion of the 
Sponsor.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  Subjects who 
choose to discontinue investigational product prior 
to termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.   
The following events are considered appropriate 
reasons for a subject to discontinue investigational 
product; however, these subjects are expected to 
continue in the study until study termination and 
8.4.3 Other Reasons for Discontinuation of Study 
of Investigational Product 
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.  
With the exception of liver transplant, if a 
subject experiences a suspected or confirmed 
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.  Subjects who 
discontinue investigational product prior to 
termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.   
The following events are considered appropriate 
reasons for a subject to discontinue 
investigational product; however, these subjects 
are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
Discontinuation of 
investigational product 
language updated to clarify the 
process that is to be followed 
after discontinuation and 
instruct subjects to continue 
regular visit schedule. 
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the study will only terminate (or at the discretion 
of the Sponsor): 
− 
Consent may be modified to discontinue 
study visits or semi-annual telephone contact 
but allow continued access to medical 
records to assess for potential adjudicated 
hepatic and/or cardiovascular events. 
Subjects who undergo a liver transplant during the 
course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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. 
 
− 
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), liver-related clinical outcomes, 
and drug-related hepatic injury events. 
The Investigator is encouraged to contact the 
Sponsor prior to discontinuing a subject from 
treatment.   
Section 9.7.3.1 
Determination for 
Dosing Regimen 
Insertion 
To determine which dosing regimen subjects 
should follow, the presence or absence of 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 is defined as a 
subject who has documented evidence or presence 
of one or more of the following cirrhosis 
indicators: 
9.7.3.1 Determination for Dosing Regimen 
To determine which dosing regimen subjects 
should follow, the presence or absence of 
cirrhosis should be assessed by the Investigator at 
Screening Visit 1.  Acceptable methods of 
confirming (via medical history) or assessing 
cirrhosis for purposes of determining dosing is 
defined as a subject who has documented 
evidence or presence of one or more of the 
following cirrhosis indicators: 
Header added to differentiate 
the assessment of cirrhosis for 
determining dosing regimen 
versus progression to cirrhosis 
Section 9.7.3.2 
Progression to 
Cirrhosis 
Insertion 
9.7.3.2 Progression to Cirrhosis  
When a subject identified as non-cirrhotic at 
baseline per the criteria listed in 
Section  9.7.3.1 exhibits any of those same 
criteria (excluding biopsy results consistent 
with PBC Stage 4), the subject should also be 
assessed by Fibroscan® TE where available 
and progression to cirrhosis confirmed by 
biopsy unless not medically indicated.  Sites 
Provides detail around the 
assessment of Progression to 
Cirrhosis as a secondary 
endpoint 
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participating in the paired biopsy sub-study 
(see Appendix C) must confirm progression to 
cirrhosis by biopsy.  All suspected cases of 
progression to cirrhosis should be submitted 
for adjudication regardless of the availability 
of transient elastography or biopsy results. 
Section 9.7.6 
Screening 
Procedures 
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments 
will be used to determine eligibility (total 
bilirubin >ULN and ≤3× ULN and/or an ALP 
>5× ULN).   
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments 
will be used to determine eligibility (total 
bilirubin >ULN and ≤5× ULN and/or an ALP 
>3× ULN).   
Reflects new inclusion criteria 
Section 9.7.7 Day 
0 Procedures 
• 
Perform transient elastography (TE; at 
selected study sites, where available) using 
the Fibroscan® TE device. If TE has been 
done within 6 months of Day 0 and a 
report/adequate data are available, a 
pretreatment TE at Day 0 is not required.   
• 
Perform transient elastography at all study 
sites with access to Fibroscan® TE device. 
If TE has been done within 3 months of Day 
0 and a report/adequate data are available, a 
pretreatment TE at Day 0 is not required.   
Clarifies use of TE and 
modifies the time during 
which an historic TE report 
remains valid 
Section 9.7.8 
Month 1 
Procedures 
 
Section 9.7.10 
Post-titration visit 
Procedures 
Insertion 
 
 
• 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit 
requirements: 
• 
Perform a physical examination.  
 
− 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit 
laboratory requirements: 
Physical examinations 1 
month after initiating dosing 
with investigational product 
will enhance safety 
monitoring 
Returning to the site for 
monthly laboratory 
assessments can present a 
significant burden on subjects, 
thus alternatives are provided 
for collecting lab samples; 
with the addition of the 
physical exam as well the 
requirement for these exams is 
provided in the context of the 
alternatives for laboratory 
specimen collection 
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Section 9.7.11 
Month 6 
Procedures 
 
Section 9.7.16 
Month 6 
Continued 
Follow-Up 
Procedures 
Insertion 
• 
Perform a physical examination 
• 
Perform TE at all study sites with access 
to Fibroscan® TE device. 
• 
Perform an ultrasound for HCC 
surveillance (if equipment is unavailable, 
sites should make every attempt to use 
available community referral sites). 
TE assessment has been added 
as biannual assessment at all 
study sites with access to 
Fibroscan® TE device 
 
Hepatic ultrasound should be 
performed biannually per 
AASLD and EASL guidelines 
for subjects with PBC 
Section 11.1.2 
Secondary 
Assessments 
Insertion 
• 
Progression to cirrhosis as assessed by the 
presence of clinical, laboratory, or 
radiological evidence of cirrhosis and/or 
liver stiffness (Fibroscan® TE), confirmed 
by biopsy unless not medically indicated. 
• 
Histological assessment of disease 
progression or improvement using paired 
biopsies in a subset of subjects (see 
Appendix C) 
Rationale  
Section 11.1.2.4 
Potential Clinical 
Outcome Events 
The events listed in Appendix A will be initially 
assessed by the Investigator to determine if they 
are Potential Clinical Outcome Events.   
The events listed in Section 12.1.5 will be 
initially assessed by the Investigator to determine 
if they are Potential Clinical Outcome Events.   
Appendix referencing clinical 
outcomes events was removed 
due to redundancy 
Section 12.1.4.2 
Reporting of 
Serious Adverse 
Events 
Insertion 
Redacted medical record source 
documentation will be requested for all SAEs 
and emergency room visits. 
 
 
Added sentence regarding 
redacted medical records to 
align with Sponsor safety 
standards 
Section 12.1.5 
Suspected Liver-
Related Clinical 
Outcome Events 
For liver-related clinical outcome events could 
also meet the criteria of a SUSAR, which would 
necessitate unblinding for expedited reporting, 
please refer to Section 11.1.2.4. 
 
 
Given that the liver-related 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 liver-related clinical outcome 
events in order to retain the study blind and 
preserve the integrity of the clinical outcomes 
Updated to align with 
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procedures and Sponsor 
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The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy),  and spontaneous 
bacterial peritonitis (preferred term: peritonitis 
bacterial). 
 
endpoint.  These events will be selected as a 
“study event” on the Adverse Event CRF and 
will be submitted for adjudication to the 
Hepatic Outcomes Committee as described in 
Section 13.4. 
 
The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy 
(preferred term: hepatic encephalopathy),  
spontaneous bacterial peritonitis (preferred term: 
peritonitis bacterial), ascites (preferred term: 
ascites), and histological progression to 
cirrhosis (preferred term: hepatic cirrhosis). 
Section 12.1.7 
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 SAE 
must be reported to the Sponsor immediately (ie, 
within 24 hours). 
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 12.1.4.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language 
Section 12.1.8 
Follow-up of AEs 
and SAEs 
Insertion 
All subjects 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 CRF. Note that longer follow-
up can sometimes reveal an off-drug repetition 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language 
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of what had appeared to be drug-induced liver 
injury, indicating that liver injury was related 
to underlying liver disease. 
Section 12.1.9 
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 investigational 
product and the Sponsor must be notified within 
24 hours of the Investigator’s learning of the 
pregnancy by completing the Pregnancy 
Notification Form and faxing or emailing to the 
Sponsor at +1 800 497 8521 or 
sae@interceptpharma.com.  
Safety will be monitored and assessed by 
AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and 
clinical laboratory assessments. The Sponsor may 
also follow the health of an infant born subsequent 
to use of investigational product. 
The subject may reinstate investigational product 
after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  
Subjects whose pregnancy is terminated early 
(planned or unplanned) may be permitted to 
resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test 
(see Section 8.4.1). 
 
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 8.4.2.1) 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 
sae@interceptpharma.com or faxed to 
+1 800 497 8521.   The subject and neonate 
must be followed for outcome information 
and/or as considered appropriate by the 
Investigator and Sponsor. 
The subject may re-start 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 subject must have a 
negative pregnancy test before restarting 
investigational product.  If a subject’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 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language 
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reporting procedures described in 
Section 12.1.4 must also be followed. 
 
Table 10 List of 
Laboratory 
Analytes 
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Other 
Insertion 
 
 
Deletion 
 
Other 
OCA-glucuronide 
 
Measurements of liver fibrosis 
are captured in a different 
section 
 
OCA-glucuronide was listed 
in the text but missing from 
the table 
Section 13.1.1 
Analysis 
Populations 
• 
The Randomized Population will include all 
randomized subjects 
Deletion 
 
Section 13.1.2.1 
Sample Size 
Monitoring 
9.1.2.1 Sample Size Re-Estimation Plan 
Therefore, starting approximately 2 years after the 
first subject is randomized, the aggregate event 
rate and sample size based on recruitment and 
retention will be evaluated in a blinded manner 
quarterly.  This evaluation will determine if any 
increases in number of subjects are required in 
order to obtain a total of 121 adjudicated events 
for the final analysis in the combined groups. 
If after 4 years of accruing subjects, despite 
increases in the number of subjects, it is 
determined that at least an additional 2 years (ie, 
total study duration of at least 10 years) are needed 
to randomize sufficient subjects to achieve a total 
of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label 
OCA.  Previously randomized subjects will 
continue to be treated in a blinded manner with 
either OCA or matching placebo.  If this 
modification is implemented, the alternative 
9.1.2.1 Sample Size Monitoring 
Therefore, the aggregate event rate and sample 
size based on recruitment and retention will be 
evaluated in a blinded manner quarterly.  This 
evaluation will determine if any increases in 
number of subjects are required in order to obtain 
a total of 127 adjudicated events for the final 
analysis in the combined groups. 
Deletion 
 
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primary efficacy analysis is specified is Section 
13.1.9. 
Any revised sample size or changes to treatment 
allocation will be justified and documented in a 
protocol amendment and in the CSR. 
Section 13.1.5.1 
Association of 
Biochemistry with 
Clinical Outcomes 
and Clinical 
Benefit 
Insertion 
13.1.5.1 Association of Biochemistry with 
Clinical Outcomes and Clinical Benefit  
The association between the effect of OCA on 
ALP and bilirubin and the clinical benefit of 
OCA will be evaluated by estimating the 
proportion of net treatment effect on the 
primary composite endpoint that is explained 
by each biochemical marker.  For each 
biochemical endpoint, this proportion will be 
estimated by applying the partial likelihood 
function to two Cox models that use the same 
failure time variable, as described in Lin 1997. 
This analysis will be based on the ITT 
population.  
Based on the association between biochemical 
changes and clinical outcomes described 
above, clinical benefit of OCA for key 
subpopulations of interest will be evaluated. 
This analysis will be further described in the 
SAP. 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
13.1.8 Supportive 
Analysis 
Insertion 
Although the study is designed as a placebo-
controlled study, the DMC may recommend 
changes to study conduct based on the pre-
specified interim analyses (see Section 13.1.12), 
including the potential use of a revised 
primary efficacy analysis.  This analysis would 
compare all subjects in the OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant 
or death (all-cause) (see Section 13.1.2.1), using 
As a placebo-controlled study, 
the alternative primary 
analysis section has been 
removed.   
Upon review of blinded data, 
the DMC may recommend 
changes to study conduct.  
However, such 
recommendations will not be 
implemented unless the 
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similar statistical methodology as specified 
above. 
Notably, the planned primary analysis would 
not be revised without prior agreement with 
regulatory authorities. 
Sponsor has received 
agreement from regulatory 
authorities. 
Section 13.1.9 
Alternative 
Primary Analysis 
13.1.9 Alternative Primary Analysis 
Based on sample size re-estimations, it may be 
determined that subjects will be enrolled to receive 
open-label OCA from that point forward, and the 
new primary efficacy analysis will become the 
comparison of all subjects in OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant or 
death (all-cause) (see Section 13.1.2.1).  Similar 
statistical methodology as specified above in 
Section 13.1.8 for supportive analyses will be 
utilized. 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare groups.  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 determined based 
on a Cox regression model stratified by 
randomization strata to estimate the magnitude of 
the effect. 
 In addition, the outcome events specified above in 
Section 13.1.8 will also be evaluated to compare 
all subjects in OCA population to all control 
subjects (randomized placebo and historical 
controls). 
Deletion 
 
As a placebo-controlled study, 
the alternative primary 
analysis section has been 
removed.   
 Upon review of blinded data, 
the DMC may recommend 
changes to study conduct.  
However, such 
recommendations will not be 
implemented unless the 
Sponsor has received 
agreement from regulatory 
authorities 
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Sensitivity analyses will be conducted limiting to 
the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC 
Study Group.  To evaluate the robustness of the 
propensity score estimations, additional 
algorithms and factors may be considered. 
 
13.1.12 
Continuous 
Monitoring and 
Interim Analyses 
Insertion 
13.1.12 Continuous Monitoring and Interim 
Analyses  
Blinded safety reports including the accrual of 
events, drop outs and/or loss of patients to 
commercially available OCA will be reviewed 
by the DMC on a regular basis.  
Two planned interim analyses of the liver-
related outcomes will be conducted using the 
Lan-DeMets O’Brien-Fleming boundaries 
(Reboussin 2000).  Both interim analyses will 
be pre-specified and will occur after accrual of 
50% and 75% of clinical outcome events, 
respectively.  
The DMC will review the available efficacy 
data in conjunction with detailed safety data 
and other relevant information to recommend 
continuation, modification, or cessation (for 
efficacy or futility) of the study beyond each 
interim analysis.  Modification of the study 
would not take place without prior agreement 
with regulatory authorities. 
Explanation of the type of 
review that will be ongoing by 
the DMC during study 
conduct. 
Section 19 List of 
References  
Insertion 
Lin DY, Fleming TR, De Gruttola V.  
Estimating the proportion of treatment effect 
explained by a surrogate marker.  Statistics in 
Medicine.  1997;16(13):1515-1527. 
 
Reboussin DM, DeMets, DL, Kim KM, et al.  
Computations for Group Sequential 
Additional relevant references 
were added. 
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Boundaries Using the Lan-DeMets Spending 
Function Method.  Controlled Clin Trials.  
2000;21(3):190-207. 
Appendix B  
List of Study 747-
302 Outcome 
Events 
Several of the specified clinical endpoints will 
also by definition (see 12.1) 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 12.1.4).  
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 
Deleted 
Redundant; Information is 
contained within the protocol 
Appendix C 
Biopsy Sub-Study 
of Protocol 
747.302: A Phase 
4, Double-Blind, 
Randomized, 
Placebo-
Controlled, 
Insertion 
See Appendix C 
The purpose of this sub-study 
is to assess the effect of OCA 
versus placebo on the 
histological severity of disease 
(fibrosis/cirrhosis) in subjects 
with PBC.  In addition, this 
sub-study will demonstrate the 
relationship between 
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Multicenter Study 
Evaluating the 
Effect of 
Obeticholic Acid 
on Clinical 
Outcomes in 
subjects with 
Primary Biliary 
Cholangitis 
histological changes and 
clinical, laboratory, and non-
invasive measures indicative 
of progression to cirrhosis in 
patients with PBC. 
 
 
 
 
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APPENDIX H. SUMMARY OF CHANGES:  PROTOCOL VERSION 3.1 TO PROTOCOL VERSION 4 
(DATED 10 MAY 2017) 
Please note that Protocol 747-302 Version 3.1 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.  A full 
accounting of the changes from Protocol Version 3 to Protocol Version 4 is provided in Appendix I. 
Rationale and Summary of Changes 
Major revisions to Protocol 747-302 Version 3.1 include: 
• Hepatocellular carcinoma (HCC) has been redefined as a secondary endpoint; 
• Following the broadening of the spectrum of disease, a commitment to enroll a minimum of 30% of subjects with abnormal 
bilirubin has been added to the protocol; 
• Clarifications have been incorporated throughout the protocol based on the addition of a biopsy substudy in Addendum 2; 
• Statistical language has been modified and added to clarify statistical assumptions and analyses including the addition of a 
Per Protocol (PP) Population;  
• Background rationale has been updated to reflect the current approval status of Ocaliva; and 
• Safety language has been updated throughout the protocol to reflect the updating of Sponsor standards. 
Minor revisions include editorial changes such as removal of hyphens and capitalization of words.  Minor revisions may be included 
in the following table when they are also part of major revisions; however, most minor/editorial changes and nonsubstantial changes 
are not listed individually. 
The text deleted from Protocol Version 3.1 is crossed out while revised text in Version 4 is indicated in bold font in the table below. 
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Justification for Change 
Study Personnel 
Contact 
Information 
Or if Not Available: 
Contact: 
 MD, PhD Medical 
Director, Clinical Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
 
Email: 
 
 (Pacific 
time zone) 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical 
Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 (Pacific time 
zone) 
 
 
 
 
 
Updating emergency medical 
monitor contact information. 
 
 
 
 
 
 
 
The contact information for 
clinical operations and project 
management personnel is no 
longer required in the protocol 
per Sponsor’s procedures. 
Synopsis, 
Objectives, 
Primary, 
Statistical 
Methods – 
Efficacy Analyses 
To assess the effect of OCA compared to placebo, 
in conjunction with established local standard of 
care, on clinical outcomes in subjects with primary 
biliary cirrhosis (PBC) as measured by time to first 
occurrence of any of the following adjudicated 
events, derived as a composite event endpoint: 
To assess the effect of OCA compared to 
placebo, in conjunction with established local 
standard of care, on clinical outcomes in subjects 
with primary biliary cholangitis (PBC) as 
measured by time to first occurrence of any of the 
following adjudicated events, derived as a 
composite event endpoint: 
Editorial correction 
 
 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Justification for Change 
Section 6.1 
Primary Objective 
Section 11.1.1 
Primary 
Assessments 
Section 13.1.3 
Primary Efficacy 
Analysis 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities unless 
confirmed by biopsy 
composite-event endpoint per 
Regulatory Authority request. 
Synopsis, 
Objectives, 
Secondary  
Section 6.2 
Secondary 
Objectives 
 
 
 
 
In Section 6.2 
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
component of the primary endpoint as listed above 
and also to include liver related death. 
 
 
To characterize the effect of OCA compared to 
placebo on progression to cirrhosis. 
To assess the PK of OCA and its conjugates in a 
subset of subjects. 
To assess the effect of OCA compared to 
placebo on time to occurrence of 
hepatocellular carcinoma (HCC). 
 
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
component of the primary endpoint as listed 
above. 
To assess the effect of OCA compared to 
placebo on time to occurrence of liver-related 
death.  
To assess the effect of OCA compared to placebo 
on progression to cirrhosis. 
To characterize the PK of OCA and its 
conjugates in a subset of subjects. 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request.  
 
 
Editorial change 
 
Editorial change 
 
Editorial change 
Synopsis, 
Methodology  
Section 7.1, 
Overall Study 
Design.  
 
A minimum of 30% of subjects will have 
elevated bilirubin (>ULN) at Screening. 
To ensure enrollment of an 
adequate number of subjects 
with abnormal total bilirubin. 
 
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Section 7.1.1 
Study Design 
Diagram,  
Fig 1 (Footnote) 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on tolerability 
and biochemical response.   
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability and biochemical response (up-titration 
should be considered when ALP and/or total 
bilirubin are >ULN).   
Clarification of biochemical 
response 
Synopsis, Number 
of Subjects 
(Planned)  
Section 7.2 
Number of 
Subjects 
Insertion in both, Synopsis and Section 7.2 
 
 
Change in Synopsis section 
Approximately 428 subjects 
In the event additional subjects are needed for 
the enrollment in the biopsy substudy (N = 45 
subjects, as defined in Addendum 2), subjects 
who agree to participate in the substudy may 
be added to the target subject enrollment 
number currently planned. 
Approximately 428 subjects are planned to be 
enrolled in the study.  
Language added to allow for 
continued enrollment into the 
biopsy substudy; additional 
subjects are not anticipated to 
prolong the duration of the 
study. 
Synopsis, Criteria 
for Evaluation 
 
Primary Objectives 
Assessments 
 
• 
Hepatocellular 
carcinoma 
confirmed by 
2 complimentary 
imaging modalities 
unless confirmed 
by biopsy. 
 
Secondary Objectives 
 
 
Primary 
Objectives 
Assessments 
 
 
 
 
 
 
 
Secondary 
Objectives 
 
HCC 
Confirmed by 
2 complimentary imaging 
modalities unless confirmed 
by biopsy 
 
 
 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request. 
Synopsis, 
Statistical 
Methods 
Analysis 
Populations 
 
The following subject populations will be 
evaluated and used for presentation and analysis of 
the data: Intent-to-Treat (ITT), Safety, PK, Overall 
Historical Control, UKPBC Historical Control, 
and the Global PBC Historical Control.  
The following subject populations will be 
evaluated and used for presentation and analysis 
of the data: Intent-to-Treat (ITT), Per Protocol 
(PP), Safety, PK, Overall Historical Control, 
UK-PBC Historical Control, and the Global PBC 
Historical Control.   
The randomized population is 
included within the Safety 
population. 
The PP population will be 
used to conduct sensitivity 
analyses for primary and key 
efficacy endpoints. 
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Synopsis, 
Statistical 
Methods, Primary 
Efficacy Endpoint 
 
Section 11.1.1  
Primary 
Assessments 
Section 13.1.3  
Primary Efficacy 
Analysis  
• 
Hepatocellular carcinoma confirmed 
by 2 complimentary imaging modalities 
 
 
 
Section 13.1.3 
• 
Hepatocellular carcinoma confirmed 
by 2 complimentary imaging modalities 
unless confirmed by biopsy 
The primary efficacy analysis will compare 
randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the 
ITT population.   
 
 
 
 
 
 
Section 13.1.3 
 
The primary efficacy analysis will compare OCA 
to placebo with respect to the primary efficacy 
endpoint using the ITT population.   
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request. 
 
 
 
Editorial change 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Analysis 
Section 13.1.3  
Primary Efficacy 
Analysis 
Insertion 
 
The same analyses for primary efficacy 
endpoints will be performed for PP population 
as a sensitivity analysis.   
The PP population will be 
used to conduct sensitivity 
analyses for primary and key 
efficacy endpoints. 
Synopsis, 
Statistical 
Methods, Key 
Secondary 
Efficacy Analyses 
Section 13.1.4  
Secondary 
Efficacy Analysis 
Insertion 
 
 
Section 13.1.4 
The key secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
in the ITT population with respect to the key 
secondary efficacy endpoints.   
 
The same analyses for key secondary efficacy 
endpoints will be performed for PP 
population as a sensitivity analysis.   
 
 
Section 13.1.4 
The key secondary efficacy analyses will 
compare OCA to placebo in the ITT population 
with respect to the key secondary efficacy 
endpoints.   
 
 
The PP population will be 
used to conduct sensitivity 
analyses for primary and key 
efficacy endpoints. 
 
 
Editorial change 
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Synopsis, 
Statistical 
Methods, 
Additional 
Secondary 
Efficacy Analyses 
Other Efficacy Analyses 
The following secondary efficacy analyses will 
compare OCA to placebo on time to the following 
events: 
• 
Each component of the primary efficacy 
endpoint (except MELD score ≥15 which 
is listed above) 
• 
Development of varix/varices 
• 
Liver-related death 
• 
Liver-related death or liver transplant 
Liver-related death, liver transplant, or MELD 
score ≥15 
Additional Secondary Efficacy Analyses 
The following time-to-event secondary efficacy 
analyses will compare OCA versus placebo using 
the ITT population: 
• 
Time to each component of the primary 
efficacy endpoint (except MELD score 
≥15 which is listed above) 
• 
Time to development of varix/varices 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
• 
Time to liver-related death 
• 
Time to liver-related death or liver 
transplant 
Time to liver-related death or liver transplant, or 
MELD score ≥15 
Editorial Change 
 
 
 
 
Progression to cirrhosis added 
as secondary endpoint in 
Version 3.1. 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite event endpoint per 
Regulatory Authority request. 
Synopsis, 
Statistical 
Methods, 
Additional 
Secondary 
Efficacy Analyses 
 
Section 13.1.5 
Additional 
Secondary 
Efficacy Analyses 
Insertion 
 
 
Analyses for the histological assessment 
conducted as part of the biopsy substudy are 
defined in Appendix C. 
For those subjects enrolled in the biopsy 
substudy (defined in Addendum 2) progression 
to cirrhosis identified by the above criteria and 
improvement in fibrosis/cirrhosis will be 
confirmed by paired biopsy.  Analyses for the 
histological assessment conducted as part of the 
biopsy substudy are defined in Addendum 2.  
Provides further details of 
progression to cirrhosis as 
outlined in the biopsy 
substudy defined in 
Addendum 2. 
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Justification for Change 
Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
 
Section 13.1.2. 
Determination of 
Sample Size 
Insertion 
 
 
 
 
The following assumptions were used in sample 
size calculations:  
• Two interim analyses and one final analysis 
are planned.   
 
 
Insertion 
 
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
The target population is subjects who are at 
higher risk of liver-related clinical 
complications. Eligible subjects will have a 
diagnosis of PBC with bilirubin levels >ULN 
and ≤5x ULN and/or ALP >3x ULN.  The 
following assumptions were used in sample size 
calculations:  
 
• Two interim analyses and one final analysis 
are planned.  The first interim analysis will be 
performed when 50% of the target events are 
accrued and the second interim will be 
performed when 75% of the target events are 
accrued.  
•  A dropout rate of 10% is assumed.  
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to liver-related outcomes, including all-
cause mortality. 
 
Incorporation of the 
broadened spectrum of disease 
into the sample size 
justification. 
 
 
Clarification of interim 
analyses. 
 
 
Clarification of the assumed 
dropout rate. 
 
 
Clarification of outcomes 
being assessed in power 
calculations. 
Section 5.1 
Overview of PBC 
and OCA 
5.1. Overview of Primary Biliary Cirrhosis and 
Obeticholic Acid 
Primary biliary cholangitis, (PBC, also known as 
primary biliary cirrhosis) 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 
5.1. Overview of Primary Biliary Cholangitis 
and Obeticholic Acid 
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 
Updating language to include 
accelerated and conditional 
approvals of OCA in the US 
and EU.  
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necessitates liver transplantation or results in 
death.   
 
Ursodeoxycholic acid (UDCA), a physiological 
constituent of human bile , is currently the only 
treatment approved for PBC (Lindor 2009).  While 
UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a 
suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of 
a poor clinical outcome due to PBC disease 
progression.  There is a clear unmet medical need 
for better therapies for patients with PBC that have 
an inadequate response to UDCA, or those who 
cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  
Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have 
an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and 
effective. 
OCA is a modified bile acid and farnesoid X 
receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid 
(CDCA).  OCA is currently being developed in the 
United States (US) and Europe for the treatment of 
PBC and other chronic liver diseases.  OCA has 
been granted Orphan Drug Designation in the US 
(09 Apr 2008) and Orphan Medicinal Product 
Designation in the European Union (EU) 
(27 Jul 2010) for the treatment of PBC.  The 
United States Food and Drug Administration 
necessitates liver transplantation or results in 
death.   
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), 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 
(Pellicciari 2002).  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. 
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(FDA) has granted accelerated approval for 
Ocaliva for the treatment of PBC.  Ocaliva is not 
yet approved outside the United States for use in 
any indication. 
Section 5.4 
Overview of PBC 
and OCA 
As of 31 Jan 2016, approximately 1726 subjects 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 458 subjects had 
PBC, 330 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver disease 
(NAFLD), 33 subjects had alcoholic 
cirrhosis/portal hypertension, and 20 subjects had 
primary sclerosing cholangitis (PSC). 
As of 31 Jan 2017, approximately 2186 subjects1 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 525 subjects had 
PBC, 686 subjects had NASH, 41 subjects had 
diabetes mellitus/nonalcoholic fatty liver disease, 
33 subjects had alcoholic cirrhosis/portal 
hypertension, and 52 subjects had primary 
sclerosing cholangitis, and 5 subjects had 
biliary atresia. 
------------------------ 
1Includes estimated numbers from ongoing 
blinded studies. 
Language updated to include 
data from current IB. 
Section 5.5.2.1  
Rationale for 
OCA Dose 
The Phase 3 PBC study subsequently evaluated 
the safety and efficacy of OCA at lower doses of 
5 mg (titrated to 10 mg after 6 months based on 
efficacy and tolerability in the double-blind phase 
and after 3 months in the open-label phase) and 
10 mg;  
 
Insertion 
 
 
 
 
Based on these data, the indicated commercial 
doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
 As such, Study 747-302 will evaluate the effect of 
OCA on clinical outcomes using the 5 mg OCA 
dose increasing to 10 mg OCA, if tolerated. 
The Phase 3 PBC study (Study 747-301) 
subsequently evaluated the safety and efficacy of 
OCA at lower doses of 5 mg (titrated to 10 mg 
after 6 months based on efficacy and tolerability 
in the double-blind phase and after 3 months in 
the open-label phase) and 10 mg;  
Study 747-301 demonstrated that titration of 
OCA from a starting dose of 5 mg to 10 mg 
improved tolerance to pruritus relative to 
10 mg (56% versus 69% of subjects who 
experienced pruritus) and minimized dropouts 
due to pruritus.   
Based on these data, the approved dosing 
regimens for OCA for the treatment of patients 
with PBC are 5 mg and 10 mg. 
Study 747-302 will evaluate the effect of OCA on 
clinical outcomes using the 5 mg OCA dose for 
at least 3 months, increasing to 10 mg OCA, if 
tolerated. 
Provides rationale for the 
dosing in alignment with 
commercial labeling. 
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Section 5.6 
Summary of 
Known Potential 
Risks with OCA 
An increase in liver enzymes and hepatic AEs, 
including jaundice, were observed in subjects with 
liver disease at OCA doses between 10 mg and 
50 mg and in healthy subjects who were treated at 
doses ≥100 mg in Phase 1, multiple-dose studies. 
 
 
These findings were seen more frequently with 
doses above 10 mg OCA. 
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).  
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). 
Language has been updated to 
reflect Sponsor standards. 
Section 7.1.2 
Schedule of Study 
Procedures,  
Table 1  
 a All subjects will have the chemistry panel 
retested to ensure subjects have two ALP and 
bilirubin assessments 2 weeks apart to calculate 
the mean result for both analytes.  The mean of 
all screening ALP and bilirubin assessments 
will be used to determine eligibility.  
 
 
 
l 
Endoscopy will be conducted at selected 
study sites where the device is available. 
 
m Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: Unless HCC has already confirmed 
by biopsy, a second confirmatory image (eg, 
MRI) should be obtained to confirm if a study 
endpoint has been met. 
a All subjects will have the chemistry panel 
retested to ensure subjects have at least two 
ALP and bilirubin assessments at least 2 weeks 
apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and 
bilirubin assessments will be used to determine 
eligibility. Refer to Section 9.7.6 for guidance 
on when an additional ALP or bilirubin 
sample may be needed to confirm eligibility. 
 
l 
Endoscopy will be conducted at all study 
sites where the device is available. 
 
m 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.   
Editorial changes 
Section 7.1.2 
Schedule of Study 
Procedures, Table 
2 
i Transient elastography (TE) will be conducted at 
6-month intervals at all study sites where the 
Fibroscan® TE device is available.  Not 
required if done within 3 months of visit. 
i Transient elastography (TE) will be conducted 
at 6-month intervals at all study sites where the 
Fibroscan® TE device is available. 
 
Editorial changes 
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j DEXA will be conducted at 12-month intervals 
at all study sites where the DEXA device is 
available.  Not required if done within 6 months 
of visit. 
 
k  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: unless HCC has already been 
confirmed by biopsy, a second confirmatory 
image (eg, MRI) should be obtained to confirm 
if a  study endpoint has been met. 
 
 
j  DEXA will be conducted at 12-month intervals 
at all study sites where the DEXA device is 
available. 
 
 
l  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, postday 0) 
ultrasounds: unless HCC has already been 
confirmed by biopsy, a second confirmatory 
image (eg, MRI) should be obtained to confirm 
suspected HCC. 
 
Section 7.4  
Dose Titration 
Criteria 
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. 
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, biochemical response, and 
clinical judgment. 
Changes in Child-Pugh Score that result from 
a transient, explainable change in laboratory 
parameters should be documented 
appropriately and should not necessarily 
result in a change to the dosing regimen 
(Appendix A). 
Editorial changes 
Section 7.4.1  
Pre-Titration 
Tolerability 
Assessment 
Requirements 
• 
There must be no clinically significant 
increase (as determined by the investigator) in the 
subject’s liver function tests.  Subjects whose total 
bilirubin is >2× baseline (and >ULN) cannot be 
up-titrated, and additional unscheduled safety visit 
procedures, outlined in Section 9.7.19 should be 
implemented, as required. 
• 
There must be no clinically significant 
increase (as determined by the Investigator) in 
the subject’s liver function tests.  
Clarification 
Section 7.4.2   
The text in this section is moved to Section 8.4.  
 
To avoid redundancy 
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Safety Criteria for 
Adjustment or 
Stopping Doses 
Section 8.4  
Dose Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
[Moved from Section 7.4.2 of Version 3] 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or 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 that 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 
when the needed number of adjudicated events has 
accrued.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, 
subjects should be strongly encouraged to both 
stay on investigational product and remain in the 
study until study termination.   
 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or by 
decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability 
concerns.  The dose of investigational product 
should be adjusted back to the maintenance dose 
in a blinded manner once the issues relating to the 
lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated 
events has accrued.  If a subject reaches an 
outcome event, he or she should continue the 
regular visit schedule and continue taking 
investigational product as long as the subject has 
not met any of the criteria for mandatory 
interruption of investigational product 
outlined in Section 8.4.1, and the Investigator 
assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on 
investigational product and remain in the study 
until study termination.   
 
Clarification 
Section 8.4.1.1   
Reasons for 
Additional 
Monitoring 
Related to Liver 
Chemistries 
Modification of 8.4.3.1 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 
 
Subjects 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.  Subjects with 
persistent elevations (eg, additional lab testing 
per Investigator discretion) should be closely 
monitored.  Concomitant elevations in total 
 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries.  
Language related to 
interruption of investigational 
product is now located in 
Section 8.4.1.2. 
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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. 
 
bilirubin or international normalized ratio 
(INR) with persistent increases in ALT or AST 
should also be closely monitored. 
Section 8.4.1.2   
Reasons for 
Investigational 
Product 
Interruption 
Related to 
Elevated Liver 
Chemistries 
Insertion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Development of any of the following clinical 
laboratory values, without explanation, during 
the study mandates investigational product 
interruption: 
• 
AST and/or ALT >3x baseline (and 
>ULN) 
• 
Total bilirubin >2x 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 AE information should also be 
collected and the subject 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 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries. 
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medications should be identified and 
discontinued if advisable.  
If symptoms persist or repeat testing shows 
AST or ALT >3x baseline (and >ULN) or total 
bilirubin >2x baseline (and >ULN), subjects 
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 study medication and 
no other cause for the elevation is identified, it 
may be assumed that the elevations were due 
to disease progression and the subject 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 
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be evaluated for drug-induced liver injury as 
provided in the guidelines below. 
If at any time a subject 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.  
 
Subjects who develop evidence of severe drug-
induced liver injury, which 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. 
 
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 
subjects 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 subject to continue 
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Section 8.4.1.1:   
Subjects who develop significant drug-induced 
liver injury which is considered 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, 
evidence of functional hepatic impairment as 
indicated by rising bilirubin or INR that cannot be 
explained by progression of disease.  
 
Insertion  
treatment.  In the event the investigational 
product is required to be discontinued, 
subjects should be encouraged to continue 
study visits for continued data collection but 
may withdraw consent at any time.  
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 13.4). 
Section 8.4.1.3   
Pregnancy 
8.4.2.1 Pregnancy 
As described in Section 12.1.9 pregnancy is not 
considered an AE for reporting purposes.  The 
subject may re-start 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 12.1.9).  New baseline 
procedures should include pregnancy testing. 
8.4.1.3 Pregnancy 
As described in Section 12.1.11 pregnancy is not 
considered an AE for reporting purposes.  The 
subject may re-start 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 12.1.11. 
Revised section number. 
 
Section 8.4.2.1  
Liver 
Transplantation 
8.4.1.2 Liver Transplantation 
Subjects must discontinue investigational product 
after undergoing liver transplantation surgery.  
Subjects should be encouraged to continue study 
visits, despite stopping investigational product, for 
continued study data collection. 
8.4.2.1 Liver Transplantation 
Subjects who undergo a liver transplant during 
the course of the study must discontinue 
investigational product and discontinue the 
study visit schedule.  However, these subjects 
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. 
Clarification on process for 
subjects who undergo a liver 
transplant. 
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Section 8.4.3 
Other Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
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.  
With the exception of liver transplant, if a subject 
experiences a suspected or confirmed 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.  Subjects who discontinue 
investigational product prior to termination of the 
study need to also continue to follow the regular 
visit schedule through to study closure.  In 
general, subjects should be strongly encouraged to 
both stay on investigational product and remain in 
the study until study termination.  Early 
termination procedures should only be conducted 
if the subject withdraws consent (See 
Section 9.7.18). 
 
− 
Consent may be modified to discontinue study 
visits or semi-annual telephone contact but 
allow continued access to medical records to 
assess suspected major adverse cardiovascular 
events (MAC), liver-related clinical 
outcomes, and drug-related hepatic injury 
events. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
− 
Consent may be modified to discontinue 
study visits or semi-annual telephone contact 
but allow continued access to medical 
records to assess suspected major adverse 
cardiovascular events (MACE) and liver-
related clinical outcomes. 
− 
Early termination procedures should be 
conducted if the subject withdraws 
consent (See Section 9.7.18). 
 
Clarification of process 
Section 9.7.1  
Visit Windows 
Screening 
 
 
Screening 
See Section 9.7.6 for 
scenario specific visit 
windows that may be 
applicable at Screening.  
 
Section 9.7.3.2  
Progression to 
Cirrhosis 
When a subject identified as non-cirrhotic at 
Baseline per the criteria listed in Section 9.7.3.1 
exhibits any of those same criteria (excluding 
biopsy results consistent with PBC Stage 4), the 
When a subject identified as noncirrhotic at 
Baseline per the criteria listed in Section 9.7.3.1 
exhibits any signs or symptoms associated with 
progression to cirrhosis, as defined by the same 
Details the assessment of 
progression to cirrhosis. 
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subject should also be assessed by Fibroscan® TE 
where available and progression to cirrhosis 
confirmed by biopsy unless not medically 
indicated.  Sites participating in the paired biopsy 
sub-study (see Appendix C) must confirm 
progression to cirrhosis by biopsy.   
criteria, the subject should also be assessed by 
Fibroscan® TE where available and progression 
to cirrhosis confirmed by biopsy (centrally read) 
unless not medically indicated.  Laboratory 
samples needed to obtain noninvasive scores of 
liver fibrosis (ELF, and aspartate 
aminotransferase to platelet ratio index 
[APRI]) will also be collected when a subject 
develops evidence of progression to cirrhosis. 
Full instructions concerning the sample 
collection methods, processing, labeling, and 
shipping will be provided by the Sponsor in a 
study-specific histology manual.  Collection 
supplies will be provided by the central 
laboratory. 
Sites participating in the paired biopsy substudy 
must confirm progression to cirrhosis by biopsy 
as per the information outlined in protocol 
Addendum 2. 
Section 9.7.6  
Screening 
Procedures 
Two Screening visits will occur from 1 to 8 weeks 
prior to Day 0 (as outlined below) allowing for the 
collection of repeated serum chemistry samples (at 
least 2 weeks apart) to confirm pretreatment ALP 
and total bilirubin values: 
 
 
Insertion 
 
 
 
 
Collection of 2 serum chemistry samples 
(collected at least 2 weeks apart) during 
Screening is required for confirmation of the 
pretreatment serum chemistry values, including 
the ALP and total bilirubin used to determine 
eligibility: 
 
• 
When the 2 bilirubin or ALP assessments 
collected at Screening Visit 1 and Screening 
Visit 2 differ by ≥30%, a third sample must be 
collected at an unscheduled visit as a 
confirmatory sample to include in the mean 
result(s) that will be used to determine 
eligibility.  
Allows repeat assessments 
when baseline laboratory 
values are discrepant between 
Screening Visit 1 and 
Screening Visit 2. 
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• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(selected study sites only), 
 
 
Insertion 
• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(at all study sites where the device is available),  
 
In the event that the 2 screening bilirubin or 
ALP assessments differ by ≥30%, and a third 
confirmatory sample is required to be 
collected, the Screening Visit window may be 
extended up to 3 additional weeks. 
Section 9.7.8  
Month 1 
Procedures 
 
Section 9.7.10  
1-Month Post-
Titration visit 
Procedures 
Insertion (9.7.8) 
 
 
Insertion (9.7.10) 
 
- 
A physical examination should be 
performed at the Month 3 visit if an onsite 
Month 1 visit was not performed. 
- 
A physical examination should be 
performed at the next scheduled visit if an 
onsite post-titration visit was not performed. 
Clarification  
Section 9.7.12  
Month 9 
Procedures 
Section 9.7.14 
Month 12 
Procedures 
Section 9.7.16 
Month 16 
Continued 
Follow-Up 
Procedures 
Section 9.7.17  
Month 12 Follow-
up Procedures 
Section 9.7.18  
EOS/EOT 
Section 9.7.12, 9.7.14, 9.7.16, 9.7.17, and 9.7.18 
 
…DEXA procedure to be done at 
selected study sites only, 
 
 
Section 9.7.14, and 9.7.17 
 
 
• 
Perform an endoscopy (at selected study 
sites, where available) 
 
Section 9.7.12, 9.7.14, 9.7.16, 9.7.17, and 9.7.18 
 
…DEXA procedure to be done at 
all study sites where the device is available  
 
 
Section 9.7.14, and 9.7.17 
 
• 
Perform an endoscopy (at all study sites, 
where device is available) 
 
Clarification 
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Section 9.7.18  
EOS/EOT 
If the subject reports having eaten within 8 hours, 
document accordingly in the source and CRF and 
remind the subject that fasting is required prior to 
all study visits. 
If the subject reports having eaten within 8 
hours, document accordingly in the source and 
CRF. 
Clarification 
Section 10.3  
Investigational 
Product Storage 
The investigational product should be stored in the 
containers in which they are received from the 
Sponsor’s supplier, at 15°C to 25°C. 
All OCA tablet strengths provided to clinical 
trial sites in support of clinical study 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. 
Updating temperature 
excursions language per 
Sponsor stability studies. 
Section 11.1.2 
Secondary 
Assessments 
Insertion 
 
• 
Histological assessment of disease 
progression or improvement using paired biopsies 
in a subset of subjects (defined in Appendix C). 
 
 
 
 
• 
Biomarkers, including other markers of 
hepatic fibrosis and/or inflammation, to be 
tested will include:  IgM, c reactive protein 
(CRP), tumor necrosis factor α (TNF-α), 
FGF 19, cytokeratin-18 (CK-18) and ELF, 
(and others as determined during the course of 
the study). 
  
• 
Individual components of the primary 
endpoint. 
• 
Histological assessment of disease 
progression or improvement using paired 
biopsies in a subset of subjects (defined in 
Addendum 2). 
• 
HCC confirmed by 2 complimentary 
imaging modalities, unless confirmed by 
biopsy. 
• 
Biomarkers, including other markers of 
hepatic fibrosis and/or inflammation, to be 
tested will include:  IgM, c reactive protein 
(CRP), tumor necrosis factor α (TNF-α), 
FGF 19, cytokeratin-18 (CK-18) ELF, and 
Fibroscan (and others as determined during 
the course of the study). 
• 
 Clinical outcomes, including individual 
component of the primary endpoint 
Clarified and re-ordered 
bullets for consistency 
throughout document. 
 
Addition of Addendum 2.  
Reflects addition of a biopsy 
substudy available to 
interested sites in 
Addendum 2. 
 
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• 
Endoscopy will be conducted at selected 
study sites where the device is available to assess 
for the presence of oesophageal varix/varices at 
baseline.  
(where available), liver transplant, and 
death will be compared to historical 
controls. 
• 
PK of OCA and its conjugates. 
• 
Endoscopy will be conducted at all study 
sites where the device is available to assess for 
the presence of oesophageal varix/varices at 
baseline.  
Section 12.1.3  
Relationship of 
Adverse Events to 
Liver Biopsy 
 
Insertion (new section) 
The Investigator will document her/his opinion 
of relationship of an AE to liver biopsy using 
the criteria outlined in Table 9.  
Table 9: Relationship of Adverse Events to 
Liver Biopsy 
Relation
ship 
Description 
Related 
A reaction that follows a 
reasonable temporal sequence 
from the liver biopsy; that 
follows a known or expected 
response pattern to the liver 
biopsy. 
Not 
Related 
Any event that does not meet the 
above criteria. 
Added with the addition of 
liver biopsies for the 
confirmation of progression to 
cirrhosis. 
Section 12.1.5.2 
Reporting of 
Serious Adverse 
Events 
•Telephone:  +1 858 964 1571 
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. 
 
If an SAE is reported by email or fax, an SAE 
Report form must also be completed in the EDC 
system as soon as the EDC system is accessible. 
Updated to align with 
modified standard safety 
procedures. 
Section 12.1.6 
Suspected Liver-
Related Clinical 
Outcome Events 
Section 12.1.5 
Given that the liver-related 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 liver-related 
clinical outcome events in order to retain the study 
Section 12.1.6 
Given that the liver-related clinical outcome 
events may also meet the criteria of a SUSAR, 
but are considered in aggregate as part of the 
primary endpoint and the DMC reviews of all 
safety and efficacy data at least quarterly, the 
Sponsor will not expeditiously report suspected 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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blind and preserve the integrity of the clinical 
outcomes endpoint. 
 
The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy),  spontaneous 
bacterial peritonitis (preferred term: peritonitis 
bacterial), ascites (preferred term: ascites), and 
histological progression to cirrhosis (preferred 
term: hepatic cirrhosis). 
liver related clinical outcome events in order to 
retain the study blind and preserve the integrity of 
the clinical outcomes endpoint. 
 
The Sponsor will consider the following list of 
clinical outcome events (MedDRA preferred 
terms) to be disease related and exempt from 
expeditious regulatory reporting, but will 
continue to report them in a nonexpeditious 
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 or oesophageal varices 
haemorrhage), hepatic encephalopathy 
(preferred term: hepatic encephalopathy),  
spontaneous bacterial peritonitis (preferred term: 
peritonitis bacterial), ascites (preferred term: 
ascites), and histological or clinical progression 
to cirrhosis (preferred term: hepatic cirrhosis). 
Section 12.1.8 
Notification of 
Post-Treatment 
SAEs for Subjects 
Who Continue in 
the Study 
Insertion (new section) 
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 
12.1.5.2. 
SAEs that occur in subjects 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 12.1.5.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language. 
Section 12.1.9 
Notification of 
Poststudy SAEs 
Section 12.1.7 
All SAEs that occur within 30 days following the 
cessation of investigational product, whether or 
Section 12.1.9 
All SAEs that occur within 30 days following 
discontinuation from the study, whether or not 
Updated to align with 
modified safety procedures 
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Justification for Change 
not they are related to the investigational product, 
must be reported to the Sponsor within 24 hours 
by following the instructions provided in Section 
12.1.4.2. 
SAEs that occur more than 30 days after a subject 
has discontinued study medication, and are not 
considered related to investigational product, must 
still be reported in the EDC system; however, 
these events are not required to be reported within 
24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to 
investigational product, action taken with study 
medication, treatment, outcome, and potential 
endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event 
summary, SAE details) may also be required to be 
entered, when requested by the Sponsor. 
they are related to the investigational product, 
must be reported to the Sponsor within 24 hours 
by following the instructions provided in Section 
12.1.5.2. 
and Sponsor standard 
language. 
Section 12.2.7  
Laboratory 
Assessments 
The list of laboratory analytes to be tested is 
shown in Table 10. 
The list of laboratory analytes to be tested is 
shown in Table 11, and the normal reference 
ranges for liver biochemistries are shown in 
Appendix C. 
Added per Regulatory 
Authority request. 
Section 13  
Statistical 
Methods 
A statistical analysis plan (SAP), providing details 
about the specific planned analyses and hypothesis 
tests, will be prepared and approved by the 
Sponsor and its designees prior to study database 
lock, propensity score determination, and 
unblinding of the double-blind subject treatment 
assignments. 
A statistical analysis plan (SAP), providing 
details about the specific planned analyses and 
hypothesis tests, will be prepared and approved 
by the Sponsor and its designees prior to the first 
interim analysis, propensity score determination, 
and unblinding of the double-blind subject 
treatment assignments. 
Reflects addition of interim 
analyses to the study protocol. 
Section 13.1.1 
Analysis 
Populations 
Insertion 
• 
The Per Protocol (PP) Population will 
include all ITT subjects who do not have any 
major protocol violations that potentially 
affect the efficacy conclusion.  Treatment 
assignment will be based on the randomized 
treatment. 
The Per Protocol Population 
will be used to conduct 
sensitivity analyses for 
primary and key efficacy 
endpoints. 
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Justification for Change 
Section 13.1.1.1  
Comparability of 
Historical 
Controls 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria where possible. 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria.  Propensity score 
matching method will be utilized to select 
historical controls that match the treated 
subjects using available covariates. The 
adequacy of matching will be assessed by 
statistical methods described under 
Section 13.1.8. 
Clarifies the use of propensity 
scores in the assessment of the 
historical control population. 
Section 13.1.5 
Additional 
Secondary 
Efficacy Analyses 
The following secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
on using the ITT population: 
The following time-to-event secondary efficacy 
analyses will compare OCA versus placebo using 
the ITT population: 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
 
Editorial Change 
Progression to cirrhosis added 
as secondary endpoint in 
Version 3.1. 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request. 
Section 13.1.5.1  
Association of 
Biochemistry with 
Clinical Outcomes 
and Clinical 
Benefit 
The association between the effect of OCA on 
ALP and bilirubin and the clinical benefit of OCA 
will be evaluated by estimating the proportion of 
net treatment effect on the primary composite 
endpoint that is explained by each biochemical 
marker.  For each biochemical endpoint, this 
proportion will be estimated by applying the 
partial likelihood function to two Cox models that 
use the same failure time variable, as described in 
Lin 1997. This analysis will be based on the ITT 
population.  
Based on the association between biochemical 
changes and clinical outcomes described above, 
clinical benefit of OCA for key subpopulations of 
interest will be evaluated. This analysis will be 
further described in the SAP. 
The association between biochemistry including 
ALP and bilirubin with clinical outcomes will be 
assessed and the clinical benefit of OCA using 
biochemistry as a surrogate endpoint will be 
evaluated.  Detailed analysis will be described in 
the SAP.  
Based on the association between biochemical 
changes and clinical outcomes described above, 
clinical benefit of OCA using biochemistry as a 
surrogate endpoint for key subpopulations of 
interest will be evaluated. This analysis will be 
further described in the SAP. 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
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Section 13.1.8  
Supportive 
Analysis 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls. 
 
 
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment. 
 
Although it might be relatively simple to assign a 
historical control based on a single observable 
characteristic, in practice, if the matching process 
is to successfully mitigate potential bias, it has to 
be done considering a full range of covariates 
across which the treatment and historical controls 
might differ. 
Only covariates and not outcome variables will be 
included in the propensity score estimation.  
Therefore, there is no chance of biasing, to avoid 
biased results that are in favor of one treatment. 
 
 
 
 
 
 
 
 
 
 
 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls, which serves as an external 
control for supportive analysis.  
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment 
between the treated subjects and the matched 
natural history subjects. 
A full range of covariates across which the 
treatment and historical controls might differ will 
be considered to mitigate potential bias. 
 
 
Only covariates and not outcome variables will 
be included in the propensity score estimation to 
avoid biased results that are in favor of one 
treatment. 
 
The baseline characteristics between treated 
and natural history subjects in the matched 
dataset will be summarized and presented in a 
tabular format.  Statistical methods such as 
Wilcoxon Rank-Sum test will be used to assess 
the balance for baseline covariates.  The 
standardized difference and variance ratios 
for these covariates will also be calculated.  In 
addition, box plots of propensity scores for 
treated and natural history subjects will be 
separately presented, to further assess the 
adequacy of matching.  
A third-party statistician(s) will perform the 
propensity score modeling and matching.  This 
Clarifies the use of the 
historical controls as an 
external control in supportive 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
 
 
Clarifies the use of the 
historical controls as an 
external control in supportive 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
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Justification for Change 
 
 
 
 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
• 
Time to hepatocellular carcinoma 
 
third-party statistician(s) will be separate and 
independent from the statistician(s) who will 
assess the success of matching and perform 
efficacy analyses. 
 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
 
 
 
Section 13.1.9  
Handling of 
Dropouts or 
Missing Data 
Insertion 
In addition, the same analyses for primary and 
key secondary endpoints based on ITT and PP 
populations will be performed to assess 
robustness of analysis results. During the 
conduct of the study, the DMC may 
recommend refining the missing data strategy 
to better address the observed pattern of 
missing data, based on blinded monitoring of 
the data. 
Clarification of statistical 
analyses to address missing 
data. 
Section 13.1.11  
Examination of 
Subgroups 
The primary and secondary efficacy endpoints will 
be analyzed for subject subgroups (eg, age, sex, 
and race) based on the ITT population.  
 
Insertion 
The primary and secondary efficacy endpoints 
will be analyzed for subject subgroups based on 
the ITT population.  
 
The primary efficacy endpoint will also be 
assessed across the spectrum of PBC disease 
stage as defined by Rotterdam criteria 
(Kuiper 2009)  
• 
Early (normal albumin and normal 
bilirubin) 
 
 
 
 
 
Added per Regulatory 
Authority request. 
 
 
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• 
Moderate (abnormal albumin or 
abnormal bilirubin) 
• 
Advanced (abnormal albumin and 
abnormal bilirubin) 
The primary efficacy endpoint will also be 
assessed for the following clinically relevant 
subpopulations. 
• 
Monotherapy in patients who are 
intolerant or non-responsive to UDCA  
• 
Elderly patients 
Assuming a strong correlation between 
biochemistry and clinical outcomes using the 
total study population (Section 13.1.5.1) is 
observed, we will further assess the 
biochemical improvement in relevant 
subpopulations as applicable (eg, Rotterdam 
disease severity and monotherapy) and 
estimate the reduction in risk of clinical 
outcomes associated with the biochemical 
improvement. 
Additional details regarding statistical 
methods and subgroup definitions will be 
provided in the SAP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
Section 13.1.12  
Continuous 
Monitoring and 
Interim Analyses 
Both interim analyses will be pre-specified and 
will occur after accrual of 50% and 75% of 
clinical outcome events, respectively. 
 
The DMC will review the available efficacy data 
in conjunction with detailed safety data and other 
relevant information to recommend continuation, 
modification, or cessation (for efficacy or futility) 
of the study beyond each interim analysis.  
Both interim analyses will be pre-specified and 
will occur after accrual of 50% (64 events) and 
75% (96 events) of clinical outcome events, 
respectively. 
 
The DMC will review the available efficacy data 
in conjunction with detailed safety data and other 
relevant information to recommend continuation, 
Added number of anticipated 
events. 
 
 
 
Clarification 
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modification, or cessation (for efficacy) of the 
study beyond each interim analysis 
Section 19  
List of References  
Lin DY, Fleming TR, De Gruttola V.  Estimating 
the proportion of treatment effect explained by a 
surrogate marker.  Statistics in Medicine.  
1997;16(13):1515-1527. 
 
Insertion 
 
 
 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Digestive and Liver 
Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Gastroenterology. 
2015b;149(6):1627-9. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
'cirrhosis' to 'cholangitis'. Hepatology. 
2015c;62(5):1620-2. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-
ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed 
with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-3572. 
Reboussin DM, DeMets, DL, Kim KM, et al.  
Computations for Group Sequential 
Boundaries Using the Lan-DeMets Spending 
Function Method.  Controlled Clin Trials.  
2000;21(3):190-207. 
 
 
Additional relevant references 
were added. 
Appendix C 
Reference 
Laboratory Values 
from Central 
Laboratories 
Insertion (new appendix) 
 
 
Deletion:  
Appendix C in Version 3.1 has been deleted.  It is 
now published as Protocol Addendum 2. 
Appendix containing reference laboratory 
values from central laboratories added. 
Added per Regulatory 
Authority request. 
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APPENDIX I. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO PROTOCOL VERSION 4 
(DATED 10 MAY 2017) 
Please note that Protocol 747-302 Version 3.1 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. Therefore, a 
full accounting of the changes from Protocol Version 3 to Protocol Version 4 is provided below. 
Rationale and Summary of Changes 
Major revisions to Protocol 747-302 include the modification of inclusion/exclusion criteria to expand the PBC disease spectrum, the 
addition of progression to cirrhosis as a secondary endpoint, and the addition of 2 interim analyses.  Additional revisions include an 
increase in subject number and the number of required clinical outcome events, a change in the study phase, an update to the 
nomenclature for PBC, and various clarifications within the protocol.  
The text deleted from Protocol Version 3 is crossed out while revised text in Version 4 is indicated in bold font.  Minor/editorial 
changes and non-substantial changes are not listed individually. For efficiency, rationales that impact multiple sections are provided 
below and referenced in the table with the corresponding rationale number.  
1. The phase of the study has been changed from “3b” to “4” to reflect that this is a post-marketing study.  Protocol 747-302 
is considered a Phase 4 study in regions where OCA has received regulatory approval for PBC, ie, in the US and the EU.  In all 
other regions, this study is considered Phase 3b.  In May 2016, the FDA granted accelerated approval for OCA (Ocaliva) for 
the treatment of PBC.  In December 2016, Ocaliva received Conditional Approval from the European Medicines Agency’s 
Committee for Medicinal Products for Human Use. 
2. The term “primary biliary cirrhosis” has been changed to “primary biliary cholangitis” to reflect recent changes in the 
nomenclature for PBC. 
3. The number of required adjudicated events for the final analysis has increased from 121 to 127 due to the addition of two 
interim analyses, which will allow an independent DMC to recommend continuation, modification, or cessation (for efficacy) 
of the study.  One interim analysis will occur at 50% information (after 64 events occur) and one at 75% information (after 
96 events occur).  In addition, inclusion of PBC subjects with earlier stage disease will increase the time to event, thereby 
requiring more events to maintain follow-up to approximately 6 years.   
4. The first-year study enrollment rate was lower than projected due to slower-than-anticipated activation of sites and required a 
re-estimation of the accrual duration.  Using observed accrual rates, the accrual duration was extended by 2 years.  The 
follow-up period was maintained at 6 years, thereby leading to a total trial duration of 10 years. 
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5.  “Encephalopathy” has been modified to “Hepatic Encephalopathy” to clarify that the relevant Clinical Outcome Event 
should be related to hepatic disease. 
6. Hepatocellular carcinoma (HCC) has been redefined as a secondary endpoint instead of a component of the primary 
composite-event endpoint per Regulatory Authority request.  
7. Histological confirmation (biopsy) has been added as an acceptable method of confirming a diagnosis of HCC. 
8. Broadening the Spectrum of Disease:  Lowering the minimum allowable baseline ALP from >5x ULN to >3x ULN and 
raising the maximum allowable baseline total bilirubin to ≤5x ULN will increase the number of subjects enrolled with early 
and advanced disease facilitating the collection of safety and efficacy data in a population that covers the spectrum of PBC 
disease and overlaps with the subject population in the Phase 3 protocol 747-301.  However, to ensure enrollment of an 
adequate number of subjects with abnormal total bilirubin, a minimum of 30% of the subjects enrolled in the study will have 
elevated bilirubin (>ULN) at Screening. 
9. The titration regimen has been updated to reflect assessment of both tolerability and biochemical response prior to up-titration 
per the USPI and SmPC.   
10. The increase in enrollment from 350 to 428 subjects is due in part to the increased number of events from two additional 
interim analyses, and in part due to the change in the estimated placebo baseline hazard rate, which resulted from changing the 
lower limit of ALP from >5x ULN to >3x ULN in the enrollment criteria #2.  
11. Progression to Cirrhosis has been added as a secondary endpoint:  Due to the chronic nature of PBC, outcomes require a very 
long time to accrue to evaluate the impact of potential therapies.  Despite the proven prognostic utility of ALP and bilirubin, 
there is a remaining need to evaluate noninvasive assessments of disease progression that can be linked to histological 
progression of the disease.  Therefore, it is important to evaluate potential noninvasive markers of fibrosis/cirrhosis and their 
relationship to clinical outcomes as part of Study 747-302. 
12. A Per Protocol (PP) population has been added to the statistical analysis section.  Sensitivity analysis for primary efficacy 
endpoints and key secondary efficacy endpoints will be performed using PP population. 
 
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Revised Text (Version 4, 10 May 2017) 
Justification for Change 
Title Page 
Synopsis, Title of 
Study 
A Phase 3b, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study Evaluating 
the Effect of Obeticholic Acid on Clinical 
Outcomes in Subjects with Primary Biliary 
Cirrhosis 
A Phase 4, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on 
Clinical Outcomes in Subjects with Primary 
Biliary Cholangitis 
 
Rationale 1 and 2  
Study Personnel 
Contact 
Information 
Or if Not Available: 
Contact: 
 MD, PhD, 
Executive Director, Clinical 
Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
 
Email: 
 
 (Pacific 
time zone) 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical 
Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
 (Pacific time 
zone) 
 
O 
 
 
 
 
 
 
 
 
 
 
 
The contact information of 
clinical operations and project 
managements personnel is no 
longer required per Sponsor’s 
procedures. 
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Email: 
 
 
 
Synopsis, Studied 
Period (Years) 
 
The study is event driven and total duration will be 
determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 and 4   
 
Synopsis,  
Phase of 
Development 
Phase 3b 
Phase 4 
Rationale 1 
Synopsis, 
Objectives, 
Primary, 
Statistical 
Methods – 
Efficacy Analyses 
Section 6.1 
Primary Objective 
Section 11.1.1 
Primary 
Assessments 
Section 13.1.3 
Primary Efficacy 
Analysis 
• 
Encephalopathy (as defined by a West Haven 
score of ≥2) 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities 
• 
Hepatic encephalopathy (as defined by a 
West Haven score of ≥2) 
 
Rationale 5   
 
Rationale 6 
Synopsis, 
Objectives, 
Secondary  
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
Rephrasing the objective 
 
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Section 6.2 
Secondary 
Objectives 
 
component of the primary endpoint as listed above 
and also to include liver related death. 
 
 
 
Insertion 
 
 
 
To assess the pharmacokinetics of OCA and its 
conjugates in a subset of subjects 
component of the primary endpoint as listed 
above.  
To assess the effect of OCA compared to 
placebo on time to occurrence of liver-related 
death. 
To assess the effect of OCA compared to 
placebo on progression to cirrhosis. 
To assess the effect of OCA compared to 
placebo on time to occurrence of 
hepatocellular carcinoma (HCC). 
To characterize the pharmacokinetics of OCA 
and its conjugates in a subset of subjects 
 
 
 
 
 
Rationale 11 
 
Rationale 6 
 
Synopsis, 
Methodology: 
 
A minimum of 30% of subjects will have 
elevated bilirubin (>ULN) at Screening. 
Rationale 8 
 
Schematic 
Diagram 
 
Section 7.1.1 
Study Design 
Diagram, Figure 1 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.   
 
 
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability and biochemical response (up-titration 
should be considered when ALP and/or total 
bilirubin are >ULN).   
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
 
Rationale 8 
 
 
 
Rationale 9 
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placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability of the product. 
 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability. Subjects 
classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 
10-mg OCA or matching placebo twice 
weekly, based on tolerability. 
 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
subject tolerability, and/or changes in cirrhosis status or 
Child-Pugh Score at any time during the study. 
 
visit following the Month 3 visit based on 
tolerability and biochemical response of the 
product. 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability and biochemical 
response. Subjects classified as Child-Pugh 
Class C should titrate to a maximum dose 
and frequency of 10-mg OCA or matching 
placebo twice weekly, based on tolerability 
and biochemical response. 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
subject tolerability, biochemical response, and/or 
changes in cirrhosis status or Child-Pugh Score at any 
time during the study. 
Synopsis, Number 
of Subjects 
(Planned)  
Section 7.2 
Number of 
Subjects 
Insertion 
 
 
Change in Synopsis section 
Approximately 350 subjects 
In the event additional subjects are needed for 
the enrollment in the biopsy substudy (N = 45 
subjects, as defined in Addendum 2), subjects 
who agree to participate in the sub study may 
be added to the target subject enrollment 
number currently planned. 
Approximately 428 subjects are planned to be 
enrolled in the study.   
Rationale 10 and 
Addendum 2 
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Change in Section 7.2 section 
It is expected that approximately 350 subjects will 
be randomized in the study to achieve 121 
adjudicated primary endpoint events. 
 
It is expected that approximately 428 subjects 
will be randomized in the study to achieve 127 
adjudicated primary endpoint events.  
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
2.  A mean total bilirubin >ULN and ≤3x ULN 
and/or a mean ALP >5x ULN 
2.  A mean total bilirubin >ULN and ≤5x ULN 
and/or a mean ALP >3x ULN 
Rationale 8 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom 
(male or female) or (b) diaphragm, with 
spermicide; or  
• 
Intrauterine device (IUD); 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 subject   
5.  Contraception:  Female subjects of 
childbearing potential must use ≥1 effective 
method of contraception during the study and 
until 30 days following the last dose of 
investigational product.  Effective methods 
of contraception are considered to be those 
listed below:   
• 
Barrier method, ie, (a) condom (male 
or female) or (b) diaphragm, with 
spermicide 
• 
Intrauterine device (IUD)  
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection) 
• 
Abstinence, if in line with the preferred 
and usual lifestyle of the subject   
Standardizing language across 
protocols; removing double-
barrier terminology. 
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Synopsis, 
Exclusion Criteria 
Section 8.3 
Subject Exclusion 
Criteria 
 
2.  Presence of clinical complications of PBC or 
clinically significant hepatic decompensation, 
including: 
 
 
 
 
 
3.  Mean total bilirubin >3x ULN 
2.  Presence of clinical complications of PBC or 
clinically significant hepatic decompensation, 
including: 
•History of liver transplant, current 
placement on a liver transplant list, or 
current MELD score >12.  Subjects who 
are placed on a transplant list despite a 
relatively early disease stage (for example 
per regional guidelines) may be eligible as 
long as they do not meet any of the other 
exclusion criteria 
3.  Mean total bilirubin >5x ULN 
 
 
 
This criterion (sub-bullet) is 
already included in Version 3 
of the protocol.  In the 
Version 4, it is added to the 
synopsis for consistency. 
 
Rationale 8 
Synopsis, 
Duration of 
Treatment 
It is estimated that subjects will be followed up for 
a minimum of 6 years.  The study is event driven 
and total duration of treatment will be determined 
by the time to accrue 121 total primary endpoint 
events. 
It is expected that subjects will be followed up 
for a minimum of 6 years.  The study is event 
driven and total duration of treatment will be 
determined by the time to accrue 127 total 
primary endpoint events. 
Rationale 3 
Synopsis, Criteria 
for Evaluation 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Encephalopathy (as 
defined by a West 
Haven score of ≥2) 
 
• 
Hepatocellular 
carcinoma 
confirmed by 
2 complimentary 
imaging modalities 
 
Secondary Objectives 
 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Hepatic 
encephalopathy (as 
defined by a West 
Haven score of ≥2) 
Secondary Objectives 
 
Progression to 
cirrhosis 
Clinical, laboratory, or 
radiological evidence of 
cirrhosis and/or liver 
stiffness (i.e., Fibroscan® 
TE) confirmed by biopsy 
unless not medically 
indicated 
Rationale 5 
 
 
 
 
 
Rationale 11 
 
 
 
 
 
Rationale 6 
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Hepatocellular 
carcinoma 
Confirmed by 
2 complimentary imaging 
modalities unless 
confirmed by biopsy 
Synopsis, 
Statistical 
Methods 
Analysis 
Populations 
 
The following subject populations will be 
evaluated and used for presentation and analysis of 
the data:  Randomized, Intent-to-Treat (ITT), 
Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical 
Control.  Descriptions of subject populations are 
provided in Section 13.1.1. 
The following subject populations will be 
evaluated and used for presentation and analysis 
of the data:  Intent-to-Treat (ITT), Per Protocol 
(PP) Safety, PK, Overall Historical Control, 
UK-PBC Historical Control, and the Global PBS 
Historical Control.  Descriptions of subject 
populations are provided in Section 13.1.1. 
 
Randomized population 
includes patients on OCA who 
withdrew prior to receiving 
drug and this is already 
collected with the safety 
population. 
 
Rationale 12 (for PP 
Population) 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Endpoint 
 
Section 11.1.1  
Primary 
Assessments 
The primary efficacy endpoint will be the time to 
first occurrence of one of the following post 
randomization:  
• 
Encephalopathy (as defined by a 
West Haven score of ≥2) 
• 
Hepatocellular carcinoma confirmed 
by 2 complimentary imaging modalities 
 
Change in Synopsis section 
Every event for enrolled subjects will be 
adjudicated by an independent committee. 
The primary efficacy endpoint will be the time to 
first occurrence of one of the following:  
• 
Hepatic encephalopathy (as defined 
by a West Haven score of ≥2) 
 
 
 
 
All events will be adjudicated by an independent 
committee. 
Rationale 5 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Analysis 
Section 13.1.3  
Primary Efficacy 
Analysis 
The primary efficacy analysis will compare 
randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the 
ITT population.   
 
Insertion 
 
The primary efficacy analysis will compare OCA 
to placebo with respect to the primary efficacy 
endpoint using the ITT population.   
 
The same analyses for primary efficacy 
endpoints will be performed for PP population 
as a sensitivity analysis.   
 
 
 
 
Rationale 12 
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Synopsis, 
Statistical 
Methods, Key 
Secondary 
Efficacy Analyses 
Section 13.1.4  
Secondary 
Efficacy Analysis 
The key secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
in ITT population with respect to the key 
secondary efficacy endpoints.   
 
Insertion 
 
The key secondary efficacy analyses will 
compare OCA to placebo in the ITT population 
with respect to the key secondary efficacy 
endpoints.   
 
The same analyses for key secondary efficacy 
endpoints will be performed for PP 
population as a sensitivity analysis.   
 
 
 
 
 
Rationale 12 
Synopsis, 
Statistical 
Methods, 
Additional 
Efficacy Analyses 
 
Section 13.1.5 
Additional 
Secondary 
Efficacy Analyses 
Other Efficacy Analyses 
The following secondary efficacy analyses will 
compare OCA to placebo on time to the following 
events: 
 
 
Insertion 
Additional Efficacy Analyses 
The following time-to-event secondary efficacy 
analyses will compare OCA to placebo using the 
ITT population: 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
 
Progression to cirrhosis will be assessed in the 
subset of subjects considered noncirrhotic at 
Baseline using available medical history, 
clinical, and laboratory assessments as well as 
Baseline transient elastography (TE), where 
available. Specifically, subjects with no 
clinical, laboratory, or radiological evidence of 
cirrhosis at baseline and/or a TE liver stiffness 
of <16.9 kPa (Corpechot 2012) will be 
considered noncirrhotic.  Progression to 
cirrhosis will be assessed by the development 
of clinical, laboratory, or radiological evidence 
of cirrhosis and/or when liver stiffness 
increases to ≥16.9 kPa during the study in 
which case histological progression to cirrhosis 
should be confirmed by biopsy unless not 
medically indicated. Using this definition for 
Rationale 6 and 
Rationale 11 
 
 
 
 
 
 
 
 
Rationale 11 
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progression to cirrhosis, the percentage of 
noncirrhotic subjects progressing to cirrhosis 
during the treatment period will be 
summarized by treatment group and 
compared using a Cochran–Mantel–Haenszel 
test stratified by the randomization 
stratification factor. 
For those subjects enrolled in the biopsy 
substudy (defined in Addendum 2) progression 
to cirrhosis identified by the above criteria and 
improvement in fibrosis/cirrhosis will be 
confirmed by paired biopsy.  Analyses for the 
histological assessment conducted as part of 
the biopsy substudy are defined in 
Addendum 2.  
Synopsis, 
Statistical 
Methods, Safety 
Analyses 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will compare OCA and placebo using the Safety 
Population. 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will be summarized by treatment group for the 
Safety Population. 
 
Clarification of summary 
analyses. 
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Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
 
Section 13.1.2. 
Determination of 
Sample Size 
 
 
 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, 
placebo survival estimate of 0.5 at 
8 years with a hazard ratio of 0.60, 
and total study duration of 8 years, 
allowing for 2 years accrual and 
6 years of follow up 
 
 
 
 
Insertion 
 
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
The target population is subjects who are at 
higher risk of liver-related clinical 
complications. Eligible subjects will have a 
diagnosis of PBC with bilirubin levels >ULN 
and ≤5x ULN and/or ALP >3x ULN.   
The following assumptions were used in sample 
size calculations:  
• Exponential survival curves, placebo survival 
estimate of 0.6 at 8 years with a hazard ratio of 
0.60, and total study duration of 10 years (from 
first subject enrolled), allowing for 4 years of 
subject accrual and 6 years of follow up.  
• Two interim analyses and one final 
analysis are planned.   The first interim 
analysis will be performed when 50% of the 
target events are accrued and the second 
interim will be performed when 75% of the 
target events are accrued.  
•  A dropout rate of 10% is assumed  
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
 
Rationale 8 
 
 
Rationale 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale 3 
 
 
 
 
 
 
Section 5.1 
Overview of PBC 
and OCA 
5.1. Overview of Primary Biliary Cirrhosis and 
Obeticholic Acid 
5.1. Overview of Primary Biliary Cholangitis 
and Obeticholic Acid 
Updating language to include 
accelerated and conditional 
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Primary biliary cholangitis, (PBC, also known as 
primary biliary cirrhosis) 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. 
ursodeoxycholic acid (UDCA), a physiological 
constituent of human bile, is currently the only 
treatment approved for PBC (Lindor 2009).  While 
UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a 
suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of 
a poor clinical outcome due to PBC disease 
progression.   
There is a clear unmet medical need for better 
therapies for patients with PBC that have an 
inadequate response to UDCA, or those who 
cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  
Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have 
an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and 
effective. 
OCA is a modified bile acid and farnesoid X 
receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid 
(CDCA).  OCA is currently being developed in the 
United States (US) and Europe for the treatment of 
PBC and other chronic liver diseases.  OCA has 
 
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. 
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), 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 
(Pellicciari 2002).  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 
approvals of OCA in the US 
and EU.  
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been granted Orphan Drug Designation in the US 
(09 Apr 2008) and Orphan Medicinal Product 
Designation in the European Union (EU) (27 Jul 
2010) for the treatment of PBC.  The United States 
Food and Drug Administration (FDA) has granted 
accelerated approval for Ocaliva for the treatment 
of PBC.  Ocaliva is not yet approved outside the 
United States for use in any indication. 
UDCA.  In December 2016, the European 
Commission granted conditional approval for 
Ocaliva for the same indication. 
Section 5.4 
Overview of PBC 
and OCA 
As of 31 Jan 2016, approximately 1726 subjects 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 458 subjects had 
PBC, 330 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver disease 
(NAFLD), 33 subjects had alcoholic 
cirrhosis/portal hypertension, and 20 subjects had 
primary sclerosing cholangitis (PSC). 
As of 31 Jan 2017, approximately 2186 subjects1 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 525 subjects had 
PBC, 686 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver 
disease, 33 subjects had alcoholic cirrhosis/portal 
hypertension, and 52 subjects had primary 
sclerosing cholangitis, and 5 subjects had 
biliary atresia. 
------------------------ 
1Includes estimated numbers from ongoing 
blinded studies. 
Language updated to include 
data from current IB. 
Section 5.5.2.1  
Rationale for 
OCA Dose 
The Phase 3 PBC study subsequently evaluated 
the safety and efficacy of OCA at lower doses of 
5 mg (titrated to 10 mg after 6 months based on 
efficacy and tolerability in the double-blind phase 
and after 3 months in the open-label phase) and 
10 mg;  
 
Insertion 
 
 
 
 
The Phase 3 PBC study (Study 747-301) 
subsequently evaluated the safety and efficacy of 
OCA at lower doses of 5 mg (titrated to 10 mg 
after 6 months based on efficacy and tolerability 
in the double-blind phase and after 3 months in 
the open-label phase) and 10 mg;  
Study 747-301 demonstrated that titration of 
OCA from a starting dose of 5 mg to 10 mg 
improved tolerance to pruritus relative to 
10 mg (56% versus 69% of subjects who 
experienced pruritus) and minimized dropouts 
due to pruritus.   
Provides rationale for the 
dosing in alignment with 
commercial labeling. 
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Based on these data, the indicated commercial 
doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
 As such, Study 747-302 will evaluate the effect of 
OCA on clinical outcomes using the 5 mg OCA 
dose increasing to 10 mg OCA, if tolerated. 
Based on these data, the approved dosing 
regimen for OCA for the treatment of patients 
with PBC are 5 mg and 10 mg. 
Study 747-302 will evaluate the effect of OCA on 
clinical outcomes using the 5 mg OCA dose for 
at least 3 months, increasing to 10 mg OCA, if 
tolerated. 
Section 5.6 
Summary of 
Known Potential 
Risks with OCA 
These findings were seen more frequently with 
doses above 10 mg OCA. 
 
Insertion 
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).   
Refer to the Investigator’s Brochure (IB) for 
additional information regarding the known 
potential risks with the investigational 
product. 
Language has been updated to 
reflect Sponsor standards. 
Section 7.1 
Overall Study 
Design 
This is a Phase 3b, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤3× ULN or ALP 
>5× ULN.   
 
Approximately 350 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 2-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
 
Investigational product will be taken orally, once 
daily….based on tolerability (see Section 7.3). 
 
This is a Phase 4, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤5x ULN and/or 
ALP >3x ULN.   
 
Approximately 428 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 4-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1). . . A 
minimum of 30% of subjects will have 
elevated bilirubin (>ULN) at Screening. 
 
Subjects will be dosed according to their 
cirrhosis status and Child-Pugh Score…based 
Rationale 1 and Rationale 8 
 
 
 
 
Rationale 10 
 
 
 
Rationale 8 
 
 
Clarification  
Rationale 9 
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The study will continue until approximately 121 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
on tolerability and biochemical response (see 
Section 7.3)   
 
The study will continue until approximately 127 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
 
 
 
Rationale 3 
Section 7.1.2 
Schedule of Study 
Procedures,  
Table 1  
Insertions 
 
 
 
 
 
 
 
 a All subjects will have the chemistry panel 
retested to ensure subjects have at least two 
ALP and bilirubin assessments 2 weeks apart to 
calculate the mean result for both analytes.  The 
mean of all screening ALP and bilirubin 
assessments will be used to determine 
eligibility.  
 
 
 
j Transient elastography (TE) will be conducted 
at selected study sites where the Fibroscan® TE 
device is available.  Similarly, DEXA will be 
conducted at selected study sites where the 
DEXA device is available.    
Physical exams have been added at: 
• 
Month 1 
• 
1-Month Post Titration 
• 
Month 6 
Fibroscan® TE has been added at Month 6 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
 
 a All subjects will have the chemistry panel 
retested to ensure subjects have at least two 
ALP and bilirubin assessments at least 2 weeks 
apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and 
bilirubin assessments will be used to determine 
eligibility. Refer to Section 9.7.6 for guidance 
on when an additional ALP or bilirubin 
sample may be needed to confirm eligibility. 
 
j Transient elastography (TE) will be conducted 
at 6-month intervals at all study sites where 
the Fibroscan® TE device is available.   
 
 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
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Insertion (subsequent footnotes are renumbered 
accordingly) 
 
 
k 
Endoscopy will be conducted at selected 
study sites where the device is available. 
 
l Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be 
obtained to confirm if a study endpoint has been 
met. 
 
 
o … The initial dose titration of investigational 
product may occur at the Month 3 visit, or any 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability. … 
 
 
u  A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of 
these samples.  Genetics samples will be 
collected at Day 0 and every other year 
beginning at Month 12. 
k DEXA will be conducted at 12-month 
intervals at all study sites where the DEXA 
device is available.  Please refer to 
Section 9.7.7 for additional information 
related to the allowed windows at Day 0 for 
this procedure. 
 
m 
Endoscopy will be conducted at all study 
sites where the device is available. 
 
m 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.   
 
p … The initial dose titration of investigational 
product may occur at the Month 3 visit, or any 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability and 
biochemical response. … 
 
v A genetics study will be conducted in a subset 
of subjects who provide consent for analyses of 
these samples.  Genetics samples will be 
collected at Day 0 and every other year 
beginning at Month 12.  If a Baseline (eg, 
Day 0) genetic sample is not obtained, 
subsequent genetic samples are not required 
to be collected during the course of the 
study. 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments at Day 0 
and Month 12). 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
 
 
 
 
Rationale 9 
 
 
 
 
Clarification 
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Section 7.1.2 
Schedule of Study 
Procedures, Table 
2 
Insertions 
 
 
 
 
 
 
i Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE 
device is available.  Similarly, DEXA will be 
conducted at selected study sites where the 
DEXA device is available.  Not required if done 
within 6 months of visit. 
   Insertion (subsequent footnotes are renumbered 
accordingly) 
  
 
j   Endoscopy will be conducted at selected study 
sites where the device is available to assess for 
the presence of oesophageal varix/varices. 
 
k  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be 
obtained to confirm if a study endpoint has been 
met. 
 
Physical exams have been added at 1-Month 
Post Titration 
Fibroscan® TE has been added at Month 6 
continued follow up 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
continued follow up 
 
i Transient elastography (TE) will be conducted 
at 6-month intervals at all study sites where 
the Fibroscan® TE device is available. 
 
 
j  DEXA will be conducted at 12-month 
intervals at all study sites where the DEXA 
device is available. 
k   Endoscopy will be conducted at all study sites 
where the device is available to assess for the 
presence of oesophageal varix/varices. 
 
l  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. 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. 
 
o … The initial dose titration of investigational 
products may occur at the Month 3 visit, or any 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring. 
 
 
 
 
Fibroscan® TE monitoring 
has been increased to every 
6 months to facilitate 
monitoring for progression to 
cirrhosis. 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments). 
 
 
Hepatic ultrasound monitoring 
has been increased to every 
6 months to conform to 
AALSD and EASL practice 
guidelines for PBC patients 
with cirrhosis. 
 
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o … The initial dose titration of investigational 
products may occur at the Month 3 visit, or any 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability. 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability and 
biochemical response. 
Rationale 9 
Section 7.1.3 
Study Duration 
The study is event driven and total duration will be 
determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 
Section 7.2 
Number of 
Subjects 
It is expected that approximately 350 subjects will 
be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
It is expected that approximately 428 subjects 
will be randomized in the study to achieve 127 
adjudicated primary endpoint events.  In the 
event additional subjects are needed to 
complete enrollment in the biopsy substudy 
(N = 45 subjects, as defined in Addendum 2), 
subjects who agree to participate in the 
substudy may be added to the target subject 
enrollment number currently planned. 
Rationale 10 
Language added to allow for 
continued enrollment into the 
biopsy substudy; additional 
subjects are not anticipated to 
prolong the duration of the 
study. 
 
Section 7.3 
Planned Dosing 
Regimen, and 
Table 3 
Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at 
the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the 
product.   
 
 
Footnotes of Table 3 were re-ordered 
b   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is dependent 
on subject tolerability and/or changes in cirrhosis 
status or Child-Pugh score at any time during the 
study 
Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at 
the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the 
product and assessment of biochemical 
response.  Up-titration should be considered if 
ALP and/or total bilirubin are >ULN.   
 
c   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is 
dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or 
Child-Pugh score at any time during the study 
Rationale 9 
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Section 7.4  
Dose Titration 
Criteria 
Insertion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
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) as 
well as biochemical response (as assessed by 
reductions in ALP and/or total bilirubin).  In 
general, down-titration will be done in 
response to tolerability concerns and can occur 
at any time while on-study.  Up-titration will 
be done per protocol when subjects have no 
tolerability concerns and have not achieved an 
adequate reduction in ALP and/or total 
bilirubin to within normal limits, or 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 for each dosing regimen as defined 
in Section 7.3. 
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, biochemical response, and 
clinical judgment. 
Changes in Child-Pugh Score that result from 
a transient, explainable change in laboratory 
parameters should be documented 
appropriately and should not necessarily 
result in a change to the dosing regimen 
(Appendix A). 
Added language to clarify 
titrations (up or down). 
Section 7.4.1  
Pre-Titration 
Tolerability 
• 
There must be no clinically significant 
increase (as determined by the investigator) in the 
subject’s liver function tests.  Subjects whose total 
bilirubin is >2× baseline (and >ULN) cannot be 
• 
There must be no clinically significant 
increase (as determined by the Investigator) in 
the subject’s liver function tests.  
Clarification 
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Assessment 
Requirements 
up-titrated, and additional unscheduled safety visit 
procedures, outlined in Section 9.7.19 should be 
implemented, as required. 
Section 7.4.2   
Safety Criteria for 
Adjustment or 
Stopping Doses 
The text in this section is moved to Section 8.4.  
 
To avoid redundancy 
Section 7.5   
Criteria for Study 
Termination 
The window of time for scheduling the visit will 
be based on a final projection of when the 
requisite 121 adjudicated events will have been 
accrued. 
The window of time for scheduling the visit will 
be based on a final projection of when the 
requisite 127 adjudicated events will have been 
accrued. 
Rationale 3 
Section 8.4  
Dose Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
[Moved from Section 7.4.2 of Version 3] 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or 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 that 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 
when the needed number of adjudicated events has 
accrued.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, 
subjects should be strongly encouraged to both 
stay on investigational product and remain in the 
study until study termination.   
 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or by 
decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability 
concerns.  The dose of investigational product 
should be adjusted back to the maintenance dose 
in a blinded manner once the issues relating to the 
lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated 
events has accrued.  If a subject reaches an 
outcome event, he or she should continue the 
regular visit schedule and continue taking 
investigational product as long as the subject has 
not met any of the criteria for mandatory 
interruption of investigational product 
outlined in Section 8.4.1, and the Investigator 
assesses it as safe.  In general, subjects should be 
 
Clarification 
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strongly encouraged to both stay on 
investigational product and remain in the study 
until study termination.   
Section 8.4.1.1   
Reasons for 
Additional 
Monitoring 
Related to Liver 
Chemistries 
Modification of 8.4.2.1 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. 
 
 
Subjects 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.  Subjects with 
persistent elevations (eg, additional lab testing 
per Investigator discretion) should be closely 
monitored.  Concomitant elevations in total 
bilirubin or international normalized ratio 
(INR) with persistent increases in ALT or AST 
should also be closely monitored. 
 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries.  
Language related to 
interruption of investigational 
product is now located in 
Section 8.4.1.2. 
Section 8.4.1.2   
Reasons for 
Investigational 
Product 
Interruption 
Related to 
Insertion 
Development of any of the following clinical 
laboratory values, without explanation, during 
the study mandates investigational product 
interruption: 
• 
AST and/or ALT >3x baseline (and 
>ULN) 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries. 
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Elevated Liver 
Chemistries 
• 
Total bilirubin >2x 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 AE information should also be 
collected and the subject 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 >3x baseline (and >ULN) or total 
bilirubin >2x baseline (and >ULN), subjects 
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 study medication and 
no other cause for the elevation is identified, it 
may be assumed that the elevations were due 
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to disease progression and the subject 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. 
If at any time a subject 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.  
Subjects who develop evidence of severe drug-
induced liver injury, which 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 
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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 
subjects 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 subject to continue 
treatment.  In the event the investigational 
product is required to be discontinued, 
subjects should be encouraged to continue 
study visits for continued data collection but 
may withdraw consent at any time.  
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 
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adjudicated by the Hepatic Safety Committee 
(see Section 13.4). 
Section 8.4.1.3   
Pregnancy 
Modification of 8.4.1 Reasons for Mandatory 
Discontinuation of Investigational Product 
If a female subject becomes pregnant, she must 
discontinue taking investigational product, but 
should continue with the study visit schedule.  The 
subject must be followed as considered 
appropriate by the Investigator and the medical 
monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an 
AE.  The subject may reinstate investigational 
product after delivery and cessation of 
breastfeeding (if applicable) at the discretion of 
the Investigator.  Subjects whose pregnancy is 
terminated early (planned or unplanned) may be 
permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotropin (β-
hCG) test performed at the central laboratory. 
8.4.1.3 Pregnancy 
If a female subject becomes pregnant, she must 
interrupt treatment with investigational product 
immediately, but should continue with the study 
visit schedule.  As described in Section 12.1.11 
pregnancy is not considered an AE for reporting 
purposes.  The subject may re-start 
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 12.1.11. 
Clarification regarding 
prolonged interruption in 
investigational product such as 
in the event of pregnancy.  
 
Section 8.4.2.1  
Liver 
Transplantation 
Text Moved from Section 8.4.2 Other Reasons 
for Discontinuation of Study or Investigational 
Product 
Subjects who undergo a liver transplant during the 
course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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. 
8.4.2.1 Liver Transplantation 
 
Subjects who undergo a liver transplant during 
the course of the study must discontinue 
investigational product and discontinue the study 
visit schedule. However, these subjects 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. 
The relocation of this 
statement from within 
Section 8.4.2 to 8.4.2.1 
clarifies procedure to 
discontinue subjects who 
undergo a liver transplant, 
from investigational product 
but not study visits. 
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Section 8.4.3 
Other Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
8.4.2 Other Reasons for Discontinuation of Study 
or Investigational Product 
Subjects that discontinue investigational product 
are expected to continue in the study until the end 
of the study, and the study will only terminate at 
the time when the needed number of adjudicated 
events has accrued or at the discretion of the 
Sponsor.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  Subjects who 
choose to discontinue investigational product prior 
to termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.  In general, subjects should be strongly 
encouraged to both stay on investigational product 
and remain in the study until study termination.  
Early termination procedures should only be 
conducted if the subject withdraws consent (See 
Section 9.7.18 Early Discontinuation and/or Early 
Termination Procedures). 
The following events are considered appropriate 
reasons for a subject to discontinue investigational 
product; however, these subjects are expected to 
continue in the study until study termination and 
the study will only terminate at the time when the 
needed number of adjudicated events has accrued 
(or at the discretion of the Sponsor): 
− 
Consent may be modified to discontinue study 
visits or semi-annual telephone contact but 
allow continued access to medical records to 
assess for potential adjudicated hepatic and/or 
cardiovascular events. 
8.4.3 Other Reasons for Discontinuation of Study 
or Investigational Product 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following events are considered appropriate 
reasons for a subject to discontinue 
investigational product; however, these subjects 
are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
 
− 
Consent may be modified to discontinue 
study visits or semi-annual telephone contact 
but allow continued access to medical 
records to assess suspected major adverse 
Clarification of process 
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Subjects who undergo a liver transplant during the 
course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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. 
 
cardiovascular events (MACE) and liver-
related clinical outcomes. 
− 
Early termination procedures should be 
conducted if the subject withdraws 
consent (See Section 9.7.18). 
The Investigator is encouraged to contact the 
Sponsor prior to discontinuing a subject from 
treatment.   
Section 9.7.1  
Visit Windows 
Screening 
 
 
Screening 
See Section 9.7.6 for 
scenario specific visit 
windows that may be 
applicable at Screening.  
 
Section 9.7.3.1  
Determination for 
Dosing Regimen 
Insertion 
Acceptable methods of confirming (via medical 
history) or assessing cirrhosis for purposes of the 
study is defined as a subject who has documented 
evidence or presence of one or more of the 
following cirrhosis indicators: 
9.7.3.1 Determination for Dosing Regimen 
Acceptable methods of confirming (via medical 
history) or assessing cirrhosis for purposes of 
determining dosing is defined as a subject who 
has documented evidence or presence of one or 
more of the following cirrhosis indicators: 
Header added to differentiate 
the assessment of cirrhosis for 
determining dosing regimen 
versus progression to 
cirrhosis. 
Section 9.7.3.2  
Progression to 
Cirrhosis 
Insertion 
9.7.3.2 Progression to Cirrhosis  
When a subject identified as noncirrhotic at 
Baseline per the criteria listed in Section 
9.7.3.1 exhibits any signs or symptoms 
associated with progression to cirrhosis, as 
defined by the same criteria, the subject 
should also be assessed by Fibroscan® TE 
where available and progression to cirrhosis 
confirmed by biopsy (centrally read) unless 
not medically indicated.  Laboratory samples 
needed to obtain noninvasive scores of liver 
Details the assessment of 
progression to cirrhosis. 
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fibrosis (ELF, and aspartate aminotransferase 
to platelet ratio index [APRI]) will also be 
collected when a subject develops evidence of 
progression to cirrhosis. 
Full instructions concerning the sample 
collection methods, processing, labeling, and 
shipping will be provided by the Sponsor in a 
study-specific histology manual.  Collection 
supplies will be provided by the central 
laboratory. 
Sites participating in the paired biopsy 
substudy must confirm progression to 
cirrhosis by biopsy as per the information 
outlined in protocol Addendum 2. 
All suspected cases of progression to cirrhosis 
should be submitted for adjudication 
regardless of the availability of transient 
elastography or biopsy results. 
Section 9.7.6  
Screening 
Procedures 
Two Screening visits will occur from 1 to 8 weeks 
prior to Day 0 (as outlined below) allowing for the 
collection of repeated serum chemistry samples (at 
least 2 weeks apart) to confirm pretreatment ALP 
and total bilirubin values: 
 
 
Insertion 
 
 
 
 
• 
The mean of all available (at least 2; including 
both scheduled and unscheduled) bilirubin and 
Collection of 2 serum chemistry samples 
(collected at least 2 weeks apart) during 
Screening is required for confirmation of the 
pretreatment serum chemistry values, including 
the ALP and total bilirubin used to determine 
eligibility: 
 
• 
When the 2 bilirubin or ALP assessments 
collected at Screening Visit 1 and Screening 
Visit 2 differ by ≥30%, a third sample must be 
collected at an unscheduled visit as a 
confirmatory sample to include in the mean 
result(s) that will be used to determine 
eligibility.  
Allows repeat assessments 
when baseline laboratory 
values are discrepant between 
Screening Visit 1 and 
Screening Visit 2. 
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ALP assessments will be used to determine 
eligibility (total bilirubin >ULN and ≤3× ULN 
and/or an ALP >5× ULN).   
• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(selected study sites only), 
 
 
 
Insertion 
 
 
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments will 
be used to determine eligibility (total bilirubin 
>ULN and ≤5x ULN and/or an ALP >3x ULN).  
• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(at all study sites where the device is available),  
 
In the event that the 2 screening bilirubin or 
ALP assessments differ by ≥30%, and a third 
confirmatory sample is required to be 
collected, the Screening Visit window may be 
extended up to 3 additional weeks. 
Section 9.7.7  
Day 0 Procedures 
• 
Perform transient elastography (TE; at 
selected study sites, where available) using the 
Fibroscan® TE device. If TE has been done within 
6 months of Day 0 and a report/adequate data are 
available, a pretreatment TE at Day 0 is not 
required.   
• 
Conduct a DEXA bone density scan (at 
selected study sites, where device is available); 
• 
Perform an esophagogastroduodenoscopy 
(endoscopy; at selected study sites, where device 
is available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform TE at all study sites with access to 
Fibroscan® TE device. If TE has been done 
within 3 months of Day 0 and a report/adequate 
data are available, a pretreatment TE at Day 0 is 
not required.   
• 
Conduct a DEXA bone density scan (at all 
study sites where the device is available); 
• 
Perform an esophagogastroduodenoscopy 
(endoscopy; at study sites, where device is 
available) to assess the presence or absence of 
oesophageal varix/varices. 
Clarifies use of TE and 
modifies the time during 
which an historic TE report 
remains valid.  
Clarifies the use of DEXA and 
endoscopy. 
Section 9.7.8  
Month 1 
Procedures 
 
Section 9.7.10  
9.7.10   Post-Titration visit Procedures 
Insertion 
 
• 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
9.7.10  1-Month Post-Titration visit Procedures 
• 
Perform a physical examination.  
 
• 
In the event it is not feasible for the subject 
to return to the site for the above referenced 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring.  Options 
for safety monitoring 
assessments are provided 
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1-Month Post-
Titration visit 
Procedures 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit requirements: 
 
 
Insertion (9.7.8) 
 
Insertion (9.7.10) 
 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit laboratory 
requirements: 
 
- 
A physical examination should be 
performed at the Month 3 visit if an onsite 
Month 1 visit was not performed. 
- 
A physical examination should be 
performed at the next scheduled visit if an 
onsite post-titration visit was not performed. 
when returning to the site 
presents significant burden on 
the subject.  
Section 9.7.11  
Month 6 
Procedures 
 
Section 9.7.16  
Month 6 
Continued 
Follow-Up 
Procedures 
Insertion 
 
 
 
 
 
 
Insertion in 9.7.11 (not 9.7.16) 
• 
Perform TE at all study sites with access 
to Fibroscan® TE device. 
• 
Perform an ultrasound for HCC 
surveillance (if equipment is unavailable, 
sites should make every attempt to use 
available community referral sites).  
 
 
• 
Perform a physical examination 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis. 
  
Hepatic ultrasound has been 
increased to every 6 months to 
conform to AASLD and 
EASL guidelines for PBC 
patients with cirrhosis. 
Section 9.7.12  
Month 9 
Procedures 
Section 9.7.14 
Month 12 
Procedures 
Section 9.7.16 
Month 16 
Continued 
…DEXA procedure to be done at 
selected study sites only, 
 
…DEXA procedure to be done at 
all study sites where the device is available  
 
Clarification 
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Follow-Up 
Procedures 
 
Section 9.7.14  
Month 12 
Procedures 
Section 9.7.17  
Month 12 Follow-
up Procedures 
Section 9.7.18  
EOS/EOT 
• 
Perform TE (at selected study sites, where 
available) using the Fibroscan® TE device. 
 
Additional edit in Section 9.7.18 
- If the subject reports having eaten within 8 
hours, document accordingly in the source and 
CRF and remind the subject that fasting is 
required prior to all study visits. 
• 
Perform TE at all study sites with access to 
the Fibroscan® TE device. 
 
 
- If the subject reports having eaten within 8 
hours, document accordingly in the source and 
CRF. 
Clarification 
Section 10.3  
Investigational 
Product Storage 
The investigational product should be stored in the 
containers in which they are received from the 
Sponsor’s supplier, at 15°C to 25°C. 
All OCA tablet strengths provided to clinical 
trial sites in support of clinical study 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. 
Updating temperature 
excursions language per 
Sponsor stability studies. 
Section 11.1.2 
Secondary 
Assessments 
Insertion 
 
 
 
 
 
 
• 
Individual components of the primary 
endpoint. 
• 
Progression to cirrhosis as assessed by the 
presence of clinical, laboratory, or radiological 
evidence of cirrhosis and/or liver stiffness 
(Fibroscan® TE), confirmed by biopsy unless 
not medically indicated.  
 
Rationale 11 
 
 
 
 
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• 
Biomarkers, including markers of hepatic 
fibrosis and/or inflammation, to be tested will 
include:  IgM, c-reactive protein (CRP), tumor 
necrosis factor-α (TNF-α), FGF-19, cytokeratin-18 
(CK-18) and ELF, Fibroscan (and others as 
determined during the course of the study). 
 
 
 
 
 
• 
Endoscopy will be conducted at all study sites 
where the device is available to assess for the 
presence of oesophageal varix/varices at baseline.  
• 
Histological assessment of disease 
progression or improvement using paired 
biopsies in a subset of subjects (defined in 
Addendum 2). 
- 
HCC confirmed by 2 complimentary 
imaging modalities, unless confirmed 
by biopsy. 
• 
Biomarkers, including other markers of 
hepatic fibrosis and/or inflammation, to be tested 
will include:  IgM, c-reactive protein (CRP), 
tumor necrosis factor-α (TNF-α), FGF-19, 
cytokeratin-18 (CK-18) ELF, and Fibroscan (and 
others as determined during the course of the 
study).  
• 
Clinical outcomes, including individual 
component of the primary endpoint (where 
available), liver transplant, and death will be 
compared to historical controls. 
• 
PK of OCA and its conjugates. 
• 
Endoscopy will be conducted at all study 
sites where the device is available to assess for 
the presence of oesophageal varix/varices at 
baseline.  
Reflects addition of a biopsy 
substudy available to 
interested sites in 
Addendum 2. 
 
Section 12.1.3  
Relationship of 
AEs to Liver 
Biopsy 
 
Insertion (new section) 
The Investigator will document her/his opinion 
of relationship of an AE to liver biopsy using 
the criteria outlined in Table 9.  
Table 9: Relationship of Adverse Events to 
Liver Biopsy 
Added with the addition of 
liver biopsies for the 
confirmation of progression to 
cirrhosis. 
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Relatio
nship 
Description 
Relate
d 
A reaction that follows a 
reasonable temporal sequence 
from the liver biopsy; that follows 
a known or expected response 
pattern to the liver biopsy. 
Not 
Relate
d 
Any event that does not meet the 
above criteria. 
Section 12.1.5.2 
Reporting of 
Serious Adverse 
Events 
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 
•Telephone:  +1 858 964 1571 
Investigational new drug (IND) Safety Reports 
 
Insertion 
If an SAE is reported by email or fax, an SAE 
Report form must also be completed in the EDC 
system as soon as the EDC system is accessible 
 
Redacted medical record source 
documentation will be requested for all SAEs 
and emergency room visits. 
 
Updated to align with 
modified standard safety 
procedures. 
 
 
 
Added sentence regarding 
redacted medical records to 
align with Sponsor safety 
standards. 
Section 12.1.6 
Suspected Liver-
Related Clinical 
Outcome Events 
For liver-related clinical outcome events could 
also meet the criteria of a SUSAR, which would 
necessitate unblinding for expedited reporting, 
please refer to Section 11.1.2.4. 
 
 
 
 
 
 
Given that the liver-related clinical outcome 
events may also meet the criteria of a SUSAR, 
but are considered in aggregate as part of the 
primary endpoint and the DMC reviews of all 
safety and efficacy data at least quarterly, the 
Sponsor will not expeditiously report 
suspected liver‐related 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 “study event” 
on the AE CRF and will be submitted for 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy), and spontaneous 
bacterial peritonitis (preferred term: peritonitis 
bacterial). 
 
adjudication to the Hepatic Outcomes 
Committee as described in Section 13.4. 
 
The Sponsor will consider the following list of 
clinical outcome events (MedDRA preferred 
terms) to be disease related and exempt from 
expeditious regulatory reporting, but will 
continue to report them in a nonexpeditious 
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 or oesophageal varices 
haemorrhage), hepatic encephalopathy 
(preferred term: hepatic encephalopathy), 
spontaneous bacterial peritonitis (preferred term: 
peritonitis bacterial), ascites (preferred term: 
ascites), and histological or clinical progression 
to cirrhosis (preferred term: hepatic cirrhosis). 
Section 12.1.8 
Notification of 
Post-Treatment 
SAEs for Subjects 
Who Continue in 
the Study 
Insertion (new section) 
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 12.1.5.2. 
SAEs that occur in subjects 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 12.1.5.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language. 
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Section 12.1.9 
Notification of 
Poststudy SAEs 
All SAEs that occur within 30 days following the 
cessation of investigational product, 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 12.1.4.2. 
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 SAE 
must be reported to the Sponsor immediately (ie, 
within 24 hours). 
SAEs that occur more than 30 days after a subject 
has discontinued study medication, and are not 
considered related to investigational product, must 
still be reported in the EDC system; however, 
these events are not required to be reported within 
24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to 
investigational product, action taken with study 
medication, treatment, outcome, and potential 
endpoint status need to be recorded in EDC for the 
SAE.  Additional information (e.g. event 
summary, SAE details) may also be required to be 
entered, when requested by the sponsor.  
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 12.1.5.2. 
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 12.1.5.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language. 
Section 12.1.10  
Follow-up of AEs 
and SAEs 
Insertion 
All subjects 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 CRF. Note that longer follow-
up can sometimes reveal an off-drug repetition 
of what had appeared to be drug-induced liver 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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injury, indicating that liver injury was related 
to underlying liver disease. 
Section 12.1.11  
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 8.4.1.3and the Sponsor must be notified 
within 24 hours of the Investigator’s learning of 
the pregnancy by completing the Pregnancy 
Notification Form and faxing or emailing to the 
Sponsor at +1 800 497 8521 or 
sae@interceptpharma.com.  
Safety will be monitored and assessed by 
AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and 
clinical laboratory assessments. The Sponsor may 
also follow the health of an infant born subsequent 
to use of investigational product. 
The subject may reinstate investigational product 
after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  
Subjects whose pregnancy is terminated early 
(planned or unplanned) may be permitted to 
resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test 
(see Section 8.4.1). 
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 
sae@interceptpharma.com or faxed to 
+1 800 497 8521.   The subject and neonate 
must be followed for outcome information 
and/or as considered appropriate by the 
Investigator and Sponsor. 
The subject 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 subject must have a 
negative pregnancy test before restarting 
investigational product.  If a subject’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 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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reporting procedures described in 
Section 12.1.5 must also be followed. 
Section 12.2.7  
Laboratory 
Assessments 
The list of laboratory analytes to be tested is 
shown in Table 10. 
The list of laboratory analytes to be tested is 
shown in Table 11, and the normal reference 
ranges for liver biochemistries are shown in 
Appendix C. 
Added per Regulatory 
Authority request. 
Section 12.2.7  
Table 10 List of 
Laboratory 
Analytes 
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Other 
Insertion 
 
 
Deletion 
 
Other 
OCA-glucuronide 
 
Measurements of liver fibrosis 
are captured in a different 
section. 
 
OCA-glucuronide was listed 
in the text but missing from 
the table. 
Section 13  
Statistical 
Methods 
A statistical analysis plan (SAP), providing details 
about the specific planned analyses and hypothesis 
tests, will be prepared and approved by the 
Sponsor and its designees prior to study database 
lock, propensity score determination, and 
unblinding of the double-blind subject treatment 
assignments. 
A statistical analysis plan (SAP), providing 
details about the specific planned analyses and 
hypothesis tests, will be prepared and approved 
by the Sponsor and its designees prior to the first 
interim analysis, propensity score determination, 
and unblinding of the double-blind subject 
treatment assignments. 
Reflects addition of interim 
analyses to the study protocol. 
Section 13.1.1 
Analysis 
Populations 
• 
The Randomized Population will include all 
randomized subjects 
 
Insertion 
Deletion 
 
• 
The Per Protocol (PP) Population will 
include all ITT subjects who do not have any 
major protocol violations that potentially 
affect the efficacy conclusion.  Treatment 
assignment will be based on the randomized 
treatment. 
 
 
 
 
Rationale 12 
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Section 13.1.1.1  
Comparability of 
Historical 
Controls 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria where possible. 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria.  Propensity score 
matching method will be utilized to select 
historical controls that match the treated 
subjects using available covariates. The 
adequacy of matching will be assessed by 
statistical methods described under 
Section 13.1.8. 
Clarifies the use of propensity 
scores in the assessment of the 
historical control population. 
Section 13.1.2.1 
Sample Size 
Monitoring 
13.1.2.1 Sample Size Re-Estimation Plan 
Therefore, starting approximately 2 years after the 
first subject is randomized, the aggregate event 
rate and sample size based on recruitment and 
retention will be evaluated in a blinded manner 
quarterly.  This evaluation will determine if any 
increases in number of subjects are required in 
order to obtain a total of 121 adjudicated events 
for the final analysis in the combined groups. 
If after 4 years of accruing subjects, despite 
increases in the number of subjects, it is 
determined that at least an additional 2 years (ie, 
total study duration of at least 10 years) are needed 
to randomize sufficient subjects to achieve a total 
of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label 
OCA.  Previously randomized subjects will 
continue to be treated in a blinded manner with 
either OCA or matching placebo.  If this 
modification is implemented, the alternative 
primary efficacy analysis is specified is 
Section 13.1.9. 
13.1.2.1 Sample Size Monitoring 
Therefore, the aggregate event rate and sample 
size based on recruitment and retention will be 
evaluated in a blinded manner quarterly.  This 
evaluation will determine if any increases in 
number of subjects are required in order to obtain 
a total of 127 adjudicated events for the final 
analysis in the combined groups. 
Deletion 
Clarifies the ongoing 
monitoring of event rate and 
sample size. 
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Any revised sample size or changes to treatment 
allocation will be justified and documented in a 
protocol amendment and in the CSR. 
Section 13.1.5.1  
Association of 
Biochemistry with 
Clinical Outcomes 
and Clinical 
Benefit 
Insertion (new subsection) 
13.1.5.1 Association of Biochemistry with 
Clinical Outcomes and Clinical Benefit  
The association between biochemistry 
including ALP and bilirubin with clinical 
outcomes will be assessed and the clinical 
benefit of OCA using biochemistry as a 
surrogate endpoint will be evaluated.  Detailed 
analysis will be described in the SAP.  
Based on the association between biochemical 
changes and clinical outcomes described 
above, clinical benefit of OCA using 
biochemistry as a surrogate endpoint for key 
subpopulations of interest will be evaluated. 
This analysis will be further described in the 
SAP. 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
Section 13.1.8  
Supportive 
Analysis 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls. 
 
 
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment. 
 
Although it might be relatively simple to assign a 
historical control based on a single observable 
characteristic, in practice, if the matching process 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls, which serves as an external 
control for supportive analysis.  
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment 
between the treated subjects and the matched 
natural history subjects. 
A full range of covariates across which the 
treatment and historical controls might differ will 
be considered to mitigate potential bias. 
Clarifies the use of the 
historical controls as an 
external control in supportive 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
 
 
Clarifies the use of the 
historical controls as an 
external control in supportive 
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is to successfully mitigate potential bias, it has to 
be done considering a full range of covariates 
across which the treatment and historical controls 
might differ. 
Only covariates and not outcome variables will be 
included in the propensity score estimation.  
Therefore, there is no chance of biasing, to avoid 
biased results that are in favor of one treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
 
 
Only covariates and not outcome variables will 
be included in the propensity score estimation to 
avoid biased results that are in favor of one 
treatment. 
 
The baseline characteristics between treated 
and natural history subjects in the matched 
dataset will be summarized and presented in a 
tabular format.  Statistical methods such as 
Wilcoxon Rank-Sum test will be used to assess 
the balance for baseline covariates.  The 
standardized difference and variance ratios 
for these covariates will also be calculated.  In 
addition, box plots of propensity scores for 
treated and natural history subjects will be 
separately presented, to further assess the 
adequacy of matching.  
A third-party statistician(s) will perform the 
propensity score modeling and matching.  This 
third-party statistician(s) will be   separate and 
independent from the statistician(s) who will 
assess the success of matching and perform 
efficacy analyses. 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
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• 
Time to hepatocellular carcinoma 
 
(Text from Section 13.1.9 [Alternative Primary 
Analysis] modified and included in this section) 
Based on sample size re-estimations, it may be 
determined that subjects will be enrolled to receive 
open-label OCA from that point forward, and the 
new primary efficacy analysis will become the 
comparison of all subjects in OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant or 
death (all-cause) (see Section 13.1.2.1).  similar 
statistical methodology as specified above in 
Section 13.1.8 for supportive analyses will be 
utilized. 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare groups.  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 determined based 
on a Cox regression model stratified by 
randomization strata to estimate the magnitude of 
the effect. 
In addition, the outcome events specified above in 
Section 13.1.8 will also be evaluated to compare 
all subjects in OCA population to all control 
subjects (randomized placebo and historical 
controls). 
 
 
Although the study is designed as a placebo-
controlled study, the DMC may recommend 
changes to study conduct based on the pre-
specified interim analyses (see Section 13.1.12), 
including the potential use of a revised primary 
efficacy analysis.  This analysis would compare 
all subjects in the OCA population, to all control 
subjects (randomized placebo and historical 
controls) on time to liver transplant or death (all-
cause), using similar statistical methodology as 
specified above. 
Notably, the planned primary analysis would 
not be revised without prior agreement with 
regulatory authorities. 
 
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Sensitivity analyses will be conducted limiting to 
the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC 
Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms 
and factors may be considered. 
Section 13.1.9  
Handling of 
Dropouts or 
Missing Data 
Insertion 
In addition, the same analyses for primary and 
key secondary endpoints based on ITT and PP 
populations will be performed to assess 
robustness of analysis results. During the 
conduct of the study, the DMC may 
recommend refining the missing data strategy 
to better address the observed pattern of 
missing data, based on blinded monitoring of 
the data. 
Clarification of statistical 
analyses to address missing 
data. 
Section 13.1.11  
Examination of 
Subgroups 
The primary and secondary efficacy endpoints will 
be analyzed for subject subgroups (eg, age, sex, 
and race) based on the ITT population.  
 
Insertion 
The primary and secondary efficacy endpoints 
will be analyzed for subject subgroups based on 
the ITT population.  
 
The primary efficacy endpoint will also be 
assessed across the spectrum of PBC disease 
stage as defined by Rotterdam criteria 
(Kuiper 2009)  
• 
Early (normal albumin and normal 
bilirubin) 
• 
Moderate (abnormal albumin or 
abnormal bilirubin) 
• 
Advanced (abnormal albumin and 
abnormal bilirubin) 
The primary efficacy endpoint will also be 
assessed for the following clinically relevant 
subpopulations. 
 
 
 
Added per Regulatory 
Authority request. 
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• 
Monotherapy in patients who are 
intolerant or non-responsive to UDCA  
• 
Elderly patients 
Assuming a strong correlation between 
biochemistry and clinical outcomes using the 
total study population (Section 13.1.5.1) is 
observed, we will further assess the 
biochemical improvement in relevant 
subpopulations as applicable (eg, Rotterdam 
disease severity and monotherapy) and 
estimate the reduction in risk of clinical 
outcomes associated with the biochemical 
improvement. 
Additional details regarding statistical 
methods and subgroup definitions will be 
provided in the SAP. 
Section 13.1.12  
Continuous 
Monitoring and 
Interim Analyses 
Insertion 
13.1.12 Continuous Monitoring and Interim 
Analyses  
Blinded safety reports including the accrual of 
events, drop outs, and/or loss of subjects to 
commercially available OCA will be reviewed 
by the DMC on a regular basis.  
Two planned interim analyses of the liver-
related outcomes will be conducted using the 
Lan-DeMets O’Brien-Fleming boundaries 
(Reboussin 2000).  Both interim analyses will 
be pre-specified and will occur after accrual of 
50% (64 events) and 75% (96 events) of 
clinical outcome events, respectively.  
The DMC will review the available efficacy 
data in conjunction with detailed safety data 
and other relevant information to recommend 
continuation, modification, or cessation (for 
Two Interim Analyses have 
been added to the protocol. 
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Section 
Original Text (Amendment 3, 
07 September 2016) 
Revised Text (Version 4, 10 May 2017) 
Justification for Change 
efficacy) of the study beyond each interim 
analysis.  Modification of the study would not 
take place without prior agreement with 
regulatory authorities. 
Section 19  
List of References  
Insertion 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Digestive and Liver 
Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Gastroenterology. 
2015b;149(6):1627-9. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
'cirrhosis' to 'cholangitis'. Hepatology. 
2015c;62(5):1620-2. 
Lin DY, Fleming TR, De Gruttola V.  
Estimating the proportion of treatment effect 
explained by a surrogate marker.  Statistics in 
Medicine.  1997;16(13):1515-1527. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-
ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed 
with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-3572. 
Reboussin DM, DeMets, DL, Kim KM, et al.  
Computations for Group Sequential 
Boundaries Using the Lan-DeMets Spending 
Function Method.  Controlled Clin Trials.  
2000;21(3):190-207. 
Additional relevant references 
were added. 
Appendix A 
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5 mg 
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5 mg 
Rationale 9 
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Justification for Change 
Modified Dosing 
Regimen for 
Subjects with 
Child-Pugh B or C 
Hepatic 
Impairment 
OCA or matching placebo once daily, based on 
tolerability. 
OCA or matching placebo once daily, based on 
tolerability and biochemical response. 
Appendix B  
List of Study 747-
302 Outcome 
Events 
This Appendix with the following information 
has been deleted. 
 
Several of the specified clinical endpoints will also 
by definition (see 12.1) 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 12.1.4).  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 
 
Redundant; Information is 
contained within the protocol. 
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Hepatocellular carcinoma 
Appendix C 
Reference 
Laboratory Values 
from Central 
Laboratories 
Insertion (new appendix) 
Appendix containing reference laboratory 
values from central laboratories added. 
Added per Regulatory 
Authority request. 
 
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1. 
TITLE PAGE 
 
Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cholangitis 
 
THE COBALT STUDY 
Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) 
 
Version 5:  04 January 2018 
 
EudraCT Number:  2014-005012-42 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA  92121 
USA 
 
TEL: +1 858 250 6398 
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 747-302.  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 747-302 and in accordance 
with Good Clinical Practice (CPMP/ICH/135/95), 21CFR Part 312 and all applicable regulatory 
requirements. 
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 
Primary Contact: 
 MD, MPH| Senior Medical Director / Medical Affairs 
Syneos Health | Chapel Hill, NC 27514 |U.S.A. 
Tel: 
 Mobile: 
 
 
Secondary Contact: 
 DO, MSPH  
Senior Medical Director  
Intercept Pharmaceuticals, Inc. (Intercept) 
 
24-hour Telephone: + 1 844 250 6398 
SAE Fax: 
+1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product: 
Obeticholic Acid (OCA) 
Name of Active Ingredient: 
Obeticholic acid (OCA); 6α-ethyl-chenodeoxycholic acid; (6-ECDCA); INT-747 
Title of Study:  
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Effect of 
Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary Cholangitis 
Investigators and/or Study Center(s):  
Approximately 170 investigational study sites, globally. 
Studied Period (Years):  
The study is event driven and total duration will be determined by the 
time required to accrue approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects are expected to have a 
minimum follow-up time of approximately 6 years. 
Phase of Development:   
Phase 4:  US, Canada, and the EU 
Phase 3b:  All other regions 
 
Objectives: 
Primary  
To assess the effect of OCA compared to placebo, in conjunction with established local standard of care, on 
clinical outcomes in subjects with primary biliary cholangitis (PBC) as measured by time to first occurrence of 
any of the following adjudicated events, derived as a composite event endpoint:  
• 
Death (all-cause) 
• 
Liver transplant 
• 
Model of end stage liver disease (MELD) score ≥15 
• 
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 (confirmed by diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of 
at least twice in a month) 
Secondary  
To assess the effect of OCA compared to placebo on time to first occurrence of each individual component of 
the primary endpoint as listed above.  
To assess the effect of OCA compared to placebo on time to occurrence of liver-related death. 
To assess the effect of OCA compared to placebo on progression to cirrhosis.  
To assess the effect of OCA compared to placebo on time to occurrence of hepatocellular carcinoma (HCC). 
To assess the effect of OCA compared to placebo on disease progression via the following: 
• 
Liver biochemistry  
• 
Markers of inflammation and fibrosis 
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To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To characterize the pharmacokinetics (PK) of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource utilization, and 
quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
Methodology: 
This Phase 4, double-blind, randomized, placebo-controlled, multicenter study will evaluate the effect of OCA 
on clinical outcomes in subjects with PBC.  Subjects will be screened twice during a 1- to 8-week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples (at least 2 weeks 
apart) to confirm pretreatment alkaline phosphatase (ALP) and total bilirubin values (refer to Section 9.7.3). 
Investigational product will be taken orally, once daily for the majority of subjects; dose and frequency will be 
modified for subjects with cirrhosis (including subjects progressing to cirrhosis during the study) and classified 
as Child-Pugh B or C.  The randomization will be stratified by ursodeoxycholic acid (UDCA) treatment (yes/no) 
and baseline bilirubin categories (> upper limit of normal [ULN]/ ≤ULN).  A minimum of 30% of subjects will 
have elevated bilirubin (>ULN) at Screening. 
Schematic Diagram Study 747-302:  
 
 
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for subjects on all dosing 
regimens, based on tolerability and biochemical response (up-titration should be considered when ALP and/or total bilirubin are >ULN).  
Subsequent dose titration(s) for subjects classified as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur 
no earlier than 6 weeks after the previous dose titration. 
 
Dosing frequency will be determined by the presence or absence of cirrhosis and, if cirrhosis is present, by 
Child-Pugh Score as described below: 
• 
Noncirrhotic subjects or subjects classified as Child-Pugh A at screening will receive 5-mg OCA 
or matching placebo once daily for 3 months.  Subjects should titrate to a maximum dose of 10-mg 
OCA once daily (or matching placebo) at the Month 3 visit or at any study visit following the 
Month 3 visit based on tolerability and biochemical response of the product.    
• 
For those subjects that up-titrate to 10 mg, dosing may be decreased to 5 mg at any time during the 
study as considered clinically appropriate (eg, based on tolerability). Subjects may be titrated back 
to a maximum dose of 10 mg once daily based on tolerability and clinical judgment of the 
Investigator.    
• 
Subjects who are cirrhotic and classified as Child-Pugh Class B or Child-Pugh Class C will initiate 
a modified treatment regimen with 5-mg OCA or matching placebo once weekly for at least 
3 months.  Subjects classified as Child-Pugh Class B or Child-Pugh Class C should titrate to a 
maximum dose and frequency of 10-mg OCA or matching placebo twice weekly (at least 3 days 
apart), based on tolerability and biochemical response.
 
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Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Planned Dosing Regimen 
Standard 
Modified 
Noncirrhotic/ 
Child-Pugh A 
Child-Pugh B or  
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weekly 
 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weekly 
 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or 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 Subjects (Planned):  
Approximately 428 subjects are planned to be enrolled in the study.  In the event additional subjects are needed 
for the enrollment in the biopsy substudy (N = 45 subjects, as defined in Addendum 2), subjects who agree to 
participate in the substudy may be added to the target subject enrollment number currently planned.   
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver 
Diseases [AASLD] and the European Association for the Study of the Liver [EASL] practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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 
2. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN 
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past ≥3 months) or has been taking UDCA for at 
least 12 months with a stable dose for ≥3 months prior to Day 0 
5. Contraception:  Female subjects of childbearing potential must use ≥1 effective method of 
contraception during the study and until 30 days following the last dose of investigational product.  
Effective methods of contraception are considered to be those listed below: 
• 
Barrier method, ie, (a) condom (male or female) or (b) diaphragm, with spermicide 
• 
Intrauterine device (IUD) 
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection) 
• 
Abstinence, if in line with the preferred and usual lifestyle of the subject   
6. Must provide written informed consent and agree to comply with the study protocol 
Exclusion Criteria 
1. History or presence of other concomitant liver diseases including: 
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• 
Hepatitis C virus infection 
• 
Active hepatitis B infection; however, subjects 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 
• 
Nonalcoholic steatohepatitis 
• 
Gilbert's Syndrome 
2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including: 
• 
History of liver transplant, current placement on a liver transplant list, or current MELD score >12.  
Subjects who are placed on a transplant list despite a relatively early disease stage (for example per 
regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria 
• 
Cirrhosis with complications, including history (within the past 12 months) or presence of: 
− 
Variceal bleed 
− 
Uncontrolled ascites  
− 
Encephalopathy  
− 
Spontaneous bacterial peritonitis 
• 
Known or suspected HCC 
• 
Prior transjugular intrahepatic portosystemic shunt procedure 
• 
Hepatorenal syndrome (type I or II) or Screening (Visit 1 or 2) serum creatinine >2 mg/dL 
(178 μmol/L) 
3. Mean total bilirubin >5x ULN 
4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal 
resection or plan to undergo either of these procedures 
5. Other medical conditions that may diminish life expectancy, including known cancers (except 
carcinomas in situ or other stable, relatively benign conditions such as chronic lymphocytic leukemia) 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed 
by a positive serum pregnancy test), or lactating 
7. Known history of human immunodeficiency virus infection 
8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 
3 months prior to Day 0) 
9. Other clinically significant medical conditions that are not well controlled or for which medication 
needs are anticipated to change during the study 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 
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-month 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. History of known or suspected clinically significant hypersensitivity to OCA or any of its components 
14. UDCA naïve (unless contraindicated) 
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Investigational Product, Dosage and Mode of Administration:  
OCA (5 mg or 10 mg tablets) 
Reference Therapy, Dosage and Mode of Administration:  
Placebo (matching tablets) 
Duration of Treatment:  
It is expected that subjects will be followed up for a minimum of 6 years.  The study is event driven and total 
duration of treatment will be determined by the time to accrue 127 total primary endpoint events. 
Criteria for Evaluation: 
Primary Objectives 
Assessments 
Clinical outcomes 
• 
Death (all-cause) 
• 
Liver transplant 
• 
MELD score ≥15 
• 
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 (confirmed by 
diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic-resistant ascites requiring 
therapeutic paracentesis at a frequency of at least twice in a 
month) 
Secondary Objectives 
 
Individual components of the 
primary endpoint 
As listed above and including liver-related death 
Progression to cirrhosis 
Clinical, laboratory, or radiological evidence of cirrhosis and/or liver 
stiffness (ie, Fibroscan® transient elastography [TE]) confirmed by 
biopsy unless not medically indicated 
HCC 
Confirmed by 2 complimentary imaging modalities unless confirmed by 
biopsy 
Change in baseline liver 
biochemistry 
Liver biochemistry (see Table 12 for list of analytes to be tested)  
Inflammation and fibrosis 
IgM, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), 
fibroblast growth factor-19 (FGF-19), cytokeratin-18 (CK-18), enhanced 
liver fibrosis (ELF), and Fibroscan® TE 
Clinical outcomes compared to 
historical controls 
Similar endpoints as used for the primary objective where available 
including liver transplant and death 
PK 
OCA and its conjugates 
Health outcomes and economics 
research 
Including the following: 
Cost-effectiveness and resource utilization 
Quality of life (Fatigue Impact Score and EQ-5D-5L)  
Safety and tolerability 
Including the following: 
Treatment-emergent adverse events including adverse events of special 
interest 
Clinical laboratory values 
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Statistical Methods: 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the data: 
Intent-to-Treat (ITT), Per Protocol (PP), Safety, PK, Overall Historical Control, UK-PBC Historical Control, 
and the Global PBC Historical Control.  Descriptions of subject populations are provided in Section 13.1.1. 
Efficacy Analyses 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the time to first occurrence of one of the following:  
• 
Death (all-cause) 
• 
Liver transplant 
• 
Model of end stage liver disease (MELD) score ≥15 
• 
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 (confirmed by diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of 
at least twice in a month) 
All events will be adjudicated by an independent committee. 
Primary Efficacy Analysis 
The primary efficacy analysis will compare OCA to placebo with respect to the primary efficacy endpoint using 
the ITT population.  The 2 treatment groups will be compared 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 its 95% CI will be determined based 
on a Cox regression model stratified by randomization strata to estimate the magnitude of the effect.  The same 
analyses for primary efficacy endpoints will be performed for PP population as a sensitivity analysis.   
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints are as follows: 
• 
Time to first occurrence of MELD score ≥15 
• 
Time to liver transplant or death (all-cause) 
• 
Change from Baseline in total bilirubin at end of study 
• 
Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare OCA to placebo in the ITT population with respect to the key 
secondary efficacy endpoints.  Only adjudicated events will be included in time-to-event analyses.  The 
comparison (hypothesis testing) will be conducted in a sequential closed testing gate-keeping procedure (in the 
order in which the key secondary endpoints are stated above), provided that the primary efficacy endpoint 
comparison is statistically significant in favor of the OCA treatment group.  If the primary comparison is not 
statistically significant then comparison of the secondary endpoints will be considered as descriptive and 
exploratory.  The same analyses for key secondary efficacy endpoints will be performed for PP population as a 
sensitivity analysis. 
Additional Secondary Efficacy Analyses 
The following time-to-event secondary efficacy analyses will compare OCA versus placebo using the ITT 
population: 
• 
Time to each component of the primary efficacy endpoint (except MELD score ≥15 which is 
captured above) 
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• 
Time to development of varix/varices 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
• 
Time to liver-related death 
• 
Time to liver-related death or liver transplant 
• 
Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these secondary 
efficacy analyses.  Similar endpoints, where available, will be analyzed to compare OCA to historical controls. 
Progression to cirrhosis will be assessed in the subset of subjects considered noncirrhotic at Baseline using 
available medical history, clinical, and laboratory assessments as well as Baseline TE where available.  
Specifically, subjects with no clinical, laboratory, or radiological evidence of cirrhosis at Baseline and/or a TE 
liver stiffness of <16.9 kPa (Corpechot 2012) will be considered noncirrhotic.  Progression to cirrhosis will be 
assessed by the development of clinical, laboratory, or radiological evidence of cirrhosis and/or when liver 
stiffness increases to ≥16.9 kPa during the study in which case histological progression to cirrhosis should be 
confirmed by biopsy unless not medically indicated.  Using this definition for progression to cirrhosis, the 
percentage of noncirrhotic subjects progressing to cirrhosis during the treatment period will be summarized by 
treatment group and compared using a Cochran–Mantel–Haenszel test stratified by the randomization 
stratification factor. 
For those subjects enrolled in the biopsy substudy (defined in Addendum 2) progression to cirrhosis identified 
by the above criteria and improvement in fibrosis/cirrhosis will be confirmed by paired biopsy.  Analyses for the 
histological assessment conducted as part of the biopsy substudy are defined in Addendum 2.  
Further details on efficacy, health outcomes, and PK analyses are specified in Section 13. 
Safety Analyses 
Safety data, including AEs, AEs of special interest including pruritus and hepatic safety, vitals, 
electrocardiogram, and clinical laboratory results will be summarized by treatment group for the Safety 
Population. 
Sample Size Justification 
The target population is subjects who are at higher risk of liver-related clinical complications.  Eligible subjects 
will have a diagnosis of PBC with bilirubin levels >ULN and ≤5x ULN and/or ALP >3x ULN.  The following 
assumptions were used in sample size calculations:  
• 
Exponential survival curves, placebo survival estimate of 0.6 at 8 years with a hazard ratio of 0.60, 
and total study duration of 10 years (from first subject enrolled), allowing for 4 years of subject 
accrual and 6 years of follow-up 
• 
Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• 
The 2 groups will be compared using a 2-sided log rank test at the 5% level of significance. 
• 
Two interim analyses and one final analysis are planned.  The first interim analysis will be 
performed when 50% of the target events are accrued and the second interim will be performed 
when 75% of the target events are accrued. 
• 
A dropout rate of 10% is assumed.  
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 127 events (both 
groups combined) will provide 80% power to demonstrate a statistically significant difference between OCA 
and placebo on time to liver-related outcomes, including all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 428 subjects 
will be enrolled to attain 127 events. 
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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 .............................19 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Overview of Primary Biliary Cholangitis and Obeticholic Acid ................................22 
5.2. 
Mechanism of Action of Obeticholic Acid .................................................................22 
5.3. 
Nonclinical Experience with Obeticholic Acid ..........................................................23 
5.4. 
Clinical Experience with Obeticholic Acid ................................................................23 
5.5. 
Rationale for Study Design and Dose for Investigational Product .............................24 
5.5.1. 
Rationale for Study Design .........................................................................................24 
5.5.2. 
Rationale for Dose ......................................................................................................25 
5.5.2.1. 
Rationale for OCA Dose .............................................................................................25 
5.5.2.2. 
Rationale for Modified OCA Doses in Patients Classified with Child-Pugh B 
or Child-Pugh C Hepatic Impairment .........................................................................25 
5.5.2.3. 
Rationale for Control Groups .....................................................................................26 
5.6. 
Importance of Monitoring of Disease Progression .....................................................26 
5.7. 
Summary of Known Potential Risks with OCA .........................................................26 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................28 
6.1. 
Primary Objective .......................................................................................................28 
6.2. 
Secondary Objectives .................................................................................................28 
7. 
INVESTIGATIONAL PLAN .....................................................................................29 
7.1. 
Overall Study Design ..................................................................................................29 
7.1.1. 
Study Design Diagram ................................................................................................30 
7.1.2. 
Schedule of Study Procedures ....................................................................................31 
7.1.3. 
Study Duration ............................................................................................................36 
7.2. 
Number of Subjects ....................................................................................................36 
7.3. 
Planned Dosing Regimen ...........................................................................................36 
7.4. 
Dose Titration Criteria ................................................................................................37 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements .................................................38 
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7.5. 
Monitoring and Management of Potential Hepatic Injury and/or Disease 
Progression .................................................................................................................39 
7.5.1. 
Signs and Symptoms of Hepatic Injury or Decompensation ......................................39 
7.5.2. 
Liver Biochemistry Assessments for Suspected Hepatic Injury or Potential 
Hepatic Decompensation ............................................................................................40 
7.5.3. 
Clinical Criteria for Monitoring for Potential Hepatic Decompensation 
Events .........................................................................................................................43 
7.5.4. 
Assessing Cirrhosis .....................................................................................................44 
7.5.4.1. 
Determination for Dosing Regimen ............................................................................44 
7.5.4.2. 
Progression to Cirrhosis ..............................................................................................45 
7.5.5. 
Child-Pugh Score ........................................................................................................46 
7.5.5.1. 
Mayo Risk Score .........................................................................................................46 
7.6. 
Dose Adjustment, Interruption, and Withdrawal from Investigational 
Product or Study .........................................................................................................47 
7.7. 
Close Observation .......................................................................................................49 
7.8. 
Criteria for Study Termination ...................................................................................50 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................50 
8.1. 
Subject Population ......................................................................................................50 
8.2. 
Subject Inclusion Criteria ...........................................................................................50 
8.3. 
Subject Exclusion Criteria ..........................................................................................51 
8.4. 
Subject Withdrawal Criteria .......................................................................................52 
8.4.1. 
Other Reasons for Discontinuation of Study or Investigational Product ...................53 
8.4.2. 
Withdrawal of Consent ...............................................................................................53 
8.4.3. 
Lost to Follow-up .......................................................................................................53 
8.4.4. 
Subject Discontinuation Notification .........................................................................54 
9. 
TREATMENT OF SUBJECTS ..................................................................................54 
9.1. 
Investigational Product Treatment Regimen ..............................................................54 
9.2. 
Concomitant Medications ...........................................................................................54 
9.2.1. 
Prohibited Medications ...............................................................................................55 
9.3. 
Treatment Compliance ................................................................................................55 
9.4. 
Randomization and Blinding ......................................................................................56 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures ...................................56 
9.5. 
Assignment of Site and Subject Numbers ..................................................................57 
9.5.1. 
Site Numbers ..............................................................................................................57 
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9.5.2. 
Subject Numbers .........................................................................................................57 
9.6. 
Restrictions .................................................................................................................57 
9.7. 
Visit Procedures ..........................................................................................................57 
9.7.1. 
Visit Windows ............................................................................................................57 
9.7.2. 
Informed Consent Procedures .....................................................................................58 
9.7.3. 
Screening Procedures (1 to 8 Weeks prior to Day 0) .................................................58 
9.7.4. 
Day 0 Procedures (Randomization) ............................................................................60 
9.7.5. 
Months 1, 2 Procedures ..............................................................................................62 
9.7.6. 
Month 3 Procedures ....................................................................................................63 
9.7.7. 
Post-Titration Visit Procedures ...................................................................................64 
9.7.8. 
Month 6 Procedures ....................................................................................................65 
9.7.9. 
Month 9 Procedures ....................................................................................................66 
9.7.10. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment .................................................................................................................67 
9.7.11. 
Month 12 Procedures ..................................................................................................67 
9.7.12. 
Month 3 and Month 9 Continued Follow-Up Procedures (±2 weeks) .......................68 
9.7.13. 
Month 6 Continued Follow-Up Procedures (Semi-annually [±2 weeks]) ..................69 
9.7.14. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) .........................70 
9.7.15. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent ..................................72 
9.7.16. 
Unscheduled Safety Visit ...........................................................................................74 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............75 
10.1. 
Investigational Product ...............................................................................................75 
10.2. 
Investigational Product Packaging and Labeling .......................................................75 
10.3. 
Investigational Product Storage ..................................................................................75 
10.4. 
Investigational Product Preparation ............................................................................75 
10.5. 
Investigational Product Administration ......................................................................75 
10.6. 
Investigational Product Accountability and Disposal .................................................75 
11. 
ASSESSMENT OF EFFICACY ................................................................................76 
11.1. 
Assessment of Efficacy ...............................................................................................76 
11.1.1. 
Primary Assessments ..................................................................................................76 
11.1.2. 
Secondary Assessments ..............................................................................................76 
11.1.2.1. 
Noninvasive Assessments of Liver Fibrosis ...............................................................77 
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11.1.2.2. 
Other Secondary Assessments ....................................................................................77 
11.1.2.3. 
Other Exploratory Evaluations ...................................................................................78 
11.1.2.4. 
Potential Clinical Outcome Events .............................................................................78 
12. 
ASSESSMENT OF SAFETY .....................................................................................79 
12.1. 
Adverse Events and Serious Adverse Events .............................................................79 
12.1.1. 
Definitions of Adverse Events ....................................................................................79 
12.1.1.1. 
Adverse Event .............................................................................................................79 
12.1.1.2. 
Serious Adverse Event ................................................................................................79 
12.1.1.3. 
Treatment-Emergent Adverse Event ..........................................................................80 
12.1.1.4. 
Adverse Events of Special Interest .............................................................................80 
12.1.2. 
Relationship to Investigational Product ......................................................................81 
12.1.3. 
Relationship of Adverse Events to Liver Biopsy .......................................................81 
12.1.4. 
Recording Adverse Event Severity .............................................................................82 
12.1.5. 
Reporting of Adverse Events and Serious Adverse Events ........................................82 
12.1.5.1. 
Reporting of Adverse Events ......................................................................................82 
12.1.5.2. 
Reporting of Serious Adverse Events .........................................................................82 
12.1.6. 
Suspected Liver-Related Clinical Outcome Events ....................................................83 
12.1.7. 
Additional Investigator Responsibilities for SAEs .....................................................84 
12.1.8. 
Notification of Post-Treatment SAEs for Subjects Who Continue in the 
Study ...........................................................................................................................84 
12.1.9. 
Notification of Poststudy SAEs ..................................................................................84 
12.1.10. 
Follow-Up of AEs and SAEs ......................................................................................85 
12.1.11. 
Pregnancy and Follow-Up ..........................................................................................86 
12.2. 
Other Safety Parameters .............................................................................................86 
12.2.1. 
Medical History/Demographics ..................................................................................86 
12.2.2. 
Physical Examination .................................................................................................86 
12.2.3. 
Vital Signs ..................................................................................................................86 
12.2.4. 
Electrocardiogram .......................................................................................................87 
12.2.5. 
Subject Questionnaires ...............................................................................................87 
12.2.6. 
Laboratory Assessments .............................................................................................87 
13. 
STATISTICAL METHODS .......................................................................................89 
13.1. 
Efficacy Analysis ........................................................................................................89 
13.1.1. 
Analysis Populations ..................................................................................................89 
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13.1.1.1. 
Comparability of Historical Controls .........................................................................90 
13.1.2. 
Determination of Sample Size ....................................................................................90 
13.1.2.1. 
Sample Size Monitoring .............................................................................................90 
13.1.3. 
Primary Efficacy Analysis ..........................................................................................91 
13.1.4. 
Key Secondary Efficacy Analyses ..............................................................................91 
13.1.5. 
Additional Secondary Efficacy Analyses ...................................................................92 
13.1.5.1. 
Association of Biochemistry with Clinical Outcomes and Clinical Benefit ..............93 
13.1.6. 
Exploratory Efficacy Analyses ...................................................................................93 
13.1.6.1. 
Responder Analyses ....................................................................................................93 
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints ................................................94 
13.1.8. 
Supportive Analysis ....................................................................................................94 
13.1.9. 
Handling of Dropouts or Missing Data ......................................................................96 
13.1.9.1. 
Time to Event Endpoints ............................................................................................96 
13.1.9.2. 
Quantitative Endpoints ...............................................................................................96 
13.1.9.3. 
Responder Endpoints ..................................................................................................97 
13.1.10. 
Multiple Comparisons/Multiplicity ............................................................................97 
13.1.11. 
Examination of Subgroups .........................................................................................98 
13.1.12. 
Continuous Monitoring and Interim Analyses ...........................................................98 
13.2. 
Safety Analysis ...........................................................................................................99 
13.2.1. 
Adverse Events ...........................................................................................................99 
13.2.2. 
Clinical Laboratory Evaluations .................................................................................99 
13.2.3. 
Additional Safety Analysis .........................................................................................99 
13.2.4. 
Cardiovascular Adjudication Committee ...................................................................99 
13.3. 
Data Monitoring Committee .......................................................................................99 
13.4. 
Adjudication Committees .........................................................................................100 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................................101 
14.1. 
Study Monitoring ......................................................................................................101 
14.2. 
Audits and Inspections ..............................................................................................101 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................102 
16. 
ETHICS ....................................................................................................................102 
16.1. 
Ethics Review ...........................................................................................................102 
16.2. 
Ethical Conduct of the Study ....................................................................................102 
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16.3. 
Written Informed Consent ........................................................................................103 
16.4. 
Subject Confidentiality and Data Protection ............................................................103 
17. 
INVESTIGATOR OBLIGATIONS .........................................................................103 
17.1. 
AE Reporting ............................................................................................................104 
17.2. 
Protocol Deviations ..................................................................................................104 
17.3. 
Regulatory Documentation .......................................................................................104 
17.4. 
Ethics Review ...........................................................................................................104 
17.5. 
Archiving and Record Retention ..............................................................................104 
18. 
PUBLICATION POLICY ........................................................................................105 
19. 
LIST OF REFERENCES ..........................................................................................107 
APPENDIX A. MODIFIED DOSING REGIMEN FOR SUBJECTS WITH CHILD-
PUGH B/C HEPATIC IMPAIRMENT ..........................................................109 
APPENDIX B. 
ETHICAL CONDUCT ACCORDING TO THE DECLARATION OF 
HELSINKI FOR COUNTRIES PARTICIPATING OUTSIDE THE 
US (DECLARATION OF HELSINKI, FORTELEZA, BRAZIL, 2013) .......111 
APPENDIX C. REFERENCE LABORATORY VALUES FROM CENTRAL 
LABORATORIES ...........................................................................................116 
APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 
(DATED 29 APR 2015) ..................................................................................118 
APPENDIX E. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 
(DATED 12 NOV 2015) .................................................................................155 
APPENDIX F. 
SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 TO 
VERSION 3 (DATED 07 SEP 2016) ..............................................................157 
APPENDIX G. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO 
PROTOCOL VERSION 3.1 (DATED 23 DEC 2016) ...................................187 
APPENDIX H. SUMMARY OF CHANGES:  PROTOCOL VERSION 3.1 TO 
PROTOCOL VERSION 4 (DATED 10 MAY 2017) .....................................214 
APPENDIX I. 
SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO 
PROTOCOL VERSION 4 (DATED 10 MAY 2017) .....................................242 
APPENDIX J. 
SUMMARY OF CHANGES:  PROTOCOL VERSION 4 TO 
PROTOCOL VERSION 5 (DATED 31 OCT 2017) ......................................289 
 
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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) .......................31 
Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) ............34 
Table 3: 
Planned Dosing Regimen by Cirrhosis and Child Pugh Score ...................................36 
Table 4: 
Liver Laboratory Criteria for Monitoring of Suspected Hepatic Injury or 
Potential Hepatic Decompensation and Criteria for Interruption or 
Discontinuation of Investigational Product ................................................................42 
Table 5: 
Clinical Criteria for Monitoring Potential Hepatic Decompensation Events 
and Interruption / Discontinuation of Investigational Product ...................................44 
Table 6: 
Child-Pugh Scoring System ........................................................................................46 
Table 7: 
Criteria for Dose Adjustment, Interruption, Discontinuation and Rechallenge .........47 
Table 8: 
Early Discontinuation Scenarios .................................................................................72 
Table 9: 
Relationship of Adverse Events to Investigational Product .......................................81 
Table 10: Relationship of Adverse Events to Liver Biopsy .......................................................82 
Table 11: Severity of Adverse Events ........................................................................................82 
Table 12: List of Laboratory Analytes to be Tested ...................................................................88 
Table 13: Planned Dosing Regimen by Cirrhosis and Child-Pugh Score ................................109 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram Study 747-302 ............................................................................30 
Figure 2: 
DILI Management Algorithm .....................................................................................41 
Figure 3: 
Dosing by Cirrhosis Status and Child-Pugh Score ...................................................109 
  
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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 
APRI 
aspartate aminotransferase to platelet ratio index 
AST 
aspartate aminotransferase 
β-hCG 
beta human chorionic gonadotropin 
BAS 
bile acid sequestrants 
CAC 
Cardiovascular Adjudication Committee 
CDCA 
chenodeoxycholic acid 
CI 
confidence interval 
CK-18 
cytokeratin-18 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
C-reactive protein 
DILI 
Drug-induced liver injury 
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 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
FIS 
Fatigue Impact Scale 
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 
Investigator’s 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 
LDL 
low-density lipoprotein 
LTSE 
long-term safety extension 
MACE 
major adverse cardiovascular events 
MELD 
model of end stage liver disease  
MRS 
Mayo Risk Score 
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cholangitis (also known as primary biliary 
cirrhosis) 
PIS 
patient information sheet 
PK 
pharmacokinetic 
PP 
per protocol 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
SUSAR 
suspected unexpected serious adverse reaction 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
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Abbreviation or Specialist Term 
Explanation 
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 Primary Biliary Cholangitis and Obeticholic Acid 
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 United States (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.   
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), 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 (Pellicciari 2002).  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 
747-302 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. 
Mechanism of Action of Obeticholic Acid 
OCA is a 6α-ethyl derivative of the naturally occurring primary human bile acid CDCA, which is 
the endogenous ligand for FXR.  FXR is a ligand-dependent transcription factor that is part of 
the nuclear receptor superfamily.  FXR regulates a wide variety of target genes involved in the 
control of bile acid, lipid, and glucose homeostasis and in the regulation of immune responses. 
OCA’s potent FXR agonist effects are believed to account for the predominant efficacy of the 
investigational product.  Some of the pharmacological properties of OCA and other FXR 
agonists that have been elucidated in animal models of chronic liver disease relevant to the 
treatment of PBC include the following: 
• Improvement in hepatic choleresis with reduced inflammation and necrosis  
• Prevention and reversal of hepatic fibrosis 
The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and 
anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury 
and improved liver function in a cholestatic liver disease such as PBC. 
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5.3. 
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. 
5.4. 
Clinical Experience with Obeticholic Acid 
As of 13 Oct 2017, approximately 2690 subjects1 have received at least 1 dose of OCA.  Of 
these, 844 were healthy volunteers, 552 subjects had PBC, 1141 subjects had NASH, 41 subjects 
had diabetes mellitus/nonalcoholic fatty liver disease, 33 subjects had alcoholic cirrhosis/portal 
hypertension, and 73 subjects had primary sclerosing cholangitis, and 6 subjects 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.  
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. 
To date, the efficacy and safety of OCA in PBC has been evaluated in 2 placebo-controlled, 
double-blind, Phase 2 studies (747-201 and 747-202), and 1 placebo-controlled, double-blind 
Phase 3 study (747-301).  Following the double-blind phase, subjects in all 3 studies were 
eligible to continue with treatment in a long-term safety extension (LTSE) phase for up to 
5 years in Study 747-201, up to 1 year in Study 747-202, and up to 5 years in Study 747-301. 
Study 747-201 (59 subjects) 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 subjects) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus 
placebo in subjects 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. 
                                                 
1 Includes estimated numbers from ongoing blinded studies. 
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Study 747-301 (216 subjects) was a Phase 3, double-blind, placebo-controlled, parallel group 
study followed by an LTSE using OCA in subjects with PBC.  The primary endpoint for 
Study 747-301 was a composite endpoint based on the proportion of subjects reaching specific 
criteria for ALP and bilirubin (ALP <1.67× 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 <1.67× 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 10 mg OCA 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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is complete. 
5.5. 
Rationale for Study Design and Dose for Investigational Product 
5.5.1. 
Rationale for Study Design 
OCA is a modified bile acid and FXR agonist that is derived from the primary human bile acid 
chenodeoxycholic acid.  The key mechanisms of action of OCA, including its choleretic, 
anti-inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in 
attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. 
PBC is characterized by biochemical increases in ALP and GGT enzymes with or without 
elevations of hepatocellular transaminases and bilirubin (Lindor 2009).  Both the American 
Association for the Study of Liver Diseases (AASLD) (Lindor 2009) and the European 
Association for the Study of the Liver (EASL) (EASL 2009) guidelines base the biochemical 
component of PBC diagnosis on elevations of ALP.  In addition, a growing literature supports 
the use of biochemical endpoints, specifically serum ALP alone or with other parameters such as 
bilirubin, to manage subjects, test the efficacy of novel therapies in clinical studies, and gauge 
the risk of long-term adverse clinical outcomes in subjects with PBC (Beuers 2011, 
Momah 2012).  Data from the Global PBC Study Group (Lammers 2013), which has built a 
database tracking biochemical status and clinical outcomes in several thousand PBC subjects, 
provides evidence for the use of the composite biochemical endpoint of ALP and bilirubin as an 
acceptable surrogate endpoint. 
Study 747-301, a Phase 3 double-blind study, evaluated the safety and efficacy of OCA at doses 
of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability) and 10 mg and used 
a composite biochemical endpoint of ALP and bilirubin as a surrogate endpoint.  In this study, 
both treatment groups exhibited clinically meaningful improvements in liver biochemistry and 
were safe and generally well-tolerated.  As a result, starting subjects on 5 mg OCA and titrating 
to 10 mg based on tolerability and clinical response appears to be an appropriate dosing strategy 
in subjects with PBC.  
Study 747-302 is a clinical outcomes study, supportive of Phase 3 Study 747-301 which was 
based on a surrogate biochemical endpoint, designed to confirm the clinical benefit of OCA 
treatment in patients with PBC.  A retrospective observational database (Global PBC Study 
Group [Lammers 2013]) of patients with PBC allowed for a rigorous patient-level meta-analysis 
and provided an opportunity for a robust assessment of ALP and bilirubin as viable surrogate 
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biochemical parameters and a comprehensive understanding of the natural history of the PBC 
disease process.  Data from the Global PBC Study Group was also utilized to inform the design 
of the confirmatory outcomes study. 
5.5.2. 
Rationale for Dose 
5.5.2.1. 
Rationale for OCA Dose 
The safety and tolerability of multiple doses of OCA have been established in subjects with PBC 
at doses up to 50 mg.  As demonstrated in the Phase 2 PBC studies (Studies 747-201 and 
747-202), OCA significantly reduced serum ALP levels at doses of 10 mg, 25 mg, and 50 mg, 
but with an increase in the incidence and severity of pruritus at higher dose levels.  The Phase 3 
PBC study (Study 747-301) subsequently evaluated the safety and efficacy of OCA at lower 
doses of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability in the 
double-blind phase and after 3 months in the open-label phase) and 10 mg; both treatment groups 
exhibited clinically meaningful improvements in liver biochemistry and were safe and generally 
well tolerated.  Study 747-301 demonstrated that titration of OCA from a starting dose of 5 mg to 
10 mg improved tolerance to pruritus relative to 10 mg (56% versus 69% of subjects who 
experienced pruritus) and minimized dropouts due to pruritus.  Based on these data, the approved 
dosing regimens for OCA for the treatment of patients with PBC are 5 mg and 10 mg. 
The majority of efficacy results with OCA, in terms of change in alkaline phosphatase, was 
observed by 3 months and the time to treatment-emergent pruritus was typically 1 month or less 
in Study 747-301.  Study 747-302 will evaluate the effect of OCA on clinical outcomes using the 
5 mg OCA dose for at least 3 months, increasing to 10 mg OCA, if tolerated. 
5.5.2.2. 
Rationale for Modified OCA Doses in Patients Classified with Child-Pugh B or 
Child-Pugh C Hepatic Impairment 
Simulations using a physiologic PK model predicted changes in systemic and liver OCA 
concentrations associated with changes in the severity of hepatic impairment (Child-Pugh Score).  
Model simulations predicted that for mild (Child-Pugh A), moderate (Child-Pugh B), and severe 
(Child-Pugh C) hepatic impairment, total OCA plasma concentrations increase 1.4-, 8.0-, and 
13-fold relative to subjects 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 (Child-Pugh B and C) subjects treated 
with OCA in Phase 1 and 2 studies experienced plasma OCA exposures >10-fold higher than 
those in healthy subjects, 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.  Collectively, the results from these analyses suggest that the doses of OCA 
administered to hepatically-impaired patients should be modestly lower than those for patients 
with normal hepatic function to achieve similar hepatic exposure.   
Per the approved FDA prescribing label, the recommended dosing regimen for OCA in subjects 
with moderate and severe hepatic impairment is a starting dose of 5-mg OCA once weekly.  
Dosage adjustments in subjects with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic 
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impairment may be made after establishing tolerability at the lower dose (full modified dosing 
regimen is described in Appendix A).   
5.5.2.3. 
Rationale for Control Groups  
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 a standard of care 
effect.  Notably, accounting for the standard of care effect is critical when designing an 
outcome-based study conducted globally when there are regional differences in the treatment of 
subjects with PBC. 
Historical Control Group 
The available robust historical PBC observational datasets (UK-PBC and Global PBC Study 
Group) will also be leveraged to provide further comparative evaluation of the clinical benefit of 
OCA.  Each database includes >6000 patients with long-term follow-up. 
Comparison of OCA treatment to the historical controls may provide utility in addressing 
potential bias or confounds associated with the placebo arm.  For example, bias associated with 
the potential addition of commercial OCA and/or differences in long-term standard of care 
between the treatment arms including ancillary treatments and diagnostics. 
Therefore, further evaluation of the effect of OCA will compare OCA treatment versus historical 
controls, and will be supportive to placebo comparisons (ie, comparisons to historical and 
placebo controls will be evaluated separately). 
5.6. 
Importance of Monitoring of Disease Progression 
Given PBC is a chronic, progressive liver disease, it is important that subjects with PBC are 
closely monitored to ensure early identification of potential disease progression to cirrhosis, 
decompensation and/or liver injury.  More extensive safety monitoring and appropriate dosing 
adjustments, interruptions, and discontinuations will be implemented to improve subject 
oversight and safety.  Investigators, together with the Sponsor’s Medical Monitor, will 
consistently and frequently assess individual subjects to determine on an ongoing basis the 
totality of a subject’s clinical profile, which includes careful evaluation of signs and symptoms 
of potential hepatic injury and/or decompensation coupled with rules based laboratory 
monitoring. 
Subjects will be monitored for potential hepatic injury and/or decompensation and progression to 
cirrhosis (Section 7.5).  Criteria for implementing dosing adjustments, interruptions, or 
discontinuations, and close monitoring procedures postdose-adjustment are described in 
Section 7.6 and Section 7.7.  The more extensive monitoring is important given the elevated risk 
of decompensation and potential for higher hepatic exposure to OCA in this population. 
5.7. 
Summary of Known Potential Risks with OCA 
The rate of progression and risk of decompensation is variable and may be rapid in certain 
patients, necessitating closer surveillance of patients at risk.   
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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 
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. 
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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care on clinical outcomes in subjects with PBC as measured by time to first occurrence of any 
of the following adjudicated events, derived as a composite event endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
6.2. 
Secondary Objectives 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above. 
To assess the effect of OCA compared to placebo on time to occurrence of liver-related death.  
To assess the effect of OCA compared to placebo on progression to cirrhosis.  
To assess the effect of OCA compared to placebo on time to occurrence of HCC. 
To assess the effect of OCA compared to placebo on disease progression via the following: 
• Liver biochemistry 
• Markers of inflammation and fibrosis 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
To characterize the PK of OCA and its conjugates in a subset of subjects. 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 4, double-blind, randomized, placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with bilirubin levels of >ULN and ≤5x ULN and/or ALP 
>3x ULN.  Subjects enrolled will be at higher risk of liver-related clinical complications. 
Approximately 428 subjects meeting all enrollment criteria will be recruited into the study over 
an approximate 4-year period, randomly allocated to treatment with either OCA or matching 
placebo in a 1:1 ratio (Figure 1).  Subjects will be screened during a 1- to 8-week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples 
(at least 2 weeks apart) to confirm pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3).  Randomization will be stratified by UDCA treatment (yes/no) and baseline 
bilirubin categories (>ULN/≤ULN).  A minimum of 30% of subjects will have elevated bilirubin 
(>ULN) at Screening.  In addition to the placebo control arm, multiple historical control groups 
(concurrent and retrospective) will be used.   
Subjects will be dosed according to their cirrhosis status and Child-Pugh Score. Subjects who are 
noncirrhotic or classified as Child-Pugh A at Screening will initiate investigational product once 
daily with 5-mg OCA or matching placebo.  Following 3 months of once daily treatment with 
investigational product, the dose should be titrated to a maximum 10 mg OCA or matching 
placebo once daily, based on tolerability and biochemical response (see Section 7.3).  
Subjects with cirrhosis (see Section 7.5.4) and classified as Child-Pugh Class B or Child-Pugh 
Class C will follow a modified dosing regimen, and will initiate investigational product once 
weekly with the 5-mg OCA or matching placebo dose.  In addition, these subjects will follow a 
modified titration plan, which is outlined in Appendix A. 
It is anticipated that subjects will be followed for a minimum of approximately 6 years.  The 
study will continue until approximately 127 adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor (eg, based on advisement by the Data 
Monitoring Committee; DMC) terminates the study. 
This study will be conducted at approximately 170 international study sites with experience in 
treating subjects with PBC.  Prospective subjects will be identified primarily from the hospital 
and/or physician’s database of subjects with PBC, or may be referred from other physicians.  
Subjects may self-refer to an Investigator if they become aware of the study through local, 
national, or international PBC subject societies, forums, and networks. 
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7.1.1.
Study Design Diagram 
Figure 1: 
Schematic Diagram Study 747-302 
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for 
subjects on all dosing regimens, based on tolerability and biochemical response (Up-titration should be considered 
when ALP and/or total bilirubin are >ULN).  Subsequent dose titration(s) for subjects classified as Child-Pugh B 
or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous 
dose titration. 
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7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) 
 
Screening Visits 
Day 0 
M 1 
M2 
M 3 
Post-Titration 
Visitsb 
M 6 
M 9 
M 12 
1 
2a 
Visit Windows (+/-)c 
3 to 8 wk 
prior to 
Day 0 
1 to 6 wk 
prior to 
Day 0 
 
+1 
wk 
+1 
wk 
±2 
wk 
±1 wk 
±2 wk 
±2 
wk 
±2 wk 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical/PBC Historyd  
X 
 
 
 
 
 
 
 
 
 
Cirrhosis Status Assessmente 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
Physical Exam  
X 
 
 
X 
X 
 
X 
X 
 
Xd 
Assessments for Child-Pugh Scoref 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (including weight) 
Xg 
 
X 
 
 
X 
 
X 
X 
Xg 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
Subject Questionnaires (5-D Pruritus Scale and 
Pruritus VAS) 
 
 
X 
 
 
 
 
X 
 
X 
Quality of Life Questionnaires (PBC-40, 
EQ-5D-5L, and FIS)h 
 
 
X 
 
 
 
 
 
 
X 
Fibroscan® TEi 
 
 
X 
 
 
 
 
X 
 
X 
Endoscopyj 
 
 
X 
 
 
 
 
 
 
X 
Hepatic Ultrasoundk 
 
X 
 
 
 
 
 
X 
 
X 
Gallbladder Assessment (Ultrasound) 
 
Xk 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health Outcome Assessmentsl 
 
 
X 
 
 
X 
 
X 
X 
X 
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Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) (Continued) 
 
Screening Visits 
Day 0 
M 1 
M2 
M 3 
Post-Titration 
Visitsb 
M 6 
M 9 
M 12 
1 
2a 
Visit Windows (+/-)c 
3 to 8 wk 
prior to 
Day 0 
1 to 6 wk 
prior to 
Day 0 
 
±1 
wk 
±1 
wk 
±2 
wk 
±1 wk 
±2 wk 
±2 
wk 
±2 wk 
Randomization/Treatment Assigned 
 
 
X 
 
 
 
 
 
 
 
Dose Titration: Standard Dosingm,n 
 
 
 
 
 
X 
 
X (if applicable) 
Dose Titration: Modified Dosing (if 
applicable)n,o 
 
 
 
 
 
X 
 
X 
X 
X  
Dispense Investigational Producto 
 
 
X 
 
 
X 
 
X 
X 
X 
IP Accountability/Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Dosing Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSp 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
X 
Urine-based β-hCG Pregnancy Testq 
X 
 
X 
 
 
 
 
 
 
 
Chemistry/Hematology/Coagulationp 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase and Lipase 
 
 
Sample to be collected if the subject experiences acute pancreatitis or cholecystitis 
Review Progression to Cirrhosis Algorithm   
 
 
 
X 
X 
X 
X 
X 
X 
X 
OCA, C4, and FGF-19 (plasma)  
 
 
X 
 
 
X 
 
X 
Xr 
X 
Markers of Hepatic Fibrosis and/or 
Inflammations 
 
 
X 
 
 
 
 
X 
 
X 
Geneticst 
 
 
X 
 
 
 
 
 
 
X 
AE = adverse event; ALP = alkaline phosphatase; β-hCG = beta human chorionic gonadotropin; eCRF = electronic case report form; EOS= End of Study; EOT = End of 
Treatment; FGF-19 = fibroblast growth factor-19; FIS = Fatigue Impact Scale; HCC = hepatocellular carcinoma;  
IP = Investigational Product; M = month, MRS = Mayo Risk Score; TE = transient elastography; VAS = Visual Analogue Scale; wk = week 
a All subjects will have the chemistry panel retested to ensure subjects have at least two ALP and bilirubin assessments at least 2 weeks apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and bilirubin assessments will be used to determine eligibility. Refer to Section 9.7.3 for guidance on when an additional ALP or 
bilirubin sample may be needed to confirm eligibility. Samples for hematology and coagulation will not be collected at Screening Visit 2. 
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b Post-Titration visits must be performed 1 month (± 1 week) and 2 months (±1 week) after any up-titration in dose and/or frequency in subjects following modified dosing due to 
Child-Pugh B and Child-Pugh C hepatic impairment.  See Appendix A  for additional guidance.  In subjects following the standard dosing regimen, the Post-Titration Visit 
must be performed 1 month (±1 week) and 2 months (±1 week) after the first up-titration to 10 mg OCA or matching placebo.  
c Visits should be based on Day 0 (not on the prior visit) with the exception of the Post-Titration Visit, which is based on the date of titration. 
d Medical history at Screening and the yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both. 
e Presence or absence of cirrhosis should be assessed per Section 7.5.4.  Cirrhosis status should be repeated as clinically indicated. 
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 Height will be collected at this visit. 
h The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2 and Section 12.2.5). 
i Transient elastography (TE) will be conducted at 6-month intervals at all study sites where the Fibroscan® TE device is available.  Please refer to Section 9.7.4 for additional 
information related to the allowed windows at Day 0 for this procedure. 
j Endoscopy will be conducted at all study sites where the device is available to assess for the presence of oesophageal varix/varices.  Please refer to Section 9.7.4 for additional 
information related to the allowed window at Day 0 for this specific procedure.  
k Ultrasound will be conducted to enhance HCC surveillance and for gallbladder assessment at Screening.  If ultrasound was not performed at Screening and the historic 
ultrasound is >3 months from Day 0, perform a hepatobiliary ultrasound at the Day 0 visit.  
l Health Outcome Assessments: Data related to nonstudy related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
m Pre-titration tolerability assessment, which include a review of AEs and a review of safety laboratory results (eg, chemistry, hematology, and coagulation), must be completed 
by the Investigator before any up-titration can occur as defined in Section 7.4.1.  Lab results obtained within 2 months prior to any up-titration may be used for assessment.  
n Dose Titration is based on cirrhosis status (Section 7.5.4) and Child-Pugh Score (Section 7.5.5).  The initial dose titration of investigational product may occur at the Month 3 
visit, or any study visit thereafter for subjects on all dosing regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for subjects who are classified 
as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.  For complete modified dose 
titration criteria, refer to Appendix A. 
o Subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1) and to take investigational product at approximately the same time of day.  Subjects 
must be instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
p The subject 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.  MELD and MRS values will be calculated based on serum chemistry and coagulation values at each visit. 
q Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry.  If positive, a confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not be enrolled in the study.  (Additional testing may be conducted where required, regionally). 
r Only OCA PK samples will be collected at Month 9 at select study sites in a subset of subjects.  Please refer to Section 9.7.10 for the PK sampling schedule. 
s Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
t A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12.  If a Baseline (eg, Day 0) genetic sample is not obtained, subsequent genetic samples are not required to be collected during the course of the study. 
 
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Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) 
 
Year 2 Through End of Study 
 
M 3 
continued follow-
up 
Post-Titration 
Visitsa 
(if applicable) 
M 6 
continued follow-up 
M 9 
continued follow-up 
M 12 
continued follow-up 
EOT/ 
EOSb 
Visit Windows (+/-)c 
±2 wk 
±1 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
Physical Examd 
 
X 
 
 
X 
X 
Assessments for Child-Pugh Scorese 
X 
X 
X 
X 
X 
X 
Vital Signs (including weight) 
 
 
X 
 
Xf 
Xf 
12-Lead Electrocardiogram 
 
 
 
 
X 
X 
Subject Questionnaires (5-D Pruritus 
Scale and Pruritus VAS) 
 
 
X 
 
X 
X 
Quality of Life Questionnaires (PBC-40, 
EQ-5D-5L, and FIS)g 
 
 
 
 
X 
X 
Fibroscan®TEh 
 
 
X 
 
X 
X 
Endoscopyi 
 
 
 
 
X 
 
Hepatic Ultrasoundj 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
Health Outcome Assessmentsk 
X 
 
X 
X 
X 
X 
Dose Titration (if applicable)l 
X 
 
X 
X 
X 
 
Dispense Investigational Product 
X 
 
X 
X 
X 
 
IP Accountability/Compliance 
X 
X 
X 
X 
X 
X 
Dosing Diary 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSm 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
X 
X 
Chemistry/Hematology/Coagulationm 
X 
X 
X 
X 
X 
X 
Amylase and Lipase 
Sample to be collected if the subject experiences acute pancreatitis or cholecystitis 
Review Progression to Cirrhosis 
Algorithm   
X 
X 
X 
X 
X 
X 
OCA, C4, and FGF-19 (plasma)m 
 
 
 
 
X 
X 
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Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) (Continued) 
 
Year 2 Through End of Study 
 
M 3 
continued follow-
up 
Post-Titration 
Visitsa 
(if applicable) 
M 6 
continued follow-up 
M 9 
continued follow-up 
M 12 
continued follow-up 
EOT/ 
EOSb 
Visit Windows (+/-)c 
±2 wk 
±1 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
Markers of Hepatic Fibrosis and/or 
Inflammationn 
 
 
X 
 
X 
X 
Geneticso 
 
 
 
 
X 
 
AE = adverse event; β-hCG = beta human chorionic gonadotropin; EOS= End of Study; EOT = End of Treatment; FGF-19 = fibroblast growth factor-19; FIS = Fatigue Impact 
Scale; IP = Investigational Product; M = month, MRS = Mayo Risk Score; TE = transient elastography; VAS = Visual Analogue Scale; wk = week 
a  Post-Titration Visits must be performed 1 month (±1 week) and 2 months (±1 week) after any up-titration in dose and/or frequency in subjects following modified dosing due to 
Child-Pugh B and Child-Pugh C hepatic impairment.  See Appendix A for additional guidance.  In subjects following the standard dosing regimen, the Post-Titration visit must 
only be performed 1 month (±1 week) and 2 months (±1 week) after the first up-titration to 10 mg OCA or matching placebo.  
b As soon as possible upon study discontinuation and as near as possible to last dose taken. 
c Visits should be based on Day 0 (not on the prior visit) with the exception of the Post-Titration Visit, which is based on the date of titration. 
d The yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both. 
e  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 case report form.  
f  The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2 and Section 12.2.5). 
g Transient elastography (TE) will be conducted at 6-month intervals at all study sites where the Fibroscan® TE device is available. 
h  Endoscopy will be conducted at all study sites where the device is available to assess for the presence of oesophageal varix/varices. 
i Ultrasound will be conducted to enhance HCC surveillance.  For all on study (eg, postday 0) ultrasounds: unless HCC has already been confirmed by biopsy, a second 
confirmatory image (eg, MRI) should be obtained to confirm suspected HCC. 
j  
Health Outcome Assessments: Data related to nonstudy related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
k   
Pre-titration tolerability assessment, which include a review of AEs and a review of safety laboratory results (eg, chemistry, hematology, and coagulation), must be completed 
by the Investigator before any up-titration can occur as defined in Section 7.4.1.  Lab results obtained within 2 months prior to any up-titration may be used for assessment.   
l  Dose Titration is based on cirrhosis status (see Section 7.5.4) and Child-Pugh Score (Section 7.5.5).  The initial dose titration of investigational products may occur at the 
Month 3 visit, or any study visit thereafter for subjects on all dosing regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for subjects who are 
classified as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.  For complete modified 
dose titration criteria, refer to Appendix A. 
m  The subject should be instructed to fast overnight (at least 8 hours) prior to each visit.  Fasting is required prior to all study visits, but water is permitted.  MELD and MRS values 
will be calculated based on serum chemistry values at each visit. 
n  Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
o  A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12. 
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7.1.3. 
Study Duration 
The study is event driven and total duration will be determined by the time required to accrue 
approximately 127 primary endpoint events, estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time of approximately 6 years. 
7.2. 
Number of Subjects 
It is expected that approximately 428 subjects will be randomized in the study to achieve 
127 adjudicated primary endpoint events.  In the event additional subjects are needed to 
complete enrollment in the biopsy substudy (N = 45 subjects, as defined in Addendum 2), 
subjects who agree to participate in the substudy may be added to the target subject enrollment 
number currently planned.  
7.3. 
Planned Dosing Regimen 
Subjects will be randomized to treatment with either OCA or matching placebo in a 1:1 ratio.  
Subjects will be dosed according to their cirrhosis status (as defined Section 7.5.4 ) and 
applicable Child-Pugh Score (see Section 7.5.5) as outlined in Section 7.4.  
Table 3: 
Planned Dosing Regimen by Cirrhosis and Child Pugh Score 
 
Scheduled Dosing Regimen 
Standard 
Modified 
Noncirrhotic/ 
Child-Pugh A 
Child-Pugh B or 
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weeklyc 
 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weeklyc 
 
a Starting dose based on subject’s cirrhosis status and Child-Pugh score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject tolerability, 
biochemical response, and/or changes in cirrhosis status or Child-Pugh score at any time during the study (see Section 7.4). 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
Non-Cirrhotic or Child-Pugh A 
Subjects who are noncirrhotic or classified as Child-Pugh A at screening will receive 5 mg OCA 
or matching placebo once daily for 3 months.  Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the product and assessment of biochemical response.  
Up-titration should be considered when ALP and/or total bilirubin are >ULN.  A review of safety 
laboratory results (eg, chemistry, hematology, and coagulation) obtained no more than 2 months 
prior to the planned up-titration visit must be completed as part of the investigational product 
tolerability assessment before up-titration can occur (see Section 7.4.1).   
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For those subjects that up-titrate to 10 mg, dose may be decreased to 5 mg at any time during the 
study as considered clinically appropriate (eg, tolerability). Subjects may be titrated back up to a 
maximum dose of 10 mg once daily based on tolerability and clinical judgment of the 
Investigator.  A review of safety laboratory results obtained within 2 months of the planned 
up-titration visit date is not required prior to re-challenging a subject up to 10 mg once daily 
dosing, as long as the decrease in dose/dosing frequency was less than 3 months in duration.  
Cirrhotic and Child-Pugh B or C 
Subjects with cirrhosis (see Section 7.5.4 ) and classified as Child-Pugh Class B or Child-Pugh 
Class C will follow a modified dosing regimen, initiating 5 mg OCA or matching placebo once 
weekly.  After a minimum of 3 months dosing once weekly with 5 mg OCA or matching 
placebo, and following review of the pre-titration laboratory results to assess safety and 
tolerability, the dosing frequency of 5 mg OCA or matching placebo should be increased to twice 
weekly (at least 3 days apart).  Subjects who have maintained the twice weekly dosing frequency 
for a minimum of at least 6 weeks, and meet the dose titration criteria should up-titrate to the 
maximum allowed dose of 10 mg OCA or matching placebo twice weekly. 
Investigators may decrease the dosing frequency (back to once weekly) or dose for any subject at 
any time during the study, as considered clinically appropriate (eg, tolerability).     
The dosing regimen should be determined as described shown in Table 13  Appendix A.  
Investigators should follow the dosing/titration schedule as shown described in Section 7.4 and 
Appendix A. 
7.4. 
Dose Titration 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 subject’s cirrhosis status (using histology or 
non-histological methods as defined in Section 7.5.4 and Section 7.5.5) or Child-Pugh 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) as well 
as biochemical response (as assessed by reductions in ALP and/or total bilirubin).  In general, 
down-titration will be done in response to tolerability concerns and can occur at any time while 
on-study.  Up-titration will be done per protocol when subjects have no tolerability concerns and 
have not achieved an adequate reduction in ALP and/or total bilirubin to within normal limits, or 
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 for each 
dosing regimen as defined in Section 7.3.  A 1-Month and 2 Month Post-Titration Assessment 
must be performed any time a subject’s dose or frequency is up-titrated (see Section 7.1.2 and 
Section 9.7.7). 
Scheduled Dose Titration - The first dose titration for any subject may occur no earlier than 
3 months following initiation of OCA or matching placebo.  Subsequent titrations in dose or 
dosing frequency for subjects following the Modified Dosing Regimens may occur no earlier 
than 6 weeks (via an unscheduled visit or regular visit- see Appendix A) following an 
up-titration. 
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Tolerability Dose Titration - Investigators may decrease the dosing frequency or dose for any 
subject at any time during the study, as considered clinically appropriate (eg, tolerability; see 
Section 7.4.1).   
Dose Titration due to Change in Cirrhosis or Child-Pugh Score - When subjects demonstrate 
a change in cirrhosis status (as assessed per Section 7.5.4) or Child-Pugh Score (Section 7.5.5) 
dosing should be reassessed and the dosing regimen modified appropriately. Changes in 
Child-Pugh Score that result from a transient, explainable change in laboratory parameters 
should be documented appropriately, and should not necessarily result in a change to the dosing 
regimen. 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, 
biochemical response, and clinical judgment.  
Subjects who exhibit development of cirrhosis at any point in the study should be assessed per 
Section 7.5.4.  If the presence of cirrhosis is confirmed and the subject’s Child-Pugh score is 
either B or C, the appropriate modified dosing regimen should be followed.  The dose or 
frequency of investigational product should be down-titrated to the next lowest dosing frequency 
in the appropriate modified dosing regimen unless the subject is currently taking a dose and 
frequency also specified in the modified dosing regimen and the Investigator determines that it is 
clinically appropriate for the subject to continue at that dose (Appendix A). 
Subjects with pre-existing cirrhosis who demonstrate a change in the Child-Pugh Score from A 
to B or C at any point in the study should also have their dosing modified per the appropriate 
dosing regimen.  Changes in Child-Pugh Score that result from a transient, explainable change in 
laboratory parameters (eg, increase in vitamin K resulting in change in INR) should be 
documented appropriately and discussed with the Medical Monitor before any continuation or 
change to the dosing regimen (Appendix A).  
Child-Pugh Scores will be calculated during screening, at each scheduled study visits, and at 
unscheduled visits in the event of signs or symptoms of suspected hepatic injury or 
decompensation are present. All associated visit data (including central laboratory results) should 
be entered into the eCRF in a timely fashion to confirm that the subject’s Child Pugh Score has 
not changed.  If a change in cirrhosis status (as defined in Section 7.5.4) and/or Child-Pugh 
Score is observed independent of a study visit, the subject 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. 
Subjects’ dose and dosing frequency may be titrated up or down within the appropriate dosing 
regimen based on the calculated Child-Pugh Scores.  Up-titration should be done per Investigator 
discretion and be guided by the pre-titration tolerability assessments. 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements 
Tolerability of investigational product must be assessed prior to titrating a subject to a higher 
dose.  A review of adverse events and safety laboratory results (eg, chemistry, hematology, and 
coagulation) obtained within 2 months of the up-titration visit must be performed as part of the 
investigational product tolerability assessment, prior to any planned up-titration in investigative 
product (eg, Month 3, Month 6).  Safety laboratory results obtained at the Month 1 visit (for 
titration at Month 3) or at the Post-Titration Assessment visits (for titration prior to or at the 
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subsequent quarterly visit) are acceptable for review purposes; however, 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 subject to a higher 
dose.  
To be eligible for a dose up-titration: 
• Subjects 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.  
• There must be no clinically significant increase (as determined by the Investigator) in 
the subject’s liver function tests.  
7.5. 
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).  Child Pugh Scores should only be applied in patients 
who have evidence of cirrhosis at screening or demonstrate evidence of cirrhosis at screening or 
progression to cirrhosis during the study based on criteria presented in Section 7.5.4.  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 the assessments of signs and symptoms of hepatic injury and liver biochemistry, the 
investigational product may be interrupted or discontinued per criteria discussed in Section 7.5.2 
and Section 7.5.3, and close monitoring procedures will be implemented (Section 7.7). 
7.5.1. 
Signs and Symptoms of Hepatic Injury or Decompensation 
Subjects 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:  eg, 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:  eg, confusion, 
swelling of the legs or abdomen 
• Non-specific signs and symptoms of impaired health:  eg, 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 subject evaluation 
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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 7.5.2), (2) assessment of clinical events for potential hepatic 
decompensation (Section 7.5 (3) triggering of investigational product interruption or 
discontinuation per criteria (Section 8.4 ), (4) documentation in the AE eCRF or the SAE eCRFs 
(Section 12.1.5.1 and Section 12.1.5.2), and (5) contact with the Medical Monitor. 
7.5.2. 
Liver Biochemistry Assessments for Suspected Hepatic Injury or Potential 
Hepatic Decompensation 
Liver biochemistry will be assessed to evaluate biochemical triggers that will prompt an 
immediate reevaluation of subjects 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 
laboratory be used for assessments whenever possible.  In the event that a subject 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 subject 
evaluation (depending on the repeat result) are summarized in Table 4. 
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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 4: 
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 subject 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 
threshold 
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 subject 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 
 
 
>0.3unit increase from baseline 
Closely monitor until 
normalization or stabilization. 
 
If values continue to increase 
relative to the baseline value, 
interrupt IP. 
The subject 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 subjects 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 subjects’ 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 
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considered appropriate based on their medical judgement but only after documented agreement 
with the Sponsor’s Medical Monitor. 
7.5.3. 
Clinical Criteria for Monitoring for Potential Hepatic Decompensation Events 
Subjects will be monitored for potential hepatic decompensation events throughout the study.  
Clinical criteria for the monitoring these events and the interruption/discontinuation of 
investigational product is summarized in Table 5. 
Investigational product should be discontinued permanently if the subject received a liver 
transplant or experiences multi-organ failure as defined in Table 5, Part A).  Subjects should 
continue to return for scheduled study visits for safety follow up.  
Subjects who experience other potential hepatic decompensation events defined in Table 5, 
Part B should be closely monitored until normalization or stabilization.  Subjects 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 5: 
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 4, 
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. 
7.5.4. 
Assessing Cirrhosis 
7.5.4.1. 
Determination for Dosing Regimen 
To determine which dosing regimen subjects should follow, the presence or absence of cirrhosis 
should be assessed by the Investigator at Screening Visit 1.  Acceptable methods of confirming 
(via medical history) or assessing cirrhosis for purposes of determining dosing is defined as a 
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subject who has documented evidence or presence of one or more of the following cirrhosis 
indicators: 
Biopsy results consistent with PBC Stage 4 (Ludwig 1978)   
• TE 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  
− elevation in prothrombin time /INR (not due to antithrombotic agent use), or 
− elevated bilirubin (2× ULN) 
Subjects who exhibit no evidence of cirrhosis by the above methods of assessment will be dosed 
using the Standard Dosing Regimen, while those who do exhibit evidence of cirrhosis by one or 
more of the above methods will be dosed using the Modified Dosing Regimen according to their 
Child-Pugh Score calculated in the electronic case report form (eCRF) (see Appendix A and 
Section 7.3). 
Cirrhosis status should be reassessed as clinically indicated throughout the study.  Any change in 
cirrhosis status will necessitate re-evaluation of the dosing regimen. 
7.5.4.2. 
Progression to Cirrhosis 
When a subject identified as noncirrhotic at Baseline per the criteria listed in Section 7.5.4 
exhibits any signs or symptoms associated with progression to cirrhosis, as defined by the same 
criteria, the subject should also be assessed by Fibroscan® TE where available and progression 
to cirrhosis confirmed by biopsy (centrally read) unless not medically indicated.  Laboratory 
samples needed to obtain noninvasive scores of liver fibrosis (ELF, and aspartate 
aminotransferase to platelet ratio index [APRI]) will also be collected when a subject develops 
evidence of progression to cirrhosis. 
Full instructions concerning the sample collection methods, processing, labeling, and shipping 
will be provided by the Sponsor in a study-specific histology manual.  Collection supplies will be 
provided by the central laboratory. 
Sites participating in the paired biopsy substudy must confirm progression to cirrhosis by biopsy 
as per the information outlined in protocol Addendum 2. 
All suspected cases of progression to cirrhosis should be submitted for adjudication regardless of 
the availability of transient elastography or biopsy results. 
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7.5.5. 
Child-Pugh Score 
Child-Pugh (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 6 and can range from 5-15.  Although CP score calculation will automatically be computed 
in all subjects, it should only be applied to subjects who meet criteria for progression to cirrhosis. 
Dose adjustment or discontinuation should not be considered based solely on the CP score, in 
subjects who do not meet criteria for presence of cirrhosis.  
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).  Sponsor 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 6: 
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 
 
No 
Grade 1 or 2 
Grade 3 or 4 
INR = international normalized ratio 
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  
 Child-Pugh criteria: Pugh 1973, Lucey 1997, Vilstrup 2014. 
7.5.5.1. 
Mayo Risk Score 
Mayo Risk Score (MRS) (Dickson 1989) is calculated and reported within the EDC system 
based on data entered into the eCRF.  Calculation of MRS includes Investigator assessment of 
peripheral edema and the use of diuretic therapy, which will be assessed during adverse event 
and concomitant medicine review at the scheduled visits and entered into the eCRF, as well as 
total bilirubin, albumin, and prothrombin time results obtained from the central laboratory data. 
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7.6. 
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 7), investigational product should be initiated at a lower dose and subjects 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 7.  Subjects that 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 terminate at the time when the needed 
number of adjudicated events has accrued.  If a subject reaches an outcome event, he or she 
should continue the regular visit schedule and continue taking investigational product as long as 
the subject has not met any of the criteria for mandatory interruption of investigational product 
outlined in Table 7, and the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and remain in the study until study 
termination.   
Table 7: 
Criteria for Dose Adjustment, Interruption, Discontinuation and 
Rechallenge 
DOSE ADJUSTMENT 
 
 
Criteria 
Action Taken with IP 
Adjustment 
Progress to cirrhosis and have 
CP A cirrhosis (CP score <7) 
Adjust to a maximum 
daily dose of 10 mg (or 
equivalent placebo) in a 
blinded fashion 
Not applicable.  Remain at maximum daily 
dose of 10 mg (or equivalent placebo) for 
remainder of study. 
Progress to CP B or C cirrhosis 
(CP score ≥7) 
Adjust IP dose to 5 mg 
once weekly, then 
titrate to a maximum 10 
mg twice weekly (at 
least 3 days apart). 
After a minimum of 3 months, if at a lower 
dose, subjects may titrate to a maximum IP 
dose of 10 mg twice weekly per Investigator 
discretion. 
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 4)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 4d 
Interrupt after 
confirmation by repeat 
testing 
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Liver biochemistries indicative of 
potential hepatic decompensation in the 
absence of symptoms (see Part B of 
Table 4)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 5) 
Closely monitor until 
normalization 
The subject 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  
Pregnancy 
Interrupt 
Patient should continue with the study visit 
schedule.  The subject may re-start IP when 
she is no longer pregnant or breastfeeding 
(if applicable) at the discretion of the 
Investigator and after discussion with the 
Medical Monitor   
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) 
Discontinue / 
No Rechallenge 
Discontinue IP permanently and continue to 
return for scheduled study visits for safety 
follow up.  
 
Monitor closely for clinical outcomes per 
protocol. 
 
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 4) are observed in the presence of 
clinical symptoms of cholestatic 
hepatitis or hepatic encephalopathyf 
Multi-Organ failure requiring 
hospitalization 
Liver transplantation 
Fully resolved = Return to baseline levels or return to within normal limits (WNL). IP = investigational product 
a If subject 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 Postbaseline ≥3x baseline, Baseline >ULN and Postbaseline ≥2x Baseline, ALT or AST >3x 
baseline (and >ULN) 
d ALT or AST ≥2x baseline, albumin <3.2 g/L or electrolytes (sodium <130 mEq/L). 
e Conjugated bilirubin >0.5 mg/dL increase from baseline; 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 conjugated bilirubin 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. 
g Multi organ failure including hepatorenal syndrome Type 1 or Type 2 and acute kidney injury, hepatopulmonary syndrome, or 
portopulmonary syndrome. 
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7.7. 
Close Observation 
If investigational product is interrupted or discontinued as described in Section 7.6, subjects 
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 subject 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 subject 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 subject 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 7.5.1, Section 7.5.2, and 
Section 7.5.3.  These cases need to be discussed with the Sponsor's medical monitor: 
• Repeating liver enzyme and serum bilirubin tests as described in Section 7.5.2.  
Frequency of retesting can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the subject 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 
product should be discussed with the Sponsor's medical monitor.  The subject 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 (HEV) when assessing for 
hepatic decompensation as infection with HEV in patients with chronic liver diseases 
such as PBC may rapidly worsen with signs and symptoms similar to drug induce 
liver injury (Kumar 2013) 
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• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin).  
• Seeking hepatology consultation, if the Investigator is not a hepatologist 
7.8. 
Criteria for Study Termination 
The Sponsor 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 DMC, it may be necessary to stop the study before all events have been accrued, and 
when subjects are still active on the study.  In addition, the Sponsor may terminate the study at 
an investigational site at any time (eg, poorly performing sites, as determined by the number of 
subjects 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 subjects for the End of Study Visit.  The window of time for 
scheduling the visit will be based on a final projection of when the requisite 127 adjudicated 
events will have been accrued. 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Population 
This study will be conducted at approximately 170 international study sites with experience in 
treating patients with PBC.  Prospective subjects 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. 
Subject Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with AASLD and EASL practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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. 
2. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN  
3. Age ≥18 years 
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4. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking 
UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0. 
5. Contraception:  Female subjects of child-bearing potential must use ≥1 effective method 
of contraception during the study and until 30 days following the last dose of 
investigational product.  Effective methods of contraception are considered to be those 
listed below:   
• Barrier method, ie, (a) condom (male or female) or (b) diaphragm, with spermicide  
• Intrauterine device (IUD)  
• Vasectomy (partner) 
• Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection) 
• Abstinence, if in line with the preferred and usual lifestyle of the subject   
6. Must provide written informed consent and agree to comply with the study protocol 
8.3. 
Subject Exclusion Criteria 
1. History or presence of other concomitant liver diseases including:  
• Hepatitis C virus infection 
• Active hepatitis B infection; however, subjects 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 
• Nonalcoholic steatohepatitis 
• Gilbert’s Syndrome  
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including:  
• History of liver transplant, current placement on a liver transplant list, or current 
MELD score >12.  Subjects who are placed on a transplant list despite a relatively 
early disease stage (for example per regional guidelines) may be eligible as long as 
they do not meet any of the other exclusion criteria. 
• Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
− Variceal bleed 
− Uncontrolled ascites 
− Encephalopathy  
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− Spontaneous bacterial peritonitis  
• Known or suspected hepatocellular carcinoma 
• Prior transjugular intrahepatic portosystemic shunt procedure 
• Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine 
>2 mg/dL (178 μmol/L)  
3. Mean total bilirubin >5x ULN 
4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) 
or ileal resection or plan to undergo either of these procedures. 
5. Other medical conditions that may diminish life expectancy, including known cancers 
(except carcinomas in situ or other stable, relatively benign conditions such as chronic 
lymphatic leukemia). 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test by the central laboratory), or lactating. 
7. Known history of human immunodeficiency virus infection. 
8. Medical conditions that may cause non-hepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months). 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study. 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0. 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components.  
14. UDCA naïve (unless contraindicated) 
8.4. 
Subject Withdrawal Criteria 
Subjects can be discontinued from investigational product by the Investigator at any time for 
clinical safety concerns.  Subjects who are discontinued from investigational product are 
expected to continue in the study and should follow the regular visit schedule for the duration of 
the study.  See Section 7.6 for withdrawal criteria related to potential hepatic injury and/or 
decompensation including liver transplantation or multi-organ failure.  Other reasons, including 
withdrawal of consent or lost to follow-up, are described in Section 8.4.1 below. 
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8.4.1. 
Other Reasons for Discontinuation of Study or Investigational Product 
The following events are considered appropriate reasons for a subject to discontinue 
investigational product; however, these subjects are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
• Subject begins treatment with commercially available OCA 
• The Investigator or Sponsor considers that it is advisable or in the best interest of the 
subject. 
• 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 subject 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 outcomes. 
− Early termination procedures should be conducted if the subject withdraws 
consent (See Section 9.7.15 ). 
The Investigator is encouraged to contact the Sponsor prior to discontinuing a subject from 
treatment.  The Investigator must notify the Sponsor study monitor by telephone or email as soon 
as possible if any subject prematurely withdraws from the study. 
8.4.2. 
Withdrawal of Consent 
If the subject 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 subjects 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 subject discontinuation.  This 
information and date must be recorded in the appropriate case report form (CRF). 
8.4.3. 
Lost to Follow-up 
If a subject fails to return to the clinic for a study visit, and the Investigator ceases to have 
contact with the subject, he or she will be withdrawn from the study. 
A reasonable effort must be made to contact the subject and determine the reason(s) why a 
subject 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 CRF. 
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8.4.4. 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by telephone or email as soon as 
possible if any subject prematurely withdraws from the study.  The date when the subject is 
withdrawn and the reason for discontinuation must be recorded in the CRF.  If a subject is “lost 
to follow up” (fails to return for a visit), a reasonable effort should be made to contact the subject 
in order to determine why the subject failed to return.  This information must be documented in 
the CRF.  If a subject is withdrawn from the study early (regardless of the cause), all of the 
EOT/EOS evaluations should be performed at the time of withdrawal, as appropriate 
(See Section 9.7.15, Early Discontinuation and/or Early Termination Procedures). 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Investigational Product Treatment Regimen 
The term investigational product refers to either OCA (provided as part of this clinical study) or 
matching 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 5 mg OCA tablet or one 
10 mg OCA tablet, or matching placebo).   
Investigational product will be taken orally, up to once daily, for the duration of the study.   
All subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1) and 
to take investigational product at approximately the same time of day.  Subjects must be 
instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
At each study visit where the daily dose of investigational product is administered at the site, all 
assessments, except for the post-dose collection of blood samples for the subset of subjects 
participating in the Month 9 PK assessment, must be completed before administration of 
investigational product. 
9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.1) 
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 CRF, as well as any dose or dose 
regimen changes that occur during the study.  Concomitant medications should be stable prior to 
Day 0.   
Drug Interactions 
Subjects 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 
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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 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 Investigator’s Brochure (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 with OCA that may be observed in study subjects. 
PBC-Specific Therapy 
In general, 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 subjects’ 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, subjects 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, subjects should be reminded to keep taking their blinded 
investigational product. 
9.2.1. 
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.  Subjects who initiate commercial OCA therapy must discontinue investigative 
product and are expected to continue through the end of the study (see Section 9.7.15).  The 
study will only terminate at the time when the needed number of adjudicated events has accrued 
or at the discretion of the Sponsor.  Subjects will need to complete EOT procedures but continue 
with regularly scheduled visits until the study is terminated (see Section 9.7.15). 
9.3. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Subjects should be instructed to complete a dosing diary to help monitor compliance to the 
prescribed dosing regimen.  Subjects should be instructed to retain all bottles of investigational 
product, even if empty, and to return them to the Investigator at the subsequent visit.  The 
Investigator or designee should perform investigational product accountability and, if applicable, 
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follow up with the subject to retrieve any investigational product bottles that have not been 
returned.  
If the Investigator has concerns about a subject’s dosing compliance s/he should discuss this with 
the subject, assess the reasons for noncompliance and the likelihood that the subject will remain 
noncompliant, and notify the Sponsor accordingly.   
9.4. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Allocation to one of 
two treatment groups (OCA or placebo) will occur on a 1:1 ratio across sites and will be 
stratified by UDCA treatment (yes/no) and mean baseline bilirubin categories (>ULN/≤ULN), as 
specified by the central laboratory.  The randomization will be based on a predefined 
randomization code (generated by the Sponsor or designee) using an interactive web response 
system (IWRS), which the Sponsor intends will serve as a computer-based subject registration 
system at Screening and Day 0.  The IWRS will also serve as an investigational product 
inventory and management system and may be integrated with the study database.  
The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide subject data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned (refer to Section 9.5.2 below) and 
investigational product dispensing information (ie, bottle number[s]) will be provided. 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects 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 subject).  If it 
is not reasonable to inform the Medical Monitor in advance of the unblinding, the Investigator 
must promptly document in the subject’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 subject’s treatment will be provided separately to the 
Investigator.  Similarly, if the Medical Monitor breaks the blind for an individual subject for the 
purpose of evaluating an emergent safety issue, the Medical Monitor will document within trial 
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 subjects.  Refer to Section 13.3 for further details regarding DMC access to 
blinded and unblinded data.  The DMC will document details about any unblinded subject data 
reviews in the closed session DMC minutes, which will be made available to the Sponsor only 
after the database is locked and the trial 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. 
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9.5. 
Assignment of Site and Subject 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 subject data and to identify the site and or Investigator 
within study documents.  This number will be recorded in the CRF. 
9.5.2. 
Subject Numbers 
Subjects 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 trial is prohibited.   
9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visits should be based on Day 0 (not on the prior visit), eg, Month 3 should ideally occur 
3 calendar months (± 2 weeks) following Day 0.   
The visit windows are as follows: 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening Visit 1 interval is 3 to 8 weeks prior to Day 0.  Screening 
Visit 2 interval is 1 to 6 weeks prior to Day 0.  The visit window for 
Screening 2 visits allows for the repeat biochemistry tests to be 
collected at least two weeks after the initial biochemistry sample 
was collected and will ensure ample time to receive lab results.  
The overall Screening interval is up to 56 days, but screening 
procedures should not be performed during the last 7 days of the 
window.  
See Section 9.7.3 for scenario specific visit windows that may be 
applicable at Screening.  
Day 0 
This is the day of randomization.  On-treatment visit scheduling 
should be calculated from this point going forward. (The first dose 
of investigational product should be taken the next day, on Day 1.) 
Month 1  
±1 week (7 days)  
Titration Visit – Standard Dosing Regimen 
≥Month 3 
Titration Visit 1 – Modified Dosing 
Regimen 
≥Month 3 
Titration Visit 2 – Modified Dosing 
Regimen 
≥6 weeks after Titration Visit 1 
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Visit or Procedure 
Visit Window and/or Interval 
Titration Visit 3 – Modified Dosing 
Regimen (Child-Pugh B ONLY) 
≥6 weeks after Titration Visit 2 
Post-Titration Visit 
1 month and 2 months (±1 week [7 days]) from date of titration   
Month 3 to Month 12 
±2 weeks (14 days)  
Quarterly visits (Months 15 to EOS) 
±2 weeks (14 days) 
EOT 
(When subject discontinues investigational 
product) 
As soon as possible upon study discontinuation and as near as 
possible to last dose taken 
EOS 
(When subject terminates the study) 
The final study visit; EOS will occur concurrent with EOT if a 
subject discontinues investigative product at the time the subject’s 
participation in the study ends (eg, withdrawal of consent or study 
termination by the Sponsor); EOS will occur after the EOT if the 
subject discontinues investigative product but continues in the 
study. 
EOS = end of study; EOT = end of treatment  
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk and benefit of / study 
to the subject and will provide his/her with a copy of the written information and informed 
consent form (ICF).  The subject will be given sufficient time to consider the study before 
deciding whether or not to participate.  The subject 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 s/he can withdraw from the study at any time.  The subject must be willing and 
able to provide written informed consent before entering the study.  The Investigator or a 
medically qualified designee is responsible for administering and documenting the written 
informed consent of the subject.  The subject will be given a copy of the written information and 
his/her signed and dated consent form. 
Any change in a subject’s consent status (eg, semi-annual telephone contact or medical record 
review) must be documented in a signed informed consent form or addendum.  The subject will 
be given a signed and dated copy of the consent document. 
9.7.3. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 week to 8 weeks prior to Day 0 to 
determine whether the subject meets all the inclusion criteria and none of the exclusion criteria.  
Screening Visit 1 will occur 3 weeks to 8 weeks prior to Day 0; Screening Visit 2 will occur 
1 week to 6 weeks prior to Day 0, depending on the date that the first serum chemistry sample 
was collected. Subjects who do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects 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.   
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Collection of 2 serum chemistry samples (collected at least 2 weeks apart) during Screening is 
required for confirmation of the pretreatment serum chemistry values, including ALP and total 
bilirubin used to determine eligibility: 
• All subjects will have 2 bilirubin and ALP assessments at least 2 weeks apart. 
• When the 2 bilirubin or ALP assessments collected at Screening Visit 1 and 
Screening Visit 2 differ by ≥30%, a third sample must be collected at an unscheduled 
visit as a confirmatory sample to include in the mean result(s) that will be used to 
determine eligibility.  
• The mean of all available (at least 2; including both scheduled and 
unscheduled) bilirubin and ALP assessments will be used to determine eligibility 
(total bilirubin >ULN and ≤5x ULN and/or an ALP >3x ULN).   
Screening Visit 1 procedures are as follows: 
• The subject is to review and sign the ICF.  Informed consent must be obtained from 
the subject 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  
• Assess for the presence/absence of cirrhosis. 
• Verify inclusion and exclusion criteria for eligibility. 
• Perform a physical examination.  
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Assess and record any pretreatment-emergent AEs. 
• Record prior (if within 30 days of Screening) and current concomitant medications. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
Screening Visit 2 procedures are as follows: 
• Verify inclusion and exclusion criteria for eligibility. 
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• Perform an ultrasound for HCC surveillance and gallbladder assessment (if 
equipment is unavailable, sites should make every attempt to use available 
community referral sites).  If an ultrasound has been done within 3 months of the 
planned Day 0 visit, and a report/adequate data are available, a pretreatment 
ultrasound is not required.  If the ultrasound cannot be performed at Screening Visit 2 
(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 must be reviewed to assess possible exclusion criteria prior to 
randomization. 
• Assess and record any pretreatment-emergent AEs. 
• Review and record prior and concomitant medications. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry tests. 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
It is acceptable to repeat laboratory evaluations or other assessments or procedures within the 
Screening period (Weeks -8 to -1), as appropriate.  In the event that the 2 screening bilirubin or 
ALP assessments differ by ≥30%, and a third confirmatory sample is required to be collected, the 
Screening Visit window may be extended up to 3 additional weeks. 
9.7.4. 
Day 0 Procedures (Randomization) 
• Review inclusion and exclusion criteria for eligibility. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.5). 
• Perform TE at all study sites with access to Fibroscan® TE device.  If TE has been 
done within 3 months of Day 0 and a report/adequate data are available, a 
pretreatment TE at Day 0 is not required.  If the TE cannot be performed on Day 0 
(eg, device/technician unavailability, scheduling issues, TE data is needed to inform 
cirrhosis assessment, etc), the procedure may be completed within the screening visit 
window, at Screening Visit 1 (if data is needed for cirrhosis assessment) or as close as 
possible to the Day 0 visit, preferably, after subject eligibility has been confirmed. 
• Perform an esophagogastroduodenoscopy (endoscopy; at study sites, where the 
device is available) to assess the presence or absence of oesophageal varix/varices.  If 
an endoscopy has been done within 12 months of Day 0 and a report/adequate data 
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are available, a pretreatment endoscopy at Day 0 is not required. If the endoscopy 
cannot be performed on Day 0 (eg, device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the screening visit window, as 
close as possible to the Day 0 visit, preferably, after subject eligibility has been 
confirmed. 
− Subsequent endoscopies should be performed annually or per standard of care and 
the Investigator’s clinical judgment throughout the course of the study.  
Endoscopies should also be performed when platelet counts are <150 × 109 /L. 
• Assess and record any pretreatment-emergent AEs. 
• Review and record prior concomitant medications. 
• Review and record any nonstudy 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 subject only if s/he meets all inclusion criteria and no exclusion 
criteria. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
• If hepatobiliary ultrasound for HCC screening and gallbladder assessment was not 
performed at Screening and the historic ultrasound is >3 months from Day 1, perform 
a hepatobiliary ultrasound. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and fibroblast growth factor-19 (FGF-19) 
− Markers of hepatic fibrosis and/or inflammation (including enhanced liver fibrosis 
[ELF]) 
− Genetics (see Section 11.1.2.3) 
• Perform assessments for calculation of Child-Pugh Score. 
• Access the IWRS and dispense investigational product. 
• Instruct the subject to begin dosing on the day after the Day 0 visit (ie, on Day 1).  
Instruct the subject to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
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• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
9.7.5. 
Months 1, 2 Procedures 
• Perform a physical examination.  
• Assess and record AEs 
• Review and record prior and concomitant medications. 
• Assess investigational product compliance, perform investigational product 
accountability, and review dosing diary with the subject. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm. 
• Provide the subject with a dosing diary to document his or her dosing. 
• In the event it is not feasible for the subject to return to the site for the above 
referenced procedures, the following alternative visit procedures are available to help 
ensure compliance with the Month 1 and Month 2 visit laboratory requirements: 
− At the Day 0 visit, the subject can be provided with the central laboratory 
collection kit and shipping materials associated with the Month 1 visit, and have 
the laboratory specimen collection performed at his or her local doctor’s office or 
designated laboratory collection center.  The subject must also be contacted via 
telephone at the visit timepoint to assess AEs, review concomitant medications, 
and assess investigational product compliance;  
− If all other options for the collection of the Month 1 and Month 2 laboratory 
samples have been exhausted, the use of a local laboratory for the Month 1 
samples would be accepted for this visit; although, any laboratory data obtained 
from a local laboratory will not be captured in the eCRF or included in the study 
analysis.  A copy of the local laboratory report would need to be provided to the 
Investigator for review and available in the source records.  The Investigator 
should contact the Medical Monitor as soon as possible to discuss any local 
laboratory values that may be of clinical concern.  The subject must also be 
contacted via telephone at the visit timepoint to assess AEs, review concomitant 
medications, and assess investigational product compliance;  
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− A physical examination should be performed at the Month 3 visit if an onsite 
Month 1 or Month 2 visit was not performed. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
Month 3 Procedures 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm  
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record AEs. 
• Review and record prior and concomitant medications. 
• 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests.  
• Obtain blood samples for: 
− OCA, C4, and FGF-19 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− NOT to take investigational product on the morning of the next visit, and  
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− 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. 
Post-Titration Visit Procedures 
• Perform a physical examination.  
• Assess and record AEs. 
• Review and record prior and concomitant medications 
• Assess investigational product compliance, perform investigational product 
accountability, and review dosing diary with the subject. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm  
• Provide the subject with a dosing diary to document his or her dosing. 
• In the event it is not feasible for the subject to return the site for the above referenced 
procedures, the following alternative visit procedures are available, to help ensure 
compliance with the Post-Titration laboratory requirements: 
− At the Up-titration Visit, the subject can be provided with the central laboratory 
collection kit and shipping materials associated with the Post-Titration Visit, and 
have the laboratory specimen collection performed at his or her local doctor’s 
office or designated laboratory collection center.  The subject must also be 
contacted via telephone at the Post-Titration Visit timepoint to assess AEs, review 
concomitant medications, and assess investigational product compliance;  
− If all other options for the collection of the Post-Titration laboratory samples have 
been exhausted, the use of a local laboratory for the Post-Titration samples would 
be accepted for this visit; although, any laboratory data obtained from a local 
laboratory will not be captured in the eCRF or included in the study analysis.  A 
copy of the local laboratory report would need to be provided to the Investigator 
for review and available in the source records.  The Investigator should contact 
the Medical Monitor as soon as possible to discuss any local laboratory values 
that may be of clinical concern.  The subject must also be contacted via telephone 
at the Post-Titration Visit timepoint to assess AEs, review concomitant 
medications, and assess investigational product compliance;  
− A physical examination should be performed at the next scheduled visit if an 
onsite Post-Titration Visit was not performed 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
- NOT to take investigational product on the morning of the next visit, and  
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- 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. 
Month 6 Procedures  
• Perform a physical examination. 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.5) 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record prior and concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
• Provide the subject with a dosing diary to document his or her dosing. 
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• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
• For subjects who will participate in the PK assessment and are taking BAS or 
aluminum hydroxide- or smectite-containing antacids, they should be instructed to 
not take their regular dose on the morning of the study visit.   
9.7.9. 
Month 9 Procedures 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record AEs. 
• Review and record prior and concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• PK assessment in participating subjects at select study sites (see Section 9.7.10). 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− NOT to take investigational product on the morning of the next visit, and  
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− 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. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic Assessment 
At selected investigational sites, subjects will have the option to consent to participate in an 
additional OCA PK assessment.  PK samples will be used to support further analysis of OCA 
exposure-response in subjects with PBC.  This is optional and subjects may decline to participate 
without affecting their involvement in the rest of the study.  Consent to participate in the 
assessment can be given at any point during study participation prior to the Month 9 visit.  
Subjects who are following the Child-Pugh B and Child-Pugh C modified dosing regimen may 
participate in the PK assessment and will dose in the clinic at this visit even if the previous dose 
was taken less than 3 days prior; however, every attempt should be made to schedule the 
Month 9 PK visit according to the subject’s established dosing schedule. 
Following collection of the Month 9 fasted samples (refer to Section 9.7.9, subjects who are 
participating in the PK assessment will each receive a single dose of investigational product 
(blinded OCA or placebo tablet) with approximately 240 mL of water.  Subjects taking BAS or 
aluminum hydroxide- or smectite-containing antacids should be instructed to stagger their dosing 
of investigative product and UDCA, ensuring at least 4 hours between doses of the BAS and/or 
these antacids and the investigative product (and UDCA).   
Serial blood samples will be obtained for measurement of OCA and its conjugates prior to 
dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours post dose.  Samples should be collected 
within a window of ±5 minutes of the scheduled sample time.  Subjects should not drink 
additional water for 1 hour after taking the dose of investigational product and will remain fasted 
until the 4-hour sample is collected.  Lunch will be provided following collection of the 4 hour 
PK sample; the lunch will be a meal replacement drink with no other food allowed until after the 
final 6-hour post-dose sample is collected.  Samples will be stored for up to 5 years after the end 
of the study and will be destroyed after 5 years if not analyzed. 
9.7.11. 
Month 12 Procedures 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Perform assessments for calculation of Child-Pugh Score 
• Review progression to cirrhosis algorithm  
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Quality of Life and Subject questionnaires and (see Section 11.1.2.2 
and Section 12.2.5). 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
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• Perform an endoscopy (at all study sites, where device is available) to assess the 
presence or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record prior and concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for: 
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
Month 3 and Month 9 Continued Follow-Up Procedures (±2 weeks) 
• Perform assessments for calculation of Child-Pugh Score. 
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• Review progression to cirrhosis algorithm  
• Assess and record AEs. 
• Review and record prior and concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
9.7.13. 
Month 6 Continued Follow-Up Procedures (Semi-annually [±2 weeks]) 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm  
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate 
and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.5) 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
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• Review and record prior and concomitant medications 
• Review and record any nonstudy 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 (refer to Section 7.4). 
• Assess investigational product compliance, perform accountability, and review dosing 
diary with the subject. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− Markers of hepatic fibrosis and/or inflammation (including ELF). 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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 
9.7.14. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.5). 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
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• Perform an endoscopy (at all study sites, where device is available) to assess the 
presence or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record prior and concomitant medications 
• Review and record any nonstudy 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 (refer to Section 7.4). 
• Assess investigational product compliance, perform accountability, and review dosing 
diary with the subject. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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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9.7.15. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent 
Subjects that discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects discontinue treatment with investigational 
product.  The EOT visit and procedures listed below must be performed as close as possible to 
the subject’s last dose of investigational product.  When a subject discontinues investigational 
product but continues with regularly scheduled study visits, the EOS visit will be completed later 
in the study as the subject’s final study visit.  The actual investigational product discontinuation 
scenario (Table 8) will determine the sequence of the EOT and EOS visits and procedures.  In 
some cases, the EOT visit and procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible to the subject’s last dose of 
investigational product.   
When a subject ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (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 subject 
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 and EOS procedures in the CRF.  
Table 8: 
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 IP 
Treatment 
Discontinuationb 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
Discontinued 
Semiannual 
contactc 
Telephone 
contact every 6 
months (±2 
weeks) 
Combined Visit, Completed as 
close as possible to last dose IP 
Discontinued 
Record review 
onlyc 
Record review 
only 
Combined visit 
Completed as close as possible 
to last dose IP 
Sponsor 
Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit 
Completed as close as possible 
to last dose IP 
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Table 8: 
Early Discontinuation Scenarios (Continued) 
 
Investigational 
Product 
Consent 
Study Visit 
Status 
EOT Visita 
EOS Visita 
Pregnancy 
Interrupted 
Retained 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
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; IP = investigational product 
a Refer to Section 7.1.2 Schedule of Study Procedures, Table 2 for all procedures and evaluations required at the 
End of Treatment and End of Study Visits.  
b   Includes initiation of commercially available OCA. 
c Outcomes data to be discussed or collected include data related to adjudicated hepatic and cardiovascular event-
related data.  Additional data such as information on concurrent medical conditions, co-morbidities, relevant 
adverse events, and concomitant medications may be collected to help facilitate adjudication of these post-study 
events.   
Some assessments noted below may be omitted if they have been completed within the 6 months 
(or the timeframe otherwise specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT/EOS Visit: 
If possible to do before the visit, when scheduling the EOT/EOS visit, reiterate dosing 
instructions and advise the subject: 
• If applicable, NOT to take investigational product on the morning of the next visit, 
and  
• To bring the investigational product bottle(s); if applicable, s/he will dose at the 
clinic, 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. 
During the EOT/EOS Visit: 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Review progression to cirrhosis algorithm  
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead ECG. 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.5). 
• Perform TE at all study sites with access to the Fibroscan® TE device (not required at 
EOT/EOS if done within 6 months). 
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• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites); not required at 
EOT/EOS if done within 6 months. 
• Assess and record AEs; all ongoing “related” AEs must be followed until stable or 
resolved. 
• Review and record concomitant medications. 
• Review and record any nonstudy 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 accountability, and review dosing 
diary with the subject; retrieve used bottles, accordingly, and document returns. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
9.7.16. 
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.   
In the event of an inexplicable and acute (for example not explained by natural progression of the 
chronic disease) increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
or total bilirubin is observed during the course of the study, refer to Section 7.5 to confirm 
whether an unscheduled safety visit is required. 
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 5 mg or 10 mg OCA 
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 subject at each visit to provide enough tablets for daily 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 trial sites in support of clinical study 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 Preparation 
The investigational product will be provided to the distribution center in bulk bottles and 
therefore may be repackaged in unit dose form for administration to subjects before shipping to 
the sites. 
10.5. 
Investigational Product Administration 
Refer to Section 9.1. 
10.6. 
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 
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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 subject 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. 
11. 
ASSESSMENT OF EFFICACY  
11.1. 
Assessment of Efficacy  
11.1.1. 
Primary Assessments 
The following primary efficacy assessments will be measured: 
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• 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 or greater) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
11.1.2. 
Secondary Assessments 
The following secondary efficacy assessments will be measured: 
• Individual components of the primary endpoint 
• Liver-related death 
• Progression to cirrhosis as assessed by the presence of clinical, laboratory, or 
radiological evidence of cirrhosis and/or liver stiffness (Fibroscan® TE), confirmed 
by biopsy unless not medically indicated.  
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− Histological assessment of disease progression or improvement using paired 
biopsies in a subset of subjects (defined in Addendum 2). 
• HCC confirmed by 2 complimentary imaging modalities, unless confirmed by biopsy. 
• Liver biochemistry (see Table 12 for list of analytes to be tested) 
• Biomarkers, including other markers of hepatic fibrosis and/or inflammation, to be 
tested will include:  IgM, c-reactive protein (CRP), tumor necrosis factor-α (TNF-α), 
FGF-19, cytokeratin-18 (CK-18) ELF, and Fibroscan (and others as determined 
during the course of the study). 
• Clinical outcomes, including individual component of the primary endpoint (where 
available), liver transplant, and death will be compared to historical controls. 
• PK of OCA and its conjugates. 
• Data will be collected to inform quality of life and cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Quality of life will be 
assessed by questionnaires (PBC-40, EQ-5D-5L, and FIS) administered annually.  
Resource utilization information will be collected from the Medical and Surgical 
Treatment Procedures and Office Visit Log or other CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician visits (subject reported), 
and use of concomitant medications.  
• Endoscopy will be conducted at all study sites where the device is available to assess 
for the presence of oesophageal varix/varices at baseline.  Throughout the study, any 
endoscopy performed as part of the annual study assessments or standard of care will 
be collected in the case report form to assess for the development of varix/varices. 
11.1.2.1. Noninvasive Assessments of Liver Fibrosis 
• Blood samples for measurement of ELF test and other analytes will be collected.  The 
ELF test assesses: hyaluronic acid (HA), procollagen-3 N-terminal peptide (P3NP), 
and a tissue inhibitor of metalloproteinase 1 (TIMP-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.   
11.1.2.2. Other Secondary Assessments 
• OCA (OCA, tauro-OCA, glyco-OCA, total OCA, OCA-glucuronide) and C4 will be 
assayed to determine bioanalytical concentrations.  Additional analyses may include 
other conjugates or metabolites not yet identified.   
• Quality of Life questionnaires. 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: 
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− 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 (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 respondent’s self-rate 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). 
− Fatigue Impact Scale (FIS):  The FIS is a validated 40 question questionnaire 
organized into 3 dimensions:  cognitive, physical, and social.  Each dimension has 
5 levels:  no problem, small problem, moderate problem, big problem, and 
extreme problem (Fisk 1994). 
11.1.2.3. Other Exploratory Evaluations 
• A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved 
in PBC will be conducted for subjects and at study sites willing to provide samples at 
Day 0, Month 12, and every other year at the yearly visits thereafter.  RNA 
expression resulting from treatment with OCA will be assessed at indicated 
timepoints during the study.   Subjects will be permitted to decline to provide a blood 
sample for the genetics study, without affecting their involvement in the study.  
IRB/IEC review and approval will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will be stored for up to 1 year 
after the end of the study and destroyed after 1 year if not analyzed. 
11.1.2.4. Potential Clinical Outcome Events 
The events listed in Section 12.1.6 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 13.4) 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 suspected 
unexpected serious adverse reaction (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 13.4. 
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12. 
ASSESSMENT OF SAFETY 
12.1. 
Adverse Events and Serious Adverse Events 
12.1.1. 
Definitions of Adverse Events 
12.1.1.1. Adverse Event  
An AE is 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) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction.  For reporting purposes, pregnancy is not 
considered an AE. 
Subjects should be questioned in a general way, without leading the subject 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. 
Subjects 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 whites of eyes, and bruising easily. 
12.1.1.2. 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-subject hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Results in a congenital abnormality or birth defect. 
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• Is an important medical event that may jeopardize the subject 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. 
12.1.1.3. Treatment-Emergent Adverse Event  
A treatment-emergent AE (TEAE) is any event not present prior to the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
12.1.1.4. Adverse Events of Special Interest 
The following decompensation events are adverse events of special interest.  A subset of these 
events are also individual components of the primary endpoint (Section 11.1.1).   
• 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, 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 
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− 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 
12.1.2. 
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/serious adverse event (SAE) and the investigational product is 
determined to be “possible” or “probable” 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 subject’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 
A reaction 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 subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
12.1.3. 
Relationship of Adverse Events to Liver Biopsy 
The Investigator will document her/his opinion of the relationship of an AE to liver biopsy using 
the criteria outlined in Table 10.  
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Table 10: 
Relationship of Adverse Events to Liver Biopsy 
Relationship 
Description 
Related 
A reaction that follows a reasonable temporal sequence from the liver biopsy; that follows 
a known or expected response pattern to the liver biopsy. 
Not Related 
Any event that does not meet the above criteria. 
12.1.4. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 11, must be entered on the AE CRF.  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 11: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Causing no limitation of usual activities; the subject may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the subject may experience annoying 
discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the subject may experience intolerable 
discomfort or pain. 
12.1.5. 
Reporting of Adverse Events and Serious Adverse Events 
12.1.5.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
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 subject’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.  
In addition, the Investigator should contact the study Medical Monitor upon awareness when any 
signs or symptoms of hepatic decompensation are observed in any subject. 
12.1.5.2. 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).   
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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 be reported by: 
• E-mail to the SAE email address:  sae@interceptpharma.com 
• Fax using a paper SAE report form:  +1 800 497 8521 
If an SAE is reported by email 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:   
• Subject 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 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 +1 800 497 8521 or 
emailed to sae@interceptpharma.com as soon as possible.  Redacted medical record source 
documentation will be requested for all SAEs and emergency room visits. 
The Investigator is responsible for submitting information on 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 IECs/IRBs must be retained in the appropriate study file(s).  
As instructed by the Sponsor, 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 12.1.6.  
12.1.6. 
Suspected Liver-Related Clinical Outcome Events 
Specified liver-related clinical outcome events may, by definition qualify as SAEs (see 
Section 12.1.1.2).  The Sponsor must be notified of any SAEs within 24 hours of the site 
becoming aware of the event (see Section 12.1.5.2).  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. 
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Given that the liver-related clinical outcome events may also meet the criteria of a SUSAR, but 
are considered in aggregate as part of the primary endpoint and the DMC reviews of all safety 
and efficacy data approximately quarterly, the Sponsor will not expeditiously report suspected 
liver-related 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 “study event” on the AE 
CRF and will be submitted for adjudication to the Hepatic Outcomes Committee as described in 
Section 13.4. 
The Sponsor will consider the following list of clinical outcome events (MedDRA preferred 
terms) to be disease related and exempt from expeditious regulatory reporting, but will continue 
to report them in a nonexpeditious 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 or oesophageal varices haemorrhage), hepatic encephalopathy (preferred term: 
hepatic encephalopathy),  spontaneous bacterial peritonitis (preferred term: peritonitis bacterial), 
ascites (preferred term: ascites), and histological or clinical progression to cirrhosis (preferred 
term: hepatic cirrhosis). 
12.1.7. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the CRF 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 subject’s AE CRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the Medical Monitor, 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 subject 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. 
12.1.8. 
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 12.1.5.2. 
SAEs that occur in subjects 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 12.1.5.2.  
12.1.9. 
Notification of Poststudy 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 12.1.5.2. 
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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 12.1.5.2. 
12.1.10. 
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 subject 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 subject 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. 
Drug-Induced Liver Injury or Disease Progression 
All subjects 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 from drug-induced liver injury 
follow-up 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 
At the time of consent for new subjects (or re-consent to the protocol amendments for ongoing 
subjects), subjects will 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.  Subjects will 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 will be instructed to 
promptly bring subjects 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 will 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. 
12.1.11. 
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 7.6 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 sae@interceptpharma.com or faxed to +1 800 497 8521.   The 
subject and neonate must be followed for outcome information and/or as considered appropriate 
by the Investigator and Sponsor. 
The subject 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 subject must have a negative pregnancy test before restarting investigational product.  If a 
subject’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 12.1.5 must also be followed. 
12.2. 
Other Safety Parameters 
12.2.1. 
Medical History/Demographics 
A complete medical history and PBC disease-specific history will be obtained from the subject at 
Screening.  Smoking and alcohol consumption history and current habits will be recorded.  
Demographic characteristics (age, gender, race, and ethnicity) will be recorded. 
12.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the timepoints specified in the Schedule of Study Procedures (Section 7.1.2).  A basic physical 
examination should be performed, including all body systems pertinent to the subject.  Any 
clinically significant abnormality should be reported on the AE CRF page for findings that 
appear after consent, and on the medical history CRF for any finding present prior to consent.  
Information about smoking and alcohol consumption habits will be collected at the same 
(follow-up) timepoints as the physical exam. 
12.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits: height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure.  When taking heart rate, respiratory rate, and blood 
pressure readings, subjects should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
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12.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected at the Screening Visit 1, Month 12, and at EOT/EOS.  
The Investigator or designee will review the 12-lead ECG and findings will be recorded in the 
CRF as normal, abnormal but not clinically significant, or abnormal and clinically significant.  
Any clinically significant abnormality on ECGs should be reported on the AE CRF page.  
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 subject’s initials, Subject ID number, 
date, and time. 
12.2.5. 
Subject Questionnaires 
Information about the subject’s PBC disease history (ie, date of diagnosis, treatment history, 
pruritus history, signs and symptoms, and including smoking history) will be collected during 
Screening.  At subsequent study visits (see Section 7.1.2), subjects will be asked to complete the 
following questionnaires; they may be asked to initial and date to document confirmation of their 
responses, and the questionnaires should be filed in the subject’s study records.  These may 
require transcription to the CRF by study site staff. 
• 5-D Pruritus Questionnaire:  This is a questionnaire that has been validated in several 
different diseases.  It assesses symptoms in terms of 5 domains: degree, duration, 
direction, disability and distribution (Elman 2010). 
• Pruritus VAS:  A Visual Analogue Scale (VAS) will also be used to assess pruritus in 
individual subjects. 
12.2.6. 
Laboratory Assessments 
Subjects will be instructed to attend any study or unscheduled laboratory visits (except 
Screening) in a fasted state, and subjects should remain fasted until their blood samples have 
been collected.  At each visit, the Investigator or designee will verify that the subject has fasted 
for at least 8 hours and record fasting status in the source and CRF.  If the subject reports having 
eaten (water is permitted) within 8 hours, the Investigator or designee will document accordingly 
in the source and CRF and remind the subject that fasting is required prior to all study visits. 
Blood samples for serum chemistry and hematology will be collected at every visit as detailed in 
the Schedule of Study Procedures (Section 7.1.2).  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 by the central clinical laboratory in a study specific laboratory 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 subjects 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 12, and the normal reference ranges 
for liver biochemistries are shown in Appendix C. 
Table 12: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry  
Albumin, blood urea nitrogen (BUN), 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 very low-density 
lipoprotein [VLDL] fractions and triglycerides[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 
Prothrombin time (PT), partial thromboplastin time 
(PTT), international normalized ratio (INR) 
Urinalysis 
pH, specific gravity, total protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, 
albumin, creatine, leucocytes, nitrates, 
albumin/creatine ratio (if positive) 
Markers of Cholecystitis and Pancreatitis 
amylase and lipase 
Biomarkers of Hepatic Fibrosis and/or Inflammation  
IgM, C-reactive protein (CRP), TNF-α, FGF-19, CK-
18, ELF, and others as determined during course of 
study  
Genetics 
DNA including single-nucleotide polymorphisms 
(SNPs) that may be involved in PBC; RNA 
Other 
OCA (parent and conjugates [glyco and tauro], 
OCA-glucuronide) and C4 
The Investigator should manage subjects with clinically significant lipoprotein abnormalities 
using local standard of care procedures as appropriate after assessing the individual subject’s 
total cardiovascular risk profile. 
Urine-based β-hCG pregnancy tests will be performed in female subjects of childbearing 
potential per protocol specified visits.  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 
subject will be followed, as outlined in Section 12.1.11 through pregnancy outcome. 
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MELD scores and Child-Pugh score will be calculated at screening, and at all visits based on 
serum chemistry and coagulation. 
13. 
STATISTICAL METHODS 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
hypothesis tests, will be prepared and approved by the Sponsor and its designees prior to the first 
interim analysis, propensity score determination, and unblinding of the double-blind subject 
treatment assignments. 
13.1. 
Efficacy Analysis 
13.1.1. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
• The Intent-to-Treat (ITT) Population will include all randomized subjects who 
receive any amount of investigational product (OCA or placebo).  The ITT 
Population will be the primary population used for efficacy analyses.  Treatment 
assignment will be based on the randomized treatment. 
• The Per Protocol (PP) Population will include all ITT subjects who do not have any 
major protocol violations that potentially affect the efficacy conclusion.  Treatment 
assignment will be based on the randomized treatment. 
• The Safety Population will include all subjects who received any amount of 
investigational product (placebo or OCA).  The Safety Population will be the primary 
population used for safety analyses.  Treatment assignment will be based on the 
treatment actually received. 
• The PK Population will include all OCA subjects who have at least one confirmed 
fasted analyzable sample.  Subjects must have been fasting for approximately 8 hours 
prior to the visit and must not have any major protocol deviations that potentially 
affect exposure levels.  The PK population will be used for OCA PK analyses.  
• The Overall Historical Control Population will include subjects from the United 
Kingdom (UK) -PBC Group and Global PBC Study Group databases with 
demonstrated comparability to randomized subjects in this clinical study (747-302) 
with respect to both subject characteristics and disease progression. 
• The UK-PBC Historical Control Population will include subjects from the UK-PBC 
Group databases with demonstrated comparability to randomized subjects in this 
clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
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• The Global PBC Historical Control Population will include subjects from the Global 
PBC Study Group database with demonstrated comparability to randomized subjects 
in this clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
13.1.1.1. Comparability of Historical Controls 
Utilization of both historical control/observational databases (UK-PBC and Global PBC Study 
Group), with more than 6000 subjects each, allow for a rigorous subject level meta-analysis.  The 
historical databases include long-term follow up, detailed subject-level information such as 
baseline clinical characteristics, longitudinal liver biochemistry, and long-term outcomes, and 
span a broad range of subject characteristics that may influence disease (disease state, age, 
gender, and regional differences in standard of care).  Historical controls from both databases 
will be chosen based on the same study inclusion/exclusion criteria.  Propensity score matching 
method will be utilized to select historical controls that match the treated subjects using available 
covariates. The adequacy of matching will be assessed by statistical methods described under 
Section 13.1.8.  
13.1.2. 
Determination of Sample Size 
The target population is subjects who are at higher risk of liver-related clinical complications. 
Eligible subjects will have a diagnosis of PBC with bilirubin levels >ULN and ≤5x ULN and/or 
ALP >3× ULN.  The following assumptions were used in sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.6 at 8 years with a hazard 
ratio of 0.60, and total study duration of 10 years (from first subject enrolled), 
allowing for 4 years of subject accrual and 6 years of follow up. 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance. 
• Two interim analyses and one final analysis are planned.  The first interim analysis 
will be performed when 50% of the target events are accrued and the second interim 
will be performed when 75% of the target events are accrued.  
• A dropout rate of 10% is assumed 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
13.1.2.1. Sample Size Monitoring 
Conducting a long-term outcomes study given the low disease prevalence, relatively slow 
disease progression, and ethical considerations, which in combination will impact recruitment 
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and event rates, is inherently difficult.  As stated in ICH E9, in long-term trials there is an 
opportunity to check the assumptions that underlay the original design and sample size 
calculations.  The power stated above depends on the total number of events.  Thus, the overall 
survival function can be estimated without unblinding. 
Therefore, the aggregate event rate and sample size based on recruitment and retention will be 
evaluated quarterly in a blinded manner.  This evaluation will determine if any increases in 
number of subjects are required in order to obtain a total of 127 adjudicated events for the final 
analysis in the combined groups.  Specifically, the pooled number of events will be available 
during the study in a blinded manner, without any knowledge of the comparative efficacy in the 
treatment groups.  This method for evaluating the sample size does not inflate the type I error 
rate.  Additional subjects may be enrolled as appropriate. 
13.1.3. 
Primary Efficacy Analysis 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
• Liver transplant 
• MELD score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
The primary efficacy analysis will compare OCA to placebo with respect to the primary efficacy 
endpoint using the ITT population.  Only adjudicated events will be included in analyses.  The 
2 treatment groups will be compared 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 determined based on a Cox regression model stratified by 
randomization strata to estimate the magnitude of the effect.  The same analyses for primary 
efficacy endpoints will be performed for PP population as a sensitivity analysis.  
13.1.4. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints will compare OCA to placebo on the following: 
• Time to first occurrence of MELD score ≥15 
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• Time to liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare OCA to placebo in the ITT population with 
respect to the key secondary efficacy endpoints.  Only adjudicated events will be included in 
time-to-event analyses.  The comparison (hypothesis testing) will be conducted as specified in 
Section 13.1.10 in a sequential closed testing gate-keeping procedure, provided that the primary 
efficacy endpoint comparison is statistically significant in favor of the OCA treatment group.  If 
the primary comparison is not statistically significant then comparison of the secondary 
endpoints will be considered as descriptive and exploratory.  This procedure controls the study-
wise type I error. 
The 2 treatment groups will be compared using the same methodology as specified for the 
primary efficacy analysis (Section 13.1.3).  The same analyses for key secondary efficacy 
endpoints will be performed for PP population as a sensitivity analysis. 
Analyses of change from Baseline to end of study in ALP and total bilirubin will be compared 
between treatment groups using analysis of covariance (ANCOVA) with change from Baseline 
as the dependent variable including treatment group and randomization stratification factor as 
fixed effects and the Baseline values as a covariate.  The same analysis will be carried out using 
percentage change from Baseline as the dependent variable. 
Descriptive statistics of the laboratory values will be summarized by treatment group.  The 
results, change from Baseline, and percentage change from Baseline values as well as estimates 
of least-square means, standard errors, and 95% CIs will be presented by treatment group.  
Estimates of the mean difference between treatment groups, the standard error of the difference, 
and 95% CI of the difference will be presented.  
13.1.5. 
Additional Secondary Efficacy Analyses 
The following time-to-event secondary efficacy analyses will compare OCA versus placebo 
using the ITT population: 
• Time to each component of the primary efficacy endpoint (except MELD score ≥15 
which is captured above) 
• Time to development of varix/varices 
• Progression to cirrhosis 
• Time to occurrence of HCC 
• Time to liver-related death 
• Time to liver-related death or liver transplant 
• Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls as described below in Section 13.1.8. 
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Analyses of changes in liver biochemistry (GGT, ALT, AST, conjugated bilirubin, albumin, and 
INR) will be summarized and analyzed using the same methodology as specified in 
Section 13.1.4 for the key secondary analyses of change in ALP and total bilirubin. 
Progression to cirrhosis will be assessed in the subset of subjects considered noncirrhotic at 
Baseline using available medical history, clinical, and laboratory assessments as well as baseline 
TE, where available.  Specifically, subjects with no clinical, laboratory, or radiological evidence 
of cirrhosis at baseline and/or a TE liver stiffness of <16.9 kPa (Corpechot 2012) will be 
considered noncirrhotic (See Section 7.5.4).  Progression to cirrhosis will be assessed by the 
development of clinical, laboratory, or radiological evidence of cirrhosis and/or when liver 
stiffness increases to ≥16.9 kPa during the study in which case histological progression to 
cirrhosis should be confirmed by biopsy unless not medically indicated. Using this definition for 
progression to cirrhosis, the percentage of noncirrhotic subjects progressing to cirrhosis during 
the treatment period will be summarized by treatment group and compared using a 
Cochran-Mantel-Haenszel test stratified by the randomization stratification factor.  
For those subjects enrolled in the biopsy substudy (defined in Addendum 2) progression to 
cirrhosis identified by the above criteria and improvement in fibrosis/cirrhosis will be confirmed 
by paired biopsy.  Analyses for the histological assessment conducted as part of the biopsy 
substudy are defined in Addendum 2). 
Analyses of changes in MELD score, Child-Pugh score, MRS, IgM, CRP, TNF-α, FGF-19, 
CK-18, C4, and ELF score will be summarized and analyzed using the Wilcoxon Rank Sum Test 
to compare treatment groups.  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. 
13.1.5.1. Association of Biochemistry with Clinical Outcomes and Clinical Benefit  
The association between biochemistry including ALP and bilirubin with clinical outcomes will 
be assessed and the clinical benefit of OCA using biochemistry as a surrogate endpoint will be 
evaluated.  Detailed analysis will be described in the SAP.  
Based on the association between biochemical changes and clinical outcomes described above, 
clinical benefit of OCA using biochemistry as a surrogate endpoint for key subpopulations of 
interest will be evaluated. This analysis will be further described in the SAP. 
13.1.6. 
Exploratory Efficacy Analyses 
13.1.6.1. Responder Analyses 
The percentage of subjects with a decrease in ALP of ≥15% and ≥40% from Baseline will be 
summarized by treatment group.  In addition, the percentage of subjects with ALP ≤ULN will be 
summarized by treatment group. 
The percentage of subjects that meet the criteria of a responder based on each of the definitions 
below will be summarized by treatment group.  The response classification at baseline will also 
be included in the summary:  
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• ALP ≤3x ULN and AST ≤2x ULN and total bilirubin ≤ULN (Corpechot 2008) 
• ALP ≤1.5x ULN and AST ≤1.5x ULN and total bilirubin ≤ULN (Corpechot 2011) 
• ALP ≤1.67x ULN and total bilirubin ≤ULN (Momah 2012) 
• Normal bilirubin (values ≤ULN) and normal albumin (values ≥lower limit of normal) 
(Kuiper 2009) 
• ALP ≤1.76x ULN (Kumagi 2010) 
Responder analyses will compare treatment groups using a Cochran–Mantel–Haenszel test 
stratified by the randomization stratification factor.  Missing values will be considered as a 
non-responder.   
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints 
Sufficient data will be collected on resource utilization and quality of life to undertake 
cost-effectiveness analyses that are relevant to the major countries taking part in this study.  
Resource utilization data on hospitalizations, healthcare provider visits, and medications will be 
combined with appropriate national unit costs to calculate a cost per patient per year in the study. 
Quality of life data from patient-reported outcomes measures will be combined with survival 
data to calculate quality adjusted time in the study per patient.  Cost-effectiveness analyses will 
report the incremental cost per major clinical outcome averted, liver-related death averted, 
life-year gained and quality-adjusted life year gained, including OCA as part of usual care versus 
usual care without OCA.  Analyses will be conducted within the study and using a lifetime 
perspective.  A separate economic analysis plan will be prepared and reported separately from 
this protocol. 
13.1.8. 
Supportive Analysis 
Per the International Conference on Harmonisation (ICH) E10 guidance, “where no obvious 
single optimal external control exists, it may be advisable to study multiple external controls”.  
In order to address the risks associated with the inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare clinical outcomes in the OCA treatment arm to 
historical controls, which serves as an external control for supportive analysis.   
In an attempt to avoid the inherent biases with historical controls and to maintain the integrity of 
this comparison, one can invoke matching methods to optimize comparability and find a 
historical control that is “similar” to a participating subject.  The historical database control 
should be as similar as possible to the study population and should have been exposed to a 
similar standard of care (see Section 5.5.2.3). 
A propensity score can be used to reduce bias through matching, stratification, regression 
adjustment, or some combination.  Propensity scores use information from a pool of patients who 
do not participate in the study (historical controls) to identify what would have happened to 
participating subjects in the absence of the treatment.  By comparing how outcomes differ for 
treated subjects relative to historical controls, it is possible to estimate the effects of the treatment 
between the treated subjects and the matched natural history subjects. 
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A full range of covariates across which the treatment and historical controls might differ will be 
considered to mitigate potential bias. Although the results of using matching controls are 
conditional only on the observed covariates, if one has the ability to measure many of the 
covariates that are believed to be related to the treatment assignment, then one can be fairly 
confident that approximately unbiased estimates for the treatment effect can be obtained.  Both 
UK-PBC Group and the Global PBC Study Group formally collect numerous covariates that 
could be used for propensity score estimation including standard of care, eg, UDCA. 
Historical controls will be chosen based on the same inclusion/exclusion criteria where possible. 
Propensity scores will be estimated using the available covariates that predict receiving the 
treatment.  Only covariates and not outcome variables will be included in the propensity score 
estimation, to avoid biased results that are in favor of one treatment.  
The covariates and factors collected in the historical databases will be specified in the SAP. 
Propensity scores will be estimated first through a logistic regression model with treatment group 
as the dependent variable and the above covariates/factors as independent variables.  Then the 
stratum boundaries are determined based on the propensity score values for both groups (OCA 
population and control [historical and randomized placebo]) combined or in the OCA population 
or historical control group alone.  Based on recommendations in the literature, quintiles of the 
estimated propensity score from the combined group will be used to determine the stratum 
boundary cut-offs for the different strata.  
The baseline characteristics between treated and natural history subjects in the matched dataset 
will be summarized and presented in a tabular format.  Statistical methods such as Wilcoxon 
Rank-Sum test will be used to assess the balance for baseline covariates.  The standardized 
difference and variance ratios for these covariates will also be calculated.  In addition, box plots 
of propensity scores for treated and natural history subjects will be separately presented, to 
further assess the adequacy of matching.  
A third-party statistician(s) will perform the propensity score modeling and matching.  This 
third-party statistician(s) will be separate and independent from the statistician(s) who will assess 
the success of matching and perform efficacy analyses.  Outcome events collected in the 
historical database are:  death (liver-related and all-cause), liver transplant, HCC, and other.  
Other is defined as cirrhosis or decompensation such as ascites, variceal bleed, and 
encephalopathy. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare randomized OCA-treated subjects in the ITT population and historical 
controls (Overall Historical Control Population: both the UK-PBC Group and Global PBC Study 
Group databases) on the following outcomes: 
• Time to death (all-cause) 
• Time to liver-related death 
• Time to liver transplant 
• Time to liver transplant or death (all-cause) 
• Time to liver transplant or liver-related death 
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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 determined based on a Cox regression 
model stratified by randomization strata to estimate the magnitude of the effect. 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
Although the study is designed as a placebo-controlled study, the DMC may recommend changes 
to study conduct based on the pre-specified interim analyses (see Section 13.1.12), including the 
potential use of a revised primary efficacy analysis.  This analysis would compare all subjects in 
the OCA population, to all control subjects (randomized placebo and historical controls) on time 
to liver transplant or death (all-cause), using similar statistical methodology as specified above. 
Notably, the planned primary analysis would not be revised without prior agreement with 
regulatory authorities. 
13.1.9. 
Handling of Dropouts or Missing Data 
Subjects who discontinue investigational product are expected to continue in the study until 
study termination. 
Missing data will be assumed to be missing at random.  In order to determine the effect of 
missing data on the analysis, efficacy endpoints will be analyzed using different methods of 
imputation as described below. In addition, the same analyses for primary and key secondary 
endpoints based on ITT and PP populations will be performed to assess robustness of analysis 
results.  During the conduct of the study, the DMC may recommend refining the missing data 
strategy to better address the observed pattern of missing data, based on blinded monitoring of 
the data. 
13.1.9.1. Time to Event Endpoints 
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 investigational product dosing). 
For analyses of the percentage of subjects with an event, subjects with no data after 
randomization will be considered to have an event. 
All time to event endpoints include only adjudicated events.  Sensitivity analyses may consider 
all events regardless of adjudication.  Events with discrepant adjudication will be analyzed using 
both results. 
13.1.9.2. Quantitative Endpoints 
For efficacy endpoints that utilize an ANCOVA model, observed cases will serve as the primary 
analysis.  Sensitivity analyses to assess the effect of missing data may be conducted where 
missing data is imputed using last observation carried forward. 
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Sensitivity analyses of ANCOVA models will also be evaluated using a restricted maximum 
likelihood based mixed-effect repeated measures model where no imputations will be made for 
missing values.   
13.1.9.3. Responder Endpoints 
In an efficacy analysis in which subjects are classified as either a responder or a non-responder 
(binary outcome) based on dichotomizing a continuous variable, any subject who does not 
provide an assessment at the specified timepoint for the defining of response will be considered 
to be a non-responder.  That is, for the percentage of responders, the subject will be included in 
the denominator and will not contribute to the numerator. 
For sensitivity analyses using only “observed cases,” subjects who do not provide an assessment 
at the specified timepoint for the defining of response will not be included.  That is, for the 
percentage of responders, the subject will not be included in the numerator or the denominator. 
13.1.10. 
Multiple Comparisons/Multiplicity 
The key secondary efficacy endpoints are as follows: 
• Time to MELD score ≥15 
• Time to first occurrence of liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The hypothesis testing of key secondary analyses will compare placebo and OCA and will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of OCA.  If the primary comparison is not statistically significant 
then comparison of the secondary endpoints will be considered as descriptive and exploratory.  
This procedure controls the study-wise type I error.  
• First (step 1) placebo and OCA will be compared with respect to the primary efficacy 
endpoint.  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• The time to MELD score ≥15 will be compared between placebo and OCA (step 2).  
If the comparison achieves statistical significance at 2-sided 0.05 level in favor of 
OCA group, then 
• The time to liver transplant or death (all-cause) will be compared between placebo 
and OCA (step 3).  If the comparison achieves statistical significance at 2-sided 
0.05 level in favor of OCA group, then 
• Change from Baseline in total bilirubin will be compared between placebo and OCA 
(step 4).  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• Change from Baseline in ALP at the end of study will be compared between placebo 
and OCA (step 5). 
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If at any step defined above the comparison is not statistically significant at the 2-sided 
0.05 level then the remaining comparisons in the stated hierarchy will be considered descriptive 
and exploratory.  The study-wise type I error will be maintained with the above closed 
procedure. 
Additional efficacy endpoints will be analyzed; however, hypothesis tests will be applied for 
descriptive and exploratory purposes only.  
13.1.11. 
Examination of Subgroups 
The primary and secondary efficacy endpoints will be analyzed for subject subgroups based on 
the ITT population.  Subgroups will be assessed at Baseline and only if there are a sufficient 
number of subjects in each group (eg, >5 subjects per group). 
Baseline subgroups of interest are as follows:  age, age at PBC diagnosis, sex, race, body mass 
index, ALP level, bilirubin level, use of UDCA, years since diagnosis of PBC, and geographic 
region. 
The primary efficacy endpoint will also be assessed across the spectrum of PBC disease stage as 
defined by Rotterdam criteria (Kuiper 2009)  
• Early (normal albumin and normal bilirubin) 
• Moderate (abnormal albumin or abnormal bilirubin) 
• Advanced (abnormal albumin and abnormal bilirubin) 
The primary efficacy endpoint will also be assessed for the following clinically relevant 
subpopulations. 
• Monotherapy in patients who are intolerant or non-responsive to UDCA  
• Elderly patients 
Assuming a strong correlation between biochemistry and clinical outcomes using the total study 
population (Section 13.1.5.1) is observed, we will further assess the biochemical improvement in 
relevant subpopulations as applicable (eg, Rotterdam disease severity and monotherapy) and 
estimate the reduction in risk of clinical outcomes associated with the biochemical improvement. 
Additional details regarding statistical methods and subgroup definitions will be provided in the 
SAP. 
13.1.12. 
Continuous Monitoring and Interim Analyses 
Blinded safety reports including the accrual of events, drop outs, and/or loss of subjects to 
commercially available OCA will be reviewed by the DMC on a regular basis.  
Two planned interim analyses of the liver-related outcomes will be conducted using the 
Lan-DeMets O’Brien-Fleming boundaries (Reboussin 2000).  Both interim analyses will be 
pre-specified and will occur after accrual of 50% (64 events) and 75% (96 events) of clinical 
outcome events, respectively.  
The DMC will review the available efficacy data in conjunction with detailed safety data and 
other relevant information to recommend continuation, modification, or cessation (for efficacy) 
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of the study beyond each interim analysis.  Modification of the study would not take place 
without prior agreement with regulatory authorities. 
13.2. 
Safety Analysis 
Safety data, including AEs and clinical laboratory observations, will be summarized by treatment 
group using the Safety Population. 
13.2.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary of Regulatory Activities.  Summary tables of 
treatment-emergent AEs will be provided.  The incidence of TEAEs will be tabulated by system 
organ class and preferred term for each treatment group, and by severity and relationship to 
treatment.  Tables of TEAEs leading to investigational product discontinuation and SAEs will be 
provided. 
Adverse events of special interest as described in Section 12.1.1.4  will be summarized for each 
treatment group.  In addition, each event is a component of the primary endpoint, and will be 
summarized as secondary endpoints as described in Section 13.1.4. 
13.2.2. 
Clinical Laboratory Evaluations 
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will be 
presented for all study visits.  Changes from pretreatment to each study visit will also be 
summarized by treatment group. 
13.2.3. 
Additional Safety Analysis 
Additional safety assessments include vital signs and ECGs.  Descriptive statistics of the vital 
sign and ECG parameters will be presented by treatment group and study visit, as well as the 
change from pretreatment at each visit. 
13.2.4. 
Cardiovascular Adjudication Committee 
In addition to potential clinical endpoint events, cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study. Adjudicated cardiovascular events include core 
MACE (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) and expanded 
MACE (unstable angina requiring hospitalization, transient ischemic attack, peripheral or 
coronary revascularization procedures, hospitalization for congestive heart failure).  Other events 
potentially related to adverse cardiovascular outcomes may be included in the Cardiovascular 
Adjudication Committee (CAC) Charter for adjudication.  The adjudication of these events will 
be handled separately from the adjudication of events for assessment of the primary endpoint in 
this study (see Section 13.4). 
13.3. 
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 
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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 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 subjects.  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 subject treatment information; 
however, the DMC will have access to the database and may unblind individual subject data as 
appropriate.  Summary tables reviewed by the DMC during closed sessions will include an 
overall column containing information regarding all subjects 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, Medical Dictionary for Regulatory Activities (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 subject safety, which alter the 
conduct of this study.  The Investigators will inform the subjects of such actions and the 
protocol, patient information sheet (PIS), and consent will be revised, as appropriate. 
13.4. 
Adjudication Committees 
All suspected liver-related clinical outcomes, and MACE/Expanded MACE, 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 
2 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 
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 
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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 subject 
treatment or site-specific information.  The assessment of events will be conducted in 
compliance with study-specific procedures, manuals, good clinical practice (GCP), and all other 
applicable regulatory requirements, including the archiving of essential documents.    
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
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 subject’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 CRF.  The CRF 
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 
subject's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
14.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC 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.   
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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the CRF 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 14.2 for more details regarding the audit 
process. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF and/or other subject 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 the Sponsor before he or she can enroll 
any subject 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 subjects to the ethics committee 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 subjects for 
the study.  The protocol must be reapproved by the IRB or 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.  
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, at a minimum annually, and after the study is complete. 
16.2. 
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. 
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16.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated ICF 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 subject. 
16.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential and confidentiality of all subjects will be maintained.  Monitors 
(eg, CRA, Medical Monitor), auditors and inspectors will require access to a subject’s medical 
notes for the purpose of source document verification but the subject’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 subject’s names and identifying information (eg, subject’s 
hospital number, unique subject number).  This list will not be collected by the Sponsor. 
The written information sheet 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 subject 
number/randomization code/subject initials/site number, only. 
When personal data on subjects are stored or processed by computer, the data must be protected 
to prevent their disclosure to unauthorized third parties.  The pertinent sections of the data 
protection laws in which the country is being conducted will be complied with in full. 
The written ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IEC/IRB may require direct access to parts of the hospital 
or study site records relevant to the study, including subject’s medical history. 
17. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the subjects 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 subjects, as applicable. 
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17.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject 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 Medical Monitor. 
17.2. 
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 subject’s safety to be compromised if immediate action is not taken. 
17.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
• Approved ICF (all versions) 
• IRB/EC approvals (of protocol/amendments, subject questionnaires, etc) 
• Form FDA 1572  
• Current medical license 
• Curriculum vitae 
• Laboratory certification and reference ranges 
• Financial disclosure forms 
17.4. 
Ethics Review 
Please see Section 16.1 for the Investigator’s responsibilities regarding ethics review. 
17.5. 
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 subject 
medical files (retained per country specific regulations), completed study subject log and 
confidential subject 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 
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assistance.  At the end of the minimum period, the Investigator should obtain written 
authorization from the Sponsor prior to 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. 
18. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it sponsors consistent 
with the Declaration of Helsinki (Seoul Revision 2008, 
[http://www.wma.net/en/30publications/10policies/b3/index.html, accessed May 22, 2013]).  
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 Study Registries (eg, 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 (when available) 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. 
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• Authorship:  The Sponsor, 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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19. 
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Beuers U, Lindor KD. A major step towards effective treatment evaluation in primary biliary 
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long term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871-877. 
Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of 
liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 
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Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: Biochemical response 
to treatment and prediction of long-term outcome. J Hepatol. 2011;55:1361–1367. 
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Elman S, Hynan L.S., Gabriel V, and Mayo M.J. The 5-D itch scale: a new measure of pruritus, 
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Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict 
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Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver 
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Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis 
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Momah N, Silveira MG, Jorgensen R, et al. Optimizing biochemical markers as endpoints for 
clinical trials in primary biliary cirrhosis. Liver Int. 2012;32(5):790-795. 
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. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-3572. 
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. 
Reboussin DM, DeMets, DL, Kim KM, et al.  Computations for Group Sequential Boundaries 
Using the Lan-DeMets Spending Function Method.  Controlled Clin Trials.  2000;21(3):190-207. 
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. 
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APPENDIX A. MODIFIED DOSING REGIMEN FOR SUBJECTS WITH 
CHILD-PUGH B/C HEPATIC IMPAIRMENT 
Subjects with cirrhosis and classified as Child-Pugh B or Child-Pugh C at Screening will follow 
a modified dosing schedule initiating 5 mg OCA or matching placebo once weekly as described 
in Figure 3.  After a minimum of 3 months dosing once weekly with 5 mg OCA or matching 
placebo, and following review of the pre-titration laboratory results to assess safety and 
tolerability, the dosing frequency of 5 mg OCA or matching placebo should be increased to twice 
weekly (at least three days apart).  Subjects who have maintained the twice weekly dosing 
frequency for a minimum of at least 6 weeks, and meet the dose titration criteria, should 
up-titrate to the maximum allowed dose of 10 mg OCA or matching placebo twice weekly 
(Table 13). 
Investigators may decrease the dosing frequency (back to once weekly) or dose for any subject at 
any time during the study, as considered clinically appropriate (eg, tolerability).   
Figure 3: 
Dosing by Cirrhosis Status and Child-Pugh Score 
 
a  Cirrhosis may be assessed by histology or non-histological methods as defined in Section 7.5.4. 
BIW = twice weekly; QW = once weekly 
Table 13: 
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Modified Dosing Regimen for  
Child-Pugh B or Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg once weekly 
 
Titration 1b  
(≥Month 3) 
5 mg twice weeklyc 
 
Titration 2b  
(≥6 weeks after Titration 1) 
10 mg twice weeklyc 
 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject 
tolerability and/or changes in cirrhosis status or Child-Pugh Score at any time during the study. 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
Dose Titration due to Change in Cirrhosis or Child-Pugh Score 
When subjects demonstrate a change in cirrhosis status (as assessed per Section 7.5.4) or 
Child-Pugh Score (Section 7.5.5 dosing should be reassessed and the dosing regimen modified 
appropriately.  Changes in Child-Pugh Score that result from a transient, explainable change in 
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laboratory parameters (eg, increase in INR due to vitamin K deficiency) should be documented 
appropriately and discussed with the Medical Monitor before any continuation or change to the 
dosing regimen.    
Possible scenarios for dosing modifications include: 
• Subjects who develop cirrhosis during the course of the trial with a classification of 
Child-Pugh B or C 
• Subjects with pre-existing cirrhosis who demonstrate a change in the Child-Pugh 
Score from A to B or C at any point in the study   
Subjects may titrate dose and dosing frequency up or down as appropriate, within the dosing 
regimen.  Up-titration should be done per Investigator discretion and be guided by the pre-
titration tolerability assessments outlined in Section 7.4.1.  A 1-Month and 2-Month Post-
Titration Assessment must be performed any time a subject’s dose or frequency is up-titrated 
(see Section 7.1.2 and Section 9.7.7). 
Unscheduled Titration Visit, Optional Visit 
An unscheduled up-titration visit may be scheduled for as early as 6 weeks after the initial 
titration visit (or subsequent titration visit) occurs for subjects who are following the modified 
dosing regimen.  The visit procedures required for the unscheduled titration visit are outlined 
below.  Subjects who up titrate at an unscheduled visit will continue to follow the regular visit 
schedule for all other study visits.   
For subjects who up titrate at an unscheduled visit the following procedures will be performed: 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Perform the pre-Titration Tolerability Assessment as outlined in Section 7.4.1. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
- 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. 
For subjects who up-titrate at an unscheduled visit:  The ±1-week window related to the 2-month 
Post-Titration Visit can be modified to occur 2 weeks earlier or 2 weeks outside of the allowed 
visit window to allow for the post-titration assessment to be performed during one of the 
subject’s regularly scheduled study visits.  If the 2-month Post-Titration Visit is performed 
during a regularly scheduled study visit, all scheduled procedures associated with that visit 
should be performed.  
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APPENDIX B. ETHICAL CONDUCT ACCORDING TO THE 
DECLARATION OF HELSINKI FOR COUNTRIES 
PARTICIPATING OUTSIDE THE US (DECLARATION 
OF HELSINKI, FORTELEZA, BRAZIL, 2013) 
 
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Copyright 2013 American Medical Association. All rights reserved.
World Medical Association Declaration of Helsinki
Ethical Principles for Medical Research
Involving Human Subjects
World Medical Association
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1. The World Medical Association (WMA) has developed the Dec-
larationofHelsinkiasastatementofethicalprinciplesformedi-
cal research involving human subjects, including research on
identifiable human material and data.
The Declaration is intended to be read as a whole and each of
its constituent paragraphs should be applied with consider-
ation of all other relevant paragraphs.
2. ConsistentwiththemandateoftheWMA,theDeclarationisad-
dressed primarily to physicians. The WMA encourages others
who are involved in medical research involving human subjects
to adopt these principles.
General Principles
3. TheDeclarationofGenevaoftheWMAbindsthephysicianwith
the words, “The health of my patient will be my first consider-
ation,”andtheInternationalCodeofMedicalEthicsdeclaresthat,
“A physician shall act in the patient's best interest when provid-
ing medical care.”
4. It is the duty of the physician to promote and safeguard the
health,well-beingandrightsofpatients,includingthosewhoare
involvedinmedicalresearch.Thephysician'sknowledgeandcon-
science are dedicated to the fulfilment of this duty.
5. Medical progress is based on research that ultimately must in-
clude studies involving human subjects.
6. Theprimarypurposeofmedicalresearchinvolvinghumansub-
jects is to understand the causes, development and effects of
diseasesandimprovepreventive,diagnosticandtherapeuticin-
terventions (methods, procedures and treatments). Even the
bestproveninterventionsmustbeevaluatedcontinuallythrough
research for their safety, effectiveness, efficiency, accessibility
and quality.
7. Medicalresearchissubjecttoethicalstandardsthatpromoteand
ensure respect for all human subjects and protect their health
and rights.
8. Whiletheprimarypurposeofmedicalresearchistogeneratenew
knowledge, this goal can never take precedence over the rights
and interests of individual research subjects.
9. Itisthedutyofphysicianswhoareinvolvedinmedicalresearch
to protect the life, health, dignity, integrity, right to self-
determination,privacy,andconfidentialityofpersonalinforma-
tion of research subjects. The responsibility for the protection
ofresearchsubjectsmustalwaysrestwiththephysicianorother
health care professionals and never with the research subjects,
even though they have given consent.
10. Physiciansmustconsidertheethical,legalandregulatorynorms
andstandardsforresearchinvolvinghumansubjectsintheirown
countries as well as applicable international norms and stan-
dards.Nonationalorinternationalethical,legalorregulatoryre-
quirementshouldreduceoreliminateanyoftheprotectionsfor
research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that mini-
mises possible harm to the environment.
12. Medicalresearchinvolvinghumansubjectsmustbeconducted
onlybyindividualswiththeappropriateethicsandscientificedu-
cation, training and qualifications. Research on patients or
healthyvolunteersrequiresthesupervisionofacompetentand
appropriately qualified physician or other health care profes-
sional.
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13. Groups that are underrepresented in medical research should
be provided appropriate access to participation in research.
14. Physicians who combine medical research with medical care
should involve their patients in research only to the extent that
this is justified by its potential preventive, diagnostic or thera-
peuticvalueandifthephysicianhasgoodreasontobelievethat
participation in the research study will not adversely affect the
health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be en-
sured.
Risks, Burdens and Benefits
16. Inmedicalpracticeandinmedicalresearch,mostinterventions
involve risks and burdens.
Medical research involving human subjects may only be con-
ductediftheimportanceoftheobjectiveoutweighstherisksand
burdens to the research subjects.
17. All medical research involving human subjects must be pre-
ceded by careful assessment of predictable risks and burdens
to the individuals and groups involved in the research in com-
parisonwithforeseeablebenefitstothemandtootherindividu-
als or groups affected by the condition under investigation.
Measurestominimisetherisksmustbeimplemented.Therisks
mustbecontinuouslymonitored,assessedanddocumentedby
the researcher.
18. Physiciansmaynotbeinvolvedinaresearchstudyinvolvinghu-
mansubjectsunlesstheyareconfidentthattheriskshavebeen
adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive proof of definitive outcomes, physi-
cians must assess whether to continue, modify or immediately
stop the study.
Vulnerable Groups and Individuals
19. Somegroupsandindividualsareparticularlyvulnerableandmay
haveanincreasedlikelihoodofbeingwrongedorofincurringad-
ditional harm.
All vulnerable groups and individuals should receive specifi-
cally considered protection.
20. Medical research with a vulnerable group is only justified if the
research is responsive to the health needs or priorities of this
group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to ben-
efit from the knowledge, practices or interventions that result
from the research.
Scientific Requirements and Research Protocols
21. Medicalresearchinvolvinghumansubjectsmustconformtogen-
erally accepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as appropriate, ani-
mal experimentation. The welfare of animals used for research
must be respected.
22. The design and performance of each research study involving
human subjects must be clearly described and justified in a re-
search protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include
information regarding funding, sponsors, institutional affilia-
tions, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compen-
sating subjects who are harmed as a consequence of participa-
tion in the research study.
In clinical trials, the protocol must also describe appropriate ar-
rangements for post-trial provisions.
Research Ethics Committees
23. Theresearchprotocolmustbesubmittedforconsideration,com-
ment, guidance and approval to the concerned research ethics
committee before the study begins. This committee must be
transparent in its functioning, must be independent of the re-
searcher, the sponsor and any other undue influence and must
be duly qualified. It must take into consideration the laws and
regulations of the country or countries in which the research is
to be performed as well as applicable international norms and
standardsbutthesemustnotbeallowedtoreduceoreliminate
anyoftheprotectionsforresearchsubjectssetforthinthisDec-
laration.
The committee must have the right to monitor ongoing stud-
ies.Theresearchermustprovidemonitoringinformationtothe
committee, especially information about any serious adverse
events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of
thestudy,theresearchersmustsubmitafinalreporttothecom-
mittee containing a summary of the study’s findings and con-
clusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of re-
search subjects and the confidentiality of their personal infor-
mation.
Informed Consent
25. Participation by individuals capable of giving informed consent
as subjects in medical research must be voluntary. Although it
Clinical Review & Education Special Communication
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2192
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may be appropriate to consult family members or community
leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving
informed consent, each potential subject must be adequately
informed of the aims, methods, sources of funding, any pos-
sible conflicts of interest, institutional affiliations of the re-
searcher,theanticipatedbenefitsandpotentialrisksofthestudy
and the discomfort it may entail, post-study provisions and any
other relevant aspects of the study. The potential subject must
be informed of the right to refuse to participate in the study or
to withdraw consent to participate at any time without repri-
sal. Special attention should be given to the specific informa-
tionneedsofindividualpotentialsubjectsaswellastothemeth-
ods used to deliver the information.
Afterensuringthatthepotentialsubjecthasunderstoodthein-
formation, the physician or another appropriately qualified in-
dividual must then seek the potential subject’s freely-given in-
formed consent, preferably in writing. If the consent cannot be
expressedinwriting,thenon-writtenconsentmustbeformally
documented and witnessed.
Allmedicalresearchsubjectsshouldbegiventheoptionofbeing
informed about the general outcome and results of the study.
27. When seeking informed consent for participation in a research
study the physician must be particularly cautious if the poten-
tial subject is in a dependent relationship with the physician or
mayconsentunderduress.Insuchsituationstheinformedcon-
sentmustbesoughtbyanappropriatelyqualifiedindividualwho
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving in-
formedconsent,thephysicianmustseekinformedconsentfrom
thelegallyauthorisedrepresentative.Theseindividualsmustnot
be included in a research study that has no likelihood of benefit
forthemunlessitisintendedtopromotethehealthofthegroup
represented by the potential subject, the research cannot in-
stead be performed with persons capable of providing in-
formed consent, and the research entails only minimal risk and
minimal burden.
29. When a potential research subject who is deemed incapable of
givinginformedconsentisabletogiveassenttodecisionsabout
participationinresearch,thephysicianmustseekthatassentin
addition to the consent of the legally authorised representa-
tive. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally in-
capable of giving consent, for example, unconscious patients,
may be done only if the physical or mental condition that pre-
ventsgivinginformedconsentisanecessarycharacteristicofthe
research group. In such circumstances the physician must seek
informedconsentfromthelegallyauthorisedrepresentative.If
nosuchrepresentativeisavailableandiftheresearchcannotbe
delayed,thestudymayproceedwithoutinformedconsentpro-
videdthatthespecificreasonsforinvolvingsubjectswithacon-
dition that renders them unable to give informed consent have
beenstatedintheresearchprotocolandthestudyhasbeenap-
provedbyaresearchethicscommittee.Consenttoremaininthe
researchmustbeobtainedassoonaspossiblefromthesubject
or a legally authorised representative.
31. Thephysicianmustfullyinformthepatientwhichaspectsoftheir
care are related to the research. The refusal of a patient to par-
ticipateinastudyorthepatient’sdecisiontowithdrawfromthe
study must never adversely affect the patient-physician rela-
tionship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or
similarrepositories,physiciansmustseekinformedconsentfor
its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracti-
cable to obtain for such research. In such situations the re-
search may be done only after consideration and approval of a
research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new inter-
vention must be tested against those of the best proven inter-
vention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary
to determine the efficacy or safety of an intervention
andthepatientswhoreceiveanyinterventionlesseffectivethan
thebestprovenone,placebo,ornointerventionwillnotbesub-
ject to additional risks of serious or irreversible harm as a result
of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. Inadvanceofaclinicaltrial,sponsors,researchersandhostcoun-
trygovernmentsshouldmakeprovisionsforpost-trialaccessfor
all participants who still need an intervention identified as ben-
eficialinthetrial.Thisinformationmustalsobedisclosedtopar-
ticipants during the informed consent process.
Research Registration and Publication and Dissemination
of Results
35. Every research study involving human subjects must be regis-
teredinapubliclyaccessibledatabasebeforerecruitmentofthe
first subject.
World Medical Association Declaration of Helsinki
Special Communication Clinical Review & Education
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36. Researchers, authors, sponsors, editors and publishers all have
ethical obligations with regard to the publication and dissemi-
nationoftheresultsofresearch.Researchershaveadutytomake
publicly available the results of their research on human sub-
jectsandareaccountableforthecompletenessandaccuracyof
their reports. All parties should adhere to accepted guidelines
for ethical reporting. Negative and inconclusive as well as posi-
tiveresultsmustbepublishedorotherwisemadepubliclyavail-
able. Sources of funding, institutional affiliations and conflicts
of interest must be declared in the publication. Reports of re-
search not in accordance with the principles of this Declaration
should not be accepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven inter-
ventions do not exist or other known interventions have been
ineffective, the physician, after seeking expert advice, with in-
formed consent from the patient or a legally authorised repre-
sentative, may use an unproven intervention if in the physi-
cian's judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should subse-
quently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be re-
corded and, where appropriate, made publicly available.
ARTICLE INFORMATION
Corresponding Author: World Medical
Association, 13, ch. du Levant, CIB - Bâtiment A,
01210 Ferney-Voltaire, France; wma@wma.net.
Published Online: October 19, 2013.
doi:10.1001/jama.2013.281053.
Disclaimer: ©2013 World Medical Association, Inc.
All Rights Reserved. All intellectual property rights
in the Declaration of Helsinki are vested in the
World Medical Association. The WMA has granted
JAMA exclusive rights to publish the
English-language version of the Declaration
through December 31, 2013.
Online-Only Content: Audio podcast is available at
www.jama.com.
Clinical Review & Education Special Communication
World Medical Association Declaration of Helsinki
2194
JAMA
November 27, 2013
Volume 310, Number 20
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APPENDIX C. REFERENCE LABORATORY VALUES FROM CENTRAL LABORATORIES 
Covance Central Laboratories (Indianapolis, Indiana, US [for North America and Latin America regions]; Geneva, Switzerland [for 
Europe]; and Singapore [for Asia-Pacific region]) will serve as the central labs for analysis or specimen management for the analytes 
listed in the Table 12 of Protocol 747-302 Version 4.  The following in text table provides the Covance Laboratory reference ranges 
for the pertinent liver biochemistries analyzed by Covance.  These reference ranges are sex and/or age specific, and can change during 
the course of the clinical trial; therefore, investigative sites should always refer to the reference ranges available on the Covance issued 
laboratory reports. 
 
Covance Indianapolis 
Covance Geneva and Covance Singapore 
Analyte 
Sex 
Agea 
Reference Range 
Agea 
Reference Range 
Albumin 
Both 
18Y – 69Y 
SI Units: 33-49 g/L 
Conventional Units: 3.3-4.9 g/dL 
18Y – 69Y 
33-49 g/L 
69Y-80Y 
SI Units: 33-46 g/L 
Conventional Units: 3.3-4.6 g/dL 
69Y-80Y 
33-46 g/L 
80Y-150Y 
SI Units: 30-46 g/L 
Conventional Units: 3.0-4.6 g/dL 
80Y-150Y 
30-46 g/L 
ALP 
Female 
18Y - 50Y 
31-106 U/L 
18Y - 50Y 
31-106 U/L 
50Y - 60Y 
35-123 U/L 
50Y - 60Y 
35-123 U/L 
60Y - 70Y 
35-123 U/L 
60Y - 70Y 
35-123 U/L 
70Y - 80Y 
35-123 U/L 
70Y - 80Y 
35-123 U/L 
80Y - 90Y 
35–135 U/L 
80Y - 90Y 
35–135 U/L 
90Y – 150Y 
35-140 U/L 
90Y – 150Y 
35-140 U/L 
ALP 
Male 
18Y - 50Y 
31-129 U/L 
18Y - 50Y 
31-129 U/L 
50Y - 60Y 
35-131 U/L 
50Y - 60Y 
35-131 U/L 
60Y - 70Y 
35-125 U/L 
60Y - 70Y 
35-125 U/L 
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Covance Indianapolis 
Covance Geneva and Covance Singapore 
Analyte 
Sex 
Agea 
Reference Range 
Agea 
Reference Range 
70Y - 80Y 
35-130 U/L 
70Y - 80Y 
35-130 U/L 
80Y - 90Y 
35–125 U/L 
80Y - 90Y 
35–125 U/L 
90Y – 150Y 
35-125 U/L 
90Y – 150Y 
35-125 U/L 
ALT 
Female 
18Y – 69Y 
6-34 U/L 
18Y – 69Y 
6-34 U/L 
69Y – 150Y 
6-32 U/L 
69Y – 150Y 
6-32 U/L 
ALT 
Male 
18Y – 69Y 
6-43 U/L 
18Y – 69Y 
6-43 U/L 
69Y – 150Y 
6-35 U/L 
69Y – 150Y 
6-35 U/L 
AST 
Female 
18Y – 59Y 
9-34 U/L 
18Y – 59Y 
9-34 U/L 
59Y – 150Y 
9-34 U/L 
59Y – 150Y 
9-34 U/L 
AST 
Male 
18Y – 59Y 
11-36 U/L 
18Y – 59Y 
11-36 U/L 
59Y – 150Y 
11-36 U/L 
59Y – 150Y 
11-36 U/L 
Direct 
Bilirubin 
Both 
18Y – 150Y 
SI Units: 2-7 umol/L 
Conventional Units: 0.1-0.4 mg/dL 
18Y – 150Y 
2-7 umol/L 
Indirect 
Bilirubin 
Both 
0Y – 150Y 
SI Units: 0-21 umol/L 
Conventional Units: 0.0-1.2 mg/dL 
0Y – 150Y 
0-21 umol/L 
Total 
Bilirubin 
Both 
18Y – 150Y 
SI Units: 3-21 umol/L 
Conventional Units: 0.2-1.2 mg/dL 
18Y – 150Y 
3-21 umol/L 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; Y = years; SI=International System of Units 
a The unstated word “to” is implied by the “dash” appearing in age specific reference ranges. A range such as “0-59 years” and “59-150 years” means: “0 up to 
but not including 59 years” and “59 up to but not including 150 years”. 
Source: Covance Laboratory Services Manual Version 5.0.0. Dates vary by region: 10 Nov 2016 (North America), 22 Nov 2016 (Europe and Singapore) 
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APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 (DATED 29 APR 2015) 
Rationale 
The changes to the Original Version of the protocol, detailed below, modify the dose titration schedule based on observed efficacy and 
tolerability of OCA, address advice provided by regulatory agencies, and clarify questions raised by study site personnel currently 
using Original protocol version 1 dated 03 October 2014. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.  (Note:  Differences are denoted in bold font; Minor 
formatting changes are not listed) 
Section 
Original Text 
Revised Text 
Title Page 
Original:  03 October 2014 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Procedures in 
Case of 
Emergency 
 
Procedures in Case of Emergency 
 
Study Personnel Contact Information 
 
Or if Not 
Available 
Contact:
 MD, 
 & 
 Development, Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
 
Contact:
 MD, Medical Director, Drug Safety, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
Synopsis 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
≤1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 
2 weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 
2 weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
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and total bilirubin values (refer to Section 9.7.3).  Subjects who 
meet all inclusion criteria and none of the exclusion criteria will be 
randomized (1:1) to OCA or placebo treatment groups.  The 
randomization will be stratified by ursodeoxycholic acid (UDCA) 
treatment (yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 6 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 6-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
 
and total bilirubin values (refer to Section 9.7.3).  Mean values for 
ALP and total bilirubin will be calculated using all available 
screening values.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment (yes/no) and baseline 
bilirubin categories (>upper limit of normal [ULN]/ ≤ ULN). 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 3 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 3-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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Synopsis 
Inclusion Criteria 
2.  A mean total  bilirubin >ULN and ≤3× ULN or an ALP 
>5×ULN  
4.  Either is not taking UDCA (UDCA naïve or  no UDCA dose in 
the past 3 months) or has been taking UDCA for at least 12 months 
with an approved, stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
contraception during the study and for 30 days after the end of 
treatment visit. 
 
Inclusion Criteria 
2. A mean total bilirubin >ULN and ≤3× ULN and/or a mean 
ALP >5× ULN 
4.  Either is not taking UDCA (no UDCA dose in the past 
3 months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
Synopsis 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
 
 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
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3. Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
4.  Other medical conditions that may diminish life expectancy to 
<2 years, including known cancers (except carcinomas in situ or 
other stable, relatively benign conditions such as chronic lymphatic 
leukemia) 
5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of screening (pretreatment) QT 
 
3.  Mean total bilirubin >3× ULN 
 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
5.  Deleted text 
Synopsis 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life 
 
 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life (Fatigue 
Impact Score and EQ-5D-
5L) 
 
Synopsis 
Statistical Methods: Other Efficacy Analyses 
• 
Added text 
Statistical Methods: Other Efficacy Analyses 
• 
Development of varix/varices 
4 
List of Abbreviations 
Added text 
 
List of Abbreviations 
EOS 
 end of study 
 
5.4 
As of 31 March 2014, OCA has been evaluated in the clinic in 
18 completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 March 2014, a total of 1023 subjects have 
received at least one dose of OCA and of these, 414 (40%) were 
subjects with PBC.   
As of 31 January 2015, OCA has been evaluated in the clinic in 
20 completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 January 2015, approximately 1650 subjects 
have received at least 1 dose of OCA and of these, 432 were 
subjects with PBC with ≤5 years of OCA treatment.   
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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 up to 4 years.  The LSTE phase of studies 
747-201 and 747-301 are ongoing; the LTSE phase of 
Study 747-202 is complete 
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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is 
complete 
5.5.2.1 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg and 10 mg; both treatment 
groups exhibited clinically meaningful improvements in liver 
biochemistry and were safe and generally well tolerated. 
 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg (titrated to 10 mg after 6 
months based on efficacy and tolerability in the double-blind 
phase and after 3 months in the open-label phase) and 10 mg; 
both treatment groups exhibited clinically meaningful 
improvements in liver biochemistry and were safe and generally 
well tolerated.  Based on these data, the intended commercial 
doses of OCA for the treatment of patients with PBC are 5 mg 
and 10 mg. 
The majority of efficacy results with OCA, in terms of change 
in alkaline phosphatase, was observed by 3 months and the 
time to treatment-emergent pruritus was typically 1 month or 
less in Study 747-301.  As such, Study 747-302 will evaluate the 
effect of OCA on clinical outcomes using the 5 mg OCA dose 
increasing to 10 mg OCA if tolerated. 
 
5.5.2.2. 
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons.   
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons (ie, comparisons to historical and placebo 
controls will be evaluated separately). 
 
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5.6 
Additionally, consistent with nonclinical findings and the 
chemical characteristics of OCA (bile acid and detergent), an 
increase in liver function tests and hepatic AEs, including 
jaundice, were observed in subjects with liver disease at doses 
between 10 mg and 50 mg and in healthy volunteers who were 
treated at doses greater than 100 mg in Phase 1 multiple dose 
studies. 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  The clinical 
significance of these lipid findings remains unclear and is being 
studied further.  Notably, despite the observed decrease, HDL 
levels have generally remained within normal limits in subjects 
treated with OCA. 
• 
Deleted text 
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 subjects with chronic liver disease such as PBC, hepatic 
findings including increased transaminases and bilirubin and 
signs or symptoms of hepatic decompensation such as 
development of jaundice were observed mainly at the highest 
dose of OCA (50mg daily). 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  Notably, in subjects 
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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated 
subjects with the exception of a modest transient and early rise 
after initiation of treatment. 
7.1 
Overall Study Design 
…Subjects will be screened during a ≤1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3)….Following 6 months of treatment with 
investigational product, subjects should be titrated in a blinded 
manner (ie, subjects randomized to OCA will increase their dose to 
10 mg OCA) based on tolerability…. 
Overall Study Design 
…Subjects will be screened during a 1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to Section 9.7.3). 
….Following 3 months of treatment with investigational product, 
subjects should be titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose to 10 mg OCA) based 
on tolerability…. 
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7.1.1 
Study Design Diagram 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
Study Design Diagram 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
7.1.2 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
1st column heading was “Screening Visit  x2) 
 
Visit Window ≤1 to 8 wks … 
Visit window in 2nd column added new text 
Added text 
 
 
 
 
 
 
 
 
 
 
 
 
Footnote a:   All subjects will have two 2 bilirubin assessments at 
least 2 weeks apart including those subjects who qualify based 
on ALP criteria.  For subjects that do not qualify based on 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
Now 2 columns: 1st column now “Screening Visit 1” 
2nd column now Screening Visit 2 
3 to 8 wks… 
1 to 6 wks prior to Day 0 
 
Added Procedures: 
Quality of Life Questionnaires (PBC-40, EQ-5D-5L, and 
FIS) g  (Day 0, Annually, EOT/EOS) 
Endoscopy I (Day 0, annually, per standard of care) 
Hepatic Ultrasound (Day 0, Annually, EOT/EOS) 
Physical Exam and Assessments for Mayo Risk Score and Child-
Pugh (every 6 months) 
Health Outcome Assessments (All visits) 
Added Dose Titration at M3 
Footnote a All subjects will have the chemistry panel retested 
to ensure subjects have 2 ALP and bilirubin assessments at 
least 2 weeks apart to calculate the mean result for both 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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ALP (ALP >5× ULN), the mean of the two 2 bilirubin 
assessments will be used to determine eligibility (total bilirubin 
>ULN and ≤3× ULN). 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2, and also 2 weeks post dose titration, to assess for AEs 
and concomitant medications and to verify that s/he is dosing as 
directed 
Footnote e:  Medical history at Screening will smoking and alcohol 
consumption history and current habits for both.   
 
Footnote g:  Subject Questionnaires include: Pruritus VAS, 5-D 
Pruritus Scale and Quality of Life questionnaires (See 
Section 11.1.2.2 and Section 12.2.5.1) 
 
 
 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.   
 
 
Footnote i: Added text 
 
 
Footnote j:  Added text 
 
 
 
 
Footnote k:  Added text 
analytes.   The mean of the all screening ALP and bilirubin 
assessments will be used to determine eligibility).  Samples for 
hematology and coagulation will not be collected at Screening 
visit 2. 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2 (± 1 week), and also 2 weeks post dose titration (up or 
down), to assess for AEs and concomitant medications and to 
verify that s/he is dosing as directed.   
Footnote e:  Medical history at Screening and the yearly physical 
exam will include an assessment of smoking and alcohol 
consumption history and current habits for both.   
Footnote g:  The EQ-5D-5L and FIS Quality of Life 
questionnaires are validated for use in multiple languages. If 
a validated translation is not available in the local language 
required for a specific study subject, the data from that 
questionnaire will not be collected.    (See Section 11.1.2.2 and 
Section 12.2.6) 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.  Please refer to Section 9.7.7 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote i: Endoscopy will be conducted at selected study sites 
where the device is available to assess for the presence of 
oesophageal varix/varices.  Please refer to Section 9.7.7 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote j:  Ultrasound will be conducted to enhanced HCC 
surveillance.  If a lesion is found, a second confirmatory 
image (eg, MRI) should be obtained.  Please refer to 
Section 9.7.7 for additional information related to the allowed 
windows at Day 0 for these specific procedures. 
Footnote k:  Child-Pugh Score will be calculated based on 
ascites assessment, hepatic encephalopathy grade, and central 
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Footnote l:  Added text 
 
 
 
Footnote m:  After 6 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 6 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit.  Fasting is required prior to all 
study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at site.  If the blood 
test is also positive, the subject may not be enrolled in the study.  
(Additional testing may be conducted where required, 
regionally). 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
laboratory evaluations per the Child-Pugh scoring system 
noted in the case report form.  Mayo Risk Score will be 
calculated based on central laboratory evaluations, diuretic 
use data, and peripheral edema assessment data captured in 
the CRF.  
Footnote l:  Health Outcome Assessments: Data related to non-
study related medical or surgical treatment procedures that 
the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the 
subject attended should be collected throughout the study. 
Footnote m:  After 3 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 3 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit (except Screening visit 1).  
Fasting is required prior to all study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not 
be enrolled in the study.  (Additional testing may be conducted 
where required, regionally). 
 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
 
7.3 
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 6 month study visit or at 
any study visit thereafter depending on tolerability.   
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 3 month study visit or 
at any study visit thereafter depending on tolerability.   
7.4 
Dose Titration Criteria 
After 6 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
Dose Titration Criteria 
After 3 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
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placebo (in a blinded manner) at the 6-month visit or any study visit 
following the 6-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
placebo (in a blinded manner) at the 3-month visit or any study visit 
following the 3-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
7.4.1 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, her or she should continue the regular 
visit schedule and continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination.  Early termination 
procedures should only be conducted if the subject withdraws 
consent. 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, he or she should continue the regular 
visit schedule and continue taking investigational product as long 
as the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination. 
7.5 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all subjects have 
completed the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the Study/Early Termination Visit. 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all events have been 
accrued, and when subjects are still active on the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the End of Study Visit. 
8.2 
Subject Inclusion Criteria  
2.  A mean total bilirubin >ULN and ≤3× ULN or an ALP >5× 
ULN 
4.  Either is not taking UDCA (UDCA naïve or no UDCA 
dose in the past 3 months) or has been taking UDCA for at 
least 12 months with an approved, stable dose for ≥3 months 
prior to Day 0 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
Subject Inclusion Criteria 
2.  A mean total bilirubin >ULN and ≤3× ULN and/or a mean ALP 
>5× ULN  
4.  Either is not taking UDCA (no UDCA dose in the past 
3 months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
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contraception during the study and for 30 days after the end of 
treatment visit. 
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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
 
 
8.3 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
3.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
4.  Other medical conditions that may diminish life expectancy 
to <2 years, including known cancers (except carcinomas in 
situ or other stable, relatively benign conditions such as chronic 
lymphatic leukemia) 
 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example, per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
3.  Mean total bilirubin >3× ULN 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
 
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5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of Screening (pretreatment) QT 
 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test), or lactating 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
 
5. Deleted text 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test by the central laboratory), or lactating 
 
8.4.1 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test. 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test performed at the central 
laboratory. 
8.4.2 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent. 
 
 
The following events are considered potential appropriate reasons 
for a subject to discontinue investigational product;…  
• 
Withdrawal of Consent 
- 
Added text 
 
 
 
 
 
 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent (See Section 9.7.18 Early 
Discontinuation and/or Early Termination Procedures). 
 
The following events are considered appropriate reasons for a 
subject to discontinue investigational product; … 
• 
Withdrawal of Consent 
- 
Consent may be fully withdrawn 
- 
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 potential adjudicated hepatic and/or 
cardiovascular events 
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The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study.   
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study.   
8.4.3 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study….This information must be documented in the CRF.  
If a subject is withdrawn from the study early (regardless of the 
cause), all of the end of treatment (EOT) evaluations should be 
performed at the time of withdrawal, as appropriate.  
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study….This information must be documented 
in the CRF.  If a subject is withdrawn from the study early 
(regardless of the cause), all of the (EOT/EOS) evaluations should 
be performed at the time of withdrawal, as appropriate (See 
Section 9.7.18 Early Discontinuation and/or Early Termination 
Procedures). 
9.1.1 
Dose Adjustment Beginning at Month 6 
After 6 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 6 visit, or at 
any study visit thereafter.   
Dose Adjustment Beginning at Month 3 
After 3 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 3 visit, or at 
any study visit thereafter.   
9.2 
Concomitant Medications 
Relevant information about all concomitant medications (including 
prescribed, over-the-counter, or herbal preparations) taken prior to 
(ie, within 30 days of Day 0) and during the study must be recorded 
in the source documents and CRF, as well as any dose or dose 
regimen changes that occur during the study.   
Concomitant Medications 
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 CRF, as well as any dose or 
dose regimen changes that occur during the study. 
9.2.1 
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.   
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.  Subjects that discontinue investigational product 
but continue commercial OCA therapy are expected to 
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continue through the end of the study, and the study will only 
terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.  Subjects 
will need to complete EOT procedures but continue with 
regularly scheduled visits until the study is terminated (See 
Section 9.7.18 Early Discontinuation and/or Early Termination 
Procedures). 
 
9.4 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN), 
as specified by the central laboratory.   
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and mean baseline bilirubin categories 
(>ULN/≤ULN), as specified by the central laboratory.   
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
• 
Added text - New section inserted. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects will be made 
available to the Investigator for emergency use only 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 is necessary for further medical management of the 
subject).  If it is not reasonable to inform the Medical Monitor 
in advance of unblinding the Investigator must promptly 
document in the subject’s source record and should 
subsequently contact the Medical Monitor to explain any 
premature unblinding of treatment assignment (such as 
unblinding which is necessary in order to treat an SAE). 
Procedures for unblinding a subject’s treatment will be 
provided separately to the Investigator.  Similarly, if the 
Medical Monitor breaks the blind for an individual subject for 
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the purpose of evaluating an emergent safety issue, the Medical 
Monitor will document within trial documentation the 
rationale, circumstances, and the person or persons being 
informed about the unblinding. 
The Data and Safety Monitoring Committee (DSMC) will have 
access to the IWRS and will be able to unblind individual 
subjects.  Refer to Section 13.3 for further details regarding 
DSMC access to blinded and unblinded data.  The DSMC will 
document details about any unblinded subject data reviews in 
the closed session DSMC minutes, which will be made available 
to the Sponsor only after the database is locked and the trial is 
unblinded.   Cases of premature unblinding, as noted above, 
will also be reviewed by the DSMC.  
Access to treatment assignments will also be made available 
through the IWRS system to the appropriate named 
individual(s) responsible for reporting SAEs and suspected 
unexpected serious adverse reactions (SUSARs) to the 
Regulatory Authorities. 
9.6 
Restrictions 
No additional restrictions. 
Restrictions 
Participation in another investigation product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the trial is prohibited. 
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9.7.1 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Interval is ≤1 to 8 weeks prior to 
Day 0, allowing for 2 Screening 2 
visits to repeat biochemistry tests, 
and ensuring ample time to receive 
lab results.  The overall Screening 
interval is up to 56 days. 
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (7 days)  
Quarterly visits (Months 
15 – EOT) 
±2 weeks (14 days) 
EOT 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOT = end of treatment 
 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening visit 1 interval is 3 to 8 
weeks prior to Day 0 for screening 
visit 1.  Screening visit 2 interval is 
1 to 6 weeks prior to Day 0.   The 
visit window for Screening 2 visits 
allows for the repeat biochemistry 
tests to be collected at least two 
weeks after the initial biochemistry 
sample was collected, and will 
ensure ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days, but 
screening procedures should not be 
performed during the last 7 days of 
the window.  
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (14 days)  
Quarterly visits 
(Months 15 – EOS) 
±2 weeks (14 days) 
EOT 
(When subject 
discontinues 
investigational 
product) 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOS 
(When subject 
terminates the study) 
The final study visit; EOS will 
occur concurrent with EOT if a 
subject discontinues investigative 
product at the time the subject’s 
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participation in the study ends (eg, 
withdrawal of consent or study 
termination by the Sponsor); EOS 
will occur after the EOT if the 
subject discontinues investigative 
product but continues in the study. 
EOT = end of treatment 
EOS = end of study 
 
9.7.2 
Informed Consent Procedures 
• 
Added text 
Informed Consent Procedures 
Any change in a subject’s consent status (eg, semi-annual 
telephone contact or medical record review) must be 
documented in a signed informed consent form or addendum.  
The subjects will be given a signed and dated copy of the 
consent document. 
9.7.3 
Screening Procedures (≤1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed ≤1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Subjects who 
do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects may be rescreened after 2 months; however, all Screening 
procedures should be repeated and a new 3-digit Screening number 
assigned.  
 
 
 
 
 
• 
All subjects will have 2 bilirubin and ALP 
assessments at least 2 weeks apart including those 
subjects who qualify based on ALP criteria. 
• 
For subjects that do not qualify based on ALP alone 
(ALP >5×  
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Screening 
Visit 1 will occur 3 to 8 weeks prior to Day 0; Screening Visit 2 
will occur 1 to 6 weeks prior to Day 0, depending on the date 
that the first serum chemistry sample was collected. Subjects 
who do not fulfill all eligibility criteria will not be enrolled in the 
study.  Subjects 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 3-digit Screening number 
assigned. 
 
• 
All subjects will have 2 bilirubin and ALP assessments at 
least 2 weeks apart 
 
• 
For subjects that do not qualify based on ALP alone (ALP 
>5× ULN), the mean of all available (at least 2; 
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ULN), the mean of the 2 bilirubin assessments will be 
used to determine eligibility (total bilirubin >ULN 
and ≤3× ULN). 
  
 
 
• 
Screening Visit procedures are as follows: 
• 
Record prior (if within 30 days of Day 0) and current 
concomitant medications 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual emission X ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
 
 
• 
Added text 
 
including both scheduled and unscheduled) bilirubin 
assessments will be used to determine eligibility (total 
bilirubin >ULN and ≤3× ULN).   
 
 
 
• 
Screening Visit 1 procedures are as follows: 
• 
Record prior (if within 30 days of Screening) and current 
concomitant medications 
• 
Deleted text  
 
• 
Deleted text 
 
 
 
 
 
 
Screening Visit 2 procedures are as follows: 
• 
Verify inclusion and exclusion criteria for eligibility 
• 
Assess and record any pretreatment-emergent AEs 
• 
Record current concomitant medications 
• 
Verify that the subject has fasted for at least 8 hours 
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- 
Record fasting status in the source and CRF 
- 
If the subject reports having eaten within 8 hours, 
document accordingly in the source and CRF and 
remind the subject that fasting is required prior to all 
study visits 
• 
Obtain blood samples for serum chemistry tests 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual-emission X-ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
9.7.4 
Day 0 Procedures (Randomization) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE has 
been done within 3 months of Day 0 and a report/adequate data 
are available, a pretreatment TE at Day 0 is not required.   
 
 
 
 
• 
Day 0 Procedures (Randomization) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6.) 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE 
has been done within 6 months of Day 0 and a 
report/adequate data are available, a pretreatment TE at 
Day 0 is not required.  If the TE cannot be performed on 
Day 0 (e.g., device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the 
screening visit window, as close as possible to the Day 0 
visit, after subject eligibility has been confirmed.   
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• 
 Conduct a DEXA bone density scan (at selected study sites, 
where available); document whether the subject stopped taking 
her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the 
scan, if applicable.  
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 Conduct a DEXA bone density scan (at selected study 
sites, where available); document whether the subject 
stopped taking her/his calcium supplements for 48 hours 
before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable.  If DEXA 
has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment 
DEXA at Day 0 is not required.  If DEXA cannot be 
performed on Day 0 (e.g., device/technician 
unavailability, scheduling issues, etc), the procedure 
may be completed within the screening visit window, as 
close as possible to the Day 0 visit, after subject 
eligibility has been confirmed. 
• 
Perform an esophagogastroduodenoscopy (endoscopy; 
at selected study sites, where available) to assess the 
presence or absence of oesophageal varix/varices. If an 
endoscopy has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment endoscopy at Day 0 is not required. If the 
endoscopy cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
- 
Subsequent endoscopies should be performed 
annually or per standard of care and the 
Investigator’s clinical judgment throughout 
the course of the study.  Endoscopies should 
also be performed when platelet counts are 
<150 × 109 /L. 
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• 
Added text 
 
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
• 
Added text 
 
• 
Record prior (within 30 days of Day 0) and current  
concomitant medications 
• 
Perform an ultrasound (if equipment is unavailable, 
sites should make every attempt to use available 
community referral sites) for HCC surveillance.  If an 
ultrasound has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment ultrasound at Day 0 is not required. If 
the ultrasound cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
 Review and record prior concomitant medications 
• 
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. 
9.7.6 
Month 3 Procedures 
• 
Added text 
• 
Added text 
Month 3 Procedures 
• 
Assess for dose titration, if eligible (refer to Section 7.4) 
• 
Obtain blood samples for: 
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- 
OCA, C4, and FGF-19 
9.7.7 
 
Month 6 Procedures 
• 
Added text 
 
Month 6 Procedures 
• 
 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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.8 
Month 9 Procedures 
• 
Added text 
Month 9 Procedures 
• 
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 
 
9.7.9 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.9), subjects who are participating in the PK assessment 
will each receive a single dose of investigational product (10 mg 
OCA tablet) with approximately 240 mL of water. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.12), subjects who are participating in the PK 
assessment will each receive a single dose of investigational 
product (blinded OCA or placebo tablet) with approximately 
240 mL of water. 
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Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours postdose.  Subjects should not drink additional water 
for 1 hour after taking the dose of investigational product and will 
remain fasted until the 4 hour sample is collected.  Lunch will be 
provided following collection of the 4 hour PK sample; the lunch 
will be a meal replacement drink. 
 
 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours post dose.  Samples should be collected within a 
window of ±5 minutes of the scheduled sample time.  Subjects 
should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until the 4 hour 
sample is collected.  Lunch will be provided following collection of 
the 4 hour PK sample; the lunch will be a meal replacement drink.  
Samples will be stored for up to 5 years after the end of the 
study and will be destroyed after 5 years if not analyzed. 
9.7.10 
 
Month 12 Procedures 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Added text 
Month 12 Procedures 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
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9.7.11 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
Subjects should come to the study center for a quarterly study 
visit for a clinical laboratory evaluation to collect blood samples 
for calculation of MELD score.  If the subject is not able to 
come to the study center for a visit, home visits may be 
arranged on a per subject basis. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
• 
Deleted text 
• 
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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
9.7.12 
Month 6 Continue Follow-up Procedures (Semi-annually 
[±2 weeks]) 
• 
Added text 
Month 6 Continue Follow-up Procedures (Semi-annually 
[±2 weeks]) 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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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9.7.13 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Added text  
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
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 physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.14 
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw Consent 
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw from Investigational Product or 
Withdraw Consent  
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
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Added text 
 
 
 
 
 
 
 
 
When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination or 
discontinuation (withdrawal of consent), an EOT visit must be 
performed as near as possible to her/his last dose of investigational 
product and the procedures, listed below, performed.  …  In these 
cases, the data will be recorded as EOT procedures in the CRF.  
 
 
Added table 
 
 
 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects 
discontinue treatment with investigational product.  The EOT 
visit and procedures listed below must be performed as close as 
possible to the subject’s last dose of investigational product.  
When a subject discontinues investigational product but 
continues with regularly scheduled study visits, the EOS visit 
will be completed later in the study as the subject’s final study 
visit.  The actual investigational product discontinuation 
scenario (Table 7) will determine the sequence of the EOT and 
EOS visits and procedures.  In some cases, the EOT visit and 
procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible 
to the subject’s last dose of investigational product.   
When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination 
(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.  ….  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 and EOS procedures in the 
CRF.  
Table 2: 
Early Discontinuation Scenarios 
 
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Investiga
tional 
Product 
Conse
nt 
Study 
Visit 
Status 
EOT 
Visita 
EOS 
Visita 
Early 
Terminati
on 
Discontin
ued 
Withdr
awn 
No 
additi
onal 
visits 
excep
t 
EOT/E
OS 
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
Treatmen
t 
Discontin
uation 
Discontin
ued 
Active 
Regul
ar 
Visit 
Sched
ule 
Comp
lete 
as 
close 
as 
possi
ble to 
last 
dose 
IP 
Comp
lete 
at 
Final 
study 
visit 
Discontin
ued 
Semia
nnual 
contac
tb 
Telep
hone 
conta
ct 
every 
6 
mont
hs (±2 
weeks
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
 
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Some assessments noted below may be omitted if they have been 
completed within the 3 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT Visit: 
During the EOT Visit: 
• 
Subject questionnaires (see Section 12.2.6) 
• 
Conduct a DEXA bone density scan (selected study sites); 
document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for 
osteoporosis or osteopenia on the day of the scan, if applicable 
 
 
• 
Added text 
 
• 
Added text 
 
• 
Added text 
 
a Refer to Section 7.1.2 Schedule of Study Procedures for all procedures 
and evaluations required at the End of Treatment and End of Study Visits. 
b Outcomes data to be discussed or collected include data related to 
adjudicated hepatic and cardiovascular event-related data.  No additional 
data (e.g. AE, concomitant medication, etc) data will be collected, except 
as indicated in Section 12.1.7. 
Some assessments noted below may be omitted if they have been 
completed within the 6 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing 
Prior to the EOT/EOS Visit: 
During the EOT/EOS Visit 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
 Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Subject and Quality of Life  questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform TE (where available) using the Fibroscan® TE 
device (not required at EOT/EOS if done within 6 months) 
• 
Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
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• 
Added text 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites); not 
required at EOT/EOS if done within 6 months 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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 
 
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.  [Added text]  As appropriate, the Medical 
Monitor should be contacted. 
 
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.   
In the event of an inexplicable and acute (for example not 
explained by natural progression of the chronic disease) 
increase in alanine aminotransferase (ALT) to >3× baseline 
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(and >upper limit of normal [ULN]) or total bilirubin >2× 
baseline (and >ULN), the subject should be followed by repeat 
testing within 48 to 72 hours of the serum chemistry to confirm 
the abnormalities and to determine if they are increasing or 
decreasing. AE information should also be collected.  If 
symptoms persist or repeat testing shows ALT >3× baseline 
(and >ULN) or total bilirubin >2× baseline (and >ULN), 
subjects should be followed until resolution of the abnormality 
and as clinically indicated depending on other laboratory and 
clinical signs and symptoms. 
 
As appropriate, the Medical Monitor should be contacted. 
10.4 
Investigational Product Preparation 
The investigational product will be provided in bulk bottles and 
therefore may be repackaged in unit dose form for administration to 
subjects. 
 
Investigational Product Preparation 
The investigational product will be provided to the distribution 
center in bulk bottles and therefore may be repackaged in unit dose 
form for administration to subjects before shipping to the sites. 
 
11.1.2 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Resource utilization information 
will be collected from CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician 
visits (subject reported), and use of concomitant medications.  
 
 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Quality of life will be assessed by 
questionnaires (PBC-40, EQ-5D-5L, and FIS) 
administered annually.  Resource utilization information will 
be collected from the Medical and Surgical Treatment 
Procedures and Office Visit Log or other CRFs such as 
number, type and duration of hospitalizations, number of 
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• 
Added text 
outpatient physician visits (subject reported), and use of 
concomitant medications.  
• 
Endoscopy will be conducted at selected study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual 
study assessments or standard of care will be collected in 
the case report form to assess for the development of 
varix/varices 
11.1.2.2 
• 
Quality of Life questionnaires.   
• 
Quality of Life questionnaires.  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: 
a. PBC-40: The PBC-40 (Jacoby 2005) 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. 
b. EQ-5D-5L:  The Eq-5D-5L consists of 2 sections – the 
descriptive system and the visual analogue scales (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 
respondent’s self-rate 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). 
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c. 
Fatigue Impact Score (FIS):  The FIS is a validated 
40-question questionnaire organized into 3 dimensions:  
cognitive, physical, and social.  Each dimension has 5 
levels:  no problem, small problem, moderate problem, 
big problem, and extreme problem (Fisk 1994) 
11.1.2.3 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. The samples will be stored for up to 1 year after the 
end of the study and destroyed after 1 year if not analyzed. 
 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their 
involvement in the study.  IRB/IEC review and approval 
will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will 
be stored for up to 1 year after the end of the study and 
destroyed after 1 year if not analyzed. 
 
12.1.1.2 
Serious Adverse Event 
• 
Added text 
Serious Adverse Event 
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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12.1.4.2 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
  
All SAEs (including Potential Clinical Outcome Events that qualify 
as serious) must be reported to the medical monitor immediately 
(ie, within 24 hours) after the Investigator identifies the SAE…. 
 
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 investigational 
new drug (IND) safety reports (SUSARs) that occur during the 
study within the time frames required by each regulatory agency.  
The Investigator is responsible for submitting information on IND 
safety reports received from the Sponsor to her/his local IRB.  
Documentation of the submissions to IRBs and health authorities 
must be retained in the appropriate study file(s). 
 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
All SAEs occurring while subjects are receiving investigational 
product or are on an investigational product holiday (including 
Potential Clinical Outcome Events that qualify as serious) must be 
reported to the medical monitor immediately (ie, within 24 hours) 
after the Investigator identifies the SAE….  
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.  A SAE assessed with a possible, probable, or definite 
causal relationship to the investigational product and 
unexpected according to IB Reference Safety Information 
(RSI), is known as a suspected unexpected serious adverse 
reaction (SUSAR).  The Sponsor will notify the appropriate 
regulatory agencies as well as all participating Investigators of 
investigational new drug (IND) safety reports (SUSARs) that occur 
during the study within the time frames required by each regulatory 
agency.  The Investigator is responsible for submitting information 
on IND safety reports/SUSARs received from the Sponsor or 
Sponsor designee to her/his local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities must be retained in the 
appropriate study file(s). 
 
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12.1.6 
Notification of Post-Study SAEs 
• 
Added text 
 Notification of Post-Study SAEs 
SAEs that occur more than 30 days after a subject has 
discontinued investigative product, and are not considered 
related to investigational product, must still be reported in the 
EDC system; however, these events are not required to be 
reported within 24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to investigational 
product, action taken with investigative product, treatment, 
outcome, and potential endpoint status need to be recorded in 
EDC for the SAE.  Additional information (e.g. event summary, 
SAE details) may also be required to be entered, when 
requested by the Sponsor. 
 
12.1.8 
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments.  
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments. The Sponsor may also 
follow the health of an infant born subsequent to use of 
investigational product. 
 
12.2.2 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page …. 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page for findings that appear after consent, and on the 
medical history CRF for any finding present prior to consent…. 
12.2.5.1 
12.2.5.1  Subject Questionnaires 
 
12.2.6 Subject Questionnaires 
12.2.6/12.2.7 
12.2.6   Laboratory Assessments 
Subjects testing positive for urine drug screen will be excluded 
from the study. 
12.2.7 Laboratory Assessments 
Deleted text 
 
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Table 4  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids, thyroid hormones (T3, 
T4, TSH) 
 
Table 5  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids 
 
12.2.6 
Laboratory Assessments 
• 
Added text 
 
 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly visits based on serum chemistry and coagulation. 
 
12.2.7  Laboratory Assessments 
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. 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly (MELD scores only) and semi-annual visits based on 
serum chemistry and coagulation. 
 
13.1.5 
Additional Secondary Efficacy Analyses 
• 
Added text 
Additional Secondary Efficacy Analyses 
• 
Time to development of varix/varices 
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13.1.8 
Supportive Analysis 
Although the results of using matching are conditional only on the 
observed covariates, if one has the ability to measure many of the 
covariates that are believed to be related to the treatment 
assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained. 
 
Supportive Analysis 
Although the results of using matching controls are conditional 
only on the observed covariates, if one has the ability to measure 
many of the covariates that are believed to be related to the 
treatment assignment, then one can be fairly confident that 
approximately unbiased estimates for the treatment effect can be 
obtained. 
13.3 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study. In addition, the DSMC statistician 
will evaluate the sample size as described in Section 13.1.2.1. 
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.   
 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study.  
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.  The DSMC will document details about 
any unblinded subject data reviews in the closed session DSMC 
minutes, which will be made available to the Sponsor only after 
the database is locked and the trial is unblinded.   Cases of 
premature unblinding, as noted above, will also be reviewed by 
the DSMC.  
 
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16.2, Ethical 
Conduct of the 
Study 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles 
that have their origin in the Declaration of Helsinki (Seoul 
Revision, 2008) and are consistent with ICH/GCP, applicable 
regulatory requirements and the Sponsor’s policies. 
Ethical Conduct of the Study 
 The study will be performed in accordance with ethical principles 
and are consistent with ICH/GCP, local applicable regulatory 
requirements (in addition to Appendix C) and the Sponsor’s 
policies. 
19 
List of References 
• 
Added text 
List of References 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact 
of fatigue: initial validation of the fatigue impact scale. Clin Infect 
Dis. 1994 Jan;18 Suppl 1:S79-83.  
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 Dec;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), 
1622-1629. 
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. 
Appendix C 
• 
Added document 
Ethical Conduct according to the Declaration of Helsinki for 
Countries Participating Outside the US 
 
 
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APPENDIX E.  SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 (DATED 12 NOV 2015) 
Rationale 
The changes to Amendment 1 of the protocol, detailed below, generated specifically for regulatory authority requests, include an 
additional exclusion criteria and changes to text precluding UDCA naïve subjects from entering the study and clarifying information 
showing that OCA may increase the exposure of narrow therapeutic index drugs that are substrates for CYP1A2, thus answering 
questions raised by regulatory authorities. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.1.  (Note:  Revised text in Amendment 1.1 is indicated in 
bold font, and the text deleted from Protocol Amendment 1 is crossed out in the table below. Minor formatting changes are not listed.) 
Section 
Original Text (Amendment 1, 29 April 2015) 
Revised Text (Amendment 1.1, 12 November 2015) 
Title Page 
Original:  03 October 2014 
Amendment 1:  29 APRIL 2015 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Amendment 1.1:  12 November 2015 
Study Personnel 
Contact 
Information 
Mobile:      
 (Pacific time zone) 
Telephone: 
 
Telephone 
 
(deleted) 
Telephone: 
 
(deleted)   
Synopsis, 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
Synopsis, 
Statistical 
Methods:  
Sample Size 
Justification 
• 
5% of the subjects will have never been treated with UDCA; 
95% of the subjects will have been on UDCA for at least 1 
year 
(deleted) 
 
8.3 Subject 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
9.2 Concomitant 
Medications 
(insertion) 
The effect of OCA on drug metabolizing enzymes has been 
evaluated in both in vitro and clinical studies.  The PK profile 
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of caffeine, a sensitive CYP1A2 substrate, 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. 
12.1.4.2 
Reporting of 
Serious Adverse 
Event 
Mobile:      
 (Pacific time zone) 
Telephone: +1 858 964 1571 
(deleted) 
Telephone: 
   
13.1.2 
Determination of 
Sample Size 
5% of the subjects will have never been treated with UDCA; 95% 
of the subjects will have been on UDCA for at least 1 year 
(deleted) 
 
 
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APPENDIX F. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 TO VERSION 3 
(DATED 07 SEP 2016) 
Rationale 
The changes to Version 3 of the protocol, include dosing adjustments based on Child-Pugh scoring, additional exclusion criteria, 
changes to text precluding UDCA-naïve subjects from entering the study.  
Please note that the Sponsor has renamed protocol “amendments” to “versions”, therefore all future revisions that require a revised 
protocol will have an associated “version” number. The table below includes substantial revisions made to Protocol 747-302 under 
Version 3, which encompass the revisions captured in Protocol Amendment 1.1. Revised text in Version 3 is indicated in bold font, 
and the text deleted from Protocol Amendment 1.1 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 (Amendment 1.1, 
12 November 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology 
...  Mean values for ALP and total bilirubin 
will be calculated using all available 
screening values.  Subjects who meet all 
inclusion criteria and none of the exclusion 
criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The 
randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment 
(yes/no) and baseline bilirubin categories 
(>upper limit of normal [ULN]/ ≤ULN). 
Investigational product (OCA or matched 
placebo) will be taken orally, once daily.  
Investigational product will be initiated at 5 
mg OCA or matched placebo.  After 3 
months of treatment with investigational 
product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched 
placebo, in a blinded manner) at the 3-
month visit or any subsequent study visit 
based on tolerability.  Subjects will be seen 
at quarterly visits for the duration of the 
study. 
...  Investigational product will be taken orally, once daily 
for the majority of subjects; dose and frequency will be 
modified for subjects with cirrhosis (including subjects 
progressing to cirrhosis during the study) and 
classified as Child-Pugh B or C.  The randomization will 
be stratified by ursodeoxycholic acid (UDCA) treatment 
(yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
To incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores, 
to align with the 
recommended dosing 
regimen found in the 
Ocaliva US Package Insert 
for patients with hepatic 
impairment. 
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Original Text (Amendment 1.1, 
12 November 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology. 
7.1.1, Study 
Design Diagram, 
Figure 1 
Schematic diagram
 
Updated schematic diagram 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.  Subsequent dose titration(s) for subjects 
classified as Child Pugh B or Child-Pugh C and 
following a modified dosing schedule may occur no 
earlier than 6 weeks after the previous dose titration 
Incorporate updated dosing 
scheme to reflect addition of 
Child-Pugh scoring. 
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Original Text (Amendment 1.1, 
12 November 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology 
(insertion) 
Dosing frequency will be determined by the presence 
or absence of cirrhosis and, if cirrhosis is present, by 
Child-Pugh Score as described below: 
• 
Non-cirrhotic subjects or subjects classified as 
Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects 
should titrate to a maximum dose of 10-mg OCA once 
daily (or matching placebo) at the Month 3 visit or at 
any study visit following the Month 3 visit based on 
tolerability of the product.    
• 
For those subjects that up-titrate to 10 mg, dosing 
may be decreased to 5 mg at any time during the study 
as considered clinically appropriate (eg, based on 
tolerability). Subjects may be titrated back to a 
maximum dose of 10 mg once daily based on 
tolerability and clinical judgment of the Investigator.    
• 
 Subjects who are cirrhotic and classified as Child-
Pugh Class B or Child-Pugh Class C will initiate a 
modified treatment regimen with 5-mg OCA or 
matching placebo once weekly for at least 3 months.  
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5-mg OCA or 
matching placebo once daily, based on tolerability.  
Subjects classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 10-mg 
OCA or matching placebo twice weekly, based on 
tolerability. 
Includes New Table: Planned Dosing Regimen by 
Cirrhosis and Child-Pugh Score 
Revised methodology to 
incorporate the changes in 
dosing for subjects based on 
the Child-Pugh Scores. 
 
5.1, Overview 
(insertion) 
The United States Food and Drug Administration 
(FDA) has granted accelerated approval for Ocaliva 
for the treatment of PBC.  Ocaliva is not yet approved 
outside the United States for use in any indication. 
Language updated as OCA 
is approved in the US with 
the trade name Ocaliva. 
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5.5.2.2, Rationale 
for Modified OCA 
Doses in Patients 
Classified with 
Child-Pugh B or 
Child-Pugh C 
Hepatic 
Impairment 
(Insertion) 
New section: Rationale for Modified OCA Doses in 
Patients Classified with Child-Pugh B or Child-Pugh C 
Hepatic Impairment 
Simulations using a physiologic PK model predicted 
changes in systemic and liver OCA concentrations 
associated with changes in the severity of hepatic 
impairment (Child-Pugh score).  Model simulations 
predicted that for mild (Child-Pugh A), moderate 
(Child-Pugh B), and severe (Child-Pugh C) hepatic 
impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to subjects 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 (Child-Pugh B and C) 
subjects treated with OCA in phase 1 and 2 studies 
experienced plasma OCA exposures >10-fold higher 
than those in healthy subjects, 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.  Collectively, the 
results from these analyses and those from bile acids in 
the literature suggest that the doses of OCA 
administered to hepatically-impaired patients should 
be modestly lower than those for patients with normal 
hepatic function to achieve similar hepatic exposure.   
Per the approved FDA prescribing label, the 
recommended dosing regimen for OCA in subjects 
with moderate and severe hepatic impairment is a 
starting dose of 5-mg OCA once weekly.   Dosage 
adjustments in subjects with moderate (Child-Pugh B) 
or severe (Child-Pugh C) hepatic impairment may be 
made after establishing tolerability at the lower dose 
Provide the rationale to 
incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores 
into the protocol. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
(full modified dosing regimen is described in 
Appendix A). 
5.6, Summary of 
Known Potential 
Risks with OCA 
(Insertion) 
…These findings were seen more frequently with doses 
above 10 mg OCA.  In addition, cholecystitis, including 
acute cholecystitis, was reported in association with 
treatment with OCA. 
Added two AE terms 
reported in the updated 
Investigator’s Brochure. 
7.1, Overall Study 
Design 
…Investigational product will be initiated 
at 5 mg OCA or matched placebo.   
Following 3 months of treatment with 
investigational product, subjects should be 
titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose 
to 10 mg OCA) based on tolerability 
Investigational product will be taken orally, once daily.  
Subjects who are non-cirrhotic or classified as Child-
Pugh A at Screening will initiate investigational 
product once daily with 5-mg OCA or matching 
placebo. Following 3 months of once daily treatment with 
investigational product, the dose should be titrated to a 
maximum 10 mg OCA or matching placebo once daily, 
based on tolerability (see Section 7.3).  
Subjects with cirrhosis and classified as Child-Pugh 
Class B or Child-Pugh Class C will follow a modified 
dosing regimen, and will initiate investigational 
product once weekly with the 5-mg OCA or matching 
placebo dose.  In addition, these subjects will follow a 
modified titration plan, which is outlined in 
Appendix A.  
Amend the protocol to 
incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores. 
7.1.2, Table 1, 
Schedule of Study 
Procedures – 
Screening to 
Month 12 (Table 1 
of 2), 9.3, 
Treatment 
compliance 
Safety Contact 
This visit has been deleted. 
Replaced with the 1 Month 
Post-Titration Visit. 
(Insertion) 
Added the following visits: 
• 
Month 1 
• 
1 Month Post-Titration Visit 
Visits were added to 
accommodate the updated 
dosing and titration regimen 
based on subject’s 
Child-Pugh Scores. 
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Justification for Change 
bThe subject should be contacted by 
telephone on a monthly basis in between at-
clinic study visits at Month 1 and Month 2 
(± 1 week), and also 2 weeks post dose 
titration (up or down), to assess for AEs and 
concomitant medications and to verify that 
s/he is dosing as directed. 
cAs soon as possible upon study 
discontinuation and as near as possible to 
last dose taken. 
nSubject to begin dosing on Day 1 
Deleted. 
Result of table being 
updated for the dosing and 
titration regimen based on 
subject’s Child-Pugh Scores. 
(Insertion) 
Added the following study procedures: 
• 
Cirrhosis Status Assessmente 
• 
Assessments for Child-Pugh Scoresg 
• 
Dose Titration: Standard Dosingn,o 
• 
Dose Titration: Modified Dosing n,o 
• 
Dosing Diary 
Study procedures were 
added to accommodate the 
updated dosing/titration 
regimen.  Dosing diary was 
added to improve 
compliance. 
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(Insertion) 
Added the following footnotes: 
• 
bSafety 
Post-Titration 
visits 
must 
be 
performed 1 month + 1 week after any up-
titration in dose and/or frequency in subjects 
following modified dosing due to Child-Pugh 
B and Child-Pugh C hepatic impairment.  In 
subjects following the standard dosing 
regimen, the post-titration visit must be 
performed only after the first up-titration to 
10 mg OCA or matching placebo, or after ≥3 
months at a decreased dose or frequency. 
• 
ePresence or absence of cirrhosis should be 
assessed per Section 9.7.3.  Cirrhosis status 
should be repeated as clinically indicated. 
• 
fMayo Risk Score will be calculated based on 
central laboratory evaluations, diuretic use 
data, and peripheral edema assessment data 
captured in the CRF. 
• 
gChild-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. 
• 
nPre-titration tolerability assessment, which 
include a review of AEs and a review of 
safety laboratory results (eg, chemistry, 
hematology, and coagulation), must be 
completed by the Investigator before any up-
titration 
can 
occur 
as 
defined 
in 
Section 7.4.1.  Lab results obtained within 2 
months prior to any up-titration may be used 
for assessment. 
• 
oDose Titration is based on cirrhosis status 
(Section 9.7.3) 
and 
Child-Pugh 
score 
(Section 7.3).  The initial dose titration of 
investigational product may occur at the 
Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.  Subsequent dose titration(s) for 
Added footnotes provide 
clarity regarding 
assessments and visits based 
on the evaluation of 
Child-Pugh scores.  
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Justification for Change 
subjects who are classified as Child-Pugh B 
or Child-Pugh C and following a modified 
dosing schedule may occur no earlier than 6 
weeks after the previous dose titration.  For 
complete modified dose titration criteria, 
refer to Appendix A. 
• 
pSubjects will be instructed to begin dosing 
on the day after the Day 0 visit (ie, on Day 1) 
and to take investigational product at 
approximately the same time of day.  
Subjects must be instructed to swallow the 
tablet whole; they must not chew, divide, or 
crush the tablet. 
7.1.2, Table 2, 
Schedule of Study 
Procedures – Year 
2 Through End of 
Study (Table 2 of 
2) 
 
New table- Schedule of Study Procedures – Year 2 
Through End of Study (Table 2 of 2) 
Divided Schedule of Study 
Procedures into 2 tables, 
updated to include visits 
added per updated 
dosing/titration information.   
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Justification for Change 
7.3, Planned 
Dosing Regimen 
7.3 Treatment Assignment 
Subjects will receive either placebo or 5 mg 
OCA and should titrate to 10 mg OCA (in a 
blinded manner) at the 3-month study visit 
or at any study visit thereafter depending on 
tolerability. 
7.3 Planned Dosing Regimen 
Subjects will be randomized to treatment with either 
OCA or matching placebo in a 1:1 ratio.  Subjects will 
be dosed according to their cirrhosis status (as defined 
in Section 9.7.3) and applicable Child-Pugh Score (see 
Section 9.7.4) as outlined in Table 3.  
Subjects who are non-cirrhotic or classified as 
Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects 
should titrate to a maximum dose of 10-mg OCA once 
daily (or matching placebo) at the Month 3 visit or at 
any study visit following the Month 3 visit based on 
tolerability of the product.  A review of safety 
laboratory results (eg, chemistry, hematology, and 
coagulation) obtained no more than 2 months prior to 
the planned up-titration visit must be completed as 
part of the product tolerability assessment before up-
titration can occur (see Section 7.4.1).   
For those subjects that up-titrate to 10 mg, dose may 
be decreased to 5 mg at any time during the study as 
considered clinically appropriate (eg, tolerability). 
Subjects may be titrated back up to a maximum dose 
of 10 mg once daily based on tolerability and clinical 
judgment of the Investigator.  A review of safety 
laboratory results obtained within 2 months of the 
planned up-titration visit date is not required prior to 
re-challenging a subject up to 10 mg once daily dosing, 
as long as the decrease in dose/dosing frequency was 
less than 3 months in duration. 
Section renamed to reflect 
changes in titration and 
dosing for subjects with 
hepatic impairment. 
(Insertion) 
New:  Table 3: Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
Tables added to clarify 
changes in titration and 
dosing. 
New: Table 4: Determination of Dosing Regimen 
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7.4 Dose Titration 
Criteria 
After 3 months of treatment at the 5 mg 
dose, the dose of OCA will be increased to 
the maximum dose of 10 mg OCA or 
matched placebo (in a blinded manner) at 
the 3-month visit or any study visit 
following the 3 month visit based on 
tolerability of investigational product.   
 
For those subjects that increased their dose 
to 10 mg, they may decrease his or her dose 
to 5 mg at any time during the study as 
considered appropriate (eg, tolerability), but 
should be titrated back to 10 mg based on 
tolerability and clinical judgment by the 
Investigator as soon as possible with the 
goal that all subjects remain on the 10-mg 
dose if tolerated 
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 
subject’s cirrhosis status (using histology or 
non-histological methods as defined in Section 9.7.3 
and Section 9.7.4) or Child-Pugh Score.   
Scheduled Dose Titration - The first dose titration for 
any subject may occur no earlier than 3 months 
following initiation of OCA or matching placebo.  
Subsequent titrations in dose or dosing frequency for 
subjects following the Modified Dosing Regimens may 
occur no earlier than 6 weeks (via an unscheduled visit 
or regular visit- see Appendix A) following an 
up-titration. 
Tolerability Dose Titration - Investigators may 
decrease the dosing frequency or dose for any subject at 
any time during the study, as considered clinically 
appropriate (eg, tolerability; see Section 7.4.2).   
Dose Titration due to Change in Cirrhosis or 
Child-Pugh Score - When subjects demonstrate a 
change in cirrhosis status (as assessed per 
Section 9.7.3) or Child-Pugh Score (Section 9.7.4), 
dosing should be reassessed and the dosing regimen 
modified appropriately.  Changes to the dosing 
regimen are not mandatory and should be based on 
clinical judgment as well as change in cirrhosis status.  
Table 5 provides an overview of the possible changes in 
dosing regimen due to changes in cirrhosis or Child-
Pugh 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.  
Entire section revised to 
reflect changes in titration 
and dosing. 
7.4 Dose Titration 
Criteria 
(Insertion) 
New: Table 5:  Changes in Dosing Regimen Due to 
Changes in Cirrhosis Status or Child-Pugh Score 
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7.4 Dose Titration 
Criteria 
(Insertion) 
Subjects who exhibit development of cirrhosis at any 
point in the study should be assessed per Section 9.7.3.  
If the presence of cirrhosis is confirmed and the 
subject’s Child-Pugh score is either B or C, the 
appropriate modified dosing regimen should be 
followed.  The dose or frequency of investigational 
product should be down-titrated to the next lowest 
dosing frequency in the appropriate modified dosing 
regimen unless the subject is currently taking a dose 
and frequency also specified in the modified dosing 
regimen and the investigator determines that it is 
clinically appropriate for the subject to continue at 
that dose (Appendix A). 
Subjects with pre-existing cirrhosis who demonstrate a 
change in the Child-Pugh Score from A to B or C at 
any point in the study should also have their dosing 
modified per the appropriate dosing regimen 
(Appendix A).  
Subjects who demonstrate an improvement in 
cirrhosis status or in Child-Pugh Score from B to A, or 
from Child-Pugh C to B, may be eligible to transition 
to the standard dosing regimen or the modified dosing 
for Child-Pugh B, respectively, based on tolerability.  
Prior to any dosing change, subjects must meet 
pre-titration assessment requirements for dosing as 
described in Section 7.4.1. 
Child-Pugh Scores will be calculated at all quarterly 
study visits. All associated visit data (including central 
laboratory results) should be entered into the eCRF in 
a timely fashion to confirm that the subject’s Child 
Pugh Score has not changed.  If a change in cirrhosis 
status (as defined in Section 9.7.3) and/or Child-Pugh 
Score is observed independent of a study visit, the 
subject 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 and table added to 
provide dosing guidelines to 
investigators. 
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Subjects’ dose and dosing frequency may be titrated 
up or down within the appropriate dosing regimen 
based on the calculated Child-Pugh Scores.  Up-
titration should be done per Investigator discretion 
and be guided by the pre-titration tolerability 
assessments. 
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7.4.1, 
Pre-Titration 
Tolerability 
Assessment 
Requirements 
(Insertion) 
7.4.1  Pre-Titration Assessment Requirements 
Tolerability of investigational product must be 
assessed prior to titrating a subject to a higher dose.  A 
review of adverse events and safety laboratory results 
(eg, chemistry, hematology, and coagulation) obtained 
within 2 months of the up-titration visit must be 
performed as part of the investigational product 
tolerability assessment, prior to any planned up-
titration in investigative product (eg, Month 3, Month 
6).  Safety laboratory results obtained at the Month 1 
visit (for titration at Month 3) or at the 1 Month 
Post-Titration Assessment visit (for titration prior to 
or at the subsequent quarterly visit) are acceptable for 
review purposes; however, 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 subject to a higher dose.  
To be eligible for a dose up-titration: 
• 
Subjects 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.  
• 
There must be no clinically significant increase (as 
determined by the investigator) in the subject’s liver 
function tests.  Subjects whose total bilirubin is 
>2× baseline (and >ULN) cannot be up-titrated, and 
additional unscheduled safety visit procedures, 
outlined in Section 9.7.19, should be implemented, as 
required 
Section added to provide 
guidance for assessing 
subject tolerability prior to 
titration. 
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8.4.2, Other 
Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
(Insertion) 
• 
Subject begins treatment with commercially 
available OCA 
… safety concerns and related to study drug 
• 
Consent may be fully withdrawn (in which case the 
subject discontinues both investigational product and 
study visits and procedures) 
…Subjects who undergo a liver transplant during the 
course of the study must discontinue investigational 
product and discontinue the study visit schedule.  
However, these subjects 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. 
Added text as Ocaliva is 
commercially available in 
the US and therefore 
subjects may be 
discontinued if they began 
off-study treatment with 
Ocaliva.   
8.4.2.1, Elevated 
Liver Enzymes 
(Insertion) 
New Section:  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. 
Section added to incorporate 
monitoring of liver test 
results during the study. 
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9.1, 
Investigational 
Product Treatment 
Regimen 
9.1.1 Dose Adjustment Beginning at 
Month 3 
After 3 months of treatment with 
investigational product, the dose of 
investigational product should be increased 
in a blinded manner and based on 
tolerability; this may occur at the Month 3 
visit, or at any study visit thereafter.  
Titration above 10 mg OCA is not 
permitted. 
At each study visit where the daily dose of 
investigational product is administered at the site, all 
assessments, except for the post-dose collection of 
blood samples for the subset of subjects participating 
in the Month 9 PK assessment, must be completed 
before administration of investigational product. 
Section revised to reflect 
changes in titration and 
dosing. 
9.2, Concomitant 
Medications 
Subjects taking bile acid sequestrants 
(BAS) 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). 
 
New sub-heading:   
Drug Interactions 
Subjects 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 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.  
(…) Information related to additional drug-drug 
interaction (DDI) studies is available in the current 
version of the Investigator’s Brochure (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 with OCA that may 
be observed in study subjects. 
Section revised to provide 
additional information on 
drug-drug interactions with 
OCA. 
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9.2.1, Prohibited 
Medications 
… the Investigator should be cognizant of 
the possibility of double dosing and 
encourage the discontinuation of open-label 
OCA therapy.  However, if commercial 
OCA therapy remains, then investigational 
product should be discontinued to avoid 
potential double dosing.  Subjects that 
discontinue investigational product but 
continue commercial OCA therapy are 
expected to continue through the end of the 
study, and the … 
… the Investigator should be cognizant of the possibility 
of double dosing.  Subjects who continue with 
commercial OCA therapy must discontinue investigative 
product and are expected to continue through the end of 
the study.  … 
Ocaliva is commercially 
available in the US and, 
therefore, subjects wishing 
to take commercially 
available drug are not 
discouraged, but they must 
discontinue investigative 
product. 
9.7.1, Visit 
Windows 
(insertion) 
Added the following visit windows: 
• 
Month 1 (+1 week [7 days]) 
• 
Titration Visit – Standard Dosing Regimen 
(≥Month 3) 
• 
Titration Visit 1 – Modified Dosing Regimen 
(≥Month 3) 
• 
Titration Visit 2 – Modified Dosing Regimen 
(≥6 weeks after Titration Visit 1) 
• 
Titration Visit 3 – Modified Dosing Regimen 
(Child-Pugh B ONLY) (≥6 weeks after 
Titration Visit 2) 
• 
Post-Titration Visit, (+1week [7 days]) from 
date of titration or after ≥3 months at a 
decreased dose or frequency) 
Added visits to 
accommodate the updated 
dosing/titration scheme. 
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9.7.3, Assessing 
Cirrhosis 
(Insertion) 
New: 9.7.3. Assessing Cirrhosis 
To determine which dosing regimen subjects should 
follow, the presence or absence of 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 
is defined as a subject 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  
− 
elevation in prothrombin time /INR (not 
due to antithrombotic agent use), or 
− 
elevated bilirubin (2× ULN) 
Subjects who exhibit no evidence of cirrhosis by the 
above methods of assessment will be dosed using the 
Standard Dosing Regimen, while those who do exhibit 
evidence of cirrhosis by one or more of the above 
methods will be dosed using the Modified Dosing 
Regimen according to their Child-Pugh Score 
calculated in the electronic case report form (eCRF) 
(see Appendix A). 
Cirrhosis status should be reassessed as clinically 
indicated throughout the study.  Any change in 
Added section to assess 
cirrhosis as this assessment 
will determine the 
acceptable dosing regimen 
based on a subject’s 
Child-Pugh score.  
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Justification for Change 
cirrhosis status will necessitate re-evaluation of the 
dosing regimen. 
9.7.4, Child-Pugh 
Score 
(Insertion) 
9.7.4. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is 
calculated and reported within the electronic data 
capture (EDC) system based on data entered into the 
eCRF adding the scores from the 5 factors outlined in 
Table 6 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 
Child-Pugh 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.   
It is important to note that subjects must have 
confirmed cirrhosis as assessed by one or more of the 
above criteria (Section 9.7.3) prior to applying the 
calculated Child-Pugh score for dosing.  Investigators 
will be responsible for determining the appropriate 
dosing regimen based on both the cirrhosis status and 
the Child-Pugh score (Table 6).  Any change in 
cirrhosis status or Child-Pugh Score will necessitate 
re-evaluation of the dosing regimen 
Section added to provide 
Investigators with 
information on the 
Child-Pugh scoring system. 
9.7.4, Child-Pugh 
Score 
(Insertion) 
Table 6 (New) Child-Pugh Scoring System 
 
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Justification for Change 
9.7.6, Screening 
Procedures (1 to 8 
Weeks prior to 
Day 0) 
(Insertion) 
The following procedures were added: 
Screening Visit 1 procedures are as follows: 
• 
Provide the subject with a dosing diary to 
document his or her dosing 
• 
Assess for the presence/absence of cirrhosis 
• 
Perform status assessment for calculation of 
Mayo Risk Score 
Screening Visit 2 procedures are as follows: 
• 
Perform an ultrasound for hepatocellular 
carcinoma (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 Visit 2, and a report/adequate data are 
available, a pretreatment ultrasound at Screening 
Visit 2 is not required.  If the ultrasound cannot 
be performed at Screening Visit 2 (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. 
Procedures added to assess 
cirrhosis. 
 
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Pr ot oc ol 7 4 7 -3 0 2  
Versi o n 5: 0 4 Ja n 2 0 1 8  
 
Pa ge 1 7 6  
 
C o nfi de ntial a n d Pr o prietar y   
Secti o n  
Ori gi n al Te xt ( A me n d me nt 1. 1, 
1 2  N o ve m ber  2 0 1 5)  
Re vise d Te xt ( Ve rsi o n 3, 0 7  Se pte m ber  2 0 1 6)  
J ustific ati o n f or C h a n ge  
9. 7. 7, Da y 0 
Pr oce d ures 
( Ra n d o mizati o n) 
9. 7. 4. 
Da y 0 Pr oce d ures  
• 
Perf or m a n ultras o u n d f or 
he pat ocell ular carci n o ma ( H C C ) 
s ur veilla nce (if e q ui p me nt is u na vaila ble, 
… 
• 
Perf or m p h ysical e xa mi nati o n a n d 
o verall stat us assess me nt f or calc ulati o n of 
Ma y o Ris k Sc ore a n d C hil d -P u g h 
Assess me nts. 
 Prese nce/a bse nce of peri p heral e de ma  
 Prese nce ( de gree)/a bse nce of ascites  
 Prese nce ( de gree)/a bse nce of he patic 
e nce p hal o pat h y  
9. 7. 7 : Da y 0 Pr oce d ures ( Ra n d o mizati o n)  
• 
Pr o vi de t he s u bject wit h a d osi n g di ar y t o 
d oc u me nt his or her d osi n g.  
 
U p date d visit t o 
acc o m m o date t he u p date d 
d osi n g/titrati o n sc he me.  
9. 7. 8, M o nt h 1 
Pr oce d ures  
9. 7. 5 Safet y C o ntact ( M o nt h 1, M o nt h 2, 
a n d 2 W ee ks P ost -Titrati o n [ b y tele p h o ne])  
9. 7. 8  M o nt h 1 Pr oce d ures  
• 
Pr o vi de t he s u bject wit h a d osi n g di ar y t o 
d oc u me nt his or her d osi n g.  
• 
I n t he e ve nt it is n ot fe asi ble f or t he s u bject t o 
ret ur n t o t he site f or t he a b o ve refere nce d pr oce d ures, 
t he f oll o wi n g alter n ati ve visit pr oce d ures are a v ail a ble 
t o hel p e ns ure c o m pli a nce wit h t he M o nt h 1 visit 
re q uire me nts:  
- 
At t he D a y 0 visit, t he s u bject c a n be pr o vi de d 
wit h t he ce ntr al l a b or at or y c ollecti o n kit a n d s hi p pi n g 
m ateri als ass oci ate d wit h t he M o nt h 1 visit, …  
- 
If all ot her o pti o ns f or t he c ollecti o n of t he M o nt h 
1 l a b or at or y s a m ples h a ve bee n e x h a uste d, t he use of a 
l oc al l a b or at or y f or t he M o nt h 1 s a m ples w o ul d be 
acce pte d f or t his visit alt h o u g h a n y l a b or at or y  d at a 
o bt ai ne d fr o m a l oc al l a b or at or y will n ot be c a pt ure d 
i n t he e C R F or i ncl u de d i n t he st u d y a n al ysis.  … 
 
Re vise d secti o n t o i ncl u de 
t he ne w M o nt h 1 visit 
pr oce d ures.  
Pa ge 1 7 6 of 3 3 3
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9.7.9, Month 3 
procedures, 
9.7.11, Month 6 
Procedures, 
9.7.12, Month 9, 
9.7.14, Month 12 
Procedures  
(Insertion) 
• 
Perform assessments for calculation of Child-Pugh 
Score 
Added procedure to 
accommodate the updated 
dosing/titration scheme. 
9.7.9 thru 9.7.17 
(Insertion) 
If up-titration will occur at this visit, complete the pre-
titration visit and visit related assessments as outlined 
to ensure all procedures required for dose titration 
eligibility have been met, including the required review 
of the dose titration laboratory parameters. 
• 
Provide the subject with a dosing diary to 
document his or her dosing 
• 
… review dosing diary with the subject 
Text added to clarify 
procedures required before 
up-titration. 
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9.7.10, Post 
Titration Visit 
Procedures 
(Insertion) 
New: 9.7.10. Post Titration Visit Procedures 
• 
Assess and record AEs. 
• 
Review and record concomitant medications. 
• 
Assess investigational product compliance, 
perform investigational product accountability, and 
review dosing diary with the subject. 
• 
Obtain blood samples for serum chemistry, 
hematology, and coagulation tests. 
• 
Provide the subject with a dosing diary to 
document his or her dosing. 
• 
In the event it is not feasible for the subject to 
return the site for the above referenced procedures, 
the following alternative visit procedures are available, 
to help ensure compliance with the Post-Titration visit 
requirements: 
- 
At the Up-titration Visit, the subject can be 
provided with the central laboratory collection kit 
and shipping materials associated with the Post-
Titration visit, and have the laboratory specimen 
collection performed at his or her local doctor’s 
office or designated laboratory collection center.  
The subject must also be contacted via telephone 
at the Post-Titration Visit time point to assess 
AEs, review concomitant medications, and assess 
investigational product compliance. 
- 
If all other options for the collection of the 
Post-Titration laboratory samples have been 
exhausted, the use of a local laboratory for the 
Post Titration samples would be accepted for this 
visit although any laboratory data obtained from 
a local laboratory will not be captured in the 
eCRF or included in the study analysis.  A copy of 
the local laboratory report would need to be 
provided to the investigator for review and 
available in the source records.  The subject must 
also be contacted via telephone at the Post-
Titration Visit time point to assess AEs, review 
Added visit to accommodate 
the updated dosing/titration 
scheme. 
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Justification for Change 
concomitant medications, and assess 
investigational product compliance. 
• 
Schedule the next visit, reiterate dosing 
instructions, and advise the subject: 
- 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… 
9.7.13, Month 9 
Procedures for 
Subjects 
Participating in 
Pharmacokinetic 
Assessment 
(Insertion) 
…Subjects who are following the Child-Pugh B and 
Child-Pugh C modified dosing regimen may 
participate in the PK assessment and will dose in the 
clinic at this visit even if the previous dose was taken 
less than 3 days prior; however, every attempt should 
be made to schedule the Month 9 PK visit according to 
the subject’s established dosing schedule. 
Clarify that subjects with 
hepatic impairment may 
continue to participate in the 
PK assessment. 
9.7.13, Month 9 
Procedures for 
Subjects 
Participating in 
Pharmacokinetic 
Assessment 
…Lunch will be provided following 
collection of the 4 hour PK sample; the 
lunch will be a meal replacement drink… 
…Lunch will be provided following collection of the 
4 hour PK sample; the lunch will be a meal replacement 
drink with no other food allowed until after the final 
6-hour post dose sample is collected… 
Clarify PK collection 
procedures. 
 
11.1.2.2, Other 
Secondary 
Assessments 
• 
OCA (and its conjugates) and C4 will 
be assayed 
• 
OCA (OCA, tauro-OCA, glyco-OCA, total OCA, 
OCA-glucuronide) and C4 will be assayed to determine 
bioanalytical concentrations.  Additional analyses may 
include other conjugates or metabolites not yet 
identified. 
Clarify the analytes to be 
measured for the PK 
analyses. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
11.1.2.4, Potential 
Clinical Outcome 
Events 
(Insertion) 
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 13.4. 
Revised to clarify that 
potential clinical outcome 
events meeting the criteria 
of a SUSAR will not be 
reported to regulatory 
authorities expeditiously.  
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12.1.4.2 Reporting 
of Serious 
Adverse Event 
In agreeing to the provisions of this 
protocol, the Investigator accepts all legal 
responsibilities for immediate reporting of 
SAEs to the medical monitor. 
All SAEs occurring while subjects are 
receiving investigational product or are on 
an investigational product holiday 
(including Potential Clinical Outcome 
Events that qualify as serious) must be 
reported to the medical monitor 
immediately (ie, within 24 hours) after the 
Investigator identifies the SAE.  SAEs are 
reported by entering the SAE data into the 
electronic data capture (EDC) system.  
Entering the SAE data into the EDC system 
will automatically notify the medical 
monitor of the event.  In the event that the 
EDC system is inaccessible, an SAE may 
be reported by telephone or fax using a 
paper SAE Report form.  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:   
subject number and initials, a description of 
the event, at least one criterion classifying 
the event as serious and the name and title 
of the reporting individual.  Additionally, 
judgment of causality by the Investigator 
must be provided as soon as possible to 
ensure timely reporting to regulatory 
authorities by the Sponsor or designee(s).  
Following the initial report, any additional 
information obtained by the Investigator 
about the SAE must be reported promptly 
to the medical monitor.  Any supporting 
source documentation should be faxed to 
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 be reported by: 
• 
E-mail to the SAE email address:  
sae@interceptpharma.com 
• 
Fax using a paper SAE report form:  
+1 800 497 8521 
• 
Telephone:  +1 858 964 1571  
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:   
• 
Subject 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 Sponsor will notify the appropriate regulatory 
agencies as well as all participating Investigators of 
investigational new drug (IND) 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 
Updated guidance for 
reporting SAEs. 
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Justification for Change 
+1 800 497 8521 or emailed to 
sae@interceptpharma.com as soon as 
possible. 
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.  A 
SAE assessed with a possible, probable, or 
definite causal relationship to the 
investigational product and unexpected 
according to IB Reference Safety 
Information (RSI), is known as a suspected 
unexpected serious adverse reaction 
(SUSAR).  The Sponsor will notify the 
appropriate regulatory agencies as well as 
all participating Investigators of 
investigational new drug (IND) safety 
reports (SUSARs) that occur during the 
study within the time frames required by 
each regulatory agency.  The Investigator is 
responsible for submitting information on 
IND safety reports/SUSARs received from 
the Sponsor or Sponsor designee to her/his 
local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities 
must be retained in the appropriate study 
file(s). 
Potential Clinical Outcome Events 
(Appendix A) as well as Anticipated Events 
(Appendix B) will not undergo expeditious 
reporting to regulatory authorities 
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 
+1 800 497 8521 or emailed to 
sae@interceptpharma.com as soon as possible.   
The Investigator is responsible for submitting 
information on IND 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 
IECs/IRBs must be retained in the appropriate study 
file(s).  As instructed by the Sponsor, IND 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 12.1.5. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Section 12.1.5, 
Suspected Liver-
related Clinical 
Outcome Events 
Clinical Outcome Events (Appendix A) as 
well as Anticipated Events (Appendix B) 
will not undergo expeditous reporting. 
12.1.5 Suspected Liver-Related Clinical Outcome 
Events 
Specified liver-related clinical outcome events may, by 
definition (see Section 12.1.1.2) qualify as SAEs.  The 
Sponsor must be notified of any SAEs within 24 hours 
of the site becoming aware of the event (see 
Section 12.1.4.2).  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. 
Given that the liver-related clinical outcome events 
could also meet the criteria of a SUSAR, please refer to 
Section 11.1.2.4. 
The Sponsor will consider the following list of clinical 
outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy), spontaneous bacterial 
and peritonitis (preferred term: peritonitis bacterial). 
Updated section to account 
for events related to hepatic 
impairment. 
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13.2.4, 
Cardiovascular 
Adjudication 
Committee 
13.2.3 
(…) 
In addition to potential clinical endpoint 
events, cardiovascular events will be 
adjudicated.  The adjudication of these 
events will be handled separately from the 
adjudication of events for assessment of the 
primary endpoint in this study and will be 
described separately. 
New Section: Cardiovascular Adjudication Committee 
In addition to potential clinical endpoint events, 
cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately 
from the adjudication of events for assessment of the 
primary endpoint in this study. Adjudicated 
cardiovascular events include core major adverse 
cardiovascular events (MACE) (cardiovascular death, 
nonfatal myocardial infarction, and nonfatal stroke) 
and expanded MACE (unstable angina requiring 
hospitalization, transient ischemic attack, peripheral 
or coronary revascularization procedures, 
hospitalization for congestive heart failure).  Other 
events potentially related to adverse cardiovascular 
outcomes may be included in the Cardiovascular 
Adjudication Committee (CAC) Charter for 
adjudication.  The adjudication of these events will be 
handled separately from the adjudication of events for 
assessment of the primary endpoint in this study (see 
Section 13.4). 
Committee added to assess 
cardiovascular events in 
subjects during the study. 
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13.4, Adjudication 
Committee 
All potential endpoint events will be 
reviewed by an adjudication committee 
before inclusion in the any analysis.  The 
adjudication of potential clinical endpoint 
events will include, but is not limited to:  
available hospital reports, histology, 
discharge summaries, and death certificates.  
The assessment of events will be conducted 
in compliance with the protocol, study-
specific procedures, manuals, Good 
Clinical Practice (GCP), and all other 
applicable regulatory requirements, 
including the archiving of essential 
documents.  A separate adjudication 
committee charter will document the entire 
data flow and process from committee 
membership, the reporting of events by the 
study site, reporting of the final assessment, 
supply of source documentation to the 
committee, the review of the events by the 
committee, and the working procedures of 
the committee.  The adjudication committee 
members will be independent hepatologists 
not involved in the study as investigators, 
DSMC members, or consultants.  All 
adjudication committee members will 
remain blinded to treatment group 
throughout the study. 
In addition to potential clinical endpoint 
events, cardiovascular events will also be 
adjudicated.  The adjudication of these 
events will be handled separately from the 
adjudication of events for assessment of the 
primary endpoint in this study and will be 
described separately. 
All suspected liver-related clinical outcomes, 
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 subject treatment or site-
specific information.  The assessment of events will be 
conducted in compliance with study-specific 
Committees added to assess 
liver impairment in subjects 
during the study. 
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Original Text (Amendment 1.1, 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
procedures, manuals, good clinical practice (GCP), 
and all other applicable regulatory requirements, 
including the archiving of essential documents. 
Appendix A, 
Modified Dosing 
Regimen for 
Subjects with 
Child-Pugh B/C 
Hepatic 
Impairment 
(Insertion) 
New: APPENDIX A. MODIFIED DOSING 
REGIMEN FOR SUBJECTS WITH CHILD-PUGH 
B/C HEPATIC IMPAIRMENT 
Added section to describe 
changes in dosing and 
titration for subjects 
assessed as cirrhotic 
Child-Pugh B or 
Child-Pugh C. 
Appendix B, LIST 
OF STUDY 747-
302 OUTCOME 
EVENTS 
Was Appendix A 
Now Appendix B  
The hepatic dosing appendix 
became Appendix B  
Appendix C 
LIST OF STUDY 747-302 ANTICIPATED 
EVENTS 
Deleted 
Replaced by Appendix B, 
more comprehensive 
description of the outcome 
events. 
 
 
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APPENDIX G. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO PROTOCOL VERSION 3.1 
(DATED 23 DEC 2016) 
Please note that Protocol 747-302 Version 3.1 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.  This 
summary of changes is provided for completeness.  A full accounting of the changes from Protocol Version 3 to Protocol 
Version 4 is provided in Appendix I. 
Rationale and Summary of Changes 
Major revisions to Protocol 747-302 include the expansion of the spectrum of stages of PBC disease, the addition of progression to 
cirrhosis as a secondary endpoint, and the addition of two interim analyses.   Additional revisions include an increase in subject 
number and the number of required clinical outcome events, a change in the study phase, an update to the nomenclature for PBC, and 
various clarifications within the protocol.   
The following table includes revisions that were made to Protocol Version 3.1 with an associated reason or justification for the 
change.  Rationales (Justifications for Change) that impact multiple sections are provided below and referenced in the table with the 
appropriate rationale number.  
1. The phase of the study has been changed from ‘3b’ to ‘4’ to reflect that this is a post-marketing study. 
2. The term ‘primary biliary cirrhosis’ has been changed to ‘primary biliary cholangitis’ throughout the document to reflect 
recent changes in nomenclature for PBC. 
3. The increase in number of required events from 121 to 127 is due to the addition of two interim analyses (IA), which will 
allow an independent DMC to recommend continuation, modification, or cessation (for efficacy or futility) of the study.  One 
IA will occur at 50% information (after 64 events occur) and one at 75% information (after 96 events occur).  Inclusion of 
patients with earlier stage disease will also increase the time to event requiring more events in order to keep follow-up to 
approximately 6 years.   
4. The first-year study enrollment rate was lower than projected due to slower-than-anticipated activation of sites and required a 
re-estimation of the accrual duration.   Using observed accrual rates, the accrual duration was extended by two years.  The 
follow-up period was maintained at 6 years, thereby leading to a total trial duration of 10 years. 
5. ‘Encephalopathy’ has been modified to ‘Hepatic Encephalopathy’ to clarify that the relevant clinical outcome endpoint should 
be related to hepatic disease. 
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6. Histological confirmation (biopsy) has been added as an acceptable method of confirming a diagnosis of Hepatocellular 
Carcinoma. 
7. Broadening the Spectrum of Disease:  Lowering the minimum allowable baseline ALP to 3x ULN and raising the maximum 
allowable baseline total bilirubin to 5x ULN will increase the number of subjects enrolled with early and advanced disease 
facilitating the collection of safety and efficacy data in a population that covers the spectrum of PBC disease and overlaps with 
the subject population in the phase 3 protocol 747-301. 
8. The titration regimen has been updated to reflect assessment of both tolerability and biochemical response prior to up-titration 
per the USPI and SmPC.   
9. The increase in enrollment from 350 to 428 is due in part to the increased number of events, and in part due to the change in 
the estimated Placebo baseline hazard rate which resulted from changing the lower limit of ALP from 5× ULN to 3× ULN in 
the enrollment criteria #2. 
10. Progression to Cirrhosis has been added as a secondary endpoint:  Due to the chronic nature of PBC, outcomes require a very 
long time to accrue to evaluate the impact of potential therapies.  Despite the proven prognostic utility of ALP and bilirubin, 
there is a remaining need to evaluate noninvasive assessments of disease progression that can be linked to histological 
progression of the disease.  Therefore, it is important to evaluate potential non-invasive markers of fibrosis/cirrhosis and their 
relationship to clinical outcomes as part of 302. 
The text deleted from Protocol Version 3 is crossed out while revised text in Version 3.1 is indicated in bold font in the table below.  
Minor/editorial changes and non-substantial changes are not listed individually in the summary table below.  
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Section 
Original Text (Amendment 3, 
07 September 2016) 
Revised Text (Version 3.1, 23 December 2016) 
Justification for Change 
Title Page 
Synopsis, Title of 
Study 
A Phase 3b, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study Evaluating 
the Effect of Obeticholic Acid on Clinical 
Outcomes in Subjects with Primary Biliary 
Cirrhosis 
A Phase 4, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on 
Clinical Outcomes in Subjects with Primary 
Biliary Cholangitis 
 
Rationale 1 and 2  
Study Personnel 
Contact 
Information 
Or if Not Available: 
Contact: 
 MD, PhD, 
Executive Director, Clinical 
Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
 
 
Email: 
 
 (Pacific 
time zone) 
 
 
Or if Not Available: 
Contact: 
 MD, PhD 
Medical Director, Clinical 
Research, 
Intercept Pharmaceuticals, 
Inc. 
Telephone: 
Mobile: 
 
Email: 
 
 (Pacific 
time zone) 
 
Back-up medical monitor 
responsibilities were 
transferred to 
 
Synopsis, Studied 
Period (years) 
 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 and 4   
 
Synopsis, Phase of 
Development  
3b 
4 
Rationale 1 
Synopsis, 
Objectives, 
Primary, 
Statistical 
• 
Encephalopathy (as defined by a West Haven 
score of ≥2) 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities 
• 
Hepatic encephalopathy (as defined by a 
West Haven score of ≥2) 
Rationale 5   
 
 
Rationale 6 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Section 
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Revised Text (Version 3.1, 23 December 2016) 
Justification for Change 
Methods – 
Efficacy Analyses 
Section 6.1 
Primary Objective 
Section 11.1.1 
Primary 
Assessments 
 
Section 13.1.3 
Primary Efficacy 
Analysis 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities unless 
confirmed by biopsy 
Synopsis, 
Objectives, 
Secondary  
Section 6.2 
Secondary 
Objectives 
 
Insertion 
 
To assess the pharmacokinetics of OCA and its 
conjugates in a subset of subjects 
To assess the effect of OCA compared to 
placebo on progression to cirrhosis 
To characterize the pharmacokinetics of OCA 
and its conjugates in a subset of subjects 
Rationale 6 
 
 
 
Synopsis, 
Methodology: 
Schematic 
Diagram 
 
Section 7.1.1 
Study Design 
Diagram, Figure 1 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.   
 
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability of the product. 
 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability and biochemical response.   
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability and biochemical response of the 
product. 
Rationale 7 
 
 
 
 
Rationale 8 
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• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability. Subjects 
classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 
10-mg OCA or matching placebo twice 
weekly, based on tolerability. 
 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the titration of 
dose and/or frequency is dependent on subject tolerability, 
and/or changes in cirrhosis status or Child-Pugh Score at any 
time during the study.  
 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability and biochemical 
response. Subjects classified as Child-Pugh 
Class C should titrate to a maximum dose 
and frequency of 10-mg OCA or matching 
placebo twice weekly, based on tolerability 
and biochemical response. 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the titration 
of dose and/or frequency is dependent on subject tolerability, 
biochemical response, and/or changes in cirrhosis status or 
Child-Pugh Score at any time during the study. 
Synopsis, Number 
of Subjects 
(planned)  
Approximately 350 subjects 
Approximately 428 subjects 
Rationale 9 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
2.  A mean total bilirubin >ULN and ≤3x ULN 
and/or a mean ALP >5x ULN 
2.  A mean total bilirubin >ULN and ≤5x ULN 
and/or a mean ALP >3x ULN 
Rationale 7 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
5.  Contraception:  Female subjects 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:   
5.  Contraception:  Female subjects of 
childbearing potential must use ≥1 effective 
method of contraception during the study and 
until 30 days following the last dose of 
investigational product.  Effective methods 
of contraception are considered to be those 
listed below:   
Standardizing language across 
protocols; removing double-
barrier terminology 
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• 
Double barrier method, ie, (a) condom 
(male or female) or (b) diaphragm, with 
spermicide; or  
• 
Intrauterine device (IUD); 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 subject   
• 
Barrier method, ie, (a) condom (male 
or female) or (b) diaphragm, with 
spermicide 
• 
Intrauterine device (IUD)  
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection) 
• 
Abstinence, if in line with the preferred 
and usual lifestyle of the subject   
Synopsis, 
Exclusion Criteria 
Section 8.3 
Subject Exclusion 
Criteria 
 
3.  Mean total bilirubin >3x ULN 
Mean total bilirubin >5x ULN 
Rationale 7 
Synopsis, Criteria 
for Evaluation 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Encephalopathy (as 
defined by a West 
Haven score of ≥2) 
 
• 
Hepatocellular 
carcinoma 
confirmed by 
2 complimentary 
imaging modalities 
 
Secondary Objectives 
 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Hepatic 
encephalopathy (as 
defined by a West 
Haven score of ≥2) 
• 
Hepatocellular 
carcinoma confirmed 
by 2 complimentary 
imaging modalities 
already confirmed by 
biopsy 
Secondary Objectives 
 
Rationale 5 
 
 
 
 
 
 
 
 
 
 
Rationale 10 
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Progression to 
cirrhosis 
Clinical, laboratory, 
or radiological 
evidence of cirrhosis 
and/or liver stiffness 
(i.e., Fibroscan® TE) 
confirmed by biopsy 
unless not medically 
indicated 
Synopsis, 
Statistical 
Methods 
Analysis 
Populations 
 
The following subject populations will be 
evaluated and used for presentation and analysis of 
the data:  Randomized, Intent-to-Treat (ITT), 
Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical 
Control.  Descriptions of subject populations are 
provided in Section 13.1.1. 
The following subject populations will be 
evaluated and used for presentation and analysis 
of the data:  Intent-to-Treat (ITT), Safety, PK, 
Overall Historical Control, UKPBC Historical 
Control, and the Global PBS Historical Control.  
Descriptions of subject populations are provided 
in Section 13.1.1. 
 
Randomized population 
includes patients on OCA who 
withdrew prior to receiving 
drug and this is already 
collected with the safety 
population. 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Analysis 
The primary efficacy analysis will compare 
randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the 
ITT population.   
The primary efficacy analysis will compare OCA 
to placebo with respect to the primary efficacy 
endpoint using the ITT population.   
 
Synopsis, 
Statistical 
Methods, Key 
Secondary 
Efficacy Analyses 
The key secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
in ITT population with respect to the key 
secondary efficacy endpoints.   
The key secondary efficacy analyses will 
compare OCA to placebo in the ITT population 
with respect to the key secondary efficacy 
endpoints.   
 
Synopsis, 
Statistical 
Methods, Other 
Efficacy Analyses 
 
Section 13.1.5 
Additional 
Insertion 
Progression to cirrhosis will be assessed in the 
subset of subjects considered non-cirrhotic at 
baseline using available medical history, 
clinical, and laboratory assessments as well as 
baseline transient elastography (TE), where 
available. Specifically, subjects with no 
clinical, laboratory, or radiological evidence of 
cirrhosis at baseline and/or a TE liver stiffness 
of <16.9 kPa (Corpechot 2012) will be 
Rationale 10 
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Secondary 
Efficacy Analyses 
considered non cirrhotic.  Progression to 
cirrhosis will be assessed by the development 
of clinical, laboratory, or radiological evidence 
of cirrhosis and/or when liver stiffness 
increases to ≥16.9 kPa during the trial in 
which case histological progression to cirrhosis 
should be confirmed by biopsy unless not 
medically indicated. Using this definition for 
progression to cirrhosis, the percentage of 
non-cirrhotic subjects progressing to cirrhosis 
during the treatment period will be 
summarized by treatment group and 
compared using a Cochran–Mantel–Haenszel 
test stratified by the randomization 
stratification factor. 
Analyses for the histological assessment 
conducted as part of the biopsy sub-study are 
defined in Appendix C. 
 
Synopsis, 
Statistical 
Methods, Safety 
Analyses 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will compare OCA and placebo using the Safety 
Population. 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will be summarized by treatment group for the 
Safety Population. 
 
Clarification of summary 
analyses 
Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
Rationale 3 
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Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
 
Section 13.1.2. 
Determination of 
Sample Size 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, placebo 
survival estimate of 0.5 at 8 years 
with a hazard ratio of 0.60, and total 
study duration of 8 years, allowing 
for 2 years accrual and 6 years of 
follow up 
 
• 
Insertion 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, 
placebo survival estimate of 0.6 at 8 
years with a hazard ratio of 0.60, 
and total study duration of 10 years 
(from first subject enrolled), 
allowing for 4 years subject accrual 
and 6 years of follow up 
• 
Two interim analyses and one 
final analysis are planned 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
 
 
 
Rationale 4 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale 3 
 
 
 
 
 
 
Section 5.6 
Summary of 
Known Potential 
Risks with OCA 
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).  
An increase in liver enzymes and hepatic AEs, 
including jaundice, were observed in subjects 
with liver disease at OCA doses between 10 mg 
and 50 mg and in healthy subjects who were 
treated at doses ≥100 mg in Phase 1, multiple-
dose studies. 
Language has been updated to 
reflect Sponsor standards 
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Insertion 
Refer to the IB for additional information 
regarding the known potential risks with the 
investigational product. 
Section 7.1 
Overall Study 
Design 
This is a Phase 3b, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤3× ULN or ALP 
>5× ULN.   
 
Approximately 350 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 2-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
Investigational product will be taken orally, once 
daily….based on tolerability (see Section 7.3). 
 
 
 
The study will continue until approximately 121 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
This is a Phase 4, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤5× ULN or ALP 
>3× ULN.   
 
Approximately 428 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 4-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
Subjects will be dosed according to their 
cirrhosis status and Child-Pugh Score….based 
on tolerability and biochemical response (see 
Section 7.3)   
 
The study will continue until approximately 127 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
Rationale 1 
 
 
 
 
 
Rationale 9 
 
 
 
 
 
Clarification  
Rationale 7 
 
 
 
Rationale 3 
Section 7.1.2 
Schedule of Study 
Procedures, Table 
1  
Insertions 
 
 
 
 
 
 
Physical exams have been added at: 
• 
Month 1 
• 
1-Month Post Titration 
• 
Month 6 
Fibroscan® TE has been added at Month 6 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring. 
 
 
 
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j Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device 
is available.  Similarly, DEXA will be conducted at 
selected study sites where the DEXA device is 
available.    
 
 
Insertion (subsequent footnotes are renumbered 
accordingly) 
 
 
 
 
 
 
 
l Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be obtained to 
confirm if a study endpoint has been met. 
 
 
 
 
o … The initial dose titration of investigational product 
may occur at the Month 3 visit, or any study visit 
thereafter for subjects on all dosing regimens, based 
on tolerability. … 
 
u  A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of these 
samples.  Genetics samples will be collected at Day 0 
and every other year beginning at Month 12. 
 
j Transient elastography (TE) will be conducted at 6-
month intervals at all study sites where the 
Fibroscan® TE device is available.   
 
 
 
 
k DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available.  Please refer to Section 9.7.7 for 
additional information related to the allowed 
windows at Day 0 for this procedure. 
 
 
 
 
m Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: unless HCC has already confirmed 
by biopsy, a second confirmatory image (eg, MRI) 
should be obtained to confirm if a study endpoint 
has been met   
 
 
 
p … The initial dose titration of investigational product 
may occur at the Month 3 visit, or any study visit 
thereafter for subjects on all dosing regimens, based 
on tolerability and biochemical response. … 
 
v A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of these 
samples.  Genetics samples will be collected at Day 
0 and every other year beginning at Month 12.  If a 
baseline (e.g. Day 0) genetic sample is not 
obtained, subsequent genetic samples are not 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments at Day 0 
and Month 12) 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
 
 
Rationale 8 
 
 
 
 
Clarification 
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required to be collected during the course of the 
study. 
 
Section 7.1.2 
Schedule of Study 
Procedures, Table 
2 
Insertions 
 
 
 
 
 
i Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device 
is available.  Similarly, DEXA will be conducted at 
selected study sites where the DEXA device is 
available.  Not required if done within 6 months of 
visit. 
   Insertion (subsequent footnotes are renumbered 
accordingly) 
  
 
j   Endoscopy will be conducted at selected study sites 
where the device is available to assess for the 
presence of oesophageal varix/varices. 
 
k  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be obtained to 
confirm if a study endpoint has been met. 
Fibroscan® TE has been added at Month 6 
continued follow up 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
continued follow up 
 
i Transient elastography (TE) will be conducted at 6-
month intervals at all study sites where the 
Fibroscan® TE device is available. Not required if 
done within 3 months of visit 
 
 
j  DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available.  Not required if done within 6 months 
of visit. 
k   Endoscopy will be conducted at all study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices. 
 
l  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: unless HCC has already been 
confirmed by biopsy, a second confirmatory image 
(eg, MRI) should be obtained to confirm if a study 
endpoint has been met. 
 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
 
 
 
 
 
 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments) 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
Section 7.1.3 
Study Duration 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
Rationale 3 
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are expected to have a minimum follow-up time of 
approximately 6 years. 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Section 7.2 
Number of 
Subjects 
It is expected that approximately 350 subjects will 
be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
It is expected that approximately 428 subjects 
will be randomized in the study.   
Rationale 9 
 
 
Section 7.3 
Planned Dosing 
Regimen 
Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at 
the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the 
product.   
 
 
 
Table 3:  Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
Footnotes were re-ordered 
b   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is dependent 
on subject tolerability and/or changes in cirrhosis 
status or Child-Pugh score at any time during the 
study 
Subjects should titrate to a maximum dose of 10 
mg OCA once daily (or matching placebo) at the 
Month 3 visit or at any study visit following the 
Month 3 visit based on tolerability of the product 
and assessment of biochemical response.  Up-
titration should be considered if ALP and/or 
total bilirubin >ULN.   
 
Table 3:  Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
 
c   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is 
dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or 
Child-Pugh score at any time during the study 
Rationale 8 
Section 7.4 Dose 
Titration Criteria 
Insertion 
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) as 
well as biochemical response (as assessed by 
reductions in ALP and/or total bilirubin).  In 
general, down-titration will be done in 
response to tolerability concerns and can occur 
at any time while on-study.  Up-titration will 
be done per protocol when subjects have no 
tolerability concerns and have not achieved an 
adequate reduction in ALP and/or total 
Added language to clarify 
titrations (up or down) 
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bilirubin to within normal limits, or 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 for each dosing regimen as defined 
in Section 7.3. 
 
Section 8.4.1.1 
Severe Drug-
Induced Liver 
Injury 
Insertion 
If a subject develops signs and symptoms of a 
severe drug-induced liver injury, regardless of 
causality, investigational product should be 
interrupted until the event has resolved or 
returned to baseline, but the subject should 
continue with the study visit schedule.  
Subjects who develop significant drug-induced 
liver injury which is considered 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, evidence of 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. 
Severe drug induced-liver injury that is not 
considered related to investigational product 
must be discussed with the Sponsor before 
investigational product is reinitiated.  Follow-
up procedures for subjects resuming 
treatment, including laboratory evaluations 
and physical examinations, must be performed 
Added guidelines for subjects 
who develop severe Drug-
Induced Liver Injury  
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after a maximum of 2 weeks of re-treatment 
and may be conducted at a local clinic if the 
subject is unable to return to the site.  Results 
must be reported immediately to the site so the 
Investigator can determine if the subject is to 
be allowed to continue treatment.  Subjects 
should be encouraged to continue study visits 
despite stopping investigational product for 
continued study data collection but may 
withdraw consent at any time. 
All suspected drug-related hepatic injury 
events will be adjudicated by the Hepatic 
Safety Committee (see Section 13.4). 
Section 8.4.1.2 
Liver 
Transplantation 
Moved from Section 8.4.2 Other Reasons for 
Discontinuation of Study or Investigational 
Product 
8.4.1.2 Liver Transplantation 
Subjects must discontinue investigational 
product after undergoing liver transplantation 
surgery.  Subjects should be encouraged to 
continue study visits, despite stopping 
investigational product, for continued study 
data collection. 
The relocation of this 
statement from within 
Section 8.4.2 to 8.4.1.2 
clarifies directions to 
discontinue subjects who 
undergo a liver transplant 
from investigational product 
but not study visits 
Section 8.4.2 
Reasons for 
Mandatory 
Interruption of 
Investigational 
Product 
Insertion/Reorganization 
8.4.2 Reasons for Mandatory Interruption of 
Investigational Product 
Prior to re-starting investigational product 
after a prolonged interruption, the subject 
must be re-consented and new baseline visit 
procedures must be performed if the interval 
from the last visit was more than 3 months 
(+2 weeks) during the first 18 months of the 
study or more than 6 months prior (+2 weeks) 
during the remainder of the study.   
 
This clarifies what should be 
done when a subject 
experiences a prolonged 
interruption in investigational 
product such as in the event of 
pregnancy  
 
Section 8.4.2.1 
Pregnancy 
Modification of 8.4.1 Reasons for Mandatory 
Discontinuation of Investigational Product 
8.4.2.1 Pregnancy 
If a female subject becomes pregnant, she must 
interrupt treatment with investigational product 
Language simplified and 
aligned with Sponsor 
standards 
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If a female subject becomes pregnant, she must 
discontinue taking investigational product, but 
should continue with the study visit schedule.  The 
subject must be followed as considered 
appropriate by the Investigator and the medical 
monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an 
AE.  The subject may reinstate investigational 
product after delivery and cessation of 
breastfeeding (if applicable) at the discretion of 
the Investigator.  Subjects whose pregnancy is 
terminated early (planned or unplanned) may be 
permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotropin (β-
hCG) test performed at the central laboratory. 
immediately, but should continue with the study 
visit schedule.  As described in Section 12.1.9 
pregnancy is not considered an AE for reporting 
purposes.  The subject may re-start 
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 12.1.9).  New baseline 
procedures should include pregnancy testing. 
Section 8.4.3 
Other Reasons for 
Discontinuation of 
Study of 
Investigational 
Product 
8.4.2 Other Reasons for Discontinuation of Study 
of Investigational Product 
Subjects that discontinue investigational product 
are expected to continue in the study until the end 
of the study, and the study will only terminate at 
the time when the needed number of adjudicated 
events has accrued or at the discretion of the 
Sponsor.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  Subjects who 
choose to discontinue investigational product prior 
to termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.   
The following events are considered appropriate 
reasons for a subject to discontinue investigational 
product; however, these subjects are expected to 
continue in the study until study termination and 
8.4.3 Other Reasons for Discontinuation of Study 
of Investigational Product 
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.  
With the exception of liver transplant, if a 
subject experiences a suspected or confirmed 
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.  Subjects who 
discontinue investigational product prior to 
termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.   
The following events are considered appropriate 
reasons for a subject to discontinue 
investigational product; however, these subjects 
are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
Discontinuation of 
investigational product 
language updated to clarify the 
process that is to be followed 
after discontinuation and 
instruct subjects to continue 
regular visit schedule. 
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the study will only terminate (or at the discretion 
of the Sponsor): 
− 
Consent may be modified to discontinue 
study visits or semi-annual telephone contact 
but allow continued access to medical 
records to assess for potential adjudicated 
hepatic and/or cardiovascular events. 
Subjects who undergo a liver transplant during the 
course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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. 
 
− 
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), liver-related clinical outcomes, 
and drug-related hepatic injury events. 
The Investigator is encouraged to contact the 
Sponsor prior to discontinuing a subject from 
treatment.   
Section 9.7.3.1 
Determination for 
Dosing Regimen 
Insertion 
To determine which dosing regimen subjects 
should follow, the presence or absence of 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 is defined as a 
subject who has documented evidence or presence 
of one or more of the following cirrhosis 
indicators: 
9.7.3.1 Determination for Dosing Regimen 
To determine which dosing regimen subjects 
should follow, the presence or absence of 
cirrhosis should be assessed by the Investigator at 
Screening Visit 1.  Acceptable methods of 
confirming (via medical history) or assessing 
cirrhosis for purposes of determining dosing is 
defined as a subject who has documented 
evidence or presence of one or more of the 
following cirrhosis indicators: 
Header added to differentiate 
the assessment of cirrhosis for 
determining dosing regimen 
versus progression to cirrhosis 
Section 9.7.3.2 
Progression to 
Cirrhosis 
Insertion 
9.7.3.2 Progression to Cirrhosis  
When a subject identified as non-cirrhotic at 
baseline per the criteria listed in 
Section  9.7.3.1 exhibits any of those same 
criteria (excluding biopsy results consistent 
with PBC Stage 4), the subject should also be 
assessed by Fibroscan® TE where available 
and progression to cirrhosis confirmed by 
biopsy unless not medically indicated.  Sites 
Provides detail around the 
assessment of Progression to 
Cirrhosis as a secondary 
endpoint 
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participating in the paired biopsy sub-study 
(see Appendix C) must confirm progression to 
cirrhosis by biopsy.  All suspected cases of 
progression to cirrhosis should be submitted 
for adjudication regardless of the availability 
of transient elastography or biopsy results. 
Section 9.7.6 
Screening 
Procedures 
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments 
will be used to determine eligibility (total 
bilirubin >ULN and ≤3× ULN and/or an ALP 
>5× ULN).   
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments 
will be used to determine eligibility (total 
bilirubin >ULN and ≤5× ULN and/or an ALP 
>3× ULN).   
Reflects new inclusion criteria 
Section 9.7.7 Day 
0 Procedures 
• 
Perform transient elastography (TE; at 
selected study sites, where available) using 
the Fibroscan® TE device. If TE has been 
done within 6 months of Day 0 and a 
report/adequate data are available, a 
pretreatment TE at Day 0 is not required.   
• 
Perform transient elastography at all study 
sites with access to Fibroscan® TE device. 
If TE has been done within 3 months of Day 
0 and a report/adequate data are available, a 
pretreatment TE at Day 0 is not required.   
Clarifies use of TE and 
modifies the time during 
which an historic TE report 
remains valid 
Section 9.7.8 
Month 1 
Procedures 
 
Section 9.7.10 
Post-titration visit 
Procedures 
Insertion 
 
 
• 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit 
requirements: 
• 
Perform a physical examination.  
 
− 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit 
laboratory requirements: 
Physical examinations 1 
month after initiating dosing 
with investigational product 
will enhance safety 
monitoring 
Returning to the site for 
monthly laboratory 
assessments can present a 
significant burden on subjects, 
thus alternatives are provided 
for collecting lab samples; 
with the addition of the 
physical exam as well the 
requirement for these exams is 
provided in the context of the 
alternatives for laboratory 
specimen collection 
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Section 9.7.11 
Month 6 
Procedures 
 
Section 9.7.16 
Month 6 
Continued 
Follow-Up 
Procedures 
Insertion 
• 
Perform a physical examination 
• 
Perform TE at all study sites with access 
to Fibroscan® TE device. 
• 
Perform an ultrasound for HCC 
surveillance (if equipment is unavailable, 
sites should make every attempt to use 
available community referral sites). 
TE assessment has been added 
as biannual assessment at all 
study sites with access to 
Fibroscan® TE device 
 
Hepatic ultrasound should be 
performed biannually per 
AASLD and EASL guidelines 
for subjects with PBC 
Section 11.1.2 
Secondary 
Assessments 
Insertion 
• 
Progression to cirrhosis as assessed by the 
presence of clinical, laboratory, or 
radiological evidence of cirrhosis and/or 
liver stiffness (Fibroscan® TE), confirmed 
by biopsy unless not medically indicated. 
• 
Histological assessment of disease 
progression or improvement using paired 
biopsies in a subset of subjects (see 
Appendix C) 
Rationale  
Section 11.1.2.4 
Potential Clinical 
Outcome Events 
The events listed in Appendix A will be initially 
assessed by the Investigator to determine if they 
are Potential Clinical Outcome Events.   
The events listed in Section 12.1.5 will be 
initially assessed by the Investigator to determine 
if they are Potential Clinical Outcome Events.   
Appendix referencing clinical 
outcomes events was removed 
due to redundancy 
Section 12.1.4.2 
Reporting of 
Serious Adverse 
Events 
Insertion 
Redacted medical record source 
documentation will be requested for all SAEs 
and emergency room visits. 
 
 
Added sentence regarding 
redacted medical records to 
align with Sponsor safety 
standards 
Section 12.1.5 
Suspected Liver-
Related Clinical 
Outcome Events 
For liver-related clinical outcome events could 
also meet the criteria of a SUSAR, which would 
necessitate unblinding for expedited reporting, 
please refer to Section 11.1.2.4. 
 
 
Given that the liver-related 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 liver-related clinical outcome 
events in order to retain the study blind and 
preserve the integrity of the clinical outcomes 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language 
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The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy),  and spontaneous 
bacterial peritonitis (preferred term: peritonitis 
bacterial). 
 
endpoint.  These events will be selected as a 
“study event” on the Adverse Event CRF and 
will be submitted for adjudication to the 
Hepatic Outcomes Committee as described in 
Section 13.4. 
 
The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy 
(preferred term: hepatic encephalopathy),  
spontaneous bacterial peritonitis (preferred term: 
peritonitis bacterial), ascites (preferred term: 
ascites), and histological progression to 
cirrhosis (preferred term: hepatic cirrhosis). 
Section 12.1.7 
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 SAE 
must be reported to the Sponsor immediately (ie, 
within 24 hours). 
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 12.1.4.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language 
Section 12.1.8 
Follow-up of AEs 
and SAEs 
Insertion 
All subjects 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 CRF. Note that longer follow-
up can sometimes reveal an off-drug repetition 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language 
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of what had appeared to be drug-induced liver 
injury, indicating that liver injury was related 
to underlying liver disease. 
Section 12.1.9 
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 investigational 
product and the Sponsor must be notified within 
24 hours of the Investigator’s learning of the 
pregnancy by completing the Pregnancy 
Notification Form and faxing or emailing to the 
Sponsor at +1 800 497 8521 or 
sae@interceptpharma.com.  
Safety will be monitored and assessed by 
AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and 
clinical laboratory assessments. The Sponsor may 
also follow the health of an infant born subsequent 
to use of investigational product. 
The subject may reinstate investigational product 
after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  
Subjects whose pregnancy is terminated early 
(planned or unplanned) may be permitted to 
resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test 
(see Section 8.4.1). 
 
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 8.4.2.1) 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 
sae@interceptpharma.com or faxed to 
+1 800 497 8521.   The subject and neonate 
must be followed for outcome information 
and/or as considered appropriate by the 
Investigator and Sponsor. 
The subject may re-start 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 subject must have a 
negative pregnancy test before restarting 
investigational product.  If a subject’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 
Updated to align with 
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procedures and Sponsor 
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reporting procedures described in 
Section 12.1.4 must also be followed. 
 
Table 10 List of 
Laboratory 
Analytes 
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Other 
Insertion 
 
 
Deletion 
 
Other 
OCA-glucuronide 
 
Measurements of liver fibrosis 
are captured in a different 
section 
 
OCA-glucuronide was listed 
in the text but missing from 
the table 
Section 13.1.1 
Analysis 
Populations 
• 
The Randomized Population will include all 
randomized subjects 
Deletion 
 
Section 13.1.2.1 
Sample Size 
Monitoring 
9.1.2.1 Sample Size Re-Estimation Plan 
Therefore, starting approximately 2 years after the 
first subject is randomized, the aggregate event 
rate and sample size based on recruitment and 
retention will be evaluated in a blinded manner 
quarterly.  This evaluation will determine if any 
increases in number of subjects are required in 
order to obtain a total of 121 adjudicated events 
for the final analysis in the combined groups. 
If after 4 years of accruing subjects, despite 
increases in the number of subjects, it is 
determined that at least an additional 2 years (ie, 
total study duration of at least 10 years) are needed 
to randomize sufficient subjects to achieve a total 
of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label 
OCA.  Previously randomized subjects will 
continue to be treated in a blinded manner with 
either OCA or matching placebo.  If this 
modification is implemented, the alternative 
9.1.2.1 Sample Size Monitoring 
Therefore, the aggregate event rate and sample 
size based on recruitment and retention will be 
evaluated in a blinded manner quarterly.  This 
evaluation will determine if any increases in 
number of subjects are required in order to obtain 
a total of 127 adjudicated events for the final 
analysis in the combined groups. 
Deletion 
 
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primary efficacy analysis is specified is Section 
13.1.9. 
Any revised sample size or changes to treatment 
allocation will be justified and documented in a 
protocol amendment and in the CSR. 
Section 13.1.5.1 
Association of 
Biochemistry with 
Clinical Outcomes 
and Clinical 
Benefit 
Insertion 
13.1.5.1 Association of Biochemistry with 
Clinical Outcomes and Clinical Benefit  
The association between the effect of OCA on 
ALP and bilirubin and the clinical benefit of 
OCA will be evaluated by estimating the 
proportion of net treatment effect on the 
primary composite endpoint that is explained 
by each biochemical marker.  For each 
biochemical endpoint, this proportion will be 
estimated by applying the partial likelihood 
function to two Cox models that use the same 
failure time variable, as described in Lin 1997. 
This analysis will be based on the ITT 
population.  
Based on the association between biochemical 
changes and clinical outcomes described 
above, clinical benefit of OCA for key 
subpopulations of interest will be evaluated. 
This analysis will be further described in the 
SAP. 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
13.1.8 Supportive 
Analysis 
Insertion 
Although the study is designed as a placebo-
controlled study, the DMC may recommend 
changes to study conduct based on the pre-
specified interim analyses (see Section 13.1.12), 
including the potential use of a revised 
primary efficacy analysis.  This analysis would 
compare all subjects in the OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant 
or death (all-cause) (see Section 13.1.2.1), using 
As a placebo-controlled study, 
the alternative primary 
analysis section has been 
removed.   
Upon review of blinded data, 
the DMC may recommend 
changes to study conduct.  
However, such 
recommendations will not be 
implemented unless the 
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similar statistical methodology as specified 
above. 
Notably, the planned primary analysis would 
not be revised without prior agreement with 
regulatory authorities. 
Sponsor has received 
agreement from regulatory 
authorities. 
Section 13.1.9 
Alternative 
Primary Analysis 
13.1.9 Alternative Primary Analysis 
Based on sample size re-estimations, it may be 
determined that subjects will be enrolled to receive 
open-label OCA from that point forward, and the 
new primary efficacy analysis will become the 
comparison of all subjects in OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant or 
death (all-cause) (see Section 13.1.2.1).  Similar 
statistical methodology as specified above in 
Section 13.1.8 for supportive analyses will be 
utilized. 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare groups.  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 determined based 
on a Cox regression model stratified by 
randomization strata to estimate the magnitude of 
the effect. 
 In addition, the outcome events specified above in 
Section 13.1.8 will also be evaluated to compare 
all subjects in OCA population to all control 
subjects (randomized placebo and historical 
controls). 
Deletion 
 
As a placebo-controlled study, 
the alternative primary 
analysis section has been 
removed.   
 Upon review of blinded data, 
the DMC may recommend 
changes to study conduct.  
However, such 
recommendations will not be 
implemented unless the 
Sponsor has received 
agreement from regulatory 
authorities 
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Sensitivity analyses will be conducted limiting to 
the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC 
Study Group.  To evaluate the robustness of the 
propensity score estimations, additional 
algorithms and factors may be considered. 
 
13.1.12 
Continuous 
Monitoring and 
Interim Analyses 
Insertion 
13.1.12 Continuous Monitoring and Interim 
Analyses  
Blinded safety reports including the accrual of 
events, drop outs and/or loss of patients to 
commercially available OCA will be reviewed 
by the DMC on a regular basis.  
Two planned interim analyses of the liver-
related outcomes will be conducted using the 
Lan-DeMets O’Brien-Fleming boundaries 
(Reboussin 2000).  Both interim analyses will 
be pre-specified and will occur after accrual of 
50% and 75% of clinical outcome events, 
respectively.  
The DMC will review the available efficacy 
data in conjunction with detailed safety data 
and other relevant information to recommend 
continuation, modification, or cessation (for 
efficacy or futility) of the study beyond each 
interim analysis.  Modification of the study 
would not take place without prior agreement 
with regulatory authorities. 
Explanation of the type of 
review that will be ongoing by 
the DMC during study 
conduct. 
Section 19 List of 
References  
Insertion 
Lin DY, Fleming TR, De Gruttola V.  
Estimating the proportion of treatment effect 
explained by a surrogate marker.  Statistics in 
Medicine.  1997;16(13):1515-1527. 
 
Reboussin DM, DeMets, DL, Kim KM, et al.  
Computations for Group Sequential 
Additional relevant references 
were added. 
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Boundaries Using the Lan-DeMets Spending 
Function Method.  Controlled Clin Trials.  
2000;21(3):190-207. 
Appendix B  
List of Study 747-
302 Outcome 
Events 
Several of the specified clinical endpoints will 
also by definition (see 12.1) 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 12.1.4).  
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 
Deleted 
Redundant; Information is 
contained within the protocol 
Appendix C 
Biopsy Sub-Study 
of Protocol 
747.302: A Phase 
4, Double-Blind, 
Randomized, 
Placebo-
Controlled, 
Insertion 
See Appendix C 
The purpose of this sub-study 
is to assess the effect of OCA 
versus placebo on the 
histological severity of disease 
(fibrosis/cirrhosis) in subjects 
with PBC.  In addition, this 
sub-study will demonstrate the 
relationship between 
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Multicenter Study 
Evaluating the 
Effect of 
Obeticholic Acid 
on Clinical 
Outcomes in 
subjects with 
Primary Biliary 
Cholangitis 
histological changes and 
clinical, laboratory, and non-
invasive measures indicative 
of progression to cirrhosis in 
patients with PBC. 
 
 
 
 
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APPENDIX H. SUMMARY OF CHANGES:  PROTOCOL VERSION 3.1 TO PROTOCOL VERSION 4 
(DATED 10 MAY 2017) 
Please note that Protocol 747-302 Version 3.1 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.  A full 
accounting of the changes from Protocol Version 3 to Protocol Version 4 is provided in Appendix I. 
Rationale and Summary of Changes 
Major revisions to Protocol 747-302 Version 3.1 include: 
• Hepatocellular carcinoma (HCC) has been redefined as a secondary endpoint; 
• Following the broadening of the spectrum of disease, a commitment to enroll a minimum of 30% of subjects with abnormal 
bilirubin has been added to the protocol; 
• Clarifications have been incorporated throughout the protocol based on the addition of a biopsy substudy in Addendum 2; 
• Statistical language has been modified and added to clarify statistical assumptions and analyses including the addition of a 
Per Protocol (PP) Population;  
• Background rationale has been updated to reflect the current approval status of Ocaliva; and 
• Safety language has been updated throughout the protocol to reflect the updating of Sponsor standards. 
Minor revisions include editorial changes such as removal of hyphens and capitalization of words.  Minor revisions may be included 
in the following table when they are also part of major revisions; however, most minor/editorial changes and nonsubstantial changes 
are not listed individually. 
The text deleted from Protocol Version 3.1 is crossed out while revised text in Version 4 is indicated in bold font in the table below. 
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(Version 4, 10 May 2017) 
Justification for Change 
Study Personnel 
Contact 
Information 
Or if Not Available: 
Contact: 
 MD, PhD Medical 
Director, Clinical Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
 
Email: 
 
 (Pacific 
time zone) 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical 
Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 (Pacific time 
zone) 
 
 
 
 
Updating emergency medical 
monitor contact information. 
 
 
 
 
 
 
 
The contact information for 
clinical operations and project 
management personnel is no 
longer required in the protocol 
per Sponsor’s procedures. 
Synopsis, 
Objectives, 
Primary, 
Statistical 
Methods – 
Efficacy Analyses 
To assess the effect of OCA compared to placebo, 
in conjunction with established local standard of 
care, on clinical outcomes in subjects with primary 
biliary cirrhosis (PBC) as measured by time to first 
occurrence of any of the following adjudicated 
events, derived as a composite event endpoint: 
To assess the effect of OCA compared to 
placebo, in conjunction with established local 
standard of care, on clinical outcomes in subjects 
with primary biliary cholangitis (PBC) as 
measured by time to first occurrence of any of the 
following adjudicated events, derived as a 
composite event endpoint: 
Editorial correction 
 
 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Section 6.1 
Primary Objective 
Section 11.1.1 
Primary 
Assessments 
Section 13.1.3 
Primary Efficacy 
Analysis 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities unless 
confirmed by biopsy 
composite-event endpoint per 
Regulatory Authority request. 
Synopsis, 
Objectives, 
Secondary  
Section 6.2 
Secondary 
Objectives 
 
 
 
 
In Section 6.2 
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
component of the primary endpoint as listed above 
and also to include liver related death. 
 
 
To characterize the effect of OCA compared to 
placebo on progression to cirrhosis. 
To assess the PK of OCA and its conjugates in a 
subset of subjects. 
To assess the effect of OCA compared to 
placebo on time to occurrence of 
hepatocellular carcinoma (HCC). 
 
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
component of the primary endpoint as listed 
above. 
To assess the effect of OCA compared to 
placebo on time to occurrence of liver-related 
death.  
To assess the effect of OCA compared to placebo 
on progression to cirrhosis. 
To characterize the PK of OCA and its 
conjugates in a subset of subjects. 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request.  
 
 
Editorial change 
 
Editorial change 
 
Editorial change 
Synopsis, 
Methodology  
Section 7.1, 
Overall Study 
Design.  
 
A minimum of 30% of subjects will have 
elevated bilirubin (>ULN) at Screening. 
To ensure enrollment of an 
adequate number of subjects 
with abnormal total bilirubin. 
 
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Section 7.1.1 
Study Design 
Diagram,  
Fig 1 (Footnote) 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on tolerability 
and biochemical response.   
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability and biochemical response (up-titration 
should be considered when ALP and/or total 
bilirubin are >ULN).   
Clarification of biochemical 
response 
Synopsis, Number 
of Subjects 
(Planned)  
Section 7.2 
Number of 
Subjects 
Insertion in both, Synopsis and Section 7.2 
 
 
Change in Synopsis section 
Approximately 428 subjects 
In the event additional subjects are needed for 
the enrollment in the biopsy substudy (N = 45 
subjects, as defined in Addendum 2), subjects 
who agree to participate in the substudy may 
be added to the target subject enrollment 
number currently planned. 
Approximately 428 subjects are planned to be 
enrolled in the study.  
Language added to allow for 
continued enrollment into the 
biopsy substudy; additional 
subjects are not anticipated to 
prolong the duration of the 
study. 
Synopsis, Criteria 
for Evaluation 
 
Primary Objectives 
Assessments 
 
• 
Hepatocellular 
carcinoma 
confirmed by 
2 complimentary 
imaging modalities 
unless confirmed 
by biopsy. 
 
Secondary Objectives 
 
 
Primary 
Objectives 
Assessments 
 
 
 
 
 
 
 
Secondary 
Objectives 
 
HCC 
Confirmed by 
2 complimentary imaging 
modalities unless confirmed 
by biopsy 
 
 
 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request. 
Synopsis, 
Statistical 
Methods 
Analysis 
Populations 
 
The following subject populations will be 
evaluated and used for presentation and analysis of 
the data: Intent-to-Treat (ITT), Safety, PK, Overall 
Historical Control, UKPBC Historical Control, 
and the Global PBC Historical Control.  
The following subject populations will be 
evaluated and used for presentation and analysis 
of the data: Intent-to-Treat (ITT), Per Protocol 
(PP), Safety, PK, Overall Historical Control, 
UK-PBC Historical Control, and the Global PBC 
Historical Control.   
The randomized population is 
included within the Safety 
population. 
The PP population will be 
used to conduct sensitivity 
analyses for primary and key 
efficacy endpoints. 
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Synopsis, 
Statistical 
Methods, Primary 
Efficacy Endpoint 
 
Section 11.1.1  
Primary 
Assessments 
Section 13.1.3  
Primary Efficacy 
Analysis  
• 
Hepatocellular carcinoma confirmed 
by 2 complimentary imaging modalities 
 
 
 
Section 13.1.3 
• 
Hepatocellular carcinoma confirmed 
by 2 complimentary imaging modalities 
unless confirmed by biopsy 
The primary efficacy analysis will compare 
randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the 
ITT population.   
 
 
 
 
 
 
Section 13.1.3 
 
The primary efficacy analysis will compare OCA 
to placebo with respect to the primary efficacy 
endpoint using the ITT population.   
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request. 
 
 
 
Editorial change 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Analysis 
Section 13.1.3  
Primary Efficacy 
Analysis 
Insertion 
 
The same analyses for primary efficacy 
endpoints will be performed for PP population 
as a sensitivity analysis.   
The PP population will be 
used to conduct sensitivity 
analyses for primary and key 
efficacy endpoints. 
Synopsis, 
Statistical 
Methods, Key 
Secondary 
Efficacy Analyses 
Section 13.1.4  
Secondary 
Efficacy Analysis 
Insertion 
 
 
Section 13.1.4 
The key secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
in the ITT population with respect to the key 
secondary efficacy endpoints.   
 
The same analyses for key secondary efficacy 
endpoints will be performed for PP 
population as a sensitivity analysis.   
 
 
Section 13.1.4 
The key secondary efficacy analyses will 
compare OCA to placebo in the ITT population 
with respect to the key secondary efficacy 
endpoints.   
 
 
The PP population will be 
used to conduct sensitivity 
analyses for primary and key 
efficacy endpoints. 
 
 
Editorial change 
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Synopsis, 
Statistical 
Methods, 
Additional 
Secondary 
Efficacy Analyses 
Other Efficacy Analyses 
The following secondary efficacy analyses will 
compare OCA to placebo on time to the following 
events: 
• 
Each component of the primary efficacy 
endpoint (except MELD score ≥15 which 
is listed above) 
• 
Development of varix/varices 
• 
Liver-related death 
• 
Liver-related death or liver transplant 
Liver-related death, liver transplant, or MELD 
score ≥15 
Additional Secondary Efficacy Analyses 
The following time-to-event secondary efficacy 
analyses will compare OCA versus placebo using 
the ITT population: 
• 
Time to each component of the primary 
efficacy endpoint (except MELD score 
≥15 which is listed above) 
• 
Time to development of varix/varices 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
• 
Time to liver-related death 
• 
Time to liver-related death or liver 
transplant 
Time to liver-related death or liver transplant, or 
MELD score ≥15 
Editorial Change 
 
 
 
 
Progression to cirrhosis added 
as secondary endpoint in 
Version 3.1. 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite event endpoint per 
Regulatory Authority request. 
Synopsis, 
Statistical 
Methods, 
Additional 
Secondary 
Efficacy Analyses 
 
Section 13.1.5 
Additional 
Secondary 
Efficacy Analyses 
Insertion 
 
 
Analyses for the histological assessment 
conducted as part of the biopsy substudy are 
defined in Appendix C. 
For those subjects enrolled in the biopsy 
substudy (defined in Addendum 2) progression 
to cirrhosis identified by the above criteria and 
improvement in fibrosis/cirrhosis will be 
confirmed by paired biopsy.  Analyses for the 
histological assessment conducted as part of the 
biopsy substudy are defined in Addendum 2.  
Provides further details of 
progression to cirrhosis as 
outlined in the biopsy 
substudy defined in 
Addendum 2. 
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Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
 
Section 13.1.2. 
Determination of 
Sample Size 
Insertion 
 
 
 
 
The following assumptions were used in sample 
size calculations:  
• Two interim analyses and one final analysis 
are planned.   
 
 
Insertion 
 
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
The target population is subjects who are at 
higher risk of liver-related clinical 
complications. Eligible subjects will have a 
diagnosis of PBC with bilirubin levels >ULN 
and ≤5x ULN and/or ALP >3x ULN.  The 
following assumptions were used in sample size 
calculations:  
 
• Two interim analyses and one final analysis 
are planned.  The first interim analysis will be 
performed when 50% of the target events are 
accrued and the second interim will be 
performed when 75% of the target events are 
accrued.  
•  A dropout rate of 10% is assumed.  
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to liver-related outcomes, including all-
cause mortality. 
 
Incorporation of the 
broadened spectrum of disease 
into the sample size 
justification. 
 
 
Clarification of interim 
analyses. 
 
 
Clarification of the assumed 
dropout rate. 
 
 
Clarification of outcomes 
being assessed in power 
calculations. 
Section 5.1 
Overview of PBC 
and OCA 
5.1. Overview of Primary Biliary Cirrhosis and 
Obeticholic Acid 
Primary biliary cholangitis, (PBC, also known as 
primary biliary cirrhosis) 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 
5.1. Overview of Primary Biliary Cholangitis 
and Obeticholic Acid 
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 
Updating language to include 
accelerated and conditional 
approvals of OCA in the US 
and EU.  
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necessitates liver transplantation or results in 
death.   
 
Ursodeoxycholic acid (UDCA), a physiological 
constituent of human bile , is currently the only 
treatment approved for PBC (Lindor 2009).  While 
UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a 
suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of 
a poor clinical outcome due to PBC disease 
progression.  There is a clear unmet medical need 
for better therapies for patients with PBC that have 
an inadequate response to UDCA, or those who 
cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  
Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have 
an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and 
effective. 
OCA is a modified bile acid and farnesoid X 
receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid 
(CDCA).  OCA is currently being developed in the 
United States (US) and Europe for the treatment of 
PBC and other chronic liver diseases.  OCA has 
been granted Orphan Drug Designation in the US 
(09 Apr 2008) and Orphan Medicinal Product 
Designation in the European Union (EU) 
(27 Jul 2010) for the treatment of PBC.  The 
United States Food and Drug Administration 
necessitates liver transplantation or results in 
death.   
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), 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 
(Pellicciari 2002).  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. 
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(FDA) has granted accelerated approval for 
Ocaliva for the treatment of PBC.  Ocaliva is not 
yet approved outside the United States for use in 
any indication. 
Section 5.4 
Overview of PBC 
and OCA 
As of 31 Jan 2016, approximately 1726 subjects 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 458 subjects had 
PBC, 330 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver disease 
(NAFLD), 33 subjects had alcoholic 
cirrhosis/portal hypertension, and 20 subjects had 
primary sclerosing cholangitis (PSC). 
As of 31 Jan 2017, approximately 2186 subjects1 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 525 subjects had 
PBC, 686 subjects had NASH, 41 subjects had 
diabetes mellitus/nonalcoholic fatty liver disease, 
33 subjects had alcoholic cirrhosis/portal 
hypertension, and 52 subjects had primary 
sclerosing cholangitis, and 5 subjects had 
biliary atresia. 
------------------------ 
1Includes estimated numbers from ongoing 
blinded studies. 
Language updated to include 
data from current IB. 
Section 5.5.2.1  
Rationale for 
OCA Dose 
The Phase 3 PBC study subsequently evaluated 
the safety and efficacy of OCA at lower doses of 
5 mg (titrated to 10 mg after 6 months based on 
efficacy and tolerability in the double-blind phase 
and after 3 months in the open-label phase) and 
10 mg;  
 
Insertion 
 
 
 
 
Based on these data, the indicated commercial 
doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
 As such, Study 747-302 will evaluate the effect of 
OCA on clinical outcomes using the 5 mg OCA 
dose increasing to 10 mg OCA, if tolerated. 
The Phase 3 PBC study (Study 747-301) 
subsequently evaluated the safety and efficacy of 
OCA at lower doses of 5 mg (titrated to 10 mg 
after 6 months based on efficacy and tolerability 
in the double-blind phase and after 3 months in 
the open-label phase) and 10 mg;  
Study 747-301 demonstrated that titration of 
OCA from a starting dose of 5 mg to 10 mg 
improved tolerance to pruritus relative to 
10 mg (56% versus 69% of subjects who 
experienced pruritus) and minimized dropouts 
due to pruritus.   
Based on these data, the approved dosing 
regimens for OCA for the treatment of patients 
with PBC are 5 mg and 10 mg. 
Study 747-302 will evaluate the effect of OCA on 
clinical outcomes using the 5 mg OCA dose for 
at least 3 months, increasing to 10 mg OCA, if 
tolerated. 
Provides rationale for the 
dosing in alignment with 
commercial labeling. 
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Section 5.6 
Summary of 
Known Potential 
Risks with OCA 
An increase in liver enzymes and hepatic AEs, 
including jaundice, were observed in subjects with 
liver disease at OCA doses between 10 mg and 
50 mg and in healthy subjects who were treated at 
doses ≥100 mg in Phase 1, multiple-dose studies. 
 
 
These findings were seen more frequently with 
doses above 10 mg OCA. 
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).  
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). 
Language has been updated to 
reflect Sponsor standards. 
Section 7.1.2 
Schedule of Study 
Procedures,  
Table 1  
 a All subjects will have the chemistry panel 
retested to ensure subjects have two ALP and 
bilirubin assessments 2 weeks apart to calculate 
the mean result for both analytes.  The mean of 
all screening ALP and bilirubin assessments 
will be used to determine eligibility.  
 
 
 
l 
Endoscopy will be conducted at selected 
study sites where the device is available. 
 
m Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: Unless HCC has already confirmed 
by biopsy, a second confirmatory image (eg, 
MRI) should be obtained to confirm if a study 
endpoint has been met. 
 a All subjects will have the chemistry panel 
retested to ensure subjects have at least two 
ALP and bilirubin assessments at least 2 weeks 
apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and 
bilirubin assessments will be used to determine 
eligibility. Refer to Section 9.7.6 for guidance 
on when an additional ALP or bilirubin 
sample may be needed to confirm eligibility. 
 
l 
Endoscopy will be conducted at all study 
sites where the device is available. 
 
m 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.   
Editorial changes 
Section 7.1.2 
Schedule of Study 
Procedures, Table 
2 
i Transient elastography (TE) will be conducted at 
6-month intervals at all study sites where the 
Fibroscan® TE device is available.  Not 
required if done within 3 months of visit. 
i Transient elastography (TE) will be conducted 
at 6-month intervals at all study sites where the 
Fibroscan® TE device is available. 
 
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j DEXA will be conducted at 12-month intervals 
at all study sites where the DEXA device is 
available.  Not required if done within 6 months 
of visit. 
 
k  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: unless HCC has already been 
confirmed by biopsy, a second confirmatory 
image (eg, MRI) should be obtained to confirm 
if a  study endpoint has been met. 
 
 
j  DEXA will be conducted at 12-month intervals 
at all study sites where the DEXA device is 
available. 
 
 
l  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, postday 0) 
ultrasounds: unless HCC has already been 
confirmed by biopsy, a second confirmatory 
image (eg, MRI) should be obtained to confirm 
suspected HCC. 
 
Section 7.4  
Dose Titration 
Criteria 
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. 
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, biochemical response, and 
clinical judgment. 
Changes in Child-Pugh Score that result from 
a transient, explainable change in laboratory 
parameters should be documented 
appropriately and should not necessarily 
result in a change to the dosing regimen 
(Appendix A). 
Editorial changes 
Section 7.4.1  
Pre-Titration 
Tolerability 
Assessment 
Requirements 
• 
There must be no clinically significant 
increase (as determined by the investigator) in the 
subject’s liver function tests.  Subjects whose total 
bilirubin is >2× baseline (and >ULN) cannot be 
up-titrated, and additional unscheduled safety visit 
procedures, outlined in Section 9.7.19 should be 
implemented, as required. 
• 
There must be no clinically significant 
increase (as determined by the Investigator) in 
the subject’s liver function tests.  
Clarification 
Section 7.4.2   
The text in this section is moved to Section 8.4.  
 
To avoid redundancy 
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Safety Criteria for 
Adjustment or 
Stopping Doses 
Section 8.4  
Dose Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
[Moved from Section 7.4.2 of Version 3] 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or 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 that 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 
when the needed number of adjudicated events has 
accrued.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, 
subjects should be strongly encouraged to both 
stay on investigational product and remain in the 
study until study termination.   
 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or by 
decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability 
concerns.  The dose of investigational product 
should be adjusted back to the maintenance dose 
in a blinded manner once the issues relating to the 
lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated 
events has accrued.  If a subject reaches an 
outcome event, he or she should continue the 
regular visit schedule and continue taking 
investigational product as long as the subject has 
not met any of the criteria for mandatory 
interruption of investigational product 
outlined in Section 8.4.1, and the Investigator 
assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on 
investigational product and remain in the study 
until study termination.   
 
Clarification 
Section 8.4.1.1   
Reasons for 
Additional 
Monitoring 
Related to Liver 
Chemistries 
Modification of 8.4.3.1 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 
 
Subjects 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.  Subjects with 
persistent elevations (eg, additional lab testing 
per Investigator discretion) should be closely 
monitored.  Concomitant elevations in total 
 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries.  
Language related to 
interruption of investigational 
product is now located in 
Section 8.4.1.2. 
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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. 
 
bilirubin or international normalized ratio 
(INR) with persistent increases in ALT or AST 
should also be closely monitored. 
Section 8.4.1.2   
Reasons for 
Investigational 
Product 
Interruption 
Related to 
Elevated Liver 
Chemistries 
Insertion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Development of any of the following clinical 
laboratory values, without explanation, during 
the study mandates investigational product 
interruption: 
• 
AST and/or ALT >3x baseline (and 
>ULN) 
• 
Total bilirubin >2x 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 AE information should also be 
collected and the subject 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 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries. 
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medications should be identified and 
discontinued if advisable.  
If symptoms persist or repeat testing shows 
AST or ALT >3x baseline (and >ULN) or total 
bilirubin >2x baseline (and >ULN), subjects 
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 investigative product 
and no other cause for the elevation is 
identified, it may be assumed that the 
elevations were due to disease progression and 
the subject 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 
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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 subject 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.  
 
Subjects who develop evidence of severe drug-
induced liver injury, which 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. 
 
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 
subjects 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 
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Section 8.4.1.1:   
Subjects who develop significant drug-induced 
liver injury which is considered 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, 
evidence of functional hepatic impairment as 
indicated by rising bilirubin or INR that cannot be 
explained by progression of disease.  
 
Insertion  
appropriate for the subject to continue 
treatment.  In the event the investigational 
product is required to be discontinued, 
subjects should be encouraged to continue 
study visits for continued data collection but 
may withdraw consent at any time.  
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 13.4). 
Section 8.4.1.3   
Pregnancy 
8.4.2.1 Pregnancy 
As described in Section 12.1.9 pregnancy is not 
considered an AE for reporting purposes.  The 
subject may re-start 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 12.1.9).  New baseline 
procedures should include pregnancy testing. 
8.4.1.3 Pregnancy 
As described in Section 12.1.11 pregnancy is not 
considered an AE for reporting purposes.  The 
subject may re-start 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 12.1.11. 
Revised section number. 
 
Section 8.4.2.1  
Liver 
Transplantation 
8.4.1.2 Liver Transplantation 
Subjects must discontinue investigational product 
after undergoing liver transplantation surgery.  
Subjects should be encouraged to continue study 
visits, despite stopping investigational product, for 
continued study data collection. 
8.4.2.1 Liver Transplantation 
Subjects who undergo a liver transplant during 
the course of the study must discontinue 
investigational product and discontinue the 
study visit schedule.  However, these subjects 
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. 
Clarification on process for 
subjects who undergo a liver 
transplant. 
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Section 8.4.3 
Other Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
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.  
With the exception of liver transplant, if a subject 
experiences a suspected or confirmed 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.  Subjects who discontinue 
investigational product prior to termination of the 
study need to also continue to follow the regular 
visit schedule through to study closure.  In 
general, subjects should be strongly encouraged to 
both stay on investigational product and remain in 
the study until study termination.  Early 
termination procedures should only be conducted 
if the subject withdraws consent (See 
Section 9.7.18). 
 
− 
Consent may be modified to discontinue study 
visits or semi-annual telephone contact but 
allow continued access to medical records to 
assess suspected major adverse cardiovascular 
events (MAC), liver-related clinical 
outcomes, and drug-related hepatic injury 
events. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
− 
Consent may be modified to discontinue 
study visits or semi-annual telephone contact 
but allow continued access to medical 
records to assess suspected major adverse 
cardiovascular events (MACE) and liver-
related clinical outcomes. 
− 
Early termination procedures should be 
conducted if the subject withdraws 
consent (See Section 9.7.18). 
 
Clarification of process 
Section 9.7.1  
Visit Windows 
Screening 
 
 
Screening 
See Section 9.7.6 for 
scenario specific visit 
windows that may be 
applicable at Screening.  
 
Section 9.7.3.2  
Progression to 
Cirrhosis 
When a subject identified as non-cirrhotic at 
Baseline per the criteria listed in Section 9.7.3.1 
exhibits any of those same criteria (excluding 
biopsy results consistent with PBC Stage 4), the 
When a subject identified as noncirrhotic at 
Baseline per the criteria listed in Section 9.7.3.1 
exhibits any signs or symptoms associated with 
progression to cirrhosis, as defined by the same 
Details the assessment of 
progression to cirrhosis. 
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subject should also be assessed by Fibroscan® TE 
where available and progression to cirrhosis 
confirmed by biopsy unless not medically 
indicated.  Sites participating in the paired biopsy 
sub-study (see Appendix C) must confirm 
progression to cirrhosis by biopsy.   
criteria, the subject should also be assessed by 
Fibroscan® TE where available and progression 
to cirrhosis confirmed by biopsy (centrally read) 
unless not medically indicated.  Laboratory 
samples needed to obtain noninvasive scores of 
liver fibrosis (ELF, and aspartate 
aminotransferase to platelet ratio index 
[APRI]) will also be collected when a subject 
develops evidence of progression to cirrhosis. 
Full instructions concerning the sample 
collection methods, processing, labeling, and 
shipping will be provided by the Sponsor in a 
study-specific histology manual.  Collection 
supplies will be provided by the central 
laboratory. 
Sites participating in the paired biopsy substudy 
must confirm progression to cirrhosis by biopsy 
as per the information outlined in protocol 
Addendum 2. 
Section 9.7.6  
Screening 
Procedures 
Two Screening visits will occur from 1 to 8 weeks 
prior to Day 0 (as outlined below) allowing for the 
collection of repeated serum chemistry samples (at 
least 2 weeks apart) to confirm pretreatment ALP 
and total bilirubin values: 
 
 
Insertion 
 
 
 
 
Collection of 2 serum chemistry samples 
(collected at least 2 weeks apart) during 
Screening is required for confirmation of the 
pretreatment serum chemistry values, including 
the ALP and total bilirubin used to determine 
eligibility: 
 
• 
When the 2 bilirubin or ALP assessments 
collected at Screening Visit 1 and Screening 
Visit 2 differ by ≥30%, a third sample must be 
collected at an unscheduled visit as a 
confirmatory sample to include in the mean 
result(s) that will be used to determine 
eligibility.  
Allows repeat assessments 
when baseline laboratory 
values are discrepant between 
Screening Visit 1 and 
Screening Visit 2. 
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• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(selected study sites only), 
 
 
Insertion 
• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(at all study sites where the device is available),   
 
In the event that the 2 screening bilirubin or 
ALP assessments differ by ≥30%, and a third 
confirmatory sample is required to be 
collected, the Screening Visit window may be 
extended up to 3 additional weeks. 
Section 9.7.8  
Month 1 
Procedures 
 
Section 9.7.10  
1-Month Post-
Titration visit 
Procedures 
Insertion (9.7.8) 
 
 
Insertion (9.7.10) 
 
- 
A physical examination should be 
performed at the Month 3 visit if an onsite 
Month 1 visit was not performed. 
- 
A physical examination should be 
performed at the next scheduled visit if an 
onsite post-titration visit was not performed. 
Clarification  
Section 9.7.12  
Month 9 
Procedures 
Section 9.7.14 
Month 12 
Procedures 
Section 9.7.16 
Month 16 
Continued 
Follow-Up 
Procedures 
Section 9.7.17  
Month 12 Follow-
up Procedures 
Section 9.7.18  
EOS/EOT 
Section 9.7.12, 9.7.14, 9.7.16, 9.7.17, and 9.7.18 
 
…DEXA procedure to be done at 
selected study sites only, 
 
 
Section 9.7.14, and 9.7.17 
 
 
• 
Perform an endoscopy (at selected study 
sites, where available) 
 
Section 9.7.12, 9.7.14, 9.7.16, 9.7.17, and 9.7.18 
 
…DEXA procedure to be done at 
all study sites where the device is available  
 
 
Section 9.7.14, and 9.7.17 
 
• 
Perform an endoscopy (at all study sites, 
where device is available) 
 
Clarification 
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Section 9.7.18  
EOS/EOT 
If the subject reports having eaten within 8 hours, 
document accordingly in the source and CRF and 
remind the subject that fasting is required prior to 
all study visits. 
If the subject reports having eaten within 8 
hours, document accordingly in the source and 
CRF. 
Clarification 
Section 10.3  
Investigational 
Product Storage 
The investigational product should be stored in the 
containers in which they are received from the 
Sponsor’s supplier, at 15°C to 25°C. 
All OCA tablet strengths provided to clinical 
trial sites in support of clinical study 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. 
Updating temperature 
excursions language per 
Sponsor stability studies. 
Section 11.1.2 
Secondary 
Assessments 
Insertion 
 
• 
Histological assessment of disease 
progression or improvement using paired biopsies 
in a subset of subjects (defined in Appendix C). 
 
 
 
 
• 
Biomarkers, including other markers of 
hepatic fibrosis and/or inflammation, to be 
tested will include:  IgM, c reactive protein 
(CRP), tumor necrosis factor α (TNF-α), 
FGF 19, cytokeratin-18 (CK-18) and ELF, 
(and others as determined during the course of 
the study). 
  
• 
Individual components of the primary 
endpoint. 
• 
Histological assessment of disease 
progression or improvement using paired 
biopsies in a subset of subjects (defined in 
Addendum 2). 
• 
HCC confirmed by 2 complimentary 
imaging modalities, unless confirmed by 
biopsy. 
• 
Biomarkers, including other markers of 
hepatic fibrosis and/or inflammation, to be 
tested will include:  IgM, c reactive protein 
(CRP), tumor necrosis factor α (TNF-α), 
FGF 19, cytokeratin-18 (CK-18) ELF, and 
Fibroscan (and others as determined during 
the course of the study). 
• 
 Clinical outcomes, including individual 
component of the primary endpoint 
Clarified and re-ordered 
bullets for consistency 
throughout document. 
 
Addition of Addendum 2.  
Reflects addition of a biopsy 
substudy available to 
interested sites in 
Addendum 2. 
 
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• 
Endoscopy will be conducted at selected 
study sites where the device is available to assess 
for the presence of oesophageal varix/varices at 
baseline.  
(where available), liver transplant, and 
death will be compared to historical 
controls. 
• 
PK of OCA and its conjugates. 
• 
Endoscopy will be conducted at all study 
sites where the device is available to assess for 
the presence of oesophageal varix/varices at 
baseline.  
Section 12.1.3  
Relationship of 
Adverse Events to 
Liver Biopsy 
 
Insertion (new section) 
The Investigator will document her/his opinion 
of relationship of an AE to liver biopsy using 
the criteria outlined in Table 9.  
Table 9: Relationship of Adverse Events to 
Liver Biopsy 
Relation
ship 
Description 
Related 
A reaction that follows a 
reasonable temporal sequence 
from the liver biopsy; that 
follows a known or expected 
response pattern to the liver 
biopsy. 
Not 
Related 
Any event that does not meet the 
above criteria. 
Added with the addition of 
liver biopsies for the 
confirmation of progression to 
cirrhosis. 
Section 12.1.5.2 
Reporting of 
Serious Adverse 
Events 
•Telephone:  +1 858 964 1571 
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. 
 
If an SAE is reported by email or fax, an SAE 
Report form must also be completed in the EDC 
system as soon as the EDC system is accessible. 
Updated to align with 
modified standard safety 
procedures. 
Section 12.1.6 
Suspected Liver-
Related Clinical 
Outcome Events 
Section 12.1.5 
Given that the liver-related 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 liver-related 
clinical outcome events in order to retain the study 
Section 12.1.6 
Given that the liver-related clinical outcome 
events may also meet the criteria of a SUSAR, 
but are considered in aggregate as part of the 
primary endpoint and the DMC reviews of all 
safety and efficacy data at least quarterly, the 
Sponsor will not expeditiously report suspected 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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blind and preserve the integrity of the clinical 
outcomes endpoint. 
 
The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy),  spontaneous 
bacterial peritonitis (preferred term: peritonitis 
bacterial), ascites (preferred term: ascites), and 
histological progression to cirrhosis (preferred 
term: hepatic cirrhosis). 
liver related clinical outcome events in order to 
retain the study blind and preserve the integrity of 
the clinical outcomes endpoint. 
 
The Sponsor will consider the following list of 
clinical outcome events (MedDRA preferred 
terms) to be disease related and exempt from 
expeditious regulatory reporting, but will 
continue to report them in a nonexpeditious 
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 or oesophageal varices 
haemorrhage), hepatic encephalopathy 
(preferred term: hepatic encephalopathy),  
spontaneous bacterial peritonitis (preferred term: 
peritonitis bacterial), ascites (preferred term: 
ascites), and histological or clinical progression 
to cirrhosis (preferred term: hepatic cirrhosis). 
Section 12.1.8 
Notification of 
Post-Treatment 
SAEs for Subjects 
Who Continue in 
the Study 
Insertion (new section) 
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 
12.1.5.2. 
SAEs that occur in subjects 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 12.1.5.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language. 
Section 12.1.9 
Notification of 
Poststudy SAEs 
Section 12.1.7 
All SAEs that occur within 30 days following the 
cessation of investigational product, whether or 
Section 12.1.9 
All SAEs that occur within 30 days following 
discontinuation from the study, whether or not 
Updated to align with 
modified safety procedures 
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not they are related to the investigational product, 
must be reported to the Sponsor within 24 hours 
by following the instructions provided in Section 
12.1.4.2. 
SAEs that occur more than 30 days after a subject 
has discontinued investigative product, and are not 
considered related to investigational product, must 
still be reported in the EDC system; however, 
these events are not required to be reported within 
24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to 
investigational product, action taken with 
investigative product, treatment, outcome, and 
potential endpoint status need to be recorded in 
EDC for the SAE.  Additional information (e.g. 
event summary, SAE details) may also be required 
to be entered, when requested by the Sponsor. 
they are related to the investigational product, 
must be reported to the Sponsor within 24 hours 
by following the instructions provided in Section 
12.1.5.2. 
and Sponsor standard 
language. 
Section 12.2.7  
Laboratory 
Assessments 
The list of laboratory analytes to be tested is 
shown in Table 10. 
The list of laboratory analytes to be tested is 
shown in Table 11, and the normal reference 
ranges for liver biochemistries are shown in 
Appendix C. 
Added per Regulatory 
Authority request. 
Section 13  
Statistical 
Methods 
A statistical analysis plan (SAP), providing details 
about the specific planned analyses and hypothesis 
tests, will be prepared and approved by the 
Sponsor and its designees prior to study database 
lock, propensity score determination, and 
unblinding of the double-blind subject treatment 
assignments. 
A statistical analysis plan (SAP), providing 
details about the specific planned analyses and 
hypothesis tests, will be prepared and approved 
by the Sponsor and its designees prior to the first 
interim analysis, propensity score determination, 
and unblinding of the double-blind subject 
treatment assignments. 
Reflects addition of interim 
analyses to the study protocol. 
Section 13.1.1 
Analysis 
Populations 
Insertion 
• 
The Per Protocol (PP) Population will 
include all ITT subjects who do not have any 
major protocol violations that potentially 
affect the efficacy conclusion.  Treatment 
assignment will be based on the randomized 
treatment. 
The Per Protocol Population 
will be used to conduct 
sensitivity analyses for 
primary and key efficacy 
endpoints. 
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Section 13.1.1.1  
Comparability of 
Historical 
Controls 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria where possible. 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria.  Propensity score 
matching method will be utilized to select 
historical controls that match the treated 
subjects using available covariates. The 
adequacy of matching will be assessed by 
statistical methods described under 
Section 13.1.8. 
Clarifies the use of propensity 
scores in the assessment of the 
historical control population. 
Section 13.1.5 
Additional 
Secondary 
Efficacy Analyses 
The following secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
on using the ITT population: 
The following time-to-event secondary efficacy 
analyses will compare OCA versus placebo using 
the ITT population: 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
 
Editorial Change 
Progression to cirrhosis added 
as secondary endpoint in 
Version 3.1. 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request. 
Section 13.1.5.1  
Association of 
Biochemistry with 
Clinical Outcomes 
and Clinical 
Benefit 
The association between the effect of OCA on 
ALP and bilirubin and the clinical benefit of OCA 
will be evaluated by estimating the proportion of 
net treatment effect on the primary composite 
endpoint that is explained by each biochemical 
marker.  For each biochemical endpoint, this 
proportion will be estimated by applying the 
partial likelihood function to two Cox models that 
use the same failure time variable, as described in 
Lin 1997. This analysis will be based on the ITT 
population.  
Based on the association between biochemical 
changes and clinical outcomes described above, 
clinical benefit of OCA for key subpopulations of 
interest will be evaluated. This analysis will be 
further described in the SAP. 
The association between biochemistry including 
ALP and bilirubin with clinical outcomes will be 
assessed and the clinical benefit of OCA using 
biochemistry as a surrogate endpoint will be 
evaluated.  Detailed analysis will be described in 
the SAP.  
Based on the association between biochemical 
changes and clinical outcomes described above, 
clinical benefit of OCA using biochemistry as a 
surrogate endpoint for key subpopulations of 
interest will be evaluated. This analysis will be 
further described in the SAP. 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
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Section 13.1.8  
Supportive 
Analysis 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls. 
 
 
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment. 
 
Although it might be relatively simple to assign a 
historical control based on a single observable 
characteristic, in practice, if the matching process 
is to successfully mitigate potential bias, it has to 
be done considering a full range of covariates 
across which the treatment and historical controls 
might differ. 
Only covariates and not outcome variables will be 
included in the propensity score estimation.  
Therefore, there is no chance of biasing, to avoid 
biased results that are in favor of one treatment. 
 
 
 
 
 
 
 
 
 
 
 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls, which serves as an external 
control for supportive analysis.  
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment 
between the treated subjects and the matched 
natural history subjects. 
A full range of covariates across which the 
treatment and historical controls might differ will 
be considered to mitigate potential bias. 
 
 
Only covariates and not outcome variables will 
be included in the propensity score estimation to 
avoid biased results that are in favor of one 
treatment. 
 
The baseline characteristics between treated 
and natural history subjects in the matched 
dataset will be summarized and presented in a 
tabular format.  Statistical methods such as 
Wilcoxon Rank-Sum test will be used to assess 
the balance for baseline covariates.  The 
standardized difference and variance ratios 
for these covariates will also be calculated.  In 
addition, box plots of propensity scores for 
treated and natural history subjects will be 
separately presented, to further assess the 
adequacy of matching.  
A third-party statistician(s) will perform the 
propensity score modeling and matching.  This 
Clarifies the use of the 
historical controls as an 
external control in supportive 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
 
 
Clarifies the use of the 
historical controls as an 
external control in supportive 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
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The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
• 
Time to hepatocellular carcinoma 
 
third-party statistician(s) will be separate and 
independent from the statistician(s) who will 
assess the success of matching and perform 
efficacy analyses. 
 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
 
 
 
Section 13.1.9  
Handling of 
Dropouts or 
Missing Data 
Insertion 
In addition, the same analyses for primary and 
key secondary endpoints based on ITT and PP 
populations will be performed to assess 
robustness of analysis results. During the 
conduct of the study, the DMC may 
recommend refining the missing data strategy 
to better address the observed pattern of 
missing data, based on blinded monitoring of 
the data. 
Clarification of statistical 
analyses to address missing 
data. 
Section 13.1.11  
Examination of 
Subgroups 
The primary and secondary efficacy endpoints will 
be analyzed for subject subgroups (eg, age, sex, 
and race) based on the ITT population.  
 
Insertion 
The primary and secondary efficacy endpoints 
will be analyzed for subject subgroups based on 
the ITT population.  
 
The primary efficacy endpoint will also be 
assessed across the spectrum of PBC disease 
stage as defined by Rotterdam criteria 
(Kuiper 2009)  
• 
Early (normal albumin and normal 
bilirubin) 
 
 
 
 
 
Added per Regulatory 
Authority request. 
 
 
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Justification for Change 
• 
Moderate (abnormal albumin or 
abnormal bilirubin) 
• 
Advanced (abnormal albumin and 
abnormal bilirubin) 
The primary efficacy endpoint will also be 
assessed for the following clinically relevant 
subpopulations. 
• 
Monotherapy in patients who are 
intolerant or non-responsive to UDCA  
• 
Elderly patients 
Assuming a strong correlation between 
biochemistry and clinical outcomes using the 
total study population (Section 13.1.5.1) is 
observed, we will further assess the 
biochemical improvement in relevant 
subpopulations as applicable (eg, Rotterdam 
disease severity and monotherapy) and 
estimate the reduction in risk of clinical 
outcomes associated with the biochemical 
improvement. 
Additional details regarding statistical 
methods and subgroup definitions will be 
provided in the SAP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
Section 13.1.12  
Continuous 
Monitoring and 
Interim Analyses 
Both interim analyses will be pre-specified and 
will occur after accrual of 50% and 75% of 
clinical outcome events, respectively. 
 
The DMC will review the available efficacy data 
in conjunction with detailed safety data and other 
relevant information to recommend continuation, 
modification, or cessation (for efficacy or futility) 
of the study beyond each interim analysis.  
Both interim analyses will be pre-specified and 
will occur after accrual of 50% (64 events) and 
75% (96 events) of clinical outcome events, 
respectively. 
 
The DMC will review the available efficacy data 
in conjunction with detailed safety data and other 
relevant information to recommend continuation, 
Added number of anticipated 
events. 
 
 
 
Clarification 
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Justification for Change 
modification, or cessation (for efficacy) of the 
study beyond each interim analysis 
Section 19  
List of References  
Lin DY, Fleming TR, De Gruttola V.  Estimating 
the proportion of treatment effect explained by a 
surrogate marker.  Statistics in Medicine.  
1997;16(13):1515-1527. 
 
Insertion 
 
 
 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Digestive and Liver 
Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Gastroenterology. 
2015b;149(6):1627-9. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
'cirrhosis' to 'cholangitis'. Hepatology. 
2015c;62(5):1620-2. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-
ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed 
with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-3572. 
Reboussin DM, DeMets, DL, Kim KM, et al.  
Computations for Group Sequential 
Boundaries Using the Lan-DeMets Spending 
Function Method.  Controlled Clin Trials.  
2000;21(3):190-207. 
 
 
Additional relevant references 
were added. 
Appendix C 
Reference 
Laboratory Values 
from Central 
Laboratories 
Insertion (new appendix) 
 
 
Deletion:  
Appendix C in Version 3.1 has been deleted.  It is 
now published as Protocol Addendum 2. 
Appendix containing reference laboratory 
values from central laboratories added. 
Added per Regulatory 
Authority request. 
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APPENDIX I. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO PROTOCOL VERSION 4 
(DATED 10 MAY 2017) 
Please note that Protocol 747-302 Version 3.1 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. Therefore, a 
full accounting of the changes from Protocol Version 3 to Protocol Version 4 is provided below. 
Rationale and Summary of Changes 
Major revisions to Protocol 747-302 include the modification of inclusion/exclusion criteria to expand the PBC disease spectrum, the 
addition of progression to cirrhosis as a secondary endpoint, and the addition of 2 interim analyses.  Additional revisions include an 
increase in subject number and the number of required clinical outcome events, a change in the study phase, an update to the 
nomenclature for PBC, and various clarifications within the protocol.  
The text deleted from Protocol Version 3 is crossed out while revised text in Version 4 is indicated in bold font.  Minor/editorial 
changes and non-substantial changes are not listed individually. For efficiency, rationales that impact multiple sections are provided 
below and referenced in the table with the corresponding rationale number.  
1. The phase of the study has been changed from “3b” to “4” to reflect that this is a post-marketing study.  Protocol 747-302 
is considered a Phase 4 study in regions where OCA has received regulatory approval for PBC, ie, in the US and the EU.  In all 
other regions, this study is considered Phase 3b.  In May 2016, the FDA granted accelerated approval for OCA (Ocaliva) for 
the treatment of PBC.  In December 2016, Ocaliva received Conditional Approval from the European Medicines Agency’s 
Committee for Medicinal Products for Human Use. 
2. The term “primary biliary cirrhosis” has been changed to “primary biliary cholangitis” to reflect recent changes in the 
nomenclature for PBC. 
3. The number of required adjudicated events for the final analysis has increased from 121 to 127 due to the addition of two 
interim analyses, which will allow an independent DMC to recommend continuation, modification, or cessation (for efficacy) 
of the study.  One interim analysis will occur at 50% information (after 64 events occur) and one at 75% information (after 
96 events occur).  In addition, inclusion of PBC subjects with earlier stage disease will increase the time to event, thereby 
requiring more events to maintain follow-up to approximately 6 years.   
4. The first-year study enrollment rate was lower than projected due to slower-than-anticipated activation of sites and required a 
re-estimation of the accrual duration.  Using observed accrual rates, the accrual duration was extended by 2 years.  The 
follow-up period was maintained at 6 years, thereby leading to a total trial duration of 10 years. 
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5.  “Encephalopathy” has been modified to “Hepatic Encephalopathy” to clarify that the relevant Clinical Outcome Event 
should be related to hepatic disease. 
6. Hepatocellular carcinoma (HCC) has been redefined as a secondary endpoint instead of a component of the primary 
composite-event endpoint per Regulatory Authority request.  
7. Histological confirmation (biopsy) has been added as an acceptable method of confirming a diagnosis of HCC. 
8. Broadening the Spectrum of Disease:  Lowering the minimum allowable baseline ALP from >5x ULN to >3x ULN and 
raising the maximum allowable baseline total bilirubin to ≤5x ULN will increase the number of subjects enrolled with early 
and advanced disease facilitating the collection of safety and efficacy data in a population that covers the spectrum of PBC 
disease and overlaps with the subject population in the Phase 3 protocol 747-301.  However, to ensure enrollment of an 
adequate number of subjects with abnormal total bilirubin, a minimum of 30% of the subjects enrolled in the study will have 
elevated bilirubin (>ULN) at Screening. 
9. The titration regimen has been updated to reflect assessment of both tolerability and biochemical response prior to up-titration 
per the USPI and SmPC.   
10. The increase in enrollment from 350 to 428 subjects is due in part to the increased number of events from two additional 
interim analyses, and in part due to the change in the estimated placebo baseline hazard rate, which resulted from changing the 
lower limit of ALP from >5x ULN to >3x ULN in the enrollment criteria #2.  
11. Progression to Cirrhosis has been added as a secondary endpoint:  Due to the chronic nature of PBC, outcomes require a very 
long time to accrue to evaluate the impact of potential therapies.  Despite the proven prognostic utility of ALP and bilirubin, 
there is a remaining need to evaluate noninvasive assessments of disease progression that can be linked to histological 
progression of the disease.  Therefore, it is important to evaluate potential noninvasive markers of fibrosis/cirrhosis and their 
relationship to clinical outcomes as part of Study 747-302. 
12. A Per Protocol (PP) population has been added to the statistical analysis section.  Sensitivity analysis for primary efficacy 
endpoints and key secondary efficacy endpoints will be performed using PP population. 
 
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Title Page 
Synopsis, Title of 
Study 
A Phase 3b, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study Evaluating 
the Effect of Obeticholic Acid on Clinical 
Outcomes in Subjects with Primary Biliary 
Cirrhosis 
A Phase 4, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on 
Clinical Outcomes in Subjects with Primary 
Biliary Cholangitis 
 
Rationale 1 and 2  
Study Personnel 
Contact 
Information 
Or if Not Available: 
Contact: 
 MD, PhD, 
Executive Director, Clinical 
Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
 
Email: 
 
 (Pacific 
time zone) 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical 
Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
 (Pacific time 
zone) 
 
O 
 
 
 
 
 
 
 
 
 
 
 
The contact information of 
clinical operations and project 
managements personnel is no 
longer required per Sponsor’s 
procedures. 
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PPD
PPD
PPD
PPD
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Email: 
 
 
Synopsis, Studied 
Period (Years) 
 
The study is event driven and total duration will be 
determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 and 4   
 
Synopsis,  
Phase of 
Development 
Phase 3b 
Phase 4 
Rationale 1 
Synopsis, 
Objectives, 
Primary, 
Statistical 
Methods – 
Efficacy Analyses 
Section 6.1 
Primary Objective 
Section 11.1.1 
Primary 
Assessments 
Section 13.1.3 
Primary Efficacy 
Analysis 
• 
Encephalopathy (as defined by a West Haven 
score of ≥2) 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities 
• 
Hepatic encephalopathy (as defined by a 
West Haven score of ≥2) 
 
Rationale 5   
 
Rationale 6 
Synopsis, 
Objectives, 
Secondary  
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
Rephrasing the objective 
 
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Section 6.2 
Secondary 
Objectives 
 
component of the primary endpoint as listed above 
and also to include liver related death. 
 
 
 
Insertion 
 
 
 
To assess the pharmacokinetics of OCA and its 
conjugates in a subset of subjects 
component of the primary endpoint as listed 
above.  
To assess the effect of OCA compared to 
placebo on time to occurrence of liver-related 
death. 
To assess the effect of OCA compared to 
placebo on progression to cirrhosis. 
To assess the effect of OCA compared to 
placebo on time to occurrence of 
hepatocellular carcinoma (HCC). 
To characterize the pharmacokinetics of OCA 
and its conjugates in a subset of subjects 
 
 
 
 
 
Rationale 11 
 
Rationale 6 
 
Synopsis, 
Methodology: 
 
A minimum of 30% of subjects will have 
elevated bilirubin (>ULN) at Screening. 
Rationale 8 
 
Schematic 
Diagram 
 
Section 7.1.1 
Study Design 
Diagram, Figure 1 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.   
 
 
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability and biochemical response (up-titration 
should be considered when ALP and/or total 
bilirubin are >ULN).   
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
 
Rationale 8 
 
 
 
Rationale 9 
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placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability of the product. 
 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability. Subjects 
classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 
10-mg OCA or matching placebo twice 
weekly, based on tolerability. 
 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
subject tolerability, and/or changes in cirrhosis status or 
Child-Pugh Score at any time during the study. 
 
visit following the Month 3 visit based on 
tolerability and biochemical response of the 
product. 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability and biochemical 
response. Subjects classified as Child-Pugh 
Class C should titrate to a maximum dose 
and frequency of 10-mg OCA or matching 
placebo twice weekly, based on tolerability 
and biochemical response. 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
subject tolerability, biochemical response, and/or 
changes in cirrhosis status or Child-Pugh Score at any 
time during the study. 
Synopsis, Number 
of Subjects 
(Planned)  
Section 7.2 
Number of 
Subjects 
Insertion 
 
 
Change in Synopsis section 
Approximately 350 subjects 
In the event additional subjects are needed for 
the enrollment in the biopsy substudy (N = 45 
subjects, as defined in Addendum 2), subjects 
who agree to participate in the sub study may 
be added to the target subject enrollment 
number currently planned. 
Approximately 428 subjects are planned to be 
enrolled in the study.   
Rationale 10 and 
Addendum 2 
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Change in Section 7.2 section 
It is expected that approximately 350 subjects will 
be randomized in the study to achieve 121 
adjudicated primary endpoint events. 
 
It is expected that approximately 428 subjects 
will be randomized in the study to achieve 127 
adjudicated primary endpoint events.  
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
2.  A mean total bilirubin >ULN and ≤3x ULN 
and/or a mean ALP >5x ULN 
2.  A mean total bilirubin >ULN and ≤5x ULN 
and/or a mean ALP >3x ULN 
Rationale 8 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom 
(male or female) or (b) diaphragm, with 
spermicide; or  
• 
Intrauterine device (IUD); 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 subject   
5.  Contraception:  Female subjects of 
childbearing potential must use ≥1 effective 
method of contraception during the study and 
until 30 days following the last dose of 
investigational product.  Effective methods 
of contraception are considered to be those 
listed below:   
• 
Barrier method, ie, (a) condom (male 
or female) or (b) diaphragm, with 
spermicide 
• 
Intrauterine device (IUD)  
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection) 
• 
Abstinence, if in line with the preferred 
and usual lifestyle of the subject   
Standardizing language across 
protocols; removing double-
barrier terminology. 
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Synopsis, 
Exclusion Criteria 
Section 8.3 
Subject Exclusion 
Criteria 
 
2.  Presence of clinical complications of PBC or 
clinically significant hepatic decompensation, 
including: 
 
 
 
 
 
3.  Mean total bilirubin >3x ULN 
2.  Presence of clinical complications of PBC or 
clinically significant hepatic decompensation, 
including: 
•History of liver transplant, current 
placement on a liver transplant list, or 
current MELD score >12.  Subjects who 
are placed on a transplant list despite a 
relatively early disease stage (for example 
per regional guidelines) may be eligible as 
long as they do not meet any of the other 
exclusion criteria 
3.  Mean total bilirubin >5x ULN 
 
 
 
This criterion (sub-bullet) is 
already included in Version 3 
of the protocol.  In the 
Version 4, it is added to the 
synopsis for consistency. 
 
Rationale 8 
Synopsis, 
Duration of 
Treatment 
It is estimated that subjects will be followed up for 
a minimum of 6 years.  The study is event driven 
and total duration of treatment will be determined 
by the time to accrue 121 total primary endpoint 
events. 
It is expected that subjects will be followed up 
for a minimum of 6 years.  The study is event 
driven and total duration of treatment will be 
determined by the time to accrue 127 total 
primary endpoint events. 
Rationale 3 
Synopsis, Criteria 
for Evaluation 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Encephalopathy (as 
defined by a West 
Haven score of ≥2) 
 
• 
Hepatocellular 
carcinoma 
confirmed by 
2 complimentary 
imaging modalities 
 
Secondary Objectives 
 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Hepatic 
encephalopathy (as 
defined by a West 
Haven score of ≥2) 
Secondary Objectives 
 
Progression to 
cirrhosis 
Clinical, laboratory, or 
radiological evidence of 
cirrhosis and/or liver 
stiffness (i.e., Fibroscan® 
TE) confirmed by biopsy 
unless not medically 
indicated 
Rationale 5 
 
 
 
 
 
Rationale 11 
 
 
 
 
 
Rationale 6 
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Hepatocellular 
carcinoma 
Confirmed by 
2 complimentary imaging 
modalities unless 
confirmed by biopsy 
Synopsis, 
Statistical 
Methods 
Analysis 
Populations 
 
The following subject populations will be 
evaluated and used for presentation and analysis of 
the data:  Randomized, Intent-to-Treat (ITT), 
Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical 
Control.  Descriptions of subject populations are 
provided in Section 13.1.1. 
The following subject populations will be 
evaluated and used for presentation and analysis 
of the data:  Intent-to-Treat (ITT), Per Protocol 
(PP) Safety, PK, Overall Historical Control, 
UK-PBC Historical Control, and the Global PBS 
Historical Control.  Descriptions of subject 
populations are provided in Section 13.1.1. 
 
Randomized population 
includes patients on OCA who 
withdrew prior to receiving 
drug and this is already 
collected with the safety 
population. 
 
Rationale 12 (for PP 
Population) 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Endpoint 
 
Section 11.1.1  
Primary 
Assessments 
The primary efficacy endpoint will be the time to 
first occurrence of one of the following post 
randomization:  
• 
Encephalopathy (as defined by a 
West Haven score of ≥2) 
• 
Hepatocellular carcinoma confirmed 
by 2 complimentary imaging modalities 
 
Change in Synopsis section 
Every event for enrolled subjects will be 
adjudicated by an independent committee. 
The primary efficacy endpoint will be the time to 
first occurrence of one of the following:  
• 
Hepatic encephalopathy (as defined 
by a West Haven score of ≥2) 
 
 
 
 
All events will be adjudicated by an independent 
committee. 
Rationale 5 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Analysis 
Section 13.1.3  
Primary Efficacy 
Analysis 
The primary efficacy analysis will compare 
randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the 
ITT population.   
 
Insertion 
 
The primary efficacy analysis will compare OCA 
to placebo with respect to the primary efficacy 
endpoint using the ITT population.   
 
The same analyses for primary efficacy 
endpoints will be performed for PP population 
as a sensitivity analysis.   
 
 
 
 
Rationale 12 
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Synopsis, 
Statistical 
Methods, Key 
Secondary 
Efficacy Analyses 
Section 13.1.4  
Secondary 
Efficacy Analysis 
The key secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
in ITT population with respect to the key 
secondary efficacy endpoints.   
 
Insertion 
 
The key secondary efficacy analyses will 
compare OCA to placebo in the ITT population 
with respect to the key secondary efficacy 
endpoints.   
 
The same analyses for key secondary efficacy 
endpoints will be performed for PP 
population as a sensitivity analysis.   
 
 
 
 
 
Rationale 12 
Synopsis, 
Statistical 
Methods, 
Additional 
Efficacy Analyses 
 
Section 13.1.5 
Additional 
Secondary 
Efficacy Analyses 
Other Efficacy Analyses 
The following secondary efficacy analyses will 
compare OCA to placebo on time to the following 
events: 
 
 
Insertion 
Additional Efficacy Analyses 
The following time-to-event secondary efficacy 
analyses will compare OCA to placebo using the 
ITT population: 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
 
Progression to cirrhosis will be assessed in the 
subset of subjects considered noncirrhotic at 
Baseline using available medical history, 
clinical, and laboratory assessments as well as 
Baseline transient elastography (TE), where 
available. Specifically, subjects with no 
clinical, laboratory, or radiological evidence of 
cirrhosis at baseline and/or a TE liver stiffness 
of <16.9 kPa (Corpechot 2012) will be 
considered noncirrhotic.  Progression to 
cirrhosis will be assessed by the development 
of clinical, laboratory, or radiological evidence 
of cirrhosis and/or when liver stiffness 
increases to ≥16.9 kPa during the study in 
which case histological progression to cirrhosis 
should be confirmed by biopsy unless not 
medically indicated. Using this definition for 
Rationale 6 and 
Rationale 11 
 
 
 
 
 
 
 
 
Rationale 11 
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progression to cirrhosis, the percentage of 
noncirrhotic subjects progressing to cirrhosis 
during the treatment period will be 
summarized by treatment group and 
compared using a Cochran–Mantel–Haenszel 
test stratified by the randomization 
stratification factor. 
For those subjects enrolled in the biopsy 
substudy (defined in Addendum 2) progression 
to cirrhosis identified by the above criteria and 
improvement in fibrosis/cirrhosis will be 
confirmed by paired biopsy.  Analyses for the 
histological assessment conducted as part of 
the biopsy substudy are defined in 
Addendum 2.  
Synopsis, 
Statistical 
Methods, Safety 
Analyses 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will compare OCA and placebo using the Safety 
Population. 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will be summarized by treatment group for the 
Safety Population. 
 
Clarification of summary 
analyses. 
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Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
 
Section 13.1.2. 
Determination of 
Sample Size 
 
 
 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, 
placebo survival estimate of 0.5 at 
8 years with a hazard ratio of 0.60, 
and total study duration of 8 years, 
allowing for 2 years accrual and 
6 years of follow up 
 
 
 
 
Insertion 
 
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
The target population is subjects who are at 
higher risk of liver-related clinical 
complications. Eligible subjects will have a 
diagnosis of PBC with bilirubin levels >ULN 
and ≤5x ULN and/or ALP >3x ULN.   
The following assumptions were used in sample 
size calculations:  
• Exponential survival curves, placebo survival 
estimate of 0.6 at 8 years with a hazard ratio of 
0.60, and total study duration of 10 years (from 
first subject enrolled), allowing for 4 years of 
subject accrual and 6 years of follow up.  
• Two interim analyses and one final 
analysis are planned.   The first interim 
analysis will be performed when 50% of the 
target events are accrued and the second 
interim will be performed when 75% of the 
target events are accrued.  
•  A dropout rate of 10% is assumed  
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
 
Rationale 8 
 
 
Rationale 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale 3 
 
 
 
 
 
 
Section 5.1 
Overview of PBC 
and OCA 
5.1. Overview of Primary Biliary Cirrhosis and 
Obeticholic Acid 
5.1. Overview of Primary Biliary Cholangitis 
and Obeticholic Acid 
Updating language to include 
accelerated and conditional 
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Primary biliary cholangitis, (PBC, also known as 
primary biliary cirrhosis) 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. 
ursodeoxycholic acid (UDCA), a physiological 
constituent of human bile, is currently the only 
treatment approved for PBC (Lindor 2009).  While 
UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a 
suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of 
a poor clinical outcome due to PBC disease 
progression.   
There is a clear unmet medical need for better 
therapies for patients with PBC that have an 
inadequate response to UDCA, or those who 
cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  
Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have 
an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and 
effective. 
OCA is a modified bile acid and farnesoid X 
receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid 
(CDCA).  OCA is currently being developed in the 
United States (US) and Europe for the treatment of 
PBC and other chronic liver diseases.  OCA has 
 
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. 
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), 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 
(Pellicciari 2002).  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 
approvals of OCA in the US 
and EU.  
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been granted Orphan Drug Designation in the US 
(09 Apr 2008) and Orphan Medicinal Product 
Designation in the European Union (EU) (27 Jul 
2010) for the treatment of PBC.  The United States 
Food and Drug Administration (FDA) has granted 
accelerated approval for Ocaliva for the treatment 
of PBC.  Ocaliva is not yet approved outside the 
United States for use in any indication. 
UDCA.  In December 2016, the European 
Commission granted conditional approval for 
Ocaliva for the same indication. 
Section 5.4 
Overview of PBC 
and OCA 
As of 31 Jan 2016, approximately 1726 subjects 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 458 subjects had 
PBC, 330 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver disease 
(NAFLD), 33 subjects had alcoholic 
cirrhosis/portal hypertension, and 20 subjects had 
primary sclerosing cholangitis (PSC). 
As of 31 Jan 2017, approximately 2186 subjects1 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 525 subjects had 
PBC, 686 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver 
disease, 33 subjects had alcoholic cirrhosis/portal 
hypertension, and 52 subjects had primary 
sclerosing cholangitis, and 5 subjects had 
biliary atresia. 
------------------------ 
1Includes estimated numbers from ongoing 
blinded studies. 
Language updated to include 
data from current IB. 
Section 5.5.2.1  
Rationale for 
OCA Dose 
The Phase 3 PBC study subsequently evaluated 
the safety and efficacy of OCA at lower doses of 
5 mg (titrated to 10 mg after 6 months based on 
efficacy and tolerability in the double-blind phase 
and after 3 months in the open-label phase) and 
10 mg;  
 
Insertion 
 
 
 
 
The Phase 3 PBC study (Study 747-301) 
subsequently evaluated the safety and efficacy of 
OCA at lower doses of 5 mg (titrated to 10 mg 
after 6 months based on efficacy and tolerability 
in the double-blind phase and after 3 months in 
the open-label phase) and 10 mg;  
Study 747-301 demonstrated that titration of 
OCA from a starting dose of 5 mg to 10 mg 
improved tolerance to pruritus relative to 
10 mg (56% versus 69% of subjects who 
experienced pruritus) and minimized dropouts 
due to pruritus.   
Provides rationale for the 
dosing in alignment with 
commercial labeling. 
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Based on these data, the indicated commercial 
doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
 As such, Study 747-302 will evaluate the effect of 
OCA on clinical outcomes using the 5 mg OCA 
dose increasing to 10 mg OCA, if tolerated. 
Based on these data, the approved dosing 
regimen for OCA for the treatment of patients 
with PBC are 5 mg and 10 mg. 
Study 747-302 will evaluate the effect of OCA on 
clinical outcomes using the 5 mg OCA dose for 
at least 3 months, increasing to 10 mg OCA, if 
tolerated. 
Section 5.6 
Summary of 
Known Potential 
Risks with OCA 
These findings were seen more frequently with 
doses above 10 mg OCA. 
 
Insertion 
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).   
Refer to the Investigator’s Brochure (IB) for 
additional information regarding the known 
potential risks with the investigational 
product. 
Language has been updated to 
reflect Sponsor standards. 
Section 7.1 
Overall Study 
Design 
This is a Phase 3b, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤3× ULN or ALP 
>5× ULN.   
 
Approximately 350 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 2-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
 
Investigational product will be taken orally, once 
daily….based on tolerability (see Section 7.3). 
 
This is a Phase 4, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤5x ULN and/or 
ALP >3x ULN.   
 
Approximately 428 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 4-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1). . . A 
minimum of 30% of subjects will have 
elevated bilirubin (>ULN) at Screening. 
 
Subjects will be dosed according to their 
cirrhosis status and Child-Pugh Score…based 
Rationale 1 and Rationale 8 
 
 
 
 
Rationale 10 
 
 
 
Rationale 8 
 
 
Clarification  
Rationale 9 
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The study will continue until approximately 121 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
on tolerability and biochemical response (see 
Section 7.3)   
 
The study will continue until approximately 127 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
 
 
 
Rationale 3 
Section 7.1.2 
Schedule of Study 
Procedures,  
Table 1  
Insertions 
 
 
 
 
 
 
 
 a All subjects will have the chemistry panel 
retested to ensure subjects have at least two 
ALP and bilirubin assessments 2 weeks apart to 
calculate the mean result for both analytes.  The 
mean of all screening ALP and bilirubin 
assessments will be used to determine 
eligibility.  
 
 
 
j Transient elastography (TE) will be conducted 
at selected study sites where the Fibroscan® TE 
device is available.  Similarly, DEXA will be 
conducted at selected study sites where the 
DEXA device is available.    
Physical exams have been added at: 
• 
Month 1 
• 
1-Month Post Titration 
• 
Month 6 
Fibroscan® TE has been added at Month 6 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
 
 a All subjects will have the chemistry panel 
retested to ensure subjects have at least two 
ALP and bilirubin assessments at least 2 weeks 
apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and 
bilirubin assessments will be used to determine 
eligibility. Refer to Section 9.7.6 for guidance 
on when an additional ALP or bilirubin 
sample may be needed to confirm eligibility. 
 
j Transient elastography (TE) will be conducted 
at 6-month intervals at all study sites where 
the Fibroscan® TE device is available.   
 
 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
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Insertion (subsequent footnotes are renumbered 
accordingly) 
 
 
k 
Endoscopy will be conducted at selected 
study sites where the device is available. 
 
l Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be 
obtained to confirm if a study endpoint has been 
met. 
 
 
o … The initial dose titration of investigational 
product may occur at the Month 3 visit, or any 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability. … 
 
 
u  A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of 
these samples.  Genetics samples will be 
collected at Day 0 and every other year 
beginning at Month 12. 
k DEXA will be conducted at 12-month 
intervals at all study sites where the DEXA 
device is available.  Please refer to 
Section 9.7.7 for additional information 
related to the allowed windows at Day 0 for 
this procedure. 
 
m 
Endoscopy will be conducted at all study 
sites where the device is available. 
 
m 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.   
 
p … The initial dose titration of investigational 
product may occur at the Month 3 visit, or any 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability and 
biochemical response. … 
 
v A genetics study will be conducted in a subset 
of subjects who provide consent for analyses of 
these samples.  Genetics samples will be 
collected at Day 0 and every other year 
beginning at Month 12.  If a Baseline (eg, 
Day 0) genetic sample is not obtained, 
subsequent genetic samples are not required 
to be collected during the course of the 
study. 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments at Day 0 
and Month 12). 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
 
 
 
 
Rationale 9 
 
 
 
 
Clarification 
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Section 7.1.2 
Schedule of Study 
Procedures, Table 
2 
Insertions 
 
 
 
 
 
 
i Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE 
device is available.  Similarly, DEXA will be 
conducted at selected study sites where the 
DEXA device is available.  Not required if done 
within 6 months of visit. 
   Insertion (subsequent footnotes are renumbered 
accordingly) 
  
 
j   Endoscopy will be conducted at selected study 
sites where the device is available to assess for 
the presence of oesophageal varix/varices. 
 
k  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be 
obtained to confirm if a study endpoint has been 
met. 
 
Physical exams have been added at 1-Month 
Post Titration 
Fibroscan® TE has been added at Month 6 
continued follow up 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
continued follow up 
 
i Transient elastography (TE) will be conducted 
at 6-month intervals at all study sites where 
the Fibroscan® TE device is available. 
 
 
j  DEXA will be conducted at 12-month 
intervals at all study sites where the DEXA 
device is available. 
k   Endoscopy will be conducted at all study sites 
where the device is available to assess for the 
presence of oesophageal varix/varices. 
 
l  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. 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. 
 
o … The initial dose titration of investigational 
products may occur at the Month 3 visit, or any 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring. 
 
 
 
 
Fibroscan® TE monitoring 
has been increased to every 
6 months to facilitate 
monitoring for progression to 
cirrhosis. 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments). 
 
 
Hepatic ultrasound monitoring 
has been increased to every 
6 months to conform to 
AALSD and EASL practice 
guidelines for PBC patients 
with cirrhosis. 
 
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o … The initial dose titration of investigational 
products may occur at the Month 3 visit, or any 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability. 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability and 
biochemical response. 
Rationale 9 
Section 7.1.3 
Study Duration 
The study is event driven and total duration will be 
determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 
Section 7.2 
Number of 
Subjects 
It is expected that approximately 350 subjects will 
be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
It is expected that approximately 428 subjects 
will be randomized in the study to achieve 127 
adjudicated primary endpoint events.  In the 
event additional subjects are needed to 
complete enrollment in the biopsy substudy 
(N = 45 subjects, as defined in Addendum 2), 
subjects who agree to participate in the 
substudy may be added to the target subject 
enrollment number currently planned. 
Rationale 10 
Language added to allow for 
continued enrollment into the 
biopsy substudy; additional 
subjects are not anticipated to 
prolong the duration of the 
study. 
 
Section 7.3 
Planned Dosing 
Regimen, and 
Table 3 
Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at 
the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the 
product.   
 
 
Footnotes of Table 3 were re-ordered 
b   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is dependent 
on subject tolerability and/or changes in cirrhosis 
status or Child-Pugh score at any time during the 
study 
Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at 
the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the 
product and assessment of biochemical 
response.  Up-titration should be considered if 
ALP and/or total bilirubin are >ULN.   
 
c   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is 
dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or 
Child-Pugh score at any time during the study 
Rationale 9 
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Section 7.4  
Dose Titration 
Criteria 
Insertion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
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) as 
well as biochemical response (as assessed by 
reductions in ALP and/or total bilirubin).  In 
general, down-titration will be done in 
response to tolerability concerns and can occur 
at any time while on-study.  Up-titration will 
be done per protocol when subjects have no 
tolerability concerns and have not achieved an 
adequate reduction in ALP and/or total 
bilirubin to within normal limits, or 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 for each dosing regimen as defined 
in Section 7.3. 
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, biochemical response, and 
clinical judgment. 
Changes in Child-Pugh Score that result from 
a transient, explainable change in laboratory 
parameters should be documented 
appropriately and should not necessarily 
result in a change to the dosing regimen 
(Appendix A). 
Added language to clarify 
titrations (up or down). 
Section 7.4.1  
Pre-Titration 
Tolerability 
• 
There must be no clinically significant 
increase (as determined by the investigator) in the 
subject’s liver function tests.  Subjects whose total 
bilirubin is >2× baseline (and >ULN) cannot be 
• 
There must be no clinically significant 
increase (as determined by the Investigator) in 
the subject’s liver function tests.  
Clarification 
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Assessment 
Requirements 
up-titrated, and additional unscheduled safety visit 
procedures, outlined in Section 9.7.19 should be 
implemented, as required. 
Section 7.4.2   
Safety Criteria for 
Adjustment or 
Stopping Doses 
The text in this section is moved to Section 8.4.  
 
To avoid redundancy 
Section 7.5   
Criteria for Study 
Termination 
The window of time for scheduling the visit will 
be based on a final projection of when the 
requisite 121 adjudicated events will have been 
accrued. 
The window of time for scheduling the visit will 
be based on a final projection of when the 
requisite 127 adjudicated events will have been 
accrued. 
Rationale 3 
Section 8.4  
Dose Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
[Moved from Section 7.4.2 of Version 3] 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or 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 that 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 
when the needed number of adjudicated events has 
accrued.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, 
subjects should be strongly encouraged to both 
stay on investigational product and remain in the 
study until study termination.   
 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or by 
decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability 
concerns.  The dose of investigational product 
should be adjusted back to the maintenance dose 
in a blinded manner once the issues relating to the 
lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated 
events has accrued.  If a subject reaches an 
outcome event, he or she should continue the 
regular visit schedule and continue taking 
investigational product as long as the subject has 
not met any of the criteria for mandatory 
interruption of investigational product 
outlined in Section 8.4.1, and the Investigator 
assesses it as safe.  In general, subjects should be 
 
Clarification 
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strongly encouraged to both stay on 
investigational product and remain in the study 
until study termination.   
Section 8.4.1.1   
Reasons for 
Additional 
Monitoring 
Related to Liver 
Chemistries 
Modification of 8.4.2.1 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. 
 
 
Subjects 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.  Subjects with 
persistent elevations (eg, additional lab testing 
per Investigator discretion) should be closely 
monitored.  Concomitant elevations in total 
bilirubin or international normalized ratio 
(INR) with persistent increases in ALT or AST 
should also be closely monitored. 
 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries.  
Language related to 
interruption of investigational 
product is now located in 
Section 8.4.1.2. 
Section 8.4.1.2   
Reasons for 
Investigational 
Product 
Interruption 
Related to 
Insertion 
Development of any of the following clinical 
laboratory values, without explanation, during 
the study mandates investigational product 
interruption: 
• 
AST and/or ALT >3x baseline (and 
>ULN) 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries. 
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Elevated Liver 
Chemistries 
• 
Total bilirubin >2x 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 AE information should also be 
collected and the subject 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 >3x baseline (and >ULN) or total 
bilirubin >2x baseline (and >ULN), subjects 
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 investigative product 
and no other cause for the elevation is 
identified, it may be assumed that the 
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elevations were due to disease progression and 
the subject 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. 
If at any time a subject 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.  
Subjects who develop evidence of severe drug-
induced liver injury, which is suspected to be 
causally related to the investigational product 
should be discontinued from investigational 
product and should not be rechallenged.  
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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 
subjects 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 subject to continue 
treatment.  In the event the investigational 
product is required to be discontinued, 
subjects should be encouraged to continue 
study visits for continued data collection but 
may withdraw consent at any time.  
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 
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adjudicated by the Hepatic Safety Committee 
(see Section 13.4). 
Section 8.4.1.3   
Pregnancy 
Modification of 8.4.1 Reasons for Mandatory 
Discontinuation of Investigational Product 
If a female subject becomes pregnant, she must 
discontinue taking investigational product, but 
should continue with the study visit schedule.  The 
subject must be followed as considered 
appropriate by the Investigator and the medical 
monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an 
AE.  The subject may reinstate investigational 
product after delivery and cessation of 
breastfeeding (if applicable) at the discretion of 
the Investigator.  Subjects whose pregnancy is 
terminated early (planned or unplanned) may be 
permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotropin (β-
hCG) test performed at the central laboratory. 
8.4.1.3 Pregnancy 
If a female subject becomes pregnant, she must 
interrupt treatment with investigational product 
immediately, but should continue with the study 
visit schedule.  As described in Section 12.1.11 
pregnancy is not considered an AE for reporting 
purposes.  The subject may re-start 
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 12.1.11. 
Clarification regarding 
prolonged interruption in 
investigational product such as 
in the event of pregnancy.  
 
Section 8.4.2.1  
Liver 
Transplantation 
Text Moved from Section 8.4.2 Other Reasons 
for Discontinuation of Study or Investigational 
Product 
Subjects who undergo a liver transplant during the 
course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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. 
8.4.2.1 Liver Transplantation 
 
Subjects who undergo a liver transplant during 
the course of the study must discontinue 
investigational product and discontinue the study 
visit schedule. However, these subjects 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. 
The relocation of this 
statement from within 
Section 8.4.2 to 8.4.2.1 
clarifies procedure to 
discontinue subjects who 
undergo a liver transplant, 
from investigational product 
but not study visits. 
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Section 8.4.3 
Other Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
8.4.2 Other Reasons for Discontinuation of Study 
or Investigational Product 
Subjects that discontinue investigational product 
are expected to continue in the study until the end 
of the study, and the study will only terminate at 
the time when the needed number of adjudicated 
events has accrued or at the discretion of the 
Sponsor.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  Subjects who 
choose to discontinue investigational product prior 
to termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.  In general, subjects should be strongly 
encouraged to both stay on investigational product 
and remain in the study until study termination.  
Early termination procedures should only be 
conducted if the subject withdraws consent (See 
Section 9.7.18 Early Discontinuation and/or Early 
Termination Procedures). 
The following events are considered appropriate 
reasons for a subject to discontinue investigational 
product; however, these subjects are expected to 
continue in the study until study termination and 
the study will only terminate at the time when the 
needed number of adjudicated events has accrued 
(or at the discretion of the Sponsor): 
− 
Consent may be modified to discontinue study 
visits or semi-annual telephone contact but 
allow continued access to medical records to 
assess for potential adjudicated hepatic and/or 
cardiovascular events. 
8.4.3 Other Reasons for Discontinuation of Study 
or Investigational Product 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following events are considered appropriate 
reasons for a subject to discontinue 
investigational product; however, these subjects 
are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
 
− 
Consent may be modified to discontinue 
study visits or semi-annual telephone contact 
but allow continued access to medical 
records to assess suspected major adverse 
Clarification of process 
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Subjects who undergo a liver transplant during the 
course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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. 
 
cardiovascular events (MACE) and liver-
related clinical outcomes. 
− 
Early termination procedures should be 
conducted if the subject withdraws 
consent (See Section 9.7.18). 
The Investigator is encouraged to contact the 
Sponsor prior to discontinuing a subject from 
treatment.   
Section 9.7.1  
Visit Windows 
Screening 
 
 
Screening 
See Section 9.7.6 for 
scenario specific visit 
windows that may be 
applicable at Screening.  
 
Section 9.7.3.1  
Determination for 
Dosing Regimen 
Insertion 
Acceptable methods of confirming (via medical 
history) or assessing cirrhosis for purposes of the 
study is defined as a subject who has documented 
evidence or presence of one or more of the 
following cirrhosis indicators: 
9.7.3.1 Determination for Dosing Regimen 
Acceptable methods of confirming (via medical 
history) or assessing cirrhosis for purposes of 
determining dosing is defined as a subject who 
has documented evidence or presence of one or 
more of the following cirrhosis indicators: 
Header added to differentiate 
the assessment of cirrhosis for 
determining dosing regimen 
versus progression to 
cirrhosis. 
Section 9.7.3.2  
Progression to 
Cirrhosis 
Insertion 
9.7.3.2 Progression to Cirrhosis  
When a subject identified as noncirrhotic at 
Baseline per the criteria listed in Section 
9.7.3.1 exhibits any signs or symptoms 
associated with progression to cirrhosis, as 
defined by the same criteria, the subject 
should also be assessed by Fibroscan® TE 
where available and progression to cirrhosis 
confirmed by biopsy (centrally read) unless 
not medically indicated.  Laboratory samples 
needed to obtain noninvasive scores of liver 
Details the assessment of 
progression to cirrhosis. 
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fibrosis (ELF, and aspartate aminotransferase 
to platelet ratio index [APRI]) will also be 
collected when a subject develops evidence of 
progression to cirrhosis. 
Full instructions concerning the sample 
collection methods, processing, labeling, and 
shipping will be provided by the Sponsor in a 
study-specific histology manual.  Collection 
supplies will be provided by the central 
laboratory. 
Sites participating in the paired biopsy 
substudy must confirm progression to 
cirrhosis by biopsy as per the information 
outlined in protocol Addendum 2. 
All suspected cases of progression to cirrhosis 
should be submitted for adjudication 
regardless of the availability of transient 
elastography or biopsy results. 
Section 9.7.6  
Screening 
Procedures 
Two Screening visits will occur from 1 to 8 weeks 
prior to Day 0 (as outlined below) allowing for the 
collection of repeated serum chemistry samples (at 
least 2 weeks apart) to confirm pretreatment ALP 
and total bilirubin values: 
 
 
Insertion 
 
 
 
 
• 
The mean of all available (at least 2; including 
both scheduled and unscheduled) bilirubin and 
Collection of 2 serum chemistry samples 
(collected at least 2 weeks apart) during 
Screening is required for confirmation of the 
pretreatment serum chemistry values, including 
the ALP and total bilirubin used to determine 
eligibility: 
 
• 
When the 2 bilirubin or ALP assessments 
collected at Screening Visit 1 and Screening 
Visit 2 differ by ≥30%, a third sample must be 
collected at an unscheduled visit as a 
confirmatory sample to include in the mean 
result(s) that will be used to determine 
eligibility.  
Allows repeat assessments 
when baseline laboratory 
values are discrepant between 
Screening Visit 1 and 
Screening Visit 2. 
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ALP assessments will be used to determine 
eligibility (total bilirubin >ULN and ≤3× ULN 
and/or an ALP >5× ULN).   
• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(selected study sites only), 
 
 
 
Insertion 
 
 
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments will 
be used to determine eligibility (total bilirubin 
>ULN and ≤5x ULN and/or an ALP >3x ULN).  
• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(at all study sites where the device is available),   
 
In the event that the 2 screening bilirubin or 
ALP assessments differ by ≥30%, and a third 
confirmatory sample is required to be 
collected, the Screening Visit window may be 
extended up to 3 additional weeks. 
Section 9.7.7  
Day 0 Procedures 
• 
Perform transient elastography (TE; at 
selected study sites, where available) using the 
Fibroscan® TE device. If TE has been done within 
6 months of Day 0 and a report/adequate data are 
available, a pretreatment TE at Day 0 is not 
required.   
• 
Conduct a DEXA bone density scan (at 
selected study sites, where device is available); 
• 
Perform an esophagogastroduodenoscopy 
(endoscopy; at selected study sites, where device 
is available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform TE at all study sites with access to 
Fibroscan® TE device. If TE has been done 
within 3 months of Day 0 and a report/adequate 
data are available, a pretreatment TE at Day 0 is 
not required.   
• 
Conduct a DEXA bone density scan (at all 
study sites where the device is available); 
• 
Perform an esophagogastroduodenoscopy 
(endoscopy; at study sites, where device is 
available) to assess the presence or absence of 
oesophageal varix/varices. 
Clarifies use of TE and 
modifies the time during 
which an historic TE report 
remains valid.  
Clarifies the use of DEXA and 
endoscopy. 
Section 9.7.8  
Month 1 
Procedures 
 
Section 9.7.10  
9.7.10   Post-Titration visit Procedures 
Insertion 
 
• 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
9.7.10  1-Month Post-Titration visit Procedures 
• 
Perform a physical examination.  
 
• 
In the event it is not feasible for the subject 
to return to the site for the above referenced 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring.  Options 
for safety monitoring 
assessments are provided 
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1-Month Post-
Titration visit 
Procedures 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit requirements: 
 
 
Insertion (9.7.8) 
 
Insertion (9.7.10) 
 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit laboratory 
requirements: 
 
- 
A physical examination should be 
performed at the Month 3 visit if an onsite 
Month 1 visit was not performed. 
- 
A physical examination should be 
performed at the next scheduled visit if an 
onsite post-titration visit was not performed. 
when returning to the site 
presents significant burden on 
the subject.  
Section 9.7.11  
Month 6 
Procedures 
 
Section 9.7.16  
Month 6 
Continued 
Follow-Up 
Procedures 
Insertion 
 
 
 
 
 
 
Insertion in 9.7.11 (not 9.7.16) 
• 
Perform TE at all study sites with access 
to Fibroscan® TE device. 
• 
Perform an ultrasound for HCC 
surveillance (if equipment is unavailable, 
sites should make every attempt to use 
available community referral sites).  
 
 
• 
Perform a physical examination 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis. 
  
Hepatic ultrasound has been 
increased to every 6 months to 
conform to AASLD and 
EASL guidelines for PBC 
patients with cirrhosis. 
Section 9.7.12  
Month 9 
Procedures 
Section 9.7.14 
Month 12 
Procedures 
Section 9.7.16 
Month 16 
Continued 
…DEXA procedure to be done at 
selected study sites only, 
 
…DEXA procedure to be done at 
all study sites where the device is available  
 
Clarification 
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Follow-Up 
Procedures 
 
Section 9.7.14  
Month 12 
Procedures 
Section 9.7.17  
Month 12 Follow-
up Procedures 
Section 9.7.18  
EOS/EOT 
• 
Perform TE (at selected study sites, where 
available) using the Fibroscan® TE device. 
 
Additional edit in Section 9.7.18 
- If the subject reports having eaten within 8 
hours, document accordingly in the source and 
CRF and remind the subject that fasting is 
required prior to all study visits. 
• 
Perform TE at all study sites with access to 
the Fibroscan® TE device. 
 
 
- If the subject reports having eaten within 8 
hours, document accordingly in the source and 
CRF. 
Clarification 
Section 10.3  
Investigational 
Product Storage 
The investigational product should be stored in the 
containers in which they are received from the 
Sponsor’s supplier, at 15°C to 25°C. 
All OCA tablet strengths provided to clinical 
trial sites in support of clinical study 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. 
Updating temperature 
excursions language per 
Sponsor stability studies. 
Section 11.1.2 
Secondary 
Assessments 
Insertion 
 
 
 
 
 
 
• 
Individual components of the primary 
endpoint. 
• 
Progression to cirrhosis as assessed by the 
presence of clinical, laboratory, or radiological 
evidence of cirrhosis and/or liver stiffness 
(Fibroscan® TE), confirmed by biopsy unless 
not medically indicated.  
 
Rationale 11 
 
 
 
 
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• 
Biomarkers, including markers of hepatic 
fibrosis and/or inflammation, to be tested will 
include:  IgM, c-reactive protein (CRP), tumor 
necrosis factor-α (TNF-α), FGF-19, cytokeratin-18 
(CK-18) and ELF, Fibroscan (and others as 
determined during the course of the study). 
 
 
 
 
 
• 
Endoscopy will be conducted at all study sites 
where the device is available to assess for the 
presence of oesophageal varix/varices at baseline.  
• 
Histological assessment of disease 
progression or improvement using paired 
biopsies in a subset of subjects (defined in 
Addendum 2). 
- 
HCC confirmed by 2 complimentary 
imaging modalities, unless confirmed 
by biopsy. 
• 
Biomarkers, including other markers of 
hepatic fibrosis and/or inflammation, to be tested 
will include:  IgM, c-reactive protein (CRP), 
tumor necrosis factor-α (TNF-α), FGF-19, 
cytokeratin-18 (CK-18) ELF, and Fibroscan (and 
others as determined during the course of the 
study).  
• 
Clinical outcomes, including individual 
component of the primary endpoint (where 
available), liver transplant, and death will be 
compared to historical controls. 
• 
PK of OCA and its conjugates. 
• 
Endoscopy will be conducted at all study 
sites where the device is available to assess for 
the presence of oesophageal varix/varices at 
baseline.  
Reflects addition of a biopsy 
substudy available to 
interested sites in 
Addendum 2. 
 
Section 12.1.3  
Relationship of 
AEs to Liver 
Biopsy 
 
Insertion (new section) 
The Investigator will document her/his opinion 
of relationship of an AE to liver biopsy using 
the criteria outlined in Table 9.  
Table 9: Relationship of Adverse Events to 
Liver Biopsy 
Added with the addition of 
liver biopsies for the 
confirmation of progression to 
cirrhosis. 
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Relatio
nship 
Description 
Relate
d 
A reaction that follows a 
reasonable temporal sequence 
from the liver biopsy; that follows 
a known or expected response 
pattern to the liver biopsy. 
Not 
Relate
d 
Any event that does not meet the 
above criteria. 
Section 12.1.5.2 
Reporting of 
Serious Adverse 
Events 
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 
•Telephone:  +1 858 964 1571 
Investigational new drug (IND) Safety Reports 
 
Insertion 
If an SAE is reported by email or fax, an SAE 
Report form must also be completed in the EDC 
system as soon as the EDC system is accessible 
 
Redacted medical record source 
documentation will be requested for all SAEs 
and emergency room visits. 
 
Updated to align with 
modified standard safety 
procedures. 
 
 
 
Added sentence regarding 
redacted medical records to 
align with Sponsor safety 
standards. 
Section 12.1.6 
Suspected Liver-
Related Clinical 
Outcome Events 
For liver-related clinical outcome events could 
also meet the criteria of a SUSAR, which would 
necessitate unblinding for expedited reporting, 
please refer to Section 11.1.2.4. 
 
 
 
 
 
 
Given that the liver-related clinical outcome 
events may also meet the criteria of a SUSAR, 
but are considered in aggregate as part of the 
primary endpoint and the DMC reviews of all 
safety and efficacy data at least quarterly, the 
Sponsor will not expeditiously report 
suspected liver-related 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 “study event” 
on the AE CRF and will be submitted for 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy), and spontaneous 
bacterial peritonitis (preferred term: peritonitis 
bacterial). 
 
adjudication to the Hepatic Outcomes 
Committee as described in Section 13.4. 
 
The Sponsor will consider the following list of 
clinical outcome events (MedDRA preferred 
terms) to be disease related and exempt from 
expeditious regulatory reporting, but will 
continue to report them in a nonexpeditious 
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 or oesophageal varices 
haemorrhage), hepatic encephalopathy 
(preferred term: hepatic encephalopathy), 
spontaneous bacterial peritonitis (preferred term: 
peritonitis bacterial), ascites (preferred term: 
ascites), and histological or clinical progression 
to cirrhosis (preferred term: hepatic cirrhosis). 
Section 12.1.8 
Notification of 
Post-Treatment 
SAEs for Subjects 
Who Continue in 
the Study 
Insertion (new section) 
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 12.1.5.2. 
SAEs that occur in subjects 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 12.1.5.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language. 
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Section 12.1.9 
Notification of 
Poststudy SAEs 
All SAEs that occur within 30 days following the 
cessation of investigational product, 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 12.1.4.2. 
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 SAE 
must be reported to the Sponsor immediately (ie, 
within 24 hours). 
SAEs that occur more than 30 days after a subject 
has discontinued investigative product, and are not 
considered related to investigational product, must 
still be reported in the EDC system; however, 
these events are not required to be reported within 
24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to 
investigational product, action taken with 
investigative product, treatment, outcome, and 
potential endpoint status need to be recorded in 
EDC for the SAE.  Additional information (e.g. 
event summary, SAE details) may also be required 
to be entered, when requested by the sponsor.  
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 12.1.5.2. 
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 12.1.5.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language. 
Section 12.1.10  
Follow-up of AEs 
and SAEs 
Insertion 
All subjects 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 CRF. Note that longer follow-
up can sometimes reveal an off-drug repetition 
of what had appeared to be drug-induced liver 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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injury, indicating that liver injury was related 
to underlying liver disease. 
Section 12.1.11  
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 8.4.1.3and the Sponsor must be notified 
within 24 hours of the Investigator’s learning of 
the pregnancy by completing the Pregnancy 
Notification Form and faxing or emailing to the 
Sponsor at +1 800 497 8521 or 
sae@interceptpharma.com.  
Safety will be monitored and assessed by 
AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and 
clinical laboratory assessments. The Sponsor may 
also follow the health of an infant born subsequent 
to use of investigational product. 
The subject may reinstate investigational product 
after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  
Subjects whose pregnancy is terminated early 
(planned or unplanned) may be permitted to 
resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test 
(see Section 8.4.1). 
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 
sae@interceptpharma.com or faxed to 
+1 800 497 8521.   The subject and neonate 
must be followed for outcome information 
and/or as considered appropriate by the 
Investigator and Sponsor. 
The subject 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 subject must have a 
negative pregnancy test before restarting 
investigational product.  If a subject’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 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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reporting procedures described in 
Section 12.1.5 must also be followed. 
Section 12.2.7  
Laboratory 
Assessments 
The list of laboratory analytes to be tested is 
shown in Table 10. 
The list of laboratory analytes to be tested is 
shown in Table 11, and the normal reference 
ranges for liver biochemistries are shown in 
Appendix C. 
Added per Regulatory 
Authority request. 
Section 12.2.7  
Table 10 List of 
Laboratory 
Analytes 
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Other 
Insertion 
 
 
Deletion 
 
Other 
OCA-glucuronide 
 
Measurements of liver fibrosis 
are captured in a different 
section. 
 
OCA-glucuronide was listed 
in the text but missing from 
the table. 
Section 13  
Statistical 
Methods 
A statistical analysis plan (SAP), providing details 
about the specific planned analyses and hypothesis 
tests, will be prepared and approved by the 
Sponsor and its designees prior to study database 
lock, propensity score determination, and 
unblinding of the double-blind subject treatment 
assignments. 
A statistical analysis plan (SAP), providing 
details about the specific planned analyses and 
hypothesis tests, will be prepared and approved 
by the Sponsor and its designees prior to the first 
interim analysis, propensity score determination, 
and unblinding of the double-blind subject 
treatment assignments. 
Reflects addition of interim 
analyses to the study protocol. 
Section 13.1.1 
Analysis 
Populations 
• 
The Randomized Population will include all 
randomized subjects 
 
Insertion 
Deletion 
 
• 
The Per Protocol (PP) Population will 
include all ITT subjects who do not have any 
major protocol violations that potentially 
affect the efficacy conclusion.  Treatment 
assignment will be based on the randomized 
treatment. 
 
 
 
 
Rationale 12 
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Section 13.1.1.1  
Comparability of 
Historical 
Controls 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria where possible. 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria.  Propensity score 
matching method will be utilized to select 
historical controls that match the treated 
subjects using available covariates. The 
adequacy of matching will be assessed by 
statistical methods described under 
Section 13.1.8. 
Clarifies the use of propensity 
scores in the assessment of the 
historical control population. 
Section 13.1.2.1 
Sample Size 
Monitoring 
13.1.2.1 Sample Size Re-Estimation Plan 
Therefore, starting approximately 2 years after the 
first subject is randomized, the aggregate event 
rate and sample size based on recruitment and 
retention will be evaluated in a blinded manner 
quarterly.  This evaluation will determine if any 
increases in number of subjects are required in 
order to obtain a total of 121 adjudicated events 
for the final analysis in the combined groups. 
If after 4 years of accruing subjects, despite 
increases in the number of subjects, it is 
determined that at least an additional 2 years (ie, 
total study duration of at least 10 years) are needed 
to randomize sufficient subjects to achieve a total 
of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label 
OCA.  Previously randomized subjects will 
continue to be treated in a blinded manner with 
either OCA or matching placebo.  If this 
modification is implemented, the alternative 
primary efficacy analysis is specified is 
Section 13.1.9. 
13.1.2.1 Sample Size Monitoring 
Therefore, the aggregate event rate and sample 
size based on recruitment and retention will be 
evaluated in a blinded manner quarterly.  This 
evaluation will determine if any increases in 
number of subjects are required in order to obtain 
a total of 127 adjudicated events for the final 
analysis in the combined groups. 
Deletion 
Clarifies the ongoing 
monitoring of event rate and 
sample size. 
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Any revised sample size or changes to treatment 
allocation will be justified and documented in a 
protocol amendment and in the CSR. 
Section 13.1.5.1  
Association of 
Biochemistry with 
Clinical Outcomes 
and Clinical 
Benefit 
Insertion (new subsection) 
13.1.5.1 Association of Biochemistry with 
Clinical Outcomes and Clinical Benefit  
The association between biochemistry 
including ALP and bilirubin with clinical 
outcomes will be assessed and the clinical 
benefit of OCA using biochemistry as a 
surrogate endpoint will be evaluated.  Detailed 
analysis will be described in the SAP.  
Based on the association between biochemical 
changes and clinical outcomes described 
above, clinical benefit of OCA using 
biochemistry as a surrogate endpoint for key 
subpopulations of interest will be evaluated. 
This analysis will be further described in the 
SAP. 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
Section 13.1.8  
Supportive 
Analysis 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls. 
 
 
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment. 
 
Although it might be relatively simple to assign a 
historical control based on a single observable 
characteristic, in practice, if the matching process 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls, which serves as an external 
control for supportive analysis.  
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment 
between the treated subjects and the matched 
natural history subjects. 
A full range of covariates across which the 
treatment and historical controls might differ will 
be considered to mitigate potential bias. 
Clarifies the use of the 
historical controls as an 
external control in supportive 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
 
 
Clarifies the use of the 
historical controls as an 
external control in supportive 
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is to successfully mitigate potential bias, it has to 
be done considering a full range of covariates 
across which the treatment and historical controls 
might differ. 
Only covariates and not outcome variables will be 
included in the propensity score estimation.  
Therefore, there is no chance of biasing, to avoid 
biased results that are in favor of one treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
 
 
Only covariates and not outcome variables will 
be included in the propensity score estimation to 
avoid biased results that are in favor of one 
treatment. 
 
The baseline characteristics between treated 
and natural history subjects in the matched 
dataset will be summarized and presented in a 
tabular format.  Statistical methods such as 
Wilcoxon Rank-Sum test will be used to assess 
the balance for baseline covariates.  The 
standardized difference and variance ratios 
for these covariates will also be calculated.  In 
addition, box plots of propensity scores for 
treated and natural history subjects will be 
separately presented, to further assess the 
adequacy of matching.  
A third-party statistician(s) will perform the 
propensity score modeling and matching.  This 
third-party statistician(s) will be   separate and 
independent from the statistician(s) who will 
assess the success of matching and perform 
efficacy analyses. 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
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• 
Time to hepatocellular carcinoma 
 
(Text from Section 13.1.9 [Alternative Primary 
Analysis] modified and included in this section) 
Based on sample size re-estimations, it may be 
determined that subjects will be enrolled to receive 
open-label OCA from that point forward, and the 
new primary efficacy analysis will become the 
comparison of all subjects in OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant or 
death (all-cause) (see Section 13.1.2.1).  similar 
statistical methodology as specified above in 
Section 13.1.8 for supportive analyses will be 
utilized. 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare groups.  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 determined based 
on a Cox regression model stratified by 
randomization strata to estimate the magnitude of 
the effect. 
In addition, the outcome events specified above in 
Section 13.1.8 will also be evaluated to compare 
all subjects in OCA population to all control 
subjects (randomized placebo and historical 
controls). 
 
 
Although the study is designed as a placebo-
controlled study, the DMC may recommend 
changes to study conduct based on the pre-
specified interim analyses (see Section 13.1.12), 
including the potential use of a revised primary 
efficacy analysis.  This analysis would compare 
all subjects in the OCA population, to all control 
subjects (randomized placebo and historical 
controls) on time to liver transplant or death (all-
cause), using similar statistical methodology as 
specified above. 
Notably, the planned primary analysis would 
not be revised without prior agreement with 
regulatory authorities. 
 
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Sensitivity analyses will be conducted limiting to 
the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC 
Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms 
and factors may be considered. 
Section 13.1.9  
Handling of 
Dropouts or 
Missing Data 
Insertion 
In addition, the same analyses for primary and 
key secondary endpoints based on ITT and PP 
populations will be performed to assess 
robustness of analysis results. During the 
conduct of the study, the DMC may 
recommend refining the missing data strategy 
to better address the observed pattern of 
missing data, based on blinded monitoring of 
the data. 
Clarification of statistical 
analyses to address missing 
data. 
Section 13.1.11  
Examination of 
Subgroups 
The primary and secondary efficacy endpoints will 
be analyzed for subject subgroups (eg, age, sex, 
and race) based on the ITT population.  
 
Insertion 
The primary and secondary efficacy endpoints 
will be analyzed for subject subgroups based on 
the ITT population.  
 
The primary efficacy endpoint will also be 
assessed across the spectrum of PBC disease 
stage as defined by Rotterdam criteria 
(Kuiper 2009)  
• 
Early (normal albumin and normal 
bilirubin) 
• 
Moderate (abnormal albumin or 
abnormal bilirubin) 
• 
Advanced (abnormal albumin and 
abnormal bilirubin) 
The primary efficacy endpoint will also be 
assessed for the following clinically relevant 
subpopulations. 
 
 
 
Added per Regulatory 
Authority request. 
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• 
Monotherapy in patients who are 
intolerant or non-responsive to UDCA  
• 
Elderly patients 
Assuming a strong correlation between 
biochemistry and clinical outcomes using the 
total study population (Section 13.1.5.1) is 
observed, we will further assess the 
biochemical improvement in relevant 
subpopulations as applicable (eg, Rotterdam 
disease severity and monotherapy) and 
estimate the reduction in risk of clinical 
outcomes associated with the biochemical 
improvement. 
Additional details regarding statistical 
methods and subgroup definitions will be 
provided in the SAP. 
Section 13.1.12  
Continuous 
Monitoring and 
Interim Analyses 
Insertion 
13.1.12 Continuous Monitoring and Interim 
Analyses  
Blinded safety reports including the accrual of 
events, drop outs, and/or loss of subjects to 
commercially available OCA will be reviewed 
by the DMC on a regular basis.  
Two planned interim analyses of the liver-
related outcomes will be conducted using the 
Lan-DeMets O’Brien-Fleming boundaries 
(Reboussin 2000).  Both interim analyses will 
be pre-specified and will occur after accrual of 
50% (64 events) and 75% (96 events) of 
clinical outcome events, respectively.  
The DMC will review the available efficacy 
data in conjunction with detailed safety data 
and other relevant information to recommend 
continuation, modification, or cessation (for 
Two Interim Analyses have 
been added to the protocol. 
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efficacy) of the study beyond each interim 
analysis.  Modification of the study would not 
take place without prior agreement with 
regulatory authorities. 
Section 19  
List of References  
Insertion 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Digestive and Liver 
Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Gastroenterology. 
2015b;149(6):1627-9. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
'cirrhosis' to 'cholangitis'. Hepatology. 
2015c;62(5):1620-2. 
Lin DY, Fleming TR, De Gruttola V.  
Estimating the proportion of treatment effect 
explained by a surrogate marker.  Statistics in 
Medicine.  1997;16(13):1515-1527. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-
ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed 
with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-3572. 
Reboussin DM, DeMets, DL, Kim KM, et al.  
Computations for Group Sequential 
Boundaries Using the Lan-DeMets Spending 
Function Method.  Controlled Clin Trials.  
2000;21(3):190-207. 
Additional relevant references 
were added. 
Appendix A 
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5 mg 
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5 mg 
Rationale 9 
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Justification for Change 
Modified Dosing 
Regimen for 
Subjects with 
Child-Pugh B or C 
Hepatic 
Impairment 
OCA or matching placebo once daily, based on 
tolerability. 
OCA or matching placebo once daily, based on 
tolerability and biochemical response. 
Appendix B  
List of Study 747-
302 Outcome 
Events 
This Appendix with the following information 
has been deleted. 
 
Several of the specified clinical endpoints will also 
by definition (see 12.1) 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 12.1.4).  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 
 
Redundant; Information is 
contained within the protocol. 
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Hepatocellular carcinoma 
Appendix C 
Reference 
Laboratory Values 
from Central 
Laboratories 
Insertion (new appendix) 
Appendix containing reference laboratory 
values from central laboratories added. 
Added per Regulatory 
Authority request. 
 
 
 
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APPENDIX J. SUMMARY OF CHANGES:  PROTOCOL VERSION 4 TO PROTOCOL VERSION 5 
(DATED 04 JAN 2018) 
Rationale 
Protocol 747-302 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 United States Package Insert dosing 
guidelines.  Titration is now only based on tolerability and not CP score. 
• 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 diagnosed acute pancreatitis.  
• Gallbladder assessments were added at Screening or Day 1. 
Summary of Changes 
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The following revisions were made to the protocol in Protocol Version 5.  Revised and new text in Version 5 is indicated in bold 
font, and the text deleted from Protocol Version 4 is crossed out in the table below.  Minor/editorial changes are not listed 
individually in the summary table below.  Section numbers and names in column 1 refer to protocol Version 5 unless otherwise 
noted. 
Section 
Original Text (Amendment 4, 10 May 2017) 
Revised Text (Version 5, 04 Jan 2018) 
Justification for Change 
Sponsor’s 
approval 
 PhD 
 Clinical Development 
Intercept Pharmaceuticals, Inc. 
 PhD 
 Clinical Development 
Intercept Pharmaceuticals, Inc. 
Change in title 
Study Personnel 
Contact 
Information 
Contact: 
 MD, Medical Director, 
Drug Safety,  
Intercept Pharmaceuticals 
Mobile: 
 (Pacific time zone) 
Telephone: 
 
Email: 
 
Primary Contact: 
 MD, MPH| 
Senior Medical Director / Medical Affairs 
Syneos Health | Chapel Hill, NC 27514 |U.S.A. 
Tel: 
 Mobile: 
 
 
 
Secondary Contact: 
 DO, MSPH  
Senior Medical Director  
Intercept Pharmaceuticals, Inc. (Intercept) 
 
Updated medical monitoring 
contact information 
Synopsis, Phase 
of Development  
 
Phase 4:   
 
Phase 4:  US, Canada, and the EU 
Phase 3b:  All other regions 
Clarified that the phase of 
the study has been changed 
from “3b” to “4” to reflect 
that this is a post-marketing 
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. 
Synopsis, 
Methodology,  
 
…Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose of 5-
mg OCA or matching placebo once daily, based 
on tolerability and biochemical response.  
Subjects classified as Child-Pugh Class B or Child-
Pugh Class C should titrate to a maximum dose and 
frequency of 10 mg OCA or matching placebo twice 
To align with label, 
maximum dose for Child-
Pugh B or C subjects is 10 
mg OCA twice weekly. 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Subjects classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 10 
mg OCA or matching placebo twice weekly, 
based on tolerability and biochemical response 
weekly (at least 3 days apart), based on tolerability 
and biochemical response. 
Synopsis, 
Methodology, 
Table -Planned 
Dosing Regimen 
by Cirrhosis and 
Child-Pugh Score, 
Section 7.3, 
Planned Dosing 
Regimen, Table 3 
 
 
 
a Starting dose based on subject’s cirrhosis status 
and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
subject tolerability, biochemical response, and/or 
changes in cirrhosis status or Child-Pugh Score at 
any time during the study 
c Dosing per the twice weekly schedule must be at 
least 3 days apart 
Titration #3 is no longer 
applicable to study.  To 
align with label, maximum 
dose for Child-Pugh B or C 
subjects is 10 mg OCA 
twice weekly. 
Synopsis, Criteria 
for Evaluation; 
Secondary 
Objectives 
Safety and tolerability 
Including the 
following: 
Treatment-emergent 
adverse events Clinical 
laboratory values 
Safety and tolerability 
Including the following: 
Treatment-emergent 
adverse events including 
adverse events of special 
interest 
Clinical laboratory values 
Per FDA request 
Synopsis, 
Statistical 
Methods, Safety 
Analysis,  
Safety data, including AEs, vitals, 
electrocardiogram 
Safety data, including AEs, AEs of special interest 
including pruritus and hepatic safety, vitals, 
electrocardiogram… 
Per FDA request 
Section 5.1, 
Overview of 
Primary Biliary 
In December 2016, the European Commission 
granted conditional approval for Ocaliva for the 
same indication 
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 747-302 is 
Clarified that the phase of 
the study has been changed 
from “3b” to “4” to reflect 
that this is a post-marketing 
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Cholangitis and 
Obeticholic Acid 
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 
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 
Section 5.4, 
Clinical 
Experience with 
Obeticholic Acid 
As of 31 Jan 2017, approximately 2186 subjects 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 525 subjects had 
PBC, 686 subjects had NASH, 41 subjects had 
diabetes mellitus/nonalcoholic fatty liver disease, 
33 subjects had alcoholic cirrhosis/portal 
hypertension, and 52 subjects had primary 
sclerosing cholangitis, and 5 subjects 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 subjects had PBC, 1141 
subjects had NASH, 41 subjects had diabetes 
mellitus/nonalcoholic fatty liver disease, 33 subjects 
had alcoholic cirrhosis/portal hypertension, and 73 
subjects had primary sclerosing cholangitis, and 6 
subjects had biliary atresia 
Updated number of subjects 
exposed to OCA 
Section 5.6, 
Importance of 
Monitoring of 
Disease 
Progression 
 
Insertion 
Given PBC is a chronic, progressive liver disease, 
it is important that subjects with PBC are closely 
monitored to ensure early identification of 
potential disease progression to cirrhosis, 
decompensation and/or liver injury.  More 
extensive safety monitoring and appropriate 
dosing adjustments, interruptions, and 
discontinuations will be implemented to improve 
subject oversight and safety.  Investigators, 
together with the Sponsor’s Medical Monitor, will 
consistently and frequently assess individual 
subjects to determine on an ongoing basis the 
totality of a subject’s clinical profile, which 
includes careful evaluation of signs and symptoms 
of potential hepatic injury and/or decompensation 
coupled with rules based laboratory monitoring. 
Subjects will be monitored for potential hepatic 
injury and/or decompensation and progression to 
cirrhosis (Section 7.5).  Criteria for implementing 
Per FDA response 
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dosing adjustments, interruptions, or 
discontinuations, and close monitoring 
procedures postdose-adjustment are described in 
Section 7.6 and Section 7.7.  The more extensive 
monitoring is important given the elevated risk of 
decompensation and potential for higher hepatic 
exposure to OCA in this population. 
Section 5.7, 
Summary of 
Known Potential 
Risks with OCA 
 
…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, but with a much lower 
frequency than that observed in subjects 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 subjects 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 (HDL) and an increase in low 
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.  
One case was reported in a subject with no 
evidence of cirrhosis at baseline, while the second 
case was reported in a subject with cirrhosis and 
hepatic impairment at baseline.  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 
Per FDA Response 
Updated section to include 
SUSARS 
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density lipoprotein (LDL).  Notably, in subjects 
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 
subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in 
OCA treated subjects with the exception of a 
modest transient and early rise after initiation of 
treatment.   
Refer to the Investigator’s Brochure (IB) for 
additional information regarding the known 
potential risks with the investigational product. 
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 
providing further support for the lack of safety 
concern and positive benefit-risk profile of OCA. 
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 
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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 
Table 1, Schedule 
of Procedures, 
Screening to 
Month 12 
Insertion 
Added column for M2 and following procedures 
at the visit 
• 
Physical Exam 
• 
Child-Pugh Assessment  
• 
Adverse Events 
• 
Prior/Concomitant Medications 
• 
IP accountability/Compliance 
• 
Dosing Diary 
• 
Chemistry/Hematology/Coagulation 
• 
Review Progression to Cirrhosis 
Algorithm 
Added to satisfy 
requirement for monthly 
visits following any titration 
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1-Month Post-Titration Visit 
Post-Titration Visits 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12; and 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study 
Insertions 
Added the following procedures 
• 
Gallbladder Assessment (Table 1 only) 
• 
Amylase and Lipase (if subject 
experiences acute pancreatitis or 
cholecystitis) 
• 
Review Progression to Cirrhosis 
Algorithm   
Added per FDA request 
Table 1, Schedule 
of Events, 
Screening to 
Month 12; and 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study 
• 
Assessments for Mayo Risk Score 
• 
DEXA 
• 
Blood samples for future analysis 
 
Central lab will calculate 
value 
 
Procedures deleted to 
streamline collection of 
laboratory samples 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
footnote b 
Post-Titration visits must be performed 1 month 
(+ 1 week) after any up-titration in dose and/or 
frequency in subjects following modified dosing 
due to Child Pugh B and Child-Pugh C hepatic 
impairment.  In subjects following the standard 
dosing regimen, the post-titration visit must be 
performed only after the first up titration to 10 
mg OCA or matching placebo, or after ≥3 months 
at a decreased dose or frequency. 
Post-Titration visits must be performed 1 month (+ 1 
week) and 2 months (+1 week) after any up-titration 
in dose and/or frequency in subjects following 
modified dosing due to Child Pugh B and Child-
Pugh C hepatic impairment.  See Appendix A for 
additional guidance.  In subjects following the 
standard dosing regimen, the post-titration visit must 
be performed 1 month (+ 1 week) and 2 months 
(+1 week) only after the first up titration to 10 mg 
OCA or matching placebo. 
Added to satisfy 
requirement for monthly 
visits following any titration 
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Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
previous footnote 
f 
Mayo Risk Score will be calculated based on 
central laboratory evaluations, diuretic use data, 
and peripheral edema assessment data captured in 
the eCRF. 
Deletion 
MRS score will be 
calculated by central lab. 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
footnote k 
DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available.  Please refer to Section 9.7.7 for 
additional information related to the allowed 
windows at Day 0 for this procedure 
deleted 
Procedures deleted to 
streamline collection of 
laboratory samples 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
footnote k 
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. 
Ultrasound will be conducted to enhance HCC 
surveillance and for gallbladder assessment at 
Screening.  If ultrasound was not performed at 
Screening and the historic ultrasound is >3 
months from Day 0, perform a hepatobiliary 
ultrasound at the Day 0 visit. 
Agreement with FDA to 
perform gallbladder 
assessments at screening. 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
footnote p 
The subject 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. 
The subject 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.  MELD and MRS values will be 
calculated based on serum chemistry and 
coagulation values at each visit. 
MELD and MRS removed 
as line items.   Central lab 
will calculate these values. 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
Please refer to Section 11.1.2.3 for description of 
the blood sample to be collected for future 
analysis 
Deletion 
Procedures deleted to 
streamline collection of 
laboratory samples 
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footnote l, Table 
1, footnote w 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study 
Column header: 
1-Month Post-Titration Visita,  
 
Post-Titration Visitsa 
Added to satisfy 
requirement for monthly 
visits following any 
titration, requirement to 
assess Child-Pugh at every 
visit. 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study 
Assessment for Mayo Risk Scoree 
DEXA 
Blood Sample for Future Analysis 
Deletion 
MRS score will be 
calculated by central lab. 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study 
Visit Windows (+/-)c 
Year 2 Through End of 
Study 
Visit Windows (+/-)c 
Year 2 Through End of 
Study 
Added per FDA  
Insertion 
 
Amylase and Lipase 
Sample to be collected if 
the subject experiences 
acute pancreatitis or 
cholecystitis 
Review Progression to 
Cirrhosis Algorithm   
 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote a 
In subjects following the standard dosing 
regimen, the post-titration visit must be 
performed only after the first up-titration to 10 
mg OCA or matching placebo, or after ≥3 months 
at a decreased dose or frequency.  Post-titration 
visits must be performed 1 month ± 1 week after 
any up-titration in dose and/or frequency in 
subjects following modified dosing due to Child-
Pugh B and Child-Pugh C hepatic impairment.   
Post-Titration Visits must be performed 1 month 
(±1 week) and 2 months (±1 week) after any up-
titration in dose and/or frequency in subjects 
following modified dosing due to Child-Pugh B and 
Child-Pugh C hepatic impairment.  See Appendix A 
for additional guidance.  In subjects following the 
standard dosing regimen, the Post-Titration visit 
must only be performed 1 month (±1 week) and 2 
months (±1 week) after the first up-titration to 10 
mg OCA or matching placebo. 
Added to satisfy 
requirement for monthly 
visits following any 
titration, requirement to 
assess Child-Pugh at every 
visit. 
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Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote e 
Mayo Risk Score will be calculated based on 
central laboratory evaluations, diuretic use data, 
and peripheral edema assessment data captured in 
the CRF 
 
MRS score will be 
calculated by central lab 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote g 
Height will be collected at this visit 
 
 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote j 
DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available 
 
Procedure deleted 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote m 
The subject 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. 
The subject 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.  MELD and MRS values will be 
calculated based on serum chemistry values at 
each visit. 
MELD and MRS removed 
as line items.   Central lab 
will calculate these values. 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote s 
Please refer to Section  for description of the 
blood sample to be collected for future analysis 
 
Procedure deleted 
Section 7.3, 
Planned Dosing 
Regimen 
Insertion 
Non-Cirrhotic or Child-Pugh A 
… 
Cirrhotic or Child-Pugh B or C 
Subjects with cirrhosis (see Section 7.5.4 ) and 
classified as Child-Pugh Class B or Child-Pugh 
Heading and text added for 
additional clarity. 
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Class C will follow a modified dosing regimen, 
initiating 5 mg OCA or matching placebo once 
weekly.  After a minimum of 3 months dosing 
once weekly with 5 mg OCA or matching placebo, 
and following review of the pre-titration 
laboratory results to assess safety and tolerability, 
the dosing frequency of 5 mg OCA or matching 
placebo should be increased to twice weekly (at 
least 3 days apart).  Subjects who have 
maintained the twice weekly dosing frequency for 
a minimum of at least 6 weeks, and meet the dose 
titration criteria should up-titrate to the 
maximum allowed dose of 10 mg OCA or 
matching placebo twice weekly. 
Investigators may decrease the dosing frequency 
(back to once weekly) or dose for any subject at 
any time during the study, as considered clinically 
appropriate (eg, tolerability).     
The dosing regimen should be determined as 
described shown in Table 13  Appendix A.  
Investigators should follow the dosing/titration 
schedule as shown described in Section 7.4 and 
Appendix A. 
Section 7.3, 
Planned Dosing 
Regimen, Table 3 
 
 
To align with label, 
maximum dose for Child-
Pugh B or C subjects is 10 
mg OCA twice weekly. 
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Section 7.3, 
Planned Dosing 
Regimen, Table 4 
 
Table deleted 
To align with label, 
maximum dose for Child-
Pugh B or C subjects is 10 
mg OCA twice weekly. 
Section 7.4, Dose 
Titration Criteria 
...  Up-titrations may only occur to the maximum 
dose and frequency for each dosing regimen as 
defined in Section 7.3.   
...  Up-titrations may only occur to the maximum 
dose and frequency for each dosing regimen as 
defined in Section 7.3.  A 1-Month and 2 Month 
Post-Titration Assessment must be performed 
any time a subject’s dose or frequency is up-
titrated (see Section 7.1.2 and Section 9.7.7). 
Clarify dosing assessments. 
Section 7.4, Dose 
Titration Criteria, 
Dose Titration 
due to Change in 
Cirrhosis or 
Child-Pugh Score 
Changes to the dosing regimen are not 
mandatory and should be based on clinical 
judgment as well as change in cirrhosis status.   
provides an overview of the possible changes in 
dosing regimen due to changes in cirrhosis or 
Child-Pugh Score. 
...  Changes in Child-Pugh Score that result from 
a transient, explainable change in laboratory 
parameters should be documented appropriately 
and should not necessarily result in a change to 
the dosing regimen 
 
 
Subjects who demonstrate an improvement in 
cirrhosis status or in Child-Pugh Score from B to 
A, or from Child-Pugh C to B, may be eligible to 
transition to the standard dosing regimen or the 
modified dosing for Child-Pugh B, respectively, 
based on tolerability.  Prior to any dosing 
change, subjects must meet pre-titration 
…Changes in Child-Pugh Score that result from a 
transient, explainable change in laboratory 
parameters should be documented 
appropriately, and should not necessarily result 
in a change to the dosing regimen 
 
...  Changes in Child-Pugh Score that result from a 
transient, explainable change in laboratory 
parameters (eg, increase in vitamin K resulting in 
change in INR) should be documented 
appropriately and discussed with the Medical 
Monitor before any continuation or change to the 
dosing regimen 
 
 
 
 
 
Clarify that changes in CP 
scores should be discussed 
with medical monitor. 
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assessment requirements for dosing as described 
in Section . 
Child-Pugh Scores will be calculated at all 
quarterly study visits 
 
 
Child-Pugh Scores will be calculated during 
screening, at each scheduled study visits, and at 
unscheduled visits in the event of signs or 
symptoms of suspected hepatic injury or 
decompensation are present. 
Section 7.4.1, Pre-
Titration 
Tolerability 
Assessment 
Requirements 
Safety laboratory results obtained at the Month 1 
visit (for titration at Month 3) or at the 1 Month 
Post- Titration Assessment visit (for titration 
prior to or at the subsequent quarterly visit) are… 
Safety laboratory results obtained at the visit (for 
titration at Month 3) or at the Post- Titration 
Assessment visits (for titration prior to or at the 
subsequent quarterly visit) are… 
Added to satisfy 
requirement for monthly 
visits following any titration 
Section 7.5, 
Monitoring and 
Management of 
Potential Hepatic 
Injury and/or 
Disease 
Progression 
Insertion 
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 (Table 1).  Child Pugh Scores should 
only be applied in patients who demonstrate 
progression to cirrhosis based on criteria 
presented in Section 7.5.4.  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 the 
assessments of signs and symptoms of hepatic 
injury and liver biochemistry, the investigational 
product may be interrupted or discontinued per 
criteria discussed in Section 7.5.2 and Section 
7.5.3, and close monitoring procedures will be 
implemented (Section 7.7). 
Per FDA response, language 
added to provide guidance 
for monitoring disease 
progression due to potential 
hepatic decompensation. 
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Section 7.5.1, 
Signs and 
Symptoms of 
Hepatic Injury or 
Decompensation 
Insertion 
7.5.1. 
Signs and Symptoms of Hepatic Injury or 
Decompensation 
Subjects 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 subject evaluation 
Other Symptoms: 
• Worsening of renal function or likely 
dehydration 
Healthcare Provider (HCP) Interactions: 
 
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• 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 7.5.2), (2) 
assessment of clinical events for potential hepatic 
decompensation (Section 7.5 (3) triggering of 
investigational product interruption or 
discontinuation per criteria (Section 8.4 ), (4) 
documentation in the AE eCRF or the SAE 
eCRFs (Section 12.1.5.1 and Section 12.1.5.2), and 
(5) contact with the Medical Monitor. 
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Section 7.5.2, 
Liver 
Biochemistry 
Assessments for 
Suspected Hepatic 
Injury or Potential 
Hepatic 
Decompensation 
Insertion 
Liver biochemistry will be assessed to evaluate 
biochemical triggers that will prompt an 
immediate reevaluation of subjects for potential 
hepatic injury or hepatic decompensation.  These 
assessments will be performed at: 
• Each protocol-specified visit 
• 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 subject 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 subject 
evaluation (depending on the repeat result) are 
summarized in Table 5. 
Figure 2:  DILI Management Algorithm. 
Table 5: Liver Laboratory Criteria for 
Monitoring of Suspected Hepatic Injury or 
Potential Hepatic Decompensation and Criteria 
for Interruption or Discontinuation of 
Investigational Product. 
Per FDA response, added to 
provide guidance for 
monitoring disease 
progression due to potential 
hepatic decompensation 
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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 
subjects’ 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. 
Section 7.5.3, 
Clinical Criteria 
for Monitoring for 
Potential Hepatic 
Decompensation 
Events 
Insertion 
Subjects will be monitored for potential hepatic 
decompensation events throughout the study.  
Clinical criteria for the monitoring these events 
and the interruption/discontinuation of 
investigational product is summarized in Table 6. 
Investigational product should be discontinued 
permanently if the subject received a liver 
transplant or experiences multi-organ failure as 
defined in Table 6, Part A).  Subjects should 
continue to return for scheduled study visits for 
safety follow up.  
Subjects who experience other potential hepatic 
decompensation events defined in Table 6, Part B 
should be closely monitored until normalization 
or stabilization.  Subjects may be rechallenged 
after a minimum of 30 days if fully resolved OR 
stable and approved by the Medical Monitor and 
Investigator. 
Table 6: Criteria for Monitoring Potential Hepatic 
Decompensation Events and Interruption / 
Discontinuation of Investigational Product 
Per FDA response, added to 
provide guidance for 
monitoring disease 
progression due to potential 
hepatic decompensation 
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Section 7.5.4, 
Assessing 
Cirrhosis 
  
Section and subsections were moved from previous 
Section 9.7.3 and subsections. 
Content moved as it 
supports new content 
described above. 
Section 7.5.5, 
Child-Pugh Score 
 
Section was moved from previous Section 9.7.4. 
Section 7.5.5.1, 
Mayo Risk Score 
 
Section was moved from previous Section 9.7.5. 
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Original Text (Amendment 4, 10 May 2017) 
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Justification for Change 
Section 7.6, Dose 
Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
Insertion 
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 8), investigational 
product should be initiated at a lower dose and 
subjects 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 
8.  Subjects that 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 terminate at 
the time when the needed number of adjudicated 
events has accrued.  If a subject reaches an 
outcome event, he or she should continue the 
regular visit schedule and continue taking 
investigational product as long as the subject has 
not met any of the criteria for mandatory 
interruption of investigational product outlined in 
Table 8, and the Investigator assesses it as safe.  
In general, subjects should be strongly 
encouraged to both stay on investigational 
product and remain in the study until study 
termination. 
Table 8: Criteria for Dose Adjustment, 
Interruption, Discontinuation and Rechallenge. 
Per FDA response, added to 
provide guidance for 
monitoring disease 
progression due to potential 
hepatic decompensation 
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Section 7.7, Close 
Observation 
Insertion 
If investigational product is interrupted or 
discontinued as described in Section 7.6, subjects 
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 subject 
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 subject 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 
subject 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 7.5.1, Section 7.5.2, and 
Section 7.5.3.  These cases need to be discussed 
with the Sponsor's medical monitor: 
• 
Repeating liver enzyme and serum bilirubin 
tests as described in Section 7.5.2.  Frequency 
of retesting can decrease to once a week or 
less if abnormalities stabilize or the study 
Per FDA response, added to 
provide guidance for 
monitoring disease 
progression due to potential 
hepatic decompensation 
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drug has been discontinued and the subject 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 product should be discussed 
with the Sponsor's medical monitor.  The 
subject 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 (HEV) when assessing for 
hepatic decompensation as infection with 
HEV in patients with chronic liver diseases 
such as PBC may rapidly worsen with signs 
and symptoms similar to drug induce liver 
injury (Kumar 2013) 
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• 
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. 
Subject 
Withdrawal 
Criteria 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or by 
decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability 
concerns.  The dose of investigational product 
should be adjusted back to the maintenance dose 
in a blinded manner once the issues relating to the 
lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated 
events has accrued.  If a subject reaches an 
outcome event, he or she should continue the 
regular visit schedule and continue taking 
investigational product as long as the subject has 
not met any of the criteria for mandatory 
interruption of investigational product outlined in 
Section 8.4.1, and the Investigator assesses it as 
safe.  In general, subjects should be strongly 
encouraged to both stay on investigational 
product and remain in the study until study 
termination. 
Subjects can be discontinued from investigational 
product by the Investigator at any time for 
clinical safety concerns.  Subjects who are 
discontinued from investigational product are 
expected to continue in the study and should follow 
the regular visit schedule for the duration of the 
study.  See Section 7.6 for withdrawal criteria 
related to potential hepatic injury and/or 
decompensation; including liver transplantation 
or multi-organ failure.  Other reasons, including 
withdrawal of consent or lost to follow-up, are 
described in Section 8.4.1 below. 
 
Section updated to conform 
with FDA response. 
Previous Section 
8.4.1.1, Reasons 
for Additional 
Monitoring 
Related to Liver 
Subjects 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.  Subjects with persistent 
elevations (eg, additional lab testing per 
 
Replaced with updated DILI 
text in Section 7.5. 
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Chemistries 
(Version 4) 
Investigator discretion) should be closely 
monitored.  Concomitant elevations in total 
bilirubin or international normalized ratio (INR) 
with persistent increases in ALT or AST should 
also be closely monitored 
Previous Section 
8.4.1.2, Reasons 
for Investigational 
Product 
Interruption 
Related to 
Elevated Liver 
Chemistries 
(Version 4) 
Development of any of the following clinical 
laboratory values, without explanation, during the 
study mandates investigational product 
interruption: 
• 
AST and/or ALT >3x baseline (and >ULN) 
• 
Total bilirubin >2x 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 AE information should also be collected 
and the subject 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 >3x baseline (and >ULN) or total 
bilirubin >2x baseline (and >ULN), subjects 
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 
 
Replaced with updated DILI 
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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 
study medication and no other cause for the 
elevation is identified, it may be assumed that the 
elevations were due to disease progression and 
the subject 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. 
If at any time a subject 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.  
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Subjects who develop evidence of severe drug-
induced liver injury, which 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 subjects 
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 subject to 
continue treatment.  In the event the 
investigational product is required to be 
discontinued, subjects should be encouraged to 
continue study visits for continued data collection 
but may withdraw consent at any time.  
The Medical Monitor must be contacted in all 
cases of persistent liver biochemistry elevations. 
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All hepatic injury events, regardless of 
relationship to investigational product, will be 
adjudicated by the Hepatic Safety Committee (see 
Section 13.4) 
Previous Section 
8.4.1.3,Pregnancy 
(Version 4) 
If a female subject becomes pregnant, she must 
interrupt treatment with investigational product 
immediately, but should continue with the study 
visit schedule.  As described in Section 12.1.11 
pregnancy is not considered an AE for reporting 
purposes.  The subject may re-start 
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 
12.1.11. 
 
Addressed in Table 8 in 
Section 7.6. 
Previous Section 
8.4.2.1, Liver 
Transplantation 
(Version 4) 
Subjects who undergo a liver transplant during 
the course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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 discussed in Table 8 in 
Section 7.6 
Section 9.7.1, 
Visit Windows 
Post-Titration Visit: 1 month (+1week [7 days]) 
from date of titration or after ≥3 months at a 
decreased dose or frequency   
Post-Titration Visit: 1 month and 2 months 
(±1week [7 days]) from date of titration   
Added to satisfy 
requirement for monthly 
visits following any titration 
Previous 9.7.3, 
Assessing 
Cirrhosis (Version 
4) 
 
Section and subsections were moved to earlier in the 
document (7.5.4 and subsections). 
Content moved. 
Section 9.7.3, 
Screening 
Procedures (1 to 8 
… 
… 
Agreement with FDA to 
perform gallbladder 
assessments at screening.   
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Weeks prior to 
Day 0) 
• 
Perform assessment for calculation of 
Mayo Risk Score 
• 
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 
Visit 2, and a report/adequate data are 
available, a pretreatment ultrasound at 
Screening Visit 2 is not required.  …  
Results from the screening ultrasound 
should be reviewed to assess possible 
exclusion criteria prior to 
randomization. 
• 
Record current concomitant 
medications 
• 
In preparation for the dual-emission X-
ray absorptiometry (DEXA) bone 
density scan to be done at Day 0 (at all 
study sites where the device is 
available), subjects who are taking 
calcium supplements should stop taking 
them for 48 hours before the scan.  If 
the subject is taking any medications for 
osteoporosis or osteopenia, s/he should 
not take them on the day of the scan. 
• 
Perform an ultrasound for HCC surveillance and 
gallbladder assessment (if equipment is 
unavailable, sites should make every attempt to 
use available community referral sites).  If an 
ultrasound has been done within 3 months of the 
planned Day 0 visit, and a report/adequate data 
are available, a pretreatment ultrasound is not 
required.  …  Results from the screening 
ultrasound must be reviewed to assess possible 
exclusion criteria, prior to randomization. 
• 
Review and record prior and concomitant 
medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DEXA removed to 
streamline laboratory 
procedures. 
Previous Section 
9.7.4, Child-Pugh 
Score (Version 4) 
 
Section was moved to earlier in the document (7.5.5). 
Content moved. 
Section 9.7.4, Day 
0 Procedures 
(Randomization) 
…  
Conduct a DEXA bone density scan (at all study 
sites where the device is available); document 
… 
• If hepatobiliary ultrasound for HCC screening 
and gallbladder assessment was not performed 
Per FDA request 
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whether the subject stopped taking her/his 
calcium supplements for 48 hours before the 
scan and medications for osteoporosis or 
osteopenia on the day of the scan, if 
applicable.  If DEXA has been done within 12 
months of Day 0 and a report/adequate data 
are available, a pretreatment DEXA at Day 0 is 
not required. If the DEXA cannot be 
performed on Day 0 (eg, device/technician 
unavailability, scheduling issues, etc), the 
procedure may be completed within the 
screening visit window, as close as possible to 
the Day 0 visit, preferably, after subject 
eligibility has been confirmed. 
… 
• 
Obtain blood samples for:  
− 
OCA, C4, and fibroblast growth factor-
19 (FGF-19) 
− 
Markers of hepatic fibrosis and/or 
inflammation (including enhanced liver 
fibrosis [ELF]) 
− 
Genetics (see Section 11.1.2.3) 
− 
Blood sample for future analysis (refer 
to Section 11.1.2.3)  
 
at Screening and the historic ultrasound is >3 
months from Day 1, perform a hepatobiliary 
ultrasound. 
… 
 
 
 
 
 
 
 
 
 
Obtain blood samples for:  
− 
OCA, C4, and fibroblast growth factor-19 
(FGF-19) 
− 
Markers of hepatic fibrosis and/or 
inflammation (including enhanced liver 
fibrosis [ELF]) 
− 
Genetics (see Section 11.1.2.3) 
• Perform assessments for calculation of 
Child-Pugh Score 
Previous Section 
9.7.5, Mayo Risk 
Score (Version 4) 
 
Section was moved to earlier in the document 
(7.5.5.1). 
Content moved. 
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Section 9.7.5, 
Months 1, 2 
Procedures 
... 
• 
Review and record concomitant medications. 
… 
 
 
 
 
 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit laboratory 
requirements: 
-At the Day 0 visit, the subject can be provided 
with the central laboratory collection kit and 
shipping materials associated with the Month 1 
visit, and have the laboratory specimen collection 
performed at his or her local doctor’s office or 
designated laboratory collection center.  The 
subject must also be contacted via telephone at 
the Month 1 visit timepoint to assess AEs, review 
concomitant medications, and assess 
investigational product compliance;  
-If all other options for the collection of the 
Month 1 laboratory samples have been exhausted, 
the use of a local laboratory for the Month 1 
samples would be accepted for this visit; 
although, any laboratory data obtained from a 
local laboratory will not be captured in the eCRF 
or included in the study analysis.  A copy of the 
local laboratory report would need to be provided 
to the Investigator for review and available in the 
source records.  The subject must also be 
contacted via telephone at the Month 1 visit 
... 
• 
Review and record prior and concomitant 
medications. 
… 
• 
Perform assessments for calculation of Child-
Pugh Score. 
• 
Review progression to cirrhosis algorithm. 
… 
In the event it is not feasible for the subject to return 
to the site for the above referenced procedures, the 
following alternative visit procedures are available to 
help ensure compliance with the Month 1 and 
Month 2 visit laboratory requirements: 
-At the Day 0 visit, the subject can be provided with 
the central laboratory collection kit and shipping 
materials associated with the Month 1 visit, and have 
the laboratory specimen collection performed at his 
or her local doctor’s office or designated laboratory 
collection center.  The subject must also be contacted 
via telephone at the visit timepoint to assess AEs, 
review concomitant medications, and assess 
investigational product compliance;  
-If all other options for the collection of the Month 1 
and Month 2 laboratory samples have been 
exhausted, the use of a local laboratory for the 
Month 1 samples would be accepted for this visit; 
although, any laboratory data obtained from a local 
laboratory will not be captured in the eCRF or 
included in the study analysis.  A copy of the local 
laboratory report would need to be provided to the 
Investigator for review and available in the source 
records.  The Investigator should contact the 
Medical Monitor as soon as possible to discuss 
any local laboratory values that may be of clinical 
concern.  The subject must also be contacted via 
Month 2 added to section 
satisfy requirement for 
monthly visits following 
any titration and assess CP 
score per FDA request. 
 
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timepoint to assess AEs, review concomitant 
medications, and assess investigational product 
compliance;  
-A physical examination should be performed at 
the Month 3 visit if an onsite Month 1 visit was 
not performed. 
 
telephone at the visit timepoint to assess AEs, review 
concomitant medications, and assess investigational 
product compliance;  
-A physical examination should be performed at the 
Month 3 visit if an onsite Month 1 or Month 2 visit 
was not performed. 
Section 9.7.6 
Month 3 
Procedures;  
Insertions. 
… 
• 
Review progression to cirrhosis algorithm 
… 
• 
Review and record prior and concomitant 
medications. 
Per FDA request 
 
Section 9.7.7, 
Post-Titration 
Visit Procedures 
… 
• 
Review and record concomitant medications. 
… 
 
 
 
 
 
If all other options for the collection of the Post-
Titration laboratory samples have been 
exhausted, the use of a local laboratory for the 
Post-Titration samples would be accepted for this 
visit although any laboratory data obtained from a 
local laboratory will not be captured in the eCRF 
or included in the study analysis.  A copy of the 
local laboratory report would need to be provided 
to the investigator for review and available in the 
source records.  The subject must also be 
contacted via telephone at the Post-Titration Visit 
… 
• 
Review and record prior and concomitant 
medications. 
… 
• 
Perform assessments for calculation of Child-
Pugh Score. 
• 
Review progression to cirrhosis algorithm. 
… 
If all other options for the collection of the Post-
Titration laboratory samples have been exhausted, 
the use of a local laboratory for the Post-Titration 
samples would be accepted for this visit; although, 
any laboratory data obtained from a local laboratory 
will not be captured in the eCRF or included in the 
study analysis.  A copy of the local laboratory report 
would need to be provided to the Investigator for 
review and available in the source records.  The 
Investigator should contact the Medical Monitor 
as soon as possible to discuss any local laboratory 
values that may be of clinical concern.  The subject 
per FDA request 
 
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time point to assess AEs, review concomitant 
medications, and assess investigational product 
compliance; 
must also be contacted via telephone at the Post-
Titration Visit timepoint to assess AEs, review 
concomitant medications, and assess investigational 
product compliance; 
Section 9.7.8, 
Month 6 
Procedures 
… 
• 
Perform assessment for calculation 
of Mayo Risk Score. 
 
… 
• 
Review and record concomitant medications. 
… 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis 
and/or inflammation (including 
ELF) 
− 
Blood sample for future 
analysis (refer to 
Section 11.1.2.2)  
… 
• 
Review progression to cirrhosis algorithm. 
… 
• 
Review and record prior and concomitant 
medications. 
… 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or 
inflammation (including ELF) 
 
Section 9.7.9 
Month 9 
Procedures 
 
… 
 
• 
Review and record concomitant medications 
… 
• 
In preparation for the DEXA bone density 
scan to be done at the Month 12 visit (at all 
study sites where the device is available), 
… 
• 
Review progression to cirrhosis algorithm  
• 
Review and record prior and concomitant 
medications 
… 
per FDA request. 
 
 
 
Procedure deleted. 
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subjects who are taking calcium supplements 
should stop taking them for 48 hours before 
the scan.  If the subject is taking any 
medications for osteoporosis or osteopenia, 
s/he should not take them on the day of the 
scan 
Section 9.7.11 
Month 12 
Procedures 
… 
Perform assessment for calculation of Mayo Risk 
Score. 
… 
• 
Conduct a DEXA bone density scan (at all 
study sites, where the device is available); 
document whether the subject stopped taking 
her/his calcium supplements for 48 hours before 
the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable 
… 
• 
Review and record concomitant medications 
… 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or 
inflammation (including ELF) 
− 
Genetics (see Section 11.1.2.3) 
Blood sample for future analysis (refer to 
Section 11.1.2.3) 
… 
• 
Perform assessments for calculation of Child-
Pugh Score 
• 
Review progression to cirrhosis algorithm 
… 
 
 
 
• 
Review and record prior and concomitant 
medications 
… 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or inflammation 
(including ELF) 
− 
Genetics (see Section 11.1.2.3) 
 
Per FDA request. 
 
Procedures deleted. 
Section 9.7.12, 
Month 3 and 
Month 9 
Continued 
Follow-Up 
Insertions 
… 
• 
Review progression to cirrhosis algorithm 
… 
 
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Procedures (±2 
weeks) 
• 
Review and record prior and concomitant 
medications 
 
Section 9.7.13, 
Month 6 
Continued 
Follow-Up 
Procedures (Semi-
annually [±2 
weeks]) 
• 
Perform assessment for calculation of Mayo 
Risk Score. 
• 
Perform assessments for calculation of 
Child-Pugh Score. 
 
 
 
… 
• 
Review and record concomitant medications 
… 
• 
Obtain blood samples for:  
− 
Markers of hepatic fibrosis 
and/or inflammation (including 
ELF). 
− 
Blood sample for future 
analysis (refer to 
Section 11.1.2.3). 
• 
At the semi-annual visit, in 
preparation for the DEXA bone 
density scan to be done at the 
annual visit (at all study sites where 
the device is available), subjects 
who are taking calcium supplements 
 
 
• 
Perform assessments for calculation of Child-
Pugh Score. 
• 
Review progression to cirrhosis algorithm  
… 
 
• 
Review and record prior and concomitant 
medications 
… 
• 
Obtain blood samples for:  
− 
Markers of hepatic fibrosis and/or 
inflammation (including ELF). 
 
per FDA request. 
 
 
Procedures deleted 
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Revised Text (Version 5, 04 Jan 2018) 
Justification for Change 
should stop taking them for 48 
hours before the scan.  If the subject 
is taking any medications for 
osteoporosis or osteopenia, s/he 
should not take them on the day of 
the scan. 
 
Section 9.7.14, 
Month 12 
Continued 
Follow-up 
Procedures 
(Annually [±2 
weeks]) 
• 
Perform assessment for calculation of Mayo 
Risk Score 
… 
• 
Conduct a DEXA bone density scan (at all 
study sites where the device is available); 
document whether the subject stopped taking 
her/his calcium supplements for 48 hours before 
the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable. 
… 
• 
Review and record concomitant medications 
… 
• Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or 
inflammation (including ELF) 
− 
Genetics (see Section 11.1.2.3) 
− 
Blood sample for future analysis (refer to 
Section 11.1.2.3 
… 
• 
Review progression to cirrhosis algorithm 
… 
 
 
 
• 
Review and record prior and concomitant 
medications 
… 
• Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or inflammation 
(including ELF) 
− 
Genetics (see Section 11.1.2.3) 
 
 
per FDA request. 
 
 
Procedures deleted 
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Section 9.7.15, 
Early 
Discontinuation 
and/or Early 
Termination 
Procedures for 
Subjects that 
Withdraw from 
Investigational 
Product or 
Withdraw 
Consent 
Table 9, footnote c 
… No Additional data (e.g. AE, concomitant 
medication, etc) data will be collected, except as 
indicated in Section . 
Some assessments noted below may be omitted if 
they have been completed within the 6 months (or 
the timeframe otherwise specified) and so long as 
safety issues do not warrant repeat testing. 
… 
 
 
• 
Perform assessment for calculation of Mayo 
Risk Score 
… 
• 
Conduct a DEXA bone density scan (at all 
study sites where the device is available); 
document whether the subject stopped taking 
her/his calcium supplements for 48 hours before 
the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable. 
 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or 
inflammation (including ELF) 
− 
Blood sample for future analysis (refer to 
Section 11.1.2.3 
Table 9, footnote c 
…  Additional data such information on 
concurrent medical conditions, co-morbidities, 
relevant and concomitant medications may be 
collected to help facilitate adjudication of these 
post-study events.  Some assessments noted below 
may be omitted if they have been completed within 
the 6 months (or the timeframe otherwise specified) 
and so long as safety issues do not warrant repeat 
testing.   
… 
 
• 
Review progression to cirrhosis algorithm  
… 
 
 
 
 
 
 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or inflammation 
(including ELF) 
 
Section 11.1.2.3, 
Other Exploratory 
Evaluations 
• 
Blood samples for future analysis of 
additional analytes, such as PBC autoantibodies 
and other cytokines and interleukins, may be 
assayed on an exploratory research basis.  Blood 
Deleted 
Procedure deleted 
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samples may also be used to assess other disease 
or investigational product characteristics.  
Appropriate serum and plasma samples will be 
collected at selected time points during the study. 
Subjects will be permitted to decline future 
analysis of blood samples without affecting their 
involvement in the study.  IRB/IEC review and 
approval will be required and willing subjects 
must specifically consent to participate in this 
evaluation.  The samples will be stored for up to 
1 year after the end of the study and destroyed 
after 1 year if not analyzed. 
Section 12.1.1.1, 
Adverse Event 
Insertions 
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) 
subject deterioration due to primary illness; (3) 
intercurrent illness; and (4) drug interaction.  For 
reporting purposes, pregnancy is not considered 
an AE 
 
Subjects 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 the or whites of 
eyes, and bruising easily. 
Per FDA request 
Section 12.1.1.4, 
Adverse Events of 
Special Interest 
Insertion 
The following decompensation events are adverse 
events of special interest.  A subset of these events 
are also individual components of the primary 
endpoint (Section 11.1.1).   
Per FDA request 
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• 
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, 
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 
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− 
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 
Section 12.1.5.1, 
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 subject. 
Per FDA request 
Section 12.1.10, 
Follow-up of AEs 
and SAEs 
…  Drug-induced liver injury may develop or 
progress even after the causative drug has been 
stopped.  Results should be recorded in the CRF. 
Note that longer follow-up can sometimes reveal 
an off-drug repetition. 
Drug-Induced Liver Injury or Disease 
Progression 
…  Drug-induced liver injury may develop or 
progress even after the causative drug has been 
stopped.  Results from drug induced liver injury 
follow-up should be recorded in the eCRF. Note that 
longer follow-up can sometimes reveal an off-drug 
repetition… 
 
Cholecystitis or Pancreatitis 
At the time of consent for new subjects (or re-
consent to the protocol amendments for ongoing 
subjects), subjects will 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.  
Subjects will 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 will be instructed to 
promptly bring subjects into the clinic to undergo 
 
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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 will be monitored monthly for 
3 months after onset of symptoms, irrespective of 
whether a diagnosis of cholecystitis and or 
pancreatitis is confirmed.  Results should be 
recorded promptly in the eCRF. 
Section 12.2.5, 
Dual Emission X-
Ray 
Absorptiometry 
12.2.5. Dual Emission X-Ray Absorptiometry 
A bone density assessment will be done using the 
DEXA scan. 
Deleted 
Procedure deleted 
Section 12.2.6, 
Laboratory 
Assessments 
Subjects will be instructed to attend each of their 
study visits (except Screening) in a fasted state, 
Subjects will be instructed to attend any study or 
unscheduled laboratory visits (except Screening) in 
a fasted state, 
Clarify subject should fast 
for all lab visits. 
Section 12.2.6, 
Laboratory 
Assessments, 
Table 13 
Laboratory 
Assessment 
Analyte 
Laboratory Assessment 
Analyte 
 
Labs added per FDA request 
 
 
 
 
Markers of 
Cholecystitis and 
Pancreatitis 
amylase and lipase 
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Blood Sample for 
Future Analysis 
PBC autoantibodies and 
other cytokines and 
interleukins TBD 
 
 
 
 
Procedure deleted 
Section 12.2.6, 
Laboratory 
Assessments, 
MELD scores, Child-Pugh score, and MRS will 
be calculated at screening, and at quarterly 
(MELD and Child-Pugh scores) or semi-annual 
(MRS) visits based on serum chemistry and 
coagulation. 
MELD scores and Child-Pugh score will be 
calculated at screening, and at all visits based on 
serum chemistry and coagulation. 
Clarify subject should fast 
for all lab visits 
Section 13.2.1, 
Safety Analyses, 
Adverse Events 
Insertion 
Adverse events of special interest as described in 
Section 12.1.1.4 will be summarized for each 
treatment group.  In addition, each event is a 
component of the primary endpoint, and will be 
summarized as secondary endpoints as described 
in Section 13.1.4. 
Per FDA request. 
Section 13.4, 
Adjudication 
Committees 
All suspected liver-related clinical outcomes, 
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 
All suspected liver-related clinical outcomes and 
MACE/Expanded MACE 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 2 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 
Each adjudication committee will have a charter 
that documents the reporting of events by the study 
site, definition of the suspected events to be 
There is no longer a need for 
the Hepatic Safety Committee 
given the updated guidance for 
the Investigator. 
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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, 
adjudicated, supply of source documentation to the 
committee, 
References 
 
Kumar A, Saraswat V.  Hepatitis E and Acute-on-
Chronic Liver Failure.  J Clin Exp Hepatol. 2013 
Sep;3(3):225-30. doi: 10.1016/j.jceh.2013.08.013. 
Epub 2013 Sep 16 
Banks O, Bollen T, Dervenis C, et al.  
Classification of acute pancreatitis02012: 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. 
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. 
 
Appendix A, 
Overview of 
Modified Dosing 
Regimen for 
Subjects with 
Child-Pugh B or 
C Hepatic 
Impairment 
… Overview of Modified Dosing Regimen for 
Subjects with Child-Pugh B or C Hepatic 
Impairment 
An overview of the modified dosing regimen for 
subjects with Child-Pugh Class B or Child Pugh 
Class C is presented in  and . 
Subjects who are cirrhotic and classified as 
Child-Pugh Class B or Child-Pugh Class C will 
initiate a modified treatment regimen with 5 mg 
OCA or matching placebo once weekly for at 
Subjects with cirrhosis and classified as Child-
Pugh B or Child-Pugh C at Screening will follow 
a modified dosing schedule initiating 5 mg OCA 
or matching placebo once weekly as described in 
Figure 3.  After a minimum of 3 months dosing 
once weekly with 5 mg OCA or matching placebo, 
and following review of the pre-titration 
laboratory results to assess safety and tolerability, 
the dosing frequency of 5 mg OCA or matching 
placebo should be increased to twice weekly (at 
least three days apart).  Subjects who have 
maintained the twice weekly dosing frequency for 
Deleted overview section 
and replaced with text  
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least 3 months.  Subjects classified as Child-Pugh 
Class B should eventually titrate to a maximum 
dose of 5 mg OCA or matching placebo once 
daily, based on tolerability and biochemical 
response.  Subjects classified as Child-Pugh Class 
C should titrate to a maximum dose and 
frequency of 10 mg OCA or matching placebo 
twice weekly. 
a minimum of at least 6 weeks, and meet the dose 
titration criteria, should up titrate to the 
maximum allowed dose of 10 mg OCA or 
matching placebo twice weekly (Table 14). 
Investigators may decrease the dosing frequency 
(back to once weekly) or dose for any subject at 
any time during the study, as considered clinically 
appropriate (eg, tolerability). 
Appendix A, 
Figure 3 
 
 
Same dosing scheme for 
CP-B and CP-C subjects. 
Appendix A, 
Table 14 
 
 
Titration #3 is no longer 
applicable to study.  To 
align with label, maximum 
dose for Child-Pugh B or C 
subjects is 10 mg OCA 
twice weekly. 
Appendix A 
Modified Dosing Regimen for Subjects with 
Child-Pugh B Hepatic Impairment 
Subjects with cirrhosis and classified as Child-
Pugh BC at Screening will follow a modified 
dosing schedule receiving 5 mg OCA or 
matching placebo once weekly as described in .  
After a minimum of 3 months dosing once 
weekly with 5 mg OCA or matching placebo, and 
following review of the pre-titration laboratory 
results to assess safety and tolerability, the dosing 
frequency of 5 mg OCA or matching placebo 
should be increased to twice weekly (at least 3 
days apart).  Subjects who have maintained the 
twice weekly dosing frequency for a minimum of 
 
 
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at least 6 weeks, and meet the dose titration 
criteria, should up-titrate to twice weekly dosing 
with 10 mg OCA or matching placebo.  Subjects 
with at least 6 weeks of twice weekly dosing at 
10 mg OCA or matching placebo, and meeting 
dose titration criteria, should up-titrate to the 
maximum allowed dose of 5 mg OCA or 
matching placebo once daily.  
Investigators may decrease the dosing frequency 
(back to once or twice weekly) or dose for any 
subject at any time during the study, as 
considered clinically appropriate (eg, 
tolerability). 
Appendix A, 
Dose Titration 
due to Change in 
Cirrhosis or 
Child-Pugh Score 
Subjects on a modified dosing regimen who 
demonstrate a change in cirrhosis status 7.5.4 
and/or Child-Pugh Score7.5.5 should have their 
dose of investigational product modified to match 
their current status per the appropriate dosing 
regimen (see Section , ); however, changes to the 
dosing regimen are not mandatory and should be 
based on clinical judgment as well as changes in 
status. Changes in Child-Pugh Score that result 
from a transient, explainable change in laboratory 
parameters should be documented appropriately, 
and should not necessarily result in a change to 
the dosing regimen.  Investigators may contact 
the Medical Monitor at any time to discuss 
potential changes to dosing.   
Possible scenarios for dosing modifications 
include: 
• Subjects who develop cirrhosis during the 
course of the trial with a classification of 
Child-Pugh B or C 
• Subjects with pre-existing cirrhosis who 
demonstrate a change in the Child-Pugh 
When subjects demonstrate a change in cirrhosis 
status (as assessed per Section 7.5.4) or Child-Pugh 
Score (Section 7.5.5 dosing should be reassessed 
and the dosing regimen modified appropriately.  
Changes in Child-Pugh Score that result from a 
transient, explainable change in laboratory 
parameters (eg, increase in INR due to vitamin K 
deficiency) should be documented appropriately and 
discussed with the Medical Monitor before any 
continuation or change to the dosing regimen.    
Possible scenarios for dosing modifications include: 
• 
Subjects who develop cirrhosis during the 
course of the trial with a classification of 
Child-Pugh B or C 
• 
Subjects with pre-existing cirrhosis who 
demonstrate a change in the Child-Pugh Score 
from A to B or C at any point in the study   
Subjects may titrate dose and dosing frequency up or 
down as appropriate, within the dosing regimen.  Up-
titration should be done per Investigator discretion 
and be guided by the pre-titration tolerability 
assessments outlined in Section 7.4.1.  A 1-Month 
and 2-Month Post-Titration Assessment must be 
 
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Score from A to B or C at any point in the 
study   
• Improvement in classification of Child-
Pugh Score from C to B  
• Improvement in classification of Child-
Pugh Score from B to A; these subjects 
may be eligible to transition to the standard 
dosing regimen 
Subjects may titrate dose and dosing frequency 
up or down as appropriate, within the appropriate 
dosing regimen.  Up-titration should be done per 
Investigator discretion and be guided by the pre-
titration tolerability assessments outlined in 
Section 7.4.1.  A 1-Month Post-Titration 
Assessment must be performed any time a 
subject’s dose or frequency is up-titrated (see 
Section 7.1.2 and Section 9.7.10).
performed any time a subject’s dose or frequency is 
up-titrated (see Section 7.1.2 and Section 9.7.7). 
Appendix A, 
Unscheduled 
Titration Visit, 
Optional Visit 
…:  The + 1 week window week related to the 1 
month Post-Titration Visit can be extended for up 
to an additional 5 weeks to allow for the post-
titration assessment to be performed during one 
of the subject’s regularly scheduled study visits.  
If the window is extended past +1 week allowed 
visit window, at a minimum, a telephone safety 
contact should then be performed 1-month post-
titration. 
…:  The ±1 week window related to the 2-month 
Post-Titration Visit can be modified to occur 2 
weeks earlier or 2 weeks outside of the allowed 
visit window to allow for the post-titration 
assessment to be performed during one of the 
subject’s regularly scheduled study visits.  If the 2-
month Post-Titration Visit is performed during a 
regularly scheduled study visit, all scheduled 
procedures associated with that visit should be 
performed. 
 
 
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1. 
TITLE PAGE 
 
Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cholangitis 
 
THE COBALT STUDY 
Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) 
 
Version 6:  05 November 2019 
 
EudraCT Number:  2014-005012-42 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
USA 
 
TEL: +1 858 250 6398 
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 747-3Oz
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Paee2
SPONSOR'S APPROVAL OF THE PROTOCOL
Reviewed and Approved by:
 PhD
 Clinical Development
Intercept Pharmaceuticals, Inc.
Os t-roV lO r 1
Date
Confidential and Proprietary
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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 747-302.  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 747-302 and in accordance 
with Good Clinical Practice (CPMP/ICH/135/95), 21CFR Part 312 and all applicable regulatory 
requirements. 
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 
Primary Contact: 
 MD, MPH| Senior Medical Director / Medical Affairs 
Syneos Health | Chapel Hill, NC 27514 |U.S.A. 
Tel: 
 Mobile: 
 
 
Secondary Contact: 
 MD| Executive Director, Clinical Research 
Intercept Pharmaceuticals, Inc. (Intercept)| New York, NY 10001 
Tel: 
 Mobile: 
 
 
24-hour Telephone: + 1 844 250 6398 
SAE Fax: 
+1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product: 
Obeticholic Acid (OCA) 
Name of Active Ingredient: 
Obeticholic acid (OCA); 6α-ethyl-chenodeoxycholic acid; (6-ECDCA); INT-747 
Title of Study:  
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Effect of 
Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary Cholangitis 
Investigators and/or Study Center(s):  
Approximately 170 investigational study sites, globally. 
Studied Period (Years):  
The study is event driven and total duration will be determined by the 
time required to accrue approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects are expected to have a 
minimum follow-up time of approximately 6 years. 
Phase of Development:   
Phase 4:  US, Canada, and the EU 
Phase 3b:  All other regions 
 
Objectives: 
Primary  
To assess the effect of OCA compared to placebo, in conjunction with established local standard of care, on 
clinical outcomes in subjects with primary biliary cholangitis (PBC) as measured by time to first occurrence of 
any of the following adjudicated events, derived as a composite event endpoint:  
• 
Death (all-cause) 
• 
Liver transplant 
• 
Model of end stage liver disease (MELD) score ≥15 
• 
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 (confirmed by diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of at 
least twice in a month) 
Secondary  
• 
To assess the effect of OCA compared to placebo on time to first occurrence of each individual 
component of the primary endpoint as listed above.  
• 
To assess the effect of OCA compared to placebo on time to occurrence of liver-related death. 
• 
To assess the effect of OCA compared to placebo on progression to cirrhosis.  
• 
To assess the effect of OCA compared to placebo on time to occurrence of hepatocellular carcinoma 
(HCC). 
• 
To assess the effect of OCA compared to placebo on disease progression via the following: 
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− 
Liver biochemistry  
− 
Markers of inflammation and fibrosis 
• 
To assess the effect of OCA compared to historical controls on liver-related clinical outcomes. 
• 
To characterize the pharmacokinetics (PK) of OCA and its conjugates in a subset of subjects. 
• 
To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource 
utilization, and quality of life measures in subjects treated with OCA compared to placebo. 
• 
To assess the safety and tolerability in subjects treated with OCA compared to placebo. 
Methodology: 
This Phase 3b/4, double-blind, randomized, placebo-controlled, multicenter study will evaluate the effect of OCA 
on clinical outcomes in subjects with PBC.  Subjects will be screened twice during a 1- to 8-week Screening 
period prior to entering the study to allow for the collection of repeat serum chemistry samples (at least 2 weeks 
apart) to confirm pretreatment alkaline phosphatase (ALP) and total bilirubin values (refer to Section 9.7.3). 
Investigational product will be taken orally, once daily for the majority of subjects; dose and frequency will be 
modified for subjects with cirrhosis (including subjects progressing to cirrhosis during the study) and classified as 
Child-Pugh B or C.  The randomization will be stratified by ursodeoxycholic acid (UDCA) treatment (yes/no) 
and baseline bilirubin categories (> upper limit of normal [ULN]/ ≤ULN).  A minimum of 30% of subjects will 
have elevated bilirubin (>ULN) at Screening. 
Schematic Diagram Study 747-302:  
 
 
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for subjects on all dosing 
regimens, based on tolerability and biochemical response (up-titration should be considered when ALP and/or total bilirubin are >ULN).  
Subsequent dose titration(s) for subjects classified as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no 
earlier than 6 weeks after the previous dose titration. 
 
Dosing frequency will be determined by the presence or absence of cirrhosis and, if cirrhosis is present, by 
Child-Pugh Score as described below: 
• 
Noncirrhotic subjects or subjects classified as Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects should titrate to a maximum dose of 10-mg 
OCA once daily (or matching placebo) at the Month 3 visit or at any study visit following the 
Month 3 visit based on tolerability and biochemical response of the product. 
• 
For those subjects that up-titrate to 10 mg, dosing may be decreased to 5 mg at any time during the 
study as considered clinically appropriate (eg, based on tolerability). Subjects may be titrated back 
to a maximum dose of 10 mg once daily based on tolerability and clinical judgment of the 
Investigator. 
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• 
Subjects who are cirrhotic and classified as Child-Pugh Class B or Child-Pugh Class C will initiate 
a modified treatment regimen with 5-mg OCA or matching placebo once weekly for at least 
3 months.  Subjects classified as Child-Pugh Class B or Child-Pugh Class C should titrate to a 
maximum dose and frequency of 10-mg OCA or matching placebo twice weekly (at least 3 days 
apart), based on tolerability and biochemical response. 
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Planned Dosing Regimen 
Standard 
Modified 
Noncirrhotic/ 
Child-Pugh A 
Child-Pugh B or  
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weekly 
 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weekly 
 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or Child-Pugh Score at any time during the study 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
With the exception of liver transplant, if a subject experiences a suspected or confirmed clinical outcomes event, 
the subject should continue the regular visit schedule and continue taking investigational product as long as the 
subject has not met any of the criteria for discontinuation outlined in the protocol.  Subjects who discontinue 
investigational product are expected to be followed through to study closure (or at the discretion of the Sponsor).  
Additional information regarding subject follow-up and different options available to subjects is provided in 
Section 7.9 and Section 8.4. 
Number of Subjects (Planned):  
Approximately 428 subjects are planned to be enrolled in the study.  In the event additional subjects are needed 
for the enrollment in the biopsy substudy (N = 45 subjects, as defined in Addendum 2), subjects who agree to 
participate in the substudy may be added to the target subject enrollment number currently planned.   
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver 
Diseases [AASLD] and the European Association for the Study of the Liver [EASL] practice guidelines; 
Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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 
2. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN 
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past ≥3 months) or has been taking UDCA for at least 
12 months with a stable dose for ≥3 months prior to Day 0 
5. Contraception:  Female subjects must be postmenopausal, surgically sterile, or, if premenopausal (and 
not surgically sterile), be prepared to use ≥1 highly effective method of contraception during the study 
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and for 30 days after the end of treatment. Highly effective methods of contraception per the CTFG 
guidelines are those that alone or in combination results in a failure rate of less than 1% per year when 
used consistently and correctly. Highly effective methods of contraception are as follows: 
• 
Intrauterine device 
− 
Intrauterine device (IUD) 
− 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomy (partner) 
• 
Combined (estrogen and progestogen containing) hormonal contraception (eg, oral, intravaginal or 
transdermal) associated with inhibition of ovulation. If oral contraceptives are used, they must be 
used in combination with a male or female condom. Female subjects should have been on the 
hormone contraception for at least 8 days prior to Day 1. 
• 
Progestogen-only hormonal contraception (eg oral, injectable or implantable) associated with 
inhibition of ovulation. If oral contraceptives are used, they must be used in combination with a 
male or female condom. Female subjects should have been on the hormone contraception for at 
least 8 days prior to Day 1. 
• 
Sexual abstinence, if in line with the preferred and usual lifestyle of the subject (where abstinence is 
defined as refraining from heterosexual intercourse during the entire period of risk associated with 
study treatments).  
6. Must provide written informed consent and agree to comply with the study protocol 
Exclusion Criteria 
1. History or presence of other concomitant liver diseases including: 
• 
Hepatitis C virus infection 
• 
Active hepatitis B infection; however, subjects 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 
• 
Nonalcoholic steatohepatitis 
• 
Gilbert's Syndrome 
2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including: 
• 
History of liver transplant, current placement on a liver transplant list, or current MELD score >12.  
Subjects who are placed on a transplant list despite a relatively early disease stage (for example per 
regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria 
• 
Cirrhosis with complications, including history (within the past 12 months) or presence of: 
− 
Variceal bleed 
− 
Uncontrolled ascites  
− 
Encephalopathy  
− 
Spontaneous bacterial peritonitis 
• 
Known or suspected HCC 
• 
Prior transjugular intrahepatic portosystemic shunt procedure 
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• 
Hepatorenal syndrome (type I or II) or Screening (Visit 1 or 2) serum creatinine >2 mg/dL 
(178 μmol/L) 
3. Mean total bilirubin >5x ULN 
4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal 
resection or plan to undergo either of these procedures 
5. Other medical conditions that may diminish life expectancy, including known cancers (except 
carcinomas in situ or other stable, relatively benign conditions) 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by 
a positive serum pregnancy test), or lactating 
7. Known history of human immunodeficiency virus infection 
8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 
3 months prior to Day 0) 
9. Other clinically significant medical conditions that are not well controlled or for which medication needs 
are anticipated to change during the study 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0 
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-month 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. History of known or suspected clinically significant hypersensitivity to OCA or any of its components 
14. UDCA naïve (unless contraindicated) 
Investigational Product, Dosage and Mode of Administration:  
OCA (5 mg or 10 mg tablets) 
Reference Therapy, Dosage and Mode of Administration:  
Placebo (matching tablets) 
Duration of Treatment:  
The study is event driven and total duration will be determined by the time required to accrue approximately 
127 primary endpoint events, estimated to be approximately 10 years.  Subjects are expected to have a minimum 
follow-up time of approximately 6 years. 
Criteria for Evaluation: 
Primary Objectives 
Assessments 
Clinical outcomes 
• 
Death (all-cause) 
• 
Liver transplant 
• 
MELD score ≥15 
• 
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 (confirmed by 
diagnostic paracentesis) 
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• 
Uncontrolled ascites (diuretic-resistant ascites requiring 
therapeutic paracentesis at a frequency of at least twice in a 
month) 
Secondary Objectives 
 
Individual components of the 
primary endpoint 
As listed above and including liver-related death 
Progression to cirrhosis 
Clinical, laboratory, or radiological evidence of cirrhosis and/or liver 
stiffness (ie, Fibroscan® transient elastography [TE]) confirmed by biopsy 
unless not medically indicated 
HCC 
Confirmed by 2 complimentary imaging modalities unless confirmed by 
biopsy 
Change in baseline liver 
biochemistry 
Liver biochemistry (see Table 12 for list of analytes to be tested)  
Inflammation and fibrosis 
IgM, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), 
fibroblast growth factor-19 (FGF-19), cytokeratin-18 (CK-18), enhanced 
liver fibrosis (ELF), and Fibroscan® TE 
Clinical outcomes compared to 
historical controls 
Similar endpoints as used for the primary objective where available 
including liver transplant and death 
PK 
OCA and its conjugates 
Health outcomes and economics 
research 
Including the following: 
Cost-effectiveness and resource utilization 
Quality of life (Fatigue Impact Score and EQ-5D-5L)  
Safety and tolerability 
Including the following: 
Treatment-emergent adverse events including adverse events of special 
interest 
Clinical laboratory values 
Statistical Methods: 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the data: 
Intent-to-Treat (ITT), Per Protocol (PP), Safety, PK, Overall Historical Control, UK-PBC Historical Control, and 
the Global PBC Historical Control.  Descriptions of subject populations are provided in Section 13.1.1. 
Efficacy Analyses 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the time to first occurrence of one of the following:  
• 
Death (all-cause) 
• 
Liver transplant 
• 
Model of end stage liver disease (MELD) score ≥15 
• 
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 (confirmed by diagnostic paracentesis) 
• 
Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of at 
least twice in a month) 
All events will be adjudicated by an independent committee. 
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Primary Efficacy Analysis 
The primary efficacy analysis will compare OCA to placebo with respect to the primary efficacy endpoint using 
the ITT population.  The 2 treatment groups will be compared 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 its 95% CI will be determined based 
on a Cox regression model stratified by randomization strata to estimate the magnitude of the effect.  The same 
analyses for primary efficacy endpoints will be performed for PP population as a sensitivity analysis.   
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints are as follows: 
• 
Time to first occurrence of MELD score ≥15 
• 
Time to liver transplant or death (all-cause) 
• 
Change from Baseline in total bilirubin at end of study 
• 
Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare OCA to placebo in the ITT population with respect to the key 
secondary efficacy endpoints.  Only adjudicated events will be included in time-to-event analyses.  The 
comparison (hypothesis testing) will be conducted in a sequential closed testing gate-keeping procedure (in the 
order in which the key secondary endpoints are stated above), provided that the primary efficacy endpoint 
comparison is statistically significant in favor of the OCA treatment group.  If the primary comparison is not 
statistically significant then comparison of the secondary endpoints will be considered as descriptive and 
exploratory.  The same analyses for key secondary efficacy endpoints will be performed for PP population as a 
sensitivity analysis. 
Additional Secondary Efficacy Analyses 
The following time-to-event secondary efficacy analyses will compare OCA versus placebo using the ITT 
population: 
• 
Time to each component of the primary efficacy endpoint (except MELD score ≥15 which is 
captured above) 
• 
Time to development of varix/varices 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
• 
Time to liver-related death 
• 
Time to liver-related death or liver transplant 
• 
Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these secondary 
efficacy analyses.  Similar endpoints, where available, will be analyzed to compare OCA to historical controls. 
Progression to cirrhosis will be assessed in the subset of subjects considered noncirrhotic at Baseline using 
available medical history, clinical, and laboratory assessments as well as Baseline TE where available.  
Specifically, subjects with no clinical, laboratory, or radiological evidence of cirrhosis at Baseline and/or a TE 
liver stiffness of <16.9 kPa (Corpechot 2012) will be considered noncirrhotic.  Progression to cirrhosis will be 
assessed by the development of clinical, laboratory, or radiological evidence of cirrhosis and/or when liver 
stiffness increases to ≥16.9 kPa during the study in which case histological progression to cirrhosis should be 
confirmed by biopsy unless not medically indicated.  Using this definition for progression to cirrhosis, the 
percentage of noncirrhotic subjects progressing to cirrhosis during the treatment period will be summarized by 
treatment group and compared using a Cochran–Mantel–Haenszel test stratified by the randomization 
stratification factor. 
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For those subjects enrolled in the biopsy substudy (defined in Addendum 2) progression to cirrhosis identified by 
the above criteria and improvement in fibrosis/cirrhosis will be confirmed by paired biopsy.  Analyses for the 
histological assessment conducted as part of the biopsy substudy are defined in Addendum 2.  
Further details on efficacy, health outcomes, and PK analyses are specified in Section 13. 
Safety Analyses 
Safety data, including AEs, AEs of special interest including pruritus and hepatic safety, vitals, 
electrocardiogram, and clinical laboratory results will be summarized by treatment group for the Safety 
Population. 
Sample Size Justification 
The target population is subjects who are at higher risk of liver-related clinical complications.  Eligible subjects 
will have a diagnosis of PBC with bilirubin levels >ULN and ≤5x ULN and/or ALP >3x ULN.  The following 
assumptions were used in sample size calculations:  
• 
Exponential survival curves, placebo survival estimate of 0.6 at 8 years with a hazard ratio of 0.60, 
and total study duration of 10 years (from first subject enrolled), allowing for 4 years of subject 
accrual and 6 years of follow-up 
• 
Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• 
The 2 groups will be compared using a 2-sided log rank test at the 5% level of significance. 
• 
Two interim analyses and one final analysis are planned.  The first interim analysis will be 
performed when 50% of the target events are accrued and the second interim will be performed 
when 75% of the target events are accrued. 
• 
A dropout rate of 10% is assumed.  
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 127 events (both groups 
combined) will provide 80% power to demonstrate a statistically significant difference between OCA and 
placebo on time to liver-related outcomes, including all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 428 subjects will 
be enrolled to attain 127 events. 
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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 ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Overview of Primary Biliary Cholangitis and Obeticholic Acid ................................23 
5.2. 
Mechanism of Action of Obeticholic Acid .................................................................23 
5.3. 
Nonclinical Experience with Obeticholic Acid ..........................................................24 
5.4. 
Clinical Experience with Obeticholic Acid ................................................................24 
5.5. 
Rationale for Study Design and Dose for Investigational Product .............................25 
5.5.1. 
Rationale for Study Design .........................................................................................25 
5.5.2. 
Rationale for Dose ......................................................................................................26 
5.5.2.1. 
Rationale for OCA Dose .............................................................................................26 
5.5.2.2. 
Rationale for Modified OCA Doses in Patients Classified with Child-Pugh B 
or Child-Pugh C Hepatic Impairment .........................................................................26 
5.5.2.3. 
Rationale for Control Groups .....................................................................................27 
5.6. 
Importance of Monitoring of Disease Progression .....................................................27 
5.7. 
Summary of Known Potential Risks with OCA .........................................................28 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................29 
6.1. 
Primary Objective .......................................................................................................29 
6.2. 
Secondary Objectives .................................................................................................30 
7. 
INVESTIGATIONAL PLAN .....................................................................................30 
7.1. 
Overall Study Design ..................................................................................................30 
7.1.1. 
Schedule of Study Procedures ....................................................................................33 
7.1.2. 
Study Duration ............................................................................................................38 
7.2. 
Number of Subjects ....................................................................................................38 
7.3. 
Planned Dosing Regimen ...........................................................................................38 
7.4. 
Dose Titration Criteria ................................................................................................39 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements .................................................40 
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7.5. 
Monitoring and Management of Potential Hepatic Injury and/or Disease 
Progression .................................................................................................................41 
7.5.1. 
Signs and Symptoms of Hepatic Injury or Decompensation ......................................41 
7.5.2. 
Liver Biochemistry Assessments for Suspected Hepatic Injury or Potential 
Hepatic Decompensation ............................................................................................42 
7.5.3. 
Clinical Criteria for Monitoring for Potential Hepatic Decompensation 
Events .........................................................................................................................45 
7.5.4. 
Assessing Cirrhosis .....................................................................................................46 
7.5.4.1. 
Determination for Dosing Regimen ............................................................................46 
7.5.4.2. 
Progression to Cirrhosis ..............................................................................................47 
7.5.5. 
Child-Pugh Score ........................................................................................................48 
7.5.5.1. 
Mayo Risk Score .........................................................................................................48 
7.6. 
Dose Adjustment, Interruption, and Withdrawal from Investigational 
Product or Study .........................................................................................................49 
7.7. 
Close Observation .......................................................................................................51 
7.8. 
Criteria for Study Termination ...................................................................................52 
7.9. 
Subject Retention ........................................................................................................52 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................53 
8.1. 
Subject Population ......................................................................................................53 
8.2. 
Subject Inclusion Criteria ...........................................................................................53 
8.3. 
Subject Exclusion Criteria ..........................................................................................54 
8.4. 
Subject Withdrawal Criteria .......................................................................................56 
8.4.1. 
Other Reasons for Discontinuation of Study or Investigational Product ...................56 
8.4.2. 
Withdrawal of Consent ...............................................................................................57 
8.4.3. 
Requirements to Re-Initiate Investigational Product or Re-Enter the Study ..............57 
8.4.4. 
Lost to Follow-up .......................................................................................................57 
8.4.5. 
Subject Discontinuation Notification .........................................................................58 
9. 
TREATMENT OF SUBJECTS ..................................................................................58 
9.1. 
Investigational Product Treatment Regimen ..............................................................58 
9.2. 
Concomitant Medications ...........................................................................................58 
9.2.1. 
Prohibited Medications ...............................................................................................59 
9.3. 
Treatment Compliance ................................................................................................59 
9.4. 
Randomization and Blinding ......................................................................................60 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures ...................................60 
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9.5. 
Assignment of Site and Subject Numbers ..................................................................61 
9.5.1. 
Site Numbers ..............................................................................................................61 
9.5.2. 
Subject Numbers .........................................................................................................61 
9.6. 
Restrictions .................................................................................................................61 
9.7. 
Visit Procedures ..........................................................................................................61 
9.7.1. 
Visit Windows ............................................................................................................61 
9.7.2. 
Informed Consent Procedures.....................................................................................62 
9.7.3. 
Screening Procedures (1 to 8 Weeks prior to Day 0) .................................................62 
9.7.4. 
Day 0 Procedures (Randomization) ............................................................................64 
9.7.5. 
Months 1, 2 Procedures ..............................................................................................66 
9.7.6. 
Month 3 Procedures ....................................................................................................67 
9.7.7. 
Post-Titration Visit Procedures ...................................................................................68 
9.7.8. 
Month 6 Procedures ....................................................................................................69 
9.7.9. 
Month 9 Procedures ....................................................................................................70 
9.7.10. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment .................................................................................................................71 
9.7.11. 
Month 12 Procedures ..................................................................................................71 
9.7.12. 
Month 3 and Month 9 Continued Follow-Up Procedures (±2 weeks) .......................73 
9.7.13. 
Month 6 Continued Follow-Up Procedures (Semi-annually [±2 weeks]) ..................73 
9.7.14. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) .........................74 
9.7.15. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent ..................................76 
9.7.16. 
Unscheduled Safety Visit ...........................................................................................79 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............79 
10.1. 
Investigational Product ...............................................................................................79 
10.2. 
Investigational Product Packaging and Labeling .......................................................79 
10.3. 
Investigational Product Storage ..................................................................................80 
10.4. 
Investigational Product Preparation ............................................................................80 
10.5. 
Investigational Product Administration ......................................................................80 
10.6. 
Investigational Product Accountability and Disposal .................................................80 
11. 
ASSESSMENT OF EFFICACY ................................................................................81 
11.1. 
Assessment of Efficacy ...............................................................................................81 
11.1.1. 
Primary Assessments ..................................................................................................81 
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11.1.2. 
Secondary Assessments ..............................................................................................81 
11.1.2.1. 
Noninvasive Assessments of Liver Fibrosis ...............................................................82 
11.1.2.2. 
Other Secondary Assessments ....................................................................................82 
11.1.2.3. 
Other Exploratory Evaluations ...................................................................................83 
11.1.2.4. 
Potential Clinical Outcome Events .............................................................................83 
12. 
ASSESSMENT OF SAFETY .....................................................................................83 
12.1. 
Adverse Events and Serious Adverse Events .............................................................83 
12.1.1. 
Definitions of Adverse Events ....................................................................................83 
12.1.1.1. 
Adverse Event .............................................................................................................83 
12.1.1.2. 
Serious Adverse Event ................................................................................................84 
12.1.1.3. 
Treatment-Emergent Adverse Event ..........................................................................84 
12.1.1.4. 
Adverse Events of Special Interest .............................................................................84 
12.1.1.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................85 
12.1.2. 
Relationship to Investigational Product ......................................................................86 
12.1.3. 
Relationship of Adverse Events to Liver Biopsy .......................................................86 
12.1.4. 
Recording Adverse Event Severity .............................................................................87 
12.1.5. 
Reporting of Adverse Events and Serious Adverse Events ........................................87 
12.1.5.1. 
Reporting of Adverse Events ......................................................................................87 
12.1.5.2. 
Reporting of Serious Adverse Events .........................................................................87 
12.1.6. 
Suspected Liver-Related Clinical Outcome Events ....................................................88 
12.1.7. 
Additional Investigator Responsibilities for SAEs .....................................................89 
12.1.8. 
Notification of Post-Treatment SAEs for Subjects Who Continue in the 
Study ...........................................................................................................................89 
12.1.9. 
Notification of Poststudy SAEs ..................................................................................89 
12.1.10. 
Follow-Up of AEs and SAEs ......................................................................................90 
12.1.11. 
Pregnancy and Follow-Up ..........................................................................................91 
12.2. 
Other Safety Parameters .............................................................................................91 
12.2.1. 
Medical History/Demographics ..................................................................................91 
12.2.2. 
Physical Examination .................................................................................................91 
12.2.3. 
Vital Signs ..................................................................................................................91 
12.2.4. 
Electrocardiogram .......................................................................................................92 
12.2.5. 
Subject Questionnaires ...............................................................................................92 
12.2.6. 
Laboratory Assessments .............................................................................................92 
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13. 
STATISTICAL METHODS .......................................................................................94 
13.1. 
Efficacy Analysis ........................................................................................................94 
13.1.1. 
Analysis Populations ..................................................................................................94 
13.1.1.1. 
Comparability of Historical Controls .........................................................................95 
13.1.2. 
Determination of Sample Size ....................................................................................95 
13.1.2.1. 
Sample Size Monitoring .............................................................................................95 
13.1.3. 
Primary Efficacy Analysis ..........................................................................................96 
13.1.4. 
Key Secondary Efficacy Analyses ..............................................................................96 
13.1.5. 
Additional Secondary Efficacy Analyses ...................................................................97 
13.1.5.1. 
Association of Biochemistry with Clinical Outcomes and Clinical Benefit ..............98 
13.1.6. 
Exploratory Efficacy Analyses ...................................................................................98 
13.1.6.1. 
Responder Analyses ....................................................................................................98 
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints ................................................99 
13.1.8. 
Supportive Analysis ....................................................................................................99 
13.1.9. 
Handling of Dropouts or Missing Data ....................................................................101 
13.1.9.1. 
Time to Event Endpoints ..........................................................................................101 
13.1.9.2. 
Quantitative Endpoints .............................................................................................101 
13.1.9.3. 
Responder Endpoints ................................................................................................102 
13.1.10. 
Multiple Comparisons/Multiplicity ..........................................................................102 
13.1.11. 
Examination of Subgroups .......................................................................................103 
13.1.12. 
Continuous Monitoring and Interim Analyses .........................................................103 
13.2. 
Safety Analysis .........................................................................................................104 
13.2.1. 
Adverse Events .........................................................................................................104 
13.2.2. 
Clinical Laboratory Evaluations ...............................................................................104 
13.2.3. 
Additional Safety Analysis .......................................................................................104 
13.2.4. 
Cardiovascular Adjudication Committee .................................................................104 
13.3. 
Data Monitoring Committee .....................................................................................104 
13.4. 
Adjudication Committees .........................................................................................105 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................106 
14.1. 
Study Monitoring ......................................................................................................106 
14.2. 
Audits and Inspections ..............................................................................................107 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................107 
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16. 
ETHICS ....................................................................................................................107 
16.1. 
Ethics Review ...........................................................................................................107 
16.2. 
Ethical Conduct of the Study ....................................................................................108 
16.3. 
Written Informed Consent ........................................................................................108 
16.4. 
Subject Confidentiality and Data Protection ............................................................108 
17. 
INVESTIGATOR OBLIGATIONS .........................................................................109 
17.1. 
AE Reporting ............................................................................................................109 
17.2. 
Protocol Deviations ..................................................................................................109 
17.3. 
Regulatory Documentation .......................................................................................109 
17.4. 
Ethics Review ...........................................................................................................109 
17.5. 
Archiving and Record Retention ..............................................................................109 
18. 
PUBLICATION POLICY ........................................................................................110 
19. 
LIST OF REFERENCES ..........................................................................................112 
APPENDIX A. MODIFIED DOSING REGIMEN FOR SUBJECTS WITH CHILD-
PUGH B/C HEPATIC IMPAIRMENT ............................................................114 
APPENDIX B. ETHICAL CONDUCT ACCORDING TO THE DECLARATION OF 
HELSINKI FOR COUNTRIES PARTICIPATING OUTSIDE THE US 
(DECLARATION OF HELSINKI, FORTELEZA, BRAZIL, 2013) ...............116 
APPENDIX C. REFERENCE LABORATORY VALUES FROM CENTRAL 
LABORATORIES ............................................................................................121 
APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 
(DATED 29 APR 2015)....................................................................................123 
APPENDIX E. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 
(DATED 12 NOV 2015) ...................................................................................160 
APPENDIX F. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 TO 
VERSION 3 (DATED 07 SEP 2016) ...............................................................162 
APPENDIX G. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO 
PROTOCOL VERSION 3.1 (DATED 23 DEC 2016) .....................................192 
APPENDIX H. SUMMARY OF CHANGES:  PROTOCOL VERSION 3.1 TO 
PROTOCOL VERSION 4 (DATED 10 MAY 2017).......................................219 
APPENDIX I. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO 
PROTOCOL VERSION 4 (DATED 10 MAY 2017).......................................247 
APPENDIX J. SUMMARY OF CHANGES:  PROTOCOL VERSION 4 TO 
PROTOCOL VERSION 5 (DATED 04 JAN 2018).........................................290 
APPENDIX K. SUMMARY OF CHANGES:  PROTOCOL VERSION 5 TO 
PROTOCOL VERSION 6 (DATED 05 NOV 2019) .......................................334 
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List of Tables 
Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) .......................33 
Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) ............36 
Table 3: 
Planned Dosing Regimen by Cirrhosis and Child Pugh Score ...................................38 
Table 4: 
Liver Laboratory Criteria for Monitoring of Suspected Hepatic Injury or 
Potential Hepatic Decompensation and Criteria for Interruption or 
Discontinuation of Investigational Product ................................................................44 
Table 5: 
Clinical Criteria for Monitoring Potential Hepatic Decompensation Events 
and Interruption / Discontinuation of Investigational Product ...................................46 
Table 6: 
Child-Pugh Scoring System ........................................................................................48 
Table 7: 
Criteria for Dose Adjustment, Interruption, Discontinuation and Rechallenge .........49 
Table 8: 
Early Discontinuation Scenarios .................................................................................77 
Table 9: 
Relationship of Adverse Events to Investigational Product .......................................86 
Table 10: Relationship of Adverse Events to Liver Biopsy .......................................................87 
Table 11: Severity of Adverse Events ........................................................................................87 
Table 12: List of Laboratory Analytes to be Tested ...................................................................93 
Table 13: Planned Dosing Regimen by Cirrhosis and Child-Pugh Score ................................114 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram Study 747-302 ............................................................................31 
Figure 2: 
DILI Management Algorithm .....................................................................................43 
Figure 3: 
Dosing by Cirrhosis Status and Child-Pugh Score ...................................................114 
  
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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 
APRI 
aspartate aminotransferase to platelet ratio index 
AST 
aspartate aminotransferase 
β-hCG 
beta human chorionic gonadotropin 
BAS 
bile acid sequestrants 
CAC 
Cardiovascular Adjudication Committee 
CDCA 
chenodeoxycholic acid 
CI 
confidence interval 
CK-18 
cytokeratin-18 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
C-reactive protein 
DILI 
Drug-induced liver injury 
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 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
FIS 
Fatigue Impact Scale 
FXR 
farnesoid X receptor 
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Abbreviation or Specialist Term 
Explanation 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
glyco-OCA 
glycine 6α-ethyl chenodeoxycholic acid 
HCC 
hepatocellular carcinoma 
HCP 
health care professional 
HDL 
high-density lipoprotein 
IB 
Investigator’s 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 
LDL 
low-density lipoprotein 
LTSE 
long-term safety extension 
MACE 
major adverse cardiovascular events 
MELD 
model of end stage liver disease  
MRS 
Mayo Risk Score 
OCA 
obeticholic acid (also known as INT-747) 
PBC 
primary biliary cholangitis (also known as primary biliary 
cirrhosis) 
PIS 
patient information sheet 
PK 
pharmacokinetic 
PP 
per protocol 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
SUSAR 
suspected unexpected serious adverse reaction 
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Abbreviation or Specialist Term 
Explanation 
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 Primary Biliary Cholangitis and Obeticholic Acid 
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 United States (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.   
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), 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 (Pellicciari 2002).  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 
747-302 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. 
Mechanism of Action of Obeticholic Acid 
OCA is a 6α-ethyl derivative of the naturally occurring primary human bile acid CDCA, which is 
the endogenous ligand for FXR.  FXR is a ligand-dependent transcription factor that is part of 
the nuclear receptor superfamily.  FXR regulates a wide variety of target genes involved in the 
control of bile acid, lipid, and glucose homeostasis and in the regulation of immune responses. 
OCA’s potent FXR agonist effects are believed to account for the predominant efficacy of the 
investigational product.  Some of the pharmacological properties of OCA and other FXR 
agonists that have been elucidated in animal models of chronic liver disease relevant to the 
treatment of PBC include the following: 
• Improvement in hepatic choleresis with reduced inflammation and necrosis  
• Prevention and reversal of hepatic fibrosis 
The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and 
anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury 
and improved liver function in a cholestatic liver disease such as PBC. 
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5.3. 
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. 
5.4. 
Clinical Experience with Obeticholic Acid 
As of 26 May 2019, approximately 5386 subjects have been enrolled in the clinical development 
program for OCA.  Approximately 3926 subjects have received at least 1 dose of OCA in 
completed and ongoing clinical trials. 
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. 
To date, the efficacy and safety of OCA in PBC has been evaluated in 2 placebo-controlled, 
double-blind, Phase 2 studies (747-201 and 747-202), and 1 placebo-controlled, double-blind 
Phase 3 study (747-301).  Following the double-blind phase, subjects in all 3 studies were 
eligible to continue with treatment in a long-term safety extension (LTSE) phase for up to 
5 years in Study 747-201, up to 1 year in Study 747-202, and up to 5 years in Study 747-301. 
• Study 747-201 (59 subjects) 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 subjects) evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) 
versus placebo in subjects 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 subjects) was a Phase 3, double-blind, placebo-controlled, 
parallel group study followed by an LTSE using OCA in subjects with PBC.  The 
primary endpoint for Study 747-301 was a composite endpoint based on the 
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proportion of subjects reaching specific criteria for ALP and bilirubin (ALP <1.67× 
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 
<1.67× 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 10 mg OCA 
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.  The LTSE phase of Study 747-301 
is ongoing (a final CSR is pending); the LTSE phases of Study 747-201 and Study 747-202 
are complete. 
5.5. 
Rationale for Study Design and Dose for Investigational Product 
5.5.1. 
Rationale for Study Design 
OCA is a modified bile acid and FXR agonist that is derived from the primary human bile acid 
chenodeoxycholic acid.  The key mechanisms of action of OCA, including its choleretic, 
anti-inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in 
attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. 
PBC is characterized by biochemical increases in ALP and GGT enzymes with or without 
elevations of hepatocellular transaminases and bilirubin (Lindor 2009).  Both the American 
Association for the Study of Liver Diseases (AASLD) (Lindor 2009) and the European 
Association for the Study of the Liver (EASL) (EASL 2009) guidelines base the biochemical 
component of PBC diagnosis on elevations of ALP.  In addition, a growing literature supports 
the use of biochemical endpoints, specifically serum ALP alone or with other parameters such as 
bilirubin, to manage subjects, test the efficacy of novel therapies in clinical studies, and gauge 
the risk of long-term adverse clinical outcomes in subjects with PBC (Beuers 2011, 
Momah 2012).  Data from the Global PBC Study Group (Lammers 2013), which has built a 
database tracking biochemical status and clinical outcomes in several thousand PBC subjects, 
provides evidence for the use of the composite biochemical endpoint of ALP and bilirubin as an 
acceptable surrogate endpoint. 
Study 747-301, a Phase 3 double-blind study, evaluated the safety and efficacy of OCA at doses 
of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability) and 10 mg and used 
a composite biochemical endpoint of ALP and bilirubin as a surrogate endpoint.  In this study, 
both treatment groups exhibited clinically meaningful improvements in liver biochemistry and 
were safe and generally well-tolerated.  As a result, starting subjects on 5 mg OCA and titrating 
to 10 mg based on tolerability and clinical response appears to be an appropriate dosing strategy 
in subjects with PBC.  
Study 747-302 is a clinical outcomes study, supportive of Phase 3 Study 747-301 which was 
based on a surrogate biochemical endpoint, designed to confirm the clinical benefit of OCA 
treatment in patients with PBC.  A retrospective observational database (Global PBC Study 
Group [Lammers 2013]) of patients with PBC allowed for a rigorous patient-level meta-analysis 
and provided an opportunity for a robust assessment of ALP and bilirubin as viable surrogate 
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biochemical parameters and a comprehensive understanding of the natural history of the PBC 
disease process.  Data from the Global PBC Study Group was also utilized to inform the design 
of the confirmatory outcomes study.  Despite the observational evidence that links ALP and 
bilirubin to clinical outcomes in PBC, it is necessary to prospectively validate these surrogate 
endpoints.  As such collecting outcome information in Study 747-302 is of the utmost 
importance.  
5.5.2. 
Rationale for Dose 
5.5.2.1. 
Rationale for OCA Dose 
The safety and tolerability of multiple doses of OCA have been established in subjects with PBC 
at doses up to 50 mg.  As demonstrated in the Phase 2 PBC studies (Studies 747-201 and 
747-202), OCA significantly reduced serum ALP levels at doses of 10 mg, 25 mg, and 50 mg, 
but with an increase in the incidence and severity of pruritus at higher dose levels.  The Phase 3 
PBC study (Study 747-301) subsequently evaluated the safety and efficacy of OCA at lower 
doses of 5 mg (titrated to 10 mg after 6 months based on efficacy and tolerability in the 
double-blind phase and after 3 months in the open-label phase) and 10 mg; both treatment groups 
exhibited clinically meaningful improvements in liver biochemistry and were safe and generally 
well tolerated.  Study 747-301 demonstrated that titration of OCA from a starting dose of 5 mg to 
10 mg improved tolerance to pruritus relative to 10 mg (56% versus 69% of subjects who 
experienced pruritus) and minimized dropouts due to pruritus.  Based on these data, the approved 
dosing regimens for OCA for the treatment of patients with PBC are 5 mg and 10 mg. 
The majority of efficacy results with OCA, in terms of change in alkaline phosphatase, was 
observed by 3 months and the time to treatment-emergent pruritus was typically 1 month or less 
in Study 747-301.  Study 747-302 will evaluate the effect of OCA on clinical outcomes using the 
5 mg OCA dose for at least 3 months, increasing to 10 mg OCA, if tolerated. 
5.5.2.2. 
Rationale for Modified OCA Doses in Patients Classified with Child-Pugh B or 
Child-Pugh C Hepatic Impairment 
Simulations using a physiologic PK model predicted changes in systemic and liver OCA 
concentrations associated with changes in the severity of hepatic impairment (Child-Pugh Score).  
Model simulations predicted that for mild (Child-Pugh A), moderate (Child-Pugh B), and severe 
(Child-Pugh C) hepatic impairment, total OCA plasma concentrations increase 1.4-, 8.0-, and 
13-fold relative to subjects 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 (Child-Pugh B and C) subjects treated 
with OCA in Phase 1 and 2 studies experienced plasma OCA exposures >10-fold higher than 
those in healthy subjects, 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.  Collectively, the results from these analyses suggest that the doses of OCA 
administered to hepatically-impaired patients should be modestly lower than those for patients 
with normal hepatic function to achieve similar hepatic exposure.   
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Per the approved FDA prescribing label, the recommended dosing regimen for OCA in subjects 
with moderate and severe hepatic impairment is a starting dose of 5-mg OCA once weekly.  
Dosage adjustments in subjects with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic 
impairment may be made after establishing tolerability at the lower dose (full modified dosing 
regimen is described in Appendix A).   
5.5.2.3. 
Rationale for Control Groups  
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 a standard of care 
effect.  Notably, accounting for the standard of care effect is critical when designing an 
outcome-based study conducted globally when there are regional differences in the treatment of 
subjects with PBC. 
Historical Control Group 
The available robust historical PBC observational datasets (UK-PBC and Global PBC Study 
Group) will also be leveraged to provide further comparative evaluation of the clinical benefit of 
OCA.  Each database includes >6000 patients with long-term follow-up. 
Comparison of OCA treatment to the historical controls may provide utility in addressing 
potential bias or confounds associated with the placebo arm.  For example, bias associated with 
the potential addition of commercial OCA and/or differences in long-term standard of care 
between the treatment arms including ancillary treatments and diagnostics. 
Therefore, further evaluation of the effect of OCA will compare OCA treatment versus historical 
controls, and will be supportive to placebo comparisons (ie, comparisons to historical and 
placebo controls will be evaluated separately). 
5.6. 
Importance of Monitoring of Disease Progression 
Given PBC is a chronic, progressive liver disease, it is important that subjects with PBC are 
closely monitored to ensure early identification of potential disease progression to cirrhosis, 
decompensation and/or liver injury.  More extensive safety monitoring and appropriate dosing 
adjustments, interruptions, and discontinuations will be implemented to improve subject 
oversight and safety.  Investigators, together with the Sponsor’s Medical Monitor, will 
consistently and frequently assess individual subjects to determine on an ongoing basis the 
totality of a subject’s clinical profile, which includes careful evaluation of signs and symptoms 
of potential hepatic injury and/or decompensation coupled with rules-based laboratory 
monitoring. 
Subjects will be monitored for potential hepatic injury and/or decompensation and progression to 
cirrhosis (Section 7.5).  Criteria for implementing dosing adjustments, interruptions, or 
discontinuations, and close monitoring procedures post dose-adjustment are described in 
Section 7.6 and Section 7.7.  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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5.7. 
Summary of Known Potential Risks with OCA 
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, including jaundice, worsening ascites and primary biliary cholangitis 
flare, 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), as early as one 
month after starting treatment with OCA. 
In addition, 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 current version of the OCA Investigator’s Brochure. 
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 individual 
subject and aggregate data from both the Phase 3 clinical outcomes study in subjects with PBC 
(Study 747-302) and the Phase 3 pivotal studies in subjects with NASH fibrosis (Study 747-303) 
and NASH cirrhosis (Study 747-304) on a quarterly basis, in an unblinded fashion, and in closed 
sessions (without the Sponsor’s participation).  In the quarterly DMC meetings to date, the DMC 
has recommended the studies continue without modification. 
Following a request from the FDA to provide an up-to-date DMC report analyzing unblinded 
data on respective incidence of cholecystitis, cholelithiasis, and pancreatitis by treatment group 
across all ongoing clinical studies, an ad hoc DMC review was held and the DMC recommended 
that: 
• As it concerned pancreatitis, all studies continue without changes. 
• For subjects in Study 747-303, investigational product should be uninterrupted in 
subjects who experience symptomatic cholelithiasis and/or cholecystitis. 
The Sponsor implemented the DMC recommendations across the NASH program but not the 
PBC program. 
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Post-Marketing Cases in PBC 
As of 26 May 2019, the estimated cumulative patient exposure from marketing experience is 
7694 patient-years.  
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 current version of the OCA Investigator’s Brochure for additional information 
regarding the known potential risks with the investigational product. 
6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care on clinical outcomes in subjects with PBC as measured by time to first occurrence of any 
of the following adjudicated events, derived as a composite event endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
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6.2. 
Secondary Objectives 
• To assess the effect of OCA compared to placebo on time to first occurrence of each 
individual component of the primary endpoint as listed above. 
• To assess the effect of OCA compared to placebo on time to occurrence of liver-
related death.  
• To assess the effect of OCA compared to placebo on progression to cirrhosis.  
• To assess the effect of OCA compared to placebo on time to occurrence of HCC. 
• To assess the effect of OCA compared to placebo on disease progression via the 
following: 
− Liver biochemistry 
− Markers of inflammation and fibrosis 
• To assess the effect of OCA compared to historical controls on liver-related clinical 
outcomes. 
• To characterize the PK of OCA and its conjugates in a subset of subjects. 
• To assess health outcomes and pharmacoeconomics including cost-effectiveness, 
resource utilization, and quality of life measures in subjects treated with OCA 
compared to placebo. 
• To assess the safety and tolerability in subjects treated with OCA compared to 
placebo. 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This Phase 3b/4, double-blind, randomized, placebo-controlled, multicenter study will evaluate 
the effect of OCA on clinical outcomes in subjects with PBC.  Subjects will be screened twice 
during a 1- to 8-week Screening period prior to entering the study to allow for the collection of 
repeat serum chemistry samples (at least 2 weeks apart) to confirm pretreatment ALP and total 
bilirubin values (refer to Section 9.7.3). 
Investigational product will be taken orally, once daily for the majority of subjects; dose and 
frequency will be modified for subjects with cirrhosis (including subjects progressing to cirrhosis 
during the study) and classified as Child-Pugh B or C.  The randomization will be stratified by 
UDCA treatment (yes/no) and baseline bilirubin categories (>ULN/ ≤ULN).  A minimum of 
30% of subjects will have elevated bilirubin (>ULN) at Screening.  
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Figure 1: 
Schematic Diagram Study 747-302 
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for 
subjects on all dosing regimens, based on tolerability and biochemical response (Up-titration should be considered 
when ALP and/or total bilirubin are >ULN).  Subsequent dose titration(s) for subjects classified as Child Pugh B 
or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous 
dose titration. 
Dosing frequency will be determined by the presence or absence of cirrhosis and, if cirrhosis is 
present, by Child-Pugh Score as described below: 
• Noncirrhotic subjects or subjects classified as Child-Pugh A at screening will receive 
5-mg OCA or matching placebo once daily for 3 months.  Subjects should titrate to a 
maximum dose of 10-mg OCA once daily (or matching placebo) at the Month 3 visit 
or at any study visit following the Month 3 visit based on tolerability and biochemical 
response of the product. 
• For those subjects that up-titrate to 10 mg, dosing may be decreased to 5 mg at any 
time during the study as considered clinically appropriate (eg, based on tolerability). 
Subjects may be titrated back to a maximum dose of 10 mg once daily based on 
tolerability and clinical judgment of the Investigator.  
• Subjects who are cirrhotic and classified as Child-Pugh Class B or Child-Pugh Class 
C will initiate a modified treatment regimen with 5-mg OCA or matching placebo 
once weekly for at least 3 months.  Subjects classified as Child-Pugh Class B or 
Child-Pugh Class C should titrate to a maximum dose and frequency of 10-mg OCA 
or matching placebo twice weekly (at least 3 days apart), based on tolerability and 
biochemical response. 
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Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Planned Dosing Regimen 
Standard 
Modified 
Noncirrhotic/ 
Child-Pugh A 
Child-Pugh B or  
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weekly 
 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weekly 
 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject 
tolerability, biochemical response, and/or changes in cirrhosis status or Child-Pugh Score at any time during the 
study 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
With the exception of liver transplant, if a subject experiences a suspected or confirmed clinical 
outcomes event, the subject should continue the regular visit schedule and continue taking 
investigational product as long as the subject has not met any of the criteria for discontinuation 
outlined in the protocol.  Subjects who discontinue investigational product are expected to be 
followed through to study closure (or at the discretion of the Sponsor).  Additional information 
regarding subject follow-up and different options available to subjects is provided in Section 7.9 
and Section 8.4. 
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7.1.1. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) 
 
Screening Visits 
Day 0 
M 1 
M2 
M 3 
Post-Titration 
Visitsb 
M 6 
M 9 
M 12 
1 
2a 
Visit Windows (+/-)c 
3 to 8 wk 
prior to 
Day 0 
1 to 6 wk 
prior to 
Day 0 
 
+1 
wk 
+1 
wk 
±2 
wk 
±1 wk 
±2 wk 
±2 
wk 
±2 wk 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical/PBC Historyd  
X 
 
 
 
 
 
 
 
 
 
Cirrhosis Status Assessmente 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
Physical Exam  
X 
 
 
X 
X 
 
X 
X 
 
Xd 
Assessments for Child-Pugh Scoref 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (including weight) 
Xg 
 
X 
 
 
X 
 
X 
X 
Xg 
12-Lead Electrocardiogram 
X 
 
 
 
 
 
 
 
 
X 
Subject Questionnaires (5-D Pruritus Scale and 
Pruritus VAS) 
 
 
X 
 
 
 
 
X 
 
X 
Quality of Life Questionnaires (PBC-40, 
EQ-5D-5L, and FIS)h 
 
 
X 
 
 
 
 
 
 
X 
Fibroscan® TEi 
 
 
X 
 
 
 
 
X 
 
X 
Endoscopyj 
 
 
X 
 
 
 
 
 
 
X 
Hepatic Ultrasoundk 
 
X 
 
 
 
 
 
X 
 
X 
Gallbladder Assessment (Ultrasound) 
 
Xk 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health Outcome Assessmentsl 
 
 
X 
 
 
X 
 
X 
X 
X 
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Table 1: 
Schedule of Study Procedures-Screening to Month 12 (Table 1 of 2) (Continued) 
 
Screening Visits 
Day 0 
M 1 
M2 
M 3 
Post-Titration 
Visitsb 
M 6 
M 9 
M 12 
1 
2a 
Visit Windows (+/-)c 
3 to 8 wk 
prior to 
Day 0 
1 to 6 wk 
prior to 
Day 0 
 
±1 
wk 
±1 
wk 
±2 
wk 
±1 wk 
±2 wk 
±2 
wk 
±2 wk 
Randomization/Treatment Assigned 
 
 
X 
 
 
 
 
 
 
 
Dose Titration: Standard Dosingm,n 
 
 
 
 
 
X 
 
X (if applicable) 
Dose Titration: Modified Dosing (if 
applicable)n,o 
 
 
 
 
 
X 
 
X 
X 
X  
Dispense Investigational Producto 
 
 
X 
 
 
X 
 
X 
X 
X 
IP Accountability/Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Dosing Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSp 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
X 
Urine-based β-hCG Pregnancy Testq 
X 
 
X 
 
 
 
 
 
 
 
Chemistry/Hematology/Coagulationp 
X 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase and Lipase 
 
 
Sample to be collected if the subject experiences acute pancreatitis or cholecystitis 
Review Progression to Cirrhosis Algorithm   
 
 
 
X 
X 
X 
X 
X 
X 
X 
OCA, C4, and FGF-19 (plasma)  
 
 
X 
 
 
X 
 
X 
Xr 
X 
Markers of Hepatic Fibrosis and/or 
Inflammations 
 
 
X 
 
 
 
 
X 
 
X 
Geneticst 
 
 
X 
 
 
 
 
 
 
X 
AE = adverse event; ALP = alkaline phosphatase; β-hCG = beta human chorionic gonadotropin; eCRF = electronic case report form; EOS= End of Study; EOT = End of 
Treatment; FGF-19 = fibroblast growth factor-19; FIS = Fatigue Impact Scale; HCC = hepatocellular carcinoma;  
IP = Investigational Product; M = month, MRS = Mayo Risk Score; TE = transient elastography; VAS = Visual Analogue Scale; wk = week 
a All subjects will have the chemistry panel retested to ensure subjects have at least two ALP and bilirubin assessments at least 2 weeks apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and bilirubin assessments will be used to determine eligibility. Refer to Section 9.7.3 for guidance on when an additional ALP or 
bilirubin sample may be needed to confirm eligibility. Samples for hematology and coagulation will not be collected at Screening Visit 2. 
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b Post-Titration visits must be performed 1 month (± 1 week) and 2 months (±1 week) after any up-titration in dose and/or frequency in subjects following modified dosing due to 
Child-Pugh B and Child-Pugh C hepatic impairment.  See Appendix A  for additional guidance.  In subjects following the standard dosing regimen, the Post-Titration Visit must 
be performed 1 month (±1 week) and 2 months (±1 week) after the first up-titration to 10 mg OCA or matching placebo.  
c Visits should be based on Day 0 (not on the prior visit) with the exception of the Post-Titration Visit, which is based on the date of titration. 
d Medical history at Screening and the yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both. 
e Presence or absence of cirrhosis should be assessed per Section 7.5.4.  Cirrhosis status should be repeated as clinically indicated. 
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 Height will be collected at this visit. 
h The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2 and Section 12.2.5). 
i Transient elastography (TE) will be conducted at 6-month intervals at all study sites where the Fibroscan® TE device is available.  Please refer to Section 9.7.4 for additional 
information related to the allowed windows at Day 0 for this procedure. 
j Endoscopy will be conducted at all study sites where the device is available to assess for the presence of oesophageal varix/varices.  Please refer to Section 9.7.4 for additional 
information related to the allowed window at Day 0 for this specific procedure.  
k Ultrasound will be conducted to enhance HCC surveillance and for gallbladder assessment at Screening.  If ultrasound was not performed at Screening and the historic 
ultrasound is >3 months from Day 0, perform a hepatobiliary ultrasound at the Day 0 visit.  
l Health Outcome Assessments: Data related to nonstudy related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
m Pre-titration tolerability assessment, which include a review of AEs and a review of safety laboratory results (eg, chemistry, hematology, and coagulation), must be completed 
by the Investigator before any up-titration can occur as defined in Section 7.4.1.  Lab results obtained within 2 months prior to any up-titration may be used for assessment.  
n Dose Titration is based on cirrhosis status (Section 7.5.4) and Child-Pugh Score (Section 7.5.5).  The initial dose titration of investigational product may occur at the Month 3 
visit, or any study visit thereafter for subjects on all dosing regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for subjects who are classified 
as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.  For complete modified dose 
titration criteria, refer to Appendix A. 
o Subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1) and to take investigational product at approximately the same time of day.  Subjects 
must be instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
p The subject 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.  MELD and MRS values will be calculated based on serum chemistry and coagulation values at each visit. 
q Urine β-hCG pregnancy tests must be performed in females of childbearing potential prior to entry.  If positive, a confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not be enrolled in the study.  (Additional testing may be conducted where required, regionally). 
r Only OCA PK samples will be collected at Month 9 at select study sites in a subset of subjects.  Please refer to Section 9.7.10 for the PK sampling schedule. 
s Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
t A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12.  If a Baseline (eg, Day 0) genetic sample is not obtained, subsequent genetic samples are not required to be collected during the course of the study. 
 
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Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) 
 
Year 2 Through End of Study 
 
M 3 
continued follow-
up 
Post-Titration 
Visitsa 
(if applicable) 
M 6 
continued follow-up 
M 9 
continued follow-up 
M 12 
continued follow-up 
EOT/ 
EOSb 
Visit Windows (+/-)c 
±2 wk 
±1 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
Physical Examd 
 
X 
 
 
X 
X 
Assessments for Child-Pugh Scorese 
X 
X 
X 
X 
X 
X 
Vital Signs (including weight) 
 
 
X 
 
Xf 
Xf 
12-Lead Electrocardiogram 
 
 
 
 
X 
X 
Subject Questionnaires (5-D Pruritus 
Scale and Pruritus VAS) 
 
 
X 
 
X 
X 
Quality of Life Questionnaires (PBC-40, 
EQ-5D-5L, and FIS)g 
 
 
 
 
X 
X 
Fibroscan®TEh 
 
 
X 
 
X 
X 
Endoscopyi 
 
 
 
 
X 
 
Hepatic Ultrasoundj 
 
 
X 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
Health Outcome Assessmentsk 
X 
 
X 
X 
X 
X 
Dose Titration (if applicable)l 
X 
 
X 
X 
X 
 
Dispense Investigational Product 
X 
 
X 
X 
X 
 
IP Accountability/Compliance 
X 
X 
X 
X 
X 
X 
Dosing Diary 
X 
X 
X 
X 
X 
X 
LABORATORY EVALUATIONSm 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
X 
X 
Chemistry/Hematology/Coagulationm 
X 
X 
X 
X 
X 
X 
Amylase and Lipase 
Sample to be collected if the subject experiences acute pancreatitis or cholecystitis 
Review Progression to Cirrhosis 
Algorithm   
X 
X 
X 
X 
X 
X 
OCA, C4, and FGF-19 (plasma)m 
 
 
 
 
X 
X 
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Table 2: 
Schedule of Study Procedures-Year 2 Through End of Study (Table 2 of 2) (Continued) 
 
Year 2 Through End of Study 
 
M 3 
continued follow-
up 
Post-Titration 
Visitsa 
(if applicable) 
M 6 
continued follow-up 
M 9 
continued follow-up 
M 12 
continued follow-up 
EOT/ 
EOSb 
Visit Windows (+/-)c 
±2 wk 
±1 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
Markers of Hepatic Fibrosis and/or 
Inflammationn 
 
 
X 
 
X 
X 
Geneticso 
 
 
 
 
X 
 
AE = adverse event; β-hCG = beta human chorionic gonadotropin; EOS= End of Study; EOT = End of Treatment; FGF-19 = fibroblast growth factor-19; FIS = Fatigue Impact 
Scale; IP = Investigational Product; M = month, MRS = Mayo Risk Score; TE = transient elastography; VAS = Visual Analogue Scale; wk = week 
a  Post-Titration Visits must be performed 1 month (±1 week) and 2 months (±1 week) after any up-titration in dose and/or frequency in subjects following modified dosing due to 
Child-Pugh B and Child-Pugh C hepatic impairment.  See Appendix A for additional guidance.  In subjects following the standard dosing regimen, the Post-Titration visit must 
only be performed 1 month (±1 week) and 2 months (±1 week) after the first up-titration to 10 mg OCA or matching placebo.  
b As soon as possible upon study discontinuation and as near as possible to last dose taken. 
c Visits should be based on Day 0 (not on the prior visit) with the exception of the Post-Titration Visit, which is based on the date of titration. 
d The yearly physical exam will include an assessment of smoking and alcohol consumption history and current habits for both. 
e  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 case report form.  
f  The EQ-5D-5L and FIS Quality of Life questionnaires are validated for use in multiple languages. If a validated translation is not available in the local language required for a 
specific study subject, the data from that questionnaire will not be collected (See Section 11.1.2.2 and Section 12.2.5). 
g Transient elastography (TE) will be conducted at 6-month intervals at all study sites where the Fibroscan® TE device is available. 
h  Endoscopy will be conducted at all study sites where the device is available to assess for the presence of oesophageal varix/varices. 
i Ultrasound will be conducted to enhance HCC surveillance.  For all on study (eg, postday 0) ultrasounds: unless HCC has already been confirmed by biopsy, a second 
confirmatory image (eg, MRI) should be obtained to confirm suspected HCC. 
j  
Health Outcome Assessments: Data related to nonstudy related medical or surgical treatment procedures that the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the subject attended should be collected throughout the study. 
k   
Pre-titration tolerability assessment, which include a review of AEs and a review of safety laboratory results (eg, chemistry, hematology, and coagulation), must be completed 
by the Investigator before any up-titration can occur as defined in Section 7.4.1.  Lab results obtained within 2 months prior to any up-titration may be used for assessment.   
l  Dose Titration is based on cirrhosis status (see Section 7.5.4) and Child-Pugh Score (Section 7.5.5).  The initial dose titration of investigational products may occur at the Month 
3 visit, or any study visit thereafter for subjects on all dosing regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for subjects who are 
classified as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.  For complete modified 
dose titration criteria, refer to Appendix A. 
m  The subject should be instructed to fast overnight (at least 8 hours) prior to each visit.  Fasting is required prior to all study visits, but water is permitted.  MELD and MRS values 
will be calculated based on serum chemistry values at each visit. 
n  Markers of hepatic fibrosis and/or inflammation are defined in Section 11.1.2. 
o  A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples.  Genetics samples will be collected at Day 0 and every other year 
beginning at Month 12. 
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7.1.2. 
Study Duration 
The study is event driven and total duration will be determined by the time required to accrue 
approximately 127 primary endpoint events, estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time of approximately 6 years. 
7.2. 
Number of Subjects 
It is expected that approximately 428 subjects will be randomized in the study to achieve 
127 adjudicated primary endpoint events.  In the event additional subjects are needed to 
complete enrollment in the biopsy substudy (N = 45 subjects, as defined in Addendum 2), 
subjects who agree to participate in the substudy may be added to the target subject enrollment 
number currently planned.  
7.3. 
Planned Dosing Regimen 
Subjects will be randomized to treatment with either OCA or matching placebo in a 1:1 ratio.  
Subjects will be dosed according to their cirrhosis status (as defined Section 7.5.4 ) and 
applicable Child-Pugh Score (see Section 7.5.5) as outlined in Section 7.4.  
Table 3: 
Planned Dosing Regimen by Cirrhosis and Child Pugh Score 
 
Scheduled Dosing Regimen 
Standard 
Modified 
Noncirrhotic/ 
Child-Pugh A 
Child-Pugh B or 
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weeklyc 
 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weeklyc 
 
a Starting dose based on subject’s cirrhosis status and Child-Pugh score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject tolerability, 
biochemical response, and/or changes in cirrhosis status or Child-Pugh score at any time during the study (see Section 7.4). 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
Non-Cirrhotic or Child-Pugh A 
Subjects who are noncirrhotic or classified as Child-Pugh A at screening will receive 5 mg OCA 
or matching placebo once daily for 3 months.  Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the product and assessment of biochemical response.  
Up-titration should be considered when ALP and/or total bilirubin are >ULN.  A review of safety 
laboratory results (eg, chemistry, hematology, and coagulation) obtained no more than 2 months 
prior to the planned up-titration visit must be completed as part of the investigational product 
tolerability assessment before up-titration can occur (see Section 7.4.1).   
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For those subjects that up-titrate to 10 mg, dose may be decreased to 5 mg at any time during the 
study as considered clinically appropriate (eg, tolerability). Subjects may be titrated back up to a 
maximum dose of 10 mg once daily based on tolerability and clinical judgment of the 
Investigator.  A review of safety laboratory results obtained within 2 months of the planned 
up-titration visit date is not required prior to re-challenging a subject up to 10 mg once daily 
dosing, as long as the decrease in dose/dosing frequency was less than 3 months in duration.  
Cirrhotic and Child-Pugh B or C 
Subjects with cirrhosis (see Section 7.5.4 ) and classified as Child-Pugh Class B or Child-Pugh 
Class C will follow a modified dosing regimen, initiating 5 mg OCA or matching placebo once 
weekly.  After a minimum of 3 months dosing once weekly with 5 mg OCA or matching 
placebo, and following review of the pre-titration laboratory results to assess safety and 
tolerability, the dosing frequency of 5 mg OCA or matching placebo should be increased to twice 
weekly (at least 3 days apart).  Subjects who have maintained the twice weekly dosing frequency 
for a minimum of at least 6 weeks and meet the dose titration criteria should up-titrate to the 
maximum allowed dose of 10 mg OCA or matching placebo twice weekly. 
Investigators may decrease the dosing frequency (back to once weekly) or dose for any subject at 
any time during the study, as considered clinically appropriate (eg, tolerability). 
The dosing regimen should be determined as described shown in Table 13.  Investigators should 
follow the dosing/titration schedule as shown described in Section 7.4 and Appendix A. 
7.4. 
Dose Titration 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 subject’s cirrhosis status (using histology or 
non-histological methods as defined in Section 7.5.4 and Section 7.5.5) or Child-Pugh 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) as well 
as biochemical response (as assessed by reductions in ALP and/or total bilirubin).  In general, 
down-titration will be done in response to tolerability concerns and can occur at any time while 
on-study.  Up-titration will be done per protocol when subjects have no tolerability concerns and 
have not achieved an adequate reduction in ALP and/or total bilirubin to within normal limits, or 
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 for each 
dosing regimen as defined in Section 7.3.  A 1-Month and 2 Month Post-Titration Assessment 
must be performed any time a subject’s dose or frequency is up-titrated (see Section 7.1.1 and 
Section 9.7.7). 
Scheduled Dose Titration - The first dose titration for any subject may occur no earlier than 
3 months following initiation of OCA or matching placebo.  Subsequent titrations in dose or 
dosing frequency for subjects following the Modified Dosing Regimens may occur no earlier 
than 6 weeks (via an unscheduled visit or regular visit- see Appendix A) following an 
up-titration. 
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Tolerability Dose Titration - Investigators may decrease the dosing frequency or dose for any 
subject at any time during the study, as considered clinically appropriate (eg, tolerability; see 
Section 7.4.1).   
Dose Titration due to Change in Cirrhosis or Child-Pugh Score - When subjects demonstrate 
a change in cirrhosis status (as assessed per Section 7.5.4) or Child-Pugh Score (Section 7.5.5) 
dosing should be reassessed and the dosing regimen modified appropriately. Changes in 
Child-Pugh Score that result from a transient, explainable change in laboratory parameters 
should be documented appropriately, and should not necessarily result in a change to the dosing 
regimen. 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, 
biochemical response, and clinical judgment.  
Subjects who exhibit development of cirrhosis at any point in the study should be assessed per 
Section 7.5.4.  If the presence of cirrhosis is confirmed and the subject’s Child-Pugh score is 
either B or C, the appropriate modified dosing regimen should be followed.  The dose or 
frequency of investigational product should be down-titrated to the next lowest dosing frequency 
in the appropriate modified dosing regimen unless the subject is currently taking a dose and 
frequency also specified in the modified dosing regimen and the Investigator determines that it is 
clinically appropriate for the subject to continue at that dose (Appendix A). 
Subjects with pre-existing cirrhosis who demonstrate a change in the Child-Pugh Score from A 
to B or C at any point in the study should also have their dosing modified per the appropriate 
dosing regimen.  Changes in Child-Pugh Score that result from a transient, explainable change in 
laboratory parameters (eg, increase in vitamin K resulting in change in INR) should be 
documented appropriately and discussed with the Medical Monitor before any continuation or 
change to the dosing regimen (Appendix A).  
Child-Pugh Scores will be calculated during screening, at each scheduled study visits, and at 
unscheduled visits in the event of signs or symptoms of suspected hepatic injury or 
decompensation are present. All associated visit data (including central laboratory results) should 
be entered into the eCRF in a timely fashion to confirm that the subject’s Child Pugh Score has 
not changed.  If a change in cirrhosis status (as defined in Section 7.5.4) and/or Child-Pugh 
Score is observed independent of a study visit, the subject 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. 
Subjects’ dose and dosing frequency may be titrated up or down within the appropriate dosing 
regimen based on the calculated Child-Pugh Scores.  Up-titration should be done per Investigator 
discretion and be guided by the pre-titration tolerability assessments. 
7.4.1. 
Pre-Titration Tolerability Assessment Requirements 
Tolerability of investigational product must be assessed prior to titrating a subject to a higher 
dose.  A review of adverse events and safety laboratory results (eg, chemistry, hematology, and 
coagulation) obtained within 2 months of the up-titration visit must be performed as part of the 
investigational product tolerability assessment, prior to any planned up-titration in investigative 
product (eg, Month 3, Month 6).  Safety laboratory results obtained at the Month 1 visit (for 
titration at Month 3) or at the Post-Titration Assessment visits (for titration prior to or at the 
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subsequent quarterly visit) are acceptable for review purposes; however, 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 subject to a higher 
dose.  
To be eligible for a dose up-titration: 
• Subjects 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.  
• There must be no clinically significant increase (as determined by the Investigator) in 
the subject’s liver function tests.  
7.5. 
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).  Child Pugh Scores should only be applied in patients 
who have evidence of cirrhosis at screening or demonstrate evidence of cirrhosis at screening or 
progression to cirrhosis during the study based on criteria presented in Section 7.5.4.  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 7.1.1.  Based 
on the assessments of signs and symptoms of hepatic injury and liver biochemistry, the 
investigational product may be interrupted or discontinued per criteria discussed in Section 7.5.2 
and Section 7.5.3, and close monitoring procedures will be implemented (Section 7.7). 
7.5.1. 
Signs and Symptoms of Hepatic Injury or Decompensation 
Subjects 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:  eg, 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:  eg, confusion, 
swelling of the legs or abdomen 
• Non-specific signs and symptoms of impaired health:  eg, 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 subject evaluation 
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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 7.5.2), (2) assessment of clinical events for potential hepatic 
decompensation (Section 7.5 (3) triggering of investigational product interruption or 
discontinuation per criteria (Section 8.4 ), (4) documentation in the AE eCRF or the SAE eCRFs 
(Section 12.1.5.1 and Section 12.1.5.2), and (5) contact with the Medical Monitor. 
7.5.2. 
Liver Biochemistry Assessments for Suspected Hepatic Injury or Potential 
Hepatic Decompensation 
Liver biochemistry will be assessed to evaluate biochemical triggers that will prompt an 
immediate reevaluation of subjects 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 
laboratory be used for assessments whenever possible.  In the event that a subject 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 subject 
evaluation (depending on the repeat result) are summarized in Table 4. 
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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 4: 
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 subject 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 
threshold 
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 subject 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 
 
 
>0.3unit increase from baseline 
Closely monitor until 
normalization or stabilization. 
 
If values continue to increase 
relative to the baseline value, 
interrupt IP. 
The subject 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 subjects 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 subjects’ 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 
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considered appropriate based on their medical judgement but only after documented agreement 
with the Sponsor’s Medical Monitor. 
7.5.3. 
Clinical Criteria for Monitoring for Potential Hepatic Decompensation Events 
Subjects will be monitored for potential hepatic decompensation events throughout the study.  
Clinical criteria for the monitoring these events and the interruption/discontinuation of 
investigational product is summarized in Table 5. 
Investigational product should be discontinued permanently if the subject received a liver 
transplant or experiences multi-organ failure as defined in Table 5, Part A).  Subjects should 
continue to return for scheduled study visits for safety follow up.  
Subjects who experience other potential hepatic decompensation events defined in Table 5, 
Part B should be closely monitored until normalization or stabilization.  Subjects 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 5: 
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 4, 
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. 
7.5.4. 
Assessing Cirrhosis 
7.5.4.1. 
Determination for Dosing Regimen 
To determine which dosing regimen subjects should follow, the presence or absence of cirrhosis 
should be assessed by the Investigator at Screening Visit 1.  Acceptable methods of confirming 
(via medical history) or assessing cirrhosis for purposes of determining dosing is defined as a 
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subject who has documented evidence or presence of one or more of the following cirrhosis 
indicators: 
Biopsy results consistent with PBC Stage 4 (Ludwig 1978)   
• TE 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  
− elevation in prothrombin time /INR (not due to antithrombotic agent use), or 
− elevated bilirubin (2× ULN) 
Subjects who exhibit no evidence of cirrhosis by the above methods of assessment will be dosed 
using the Standard Dosing Regimen, while those who do exhibit evidence of cirrhosis by one or 
more of the above methods will be dosed using the Modified Dosing Regimen according to their 
Child-Pugh Score calculated in the electronic case report form (eCRF) (see Appendix A and 
Section 7.3). 
Cirrhosis status should be reassessed as clinically indicated throughout the study.  Any change in 
cirrhosis status will necessitate re-evaluation of the dosing regimen. 
7.5.4.2. 
Progression to Cirrhosis 
When a subject identified as noncirrhotic at Baseline per the criteria listed in Section 7.5.4 
exhibits any signs or symptoms associated with progression to cirrhosis, as defined by the same 
criteria, the subject should also be assessed by Fibroscan® TE where available and progression 
to cirrhosis confirmed by biopsy (centrally read) unless not medically indicated.  Laboratory 
samples needed to obtain noninvasive scores of liver fibrosis (ELF, and aspartate 
aminotransferase to platelet ratio index [APRI]) will also be collected when a subject develops 
evidence of progression to cirrhosis. 
Full instructions concerning the sample collection methods, processing, labeling, and shipping 
will be provided by the Sponsor in a study-specific histology manual.  Collection supplies will be 
provided by the central laboratory. 
Sites participating in the paired biopsy substudy must confirm progression to cirrhosis by biopsy 
as per the information outlined in protocol Addendum 2. 
All suspected cases of progression to cirrhosis should be submitted for adjudication regardless of 
the availability of transient elastography or biopsy results. 
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7.5.5. 
Child-Pugh Score 
Child-Pugh (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 6 and can range from 5-15.  Although CP score calculation will automatically be computed 
in all subjects, it should only be applied to subjects who meet criteria for progression to cirrhosis. 
Dose adjustment or discontinuation should not be considered based solely on the CP score, in 
subjects who do not meet criteria for presence of cirrhosis.  
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).  Sponsor 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 6: 
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 
NA 
None 
Mild 
Moderate-
Severe 
Hepatic encephalopathya 
NA 
No 
Grade 1 or 2 
Grade 3 or 4 
INR = international normalized ratio; NA=not applicable 
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 
 Child-Pugh criteria: Pugh 1973, Lucey 1997, Vilstrup 2014. 
7.5.5.1. 
Mayo Risk Score 
Mayo Risk Score (MRS) (Dickson 1989) is calculated and reported within the EDC system 
based on data entered into the eCRF.  Calculation of MRS includes Investigator assessment of 
peripheral edema and the use of diuretic therapy, which will be assessed during adverse event 
and concomitant medicine review at the scheduled visits and entered into the eCRF, as well as 
total bilirubin, albumin, and prothrombin time results obtained from the central laboratory data. 
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7.6. 
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 safety and/or 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 7), investigational product should be initiated at a lower dose and 
subjects 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 7.  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 terminate at the time when the needed 
number of adjudicated events has accrued.  If a subject reaches an outcome event, he or she 
should continue the regular visit schedule and continue taking investigational product as long as 
the subject has not met any of the criteria for mandatory interruption of investigational product 
outlined in Table 7, and the Investigator assesses it as safe to continue.  In general, subjects 
should be strongly encouraged to both stay on investigational product and remain in the study 
until study termination.  If a subject discontinues investigational product and cannot continue to 
attend regularly scheduled study visits, the subject should be strongly encouraged to participate 
in study follow-up via phone calls or electronic medical record review as described in 
Section 7.9. 
Table 7: 
Criteria for Dose Adjustment, Interruption, Discontinuation and 
Rechallenge 
DOSE ADJUSTMENT 
 
 
Criteria 
Action Taken with IP 
Adjustment 
Progress to cirrhosis and have 
CP A cirrhosis (CP score <7) 
Adjust to a maximum 
daily dose of 10 mg (or 
equivalent placebo) in a 
blinded fashion 
Not applicable.  Remain at maximum daily 
dose of 10 mg (or equivalent placebo) for 
remainder of study. 
Progress to CP B or C cirrhosis 
(CP score ≥7) 
Adjust IP dose to 5 mg 
once weekly, then 
titrate to a maximum 
10 mg twice weekly (at 
least 3 days apart). 
After a minimum of 3 months, if at a lower 
dose, subjects may titrate to a maximum IP 
dose of 10 mg twice weekly per Investigator 
discretion. 
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 4)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. 
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Table 7: 
Criteria for Dose Adjustment, Interruption, Discontinuation and 
Rechallenge (Continued) 
Other liver biochemistries indicative of 
suspected hepatic injury are outside 
upper threshold criteria upon repeat 
testing as defined in Part A of Table 4d 
Interrupt after 
confirmation by repeat 
testing 
 
Liver biochemistries indicative of 
potential hepatic decompensation in the 
absence of symptoms (see Part B of 
Table 4)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 5) 
Closely monitor until 
normalization 
The subject 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  
Pregnancy 
Interrupt 
Patient should continue with the study visit 
schedule.  The subject may re-start IP when 
she is no longer pregnant or breastfeeding 
(if applicable) at the discretion of the 
Investigator and after discussion with the 
Medical Monitor   
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) 
Discontinue / 
No Rechallenge 
Discontinue IP permanently and continue to 
return for scheduled study visits for safety 
follow up.  
 
Monitor closely for clinical outcomes per 
protocol. 
 
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 4) are observed in the presence of 
clinical symptoms of cholestatic 
hepatitis or hepatic encephalopathyf 
Multi-Organ failure requiring 
hospitalization 
Liver transplantation 
Fully resolved = Return to baseline levels or return to within normal limits (WNL). IP = investigational product 
a If subject 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 Postbaseline ≥3x baseline, Baseline >ULN and Postbaseline ≥2x Baseline, ALT or AST >3x 
baseline (and >ULN) 
d ALT or AST ≥2x baseline, albumin <3.2 g/L or electrolytes (sodium <130 mEq/L). 
e Conjugated bilirubin >0.5 mg/dL increase from baseline; 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 
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f If INR increases ≥2.0 in the absence of clinical symptoms or if conjugated bilirubin 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. 
g Multi organ failure including hepatorenal syndrome Type 1 or Type 2 and acute kidney injury, hepatopulmonary syndrome, or 
portopulmonary syndrome. 
7.7. 
Close Observation 
If investigational product is interrupted or discontinued as described in Section 7.6, subjects 
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 subject 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 subject 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 subject 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 7.5.1, Section 7.5.2, and 
Section 7.5.3.  These cases need to be discussed with the Sponsor's medical monitor: 
• Repeating liver enzyme and serum bilirubin tests as described in Section 7.5.2.  
Frequency of retesting can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the subject 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 
product should be discussed with the Sponsor's medical monitor.  The subject 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 (HEV) when assessing for 
hepatic decompensation as infection with HEV in patients with chronic liver diseases 
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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 
7.8. 
Criteria for Study Termination 
The Sponsor 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 DMC, it may be necessary to stop the study before all events have been accrued, and 
when subjects are still active on the study.  In addition, the Sponsor may terminate the study at 
an investigational site at any time (eg, poorly performing sites, as determined by the number of 
subjects 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 subjects for the End of Study Visit.  The window 
of time for scheduling the visit will be based on a final projection of when the requisite 127 
adjudicated events will have been accrued.  
7.9. 
Subject Retention 
The primary objectives for the end of study analysis are to evaluate the effects of OCA compared 
with placebo on all-cause mortality and liver-related clinical outcomes.  The overall study 
duration is event driven and will be determined by the time required to observe the prespecified 
adjudicated events for the clinical outcomes’ composite endpoint (Section 7.1).  Therefore, it is 
critical that subjects continue to participate for the duration of the study to enable assessment of 
clinical outcomes and confirmation of the clinical benefit of OCA in PBC.  
Subjects may discontinue investigational product during the study; however, these subjects are 
expected to continue in the study until study termination and every effort will be made by the 
investigator to discuss subjects’ continuation in the study.  Even if a subject is no longer 
receiving investigational product, if the subject is attending study visits or participating in study 
follow-up, their information will contribute to the study primary endpoint and the evaluation of 
clinical benefit of OCA.  All information collected in the study during regular study visits and 
through subjects participating in follow-up will contribute to the evaluation of safety of OCA and 
the scientific and medical understanding PBC. 
Investigators should emphasize to subjects the importance of their continuation in the study even 
after withdrawal of investigational product and discuss with subjects the various options for 
continued participation in the study: 
• Continuing to attend regularly scheduled visits, or 
• Allowing semi-annual telephone visits by the Investigator, or  
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• Allowing the Investigator to have continued access to the subjects’ medical records to 
assess suspected major adverse cardiovascular events (MACE) and liver-related 
clinical outcomes 
Subjects will be asked to provide both personal and primary physician(s) contact information 
who can provide information to the Investigator about the clinical/medical status on the subjects’ 
behalf. 
Should subjects choose to discontinue treatment or withdraw consent and fully leave the study, it 
will be made clear to them that they may return to their randomized treatment group should they 
so choose. 
Additional information is described in Section 8.4. 
Given the importance of subject retention, clinical site personnel should refer to specific 
strategies and procedures as described in a separate Subject Retention Plan that will provide 
additional information to facilitate subject retention. 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Population 
This study will be conducted at approximately 170 international study sites with experience in 
treating patients with PBC.  Prospective subjects 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. 
Subject Inclusion Criteria 
1. Definite or probable PBC diagnosis (consistent with AASLD and EASL practice 
guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥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 in 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. 
2. A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN  
3. Age ≥18 years 
4. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking 
UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0. 
5. Contraception:  Female subjects must be postmenopausal, surgically sterile, or, if 
premenopausal (and not surgically sterile), be prepared to use ≥1 highly effective method 
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of contraception during the study and for 30 days after the end of treatment. Highly 
effective methods of contraception per the CTFG guidelines are those that alone or in 
combination results in a failure rate of less than 1% per year when used consistently and 
correctly. Highly effective methods of contraception are as follows: 
• Intrauterine device 
− Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomy (partner) 
• Combined (estrogen and progestogen containing) hormonal contraception (eg, oral, 
intravaginal or transdermal) associated with inhibition of ovulation. If oral 
contraceptives are used, they must be used in combination with a male or female 
condom. Female subjects should have been on the hormone contraception for at least 
8 days prior to Day 1. 
• Progestogen-only hormonal contraception (eg oral, injectable or implantable) 
associated with inhibition of ovulation. If oral contraceptives are used, they must be 
used in combination with a male or female condom. Female subjects should have 
been on the hormone contraception for at least 8 days prior to Day 1. 
• Sexual abstinence, if in line with the preferred and usual lifestyle of the subject 
(where abstinence is defined as refraining from heterosexual intercourse during the 
entire period of risk associated with study treatments). 
6. Must provide written informed consent and agree to comply with the study protocol 
8.3. 
Subject Exclusion Criteria 
1. History or presence of other concomitant liver diseases including:  
• Hepatitis C virus infection 
• Active hepatitis B infection; however, subjects 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 
• Nonalcoholic steatohepatitis 
• Gilbert’s Syndrome  
2. Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including:  
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• History of liver transplant, current placement on a liver transplant list, or current 
MELD score >12.  Subjects who are placed on a transplant list despite a relatively 
early disease stage (for example per regional guidelines) may be eligible as long as 
they do not meet any of the other exclusion criteria. 
• Cirrhosis with complications, including history (within the past 12 months) or 
presence of:  
− Variceal bleed 
− Uncontrolled ascites 
− Encephalopathy  
− Spontaneous bacterial peritonitis  
• Known or suspected hepatocellular carcinoma 
• Prior transjugular intrahepatic portosystemic shunt procedure 
• Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine 
>2 mg/dL (178 μmol/L)  
3. Mean total bilirubin >5x ULN 
4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) 
or ileal resection or plan to undergo either of these procedures. 
5. Other medical conditions that may diminish life expectancy, including known cancers 
(except carcinomas in situ or other stable, relatively benign conditions). 
6. If female:  plans to become pregnant, known pregnancy or a positive urine pregnancy test 
(confirmed by a positive serum pregnancy test by the central laboratory), or lactating. 
7. Known history of human immunodeficiency virus infection. 
8. Medical conditions that may cause non-hepatic increases in ALP (eg, Paget's disease or 
fractures within 3 months). 
9. Other clinically significant medical conditions that are not well controlled or for which 
medication needs are anticipated to change during the study. 
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0. 
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. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components.  
14. UDCA naïve (unless contraindicated) 
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8.4. 
Subject Withdrawal Criteria 
Subjects can be discontinued from investigational product by the Investigator at any time for 
clinical safety concerns.  Subjects who are discontinued from investigational product are 
expected to continue in the study and should follow the regular visit schedule for the duration of 
the study.  See Section 7.6 for withdrawal criteria related to potential hepatic injury and/or 
decompensation including liver transplantation or multi-organ failure.  Other reasons, including 
withdrawal of consent or lost to follow-up, are described in Section 8.4.1. The specific reason(s) 
for discontinuation from investigational product and/or withdrawal of consent should be 
recorded on the appropriate CRF.  
8.4.1. 
Other Reasons for Discontinuation of Study or Investigational Product 
In general, the site should counsel the subject on the importance of maintaining the regular visit 
schedule and remaining on investigational product.  Subjects should be strongly encouraged to 
both stay on investigational product and remain in the study until study termination.   Subjects 
who discontinue investigational product prior to termination of the study need to also continue to 
follow the regular visit schedule through to study closure.  With the exception of liver transplant, 
if a subject experiences a suspected or confirmed 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.  Specific strategies to encourage continued subject participation 
in the study will be outlined in a Subject Retention Plan.  Subjects who discontinue 
investigational product, but agree to follow up either through phone calls or review of electronic 
medical records are expected to continue to provide information regarding clinical outcomes or 
new interventions for PBC (such as initiating commercial OCALIVA). Early termination 
procedures should only be conducted if the subject withdraws consent (see Section 9.7.15 ). 
The following events are considered appropriate reasons for a subject to discontinue 
investigational product; however, these subjects are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
• Subject begins treatment with commercially available OCALIVA. 
− If a subject begins treatment with commercially available OCALIVA, they must 
interrupt IP immediately and this must be reported in the treatment 
discontinuation eCRF to prevent double dosing and for notification of the sponsor 
and medical monitor. 
• The Investigator or Sponsor considers that it is advisable or in the best interest of the 
subject. 
• 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 subject discontinues both 
investigational product and study visits and procedures). 
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− Consent may be modified to discontinue study visits, but allow semi-annual 
telephone contact of subject, subject’s primary care physician, or personal 
contacts who can provide information on behalf of the subject by the Investigator 
− Consent may be modified to discontinue study visits or semi-annual telephone 
contact, but may allow for continued access to medical records to assess for 
suspected MACE, liver-related clinical outcomes, and new interventions and 
medications for treatment of PBC. 
− Other subject follow-up options to collect study outcomes should be pursued 
according to local laws and regulations. If one of these alternate methods to 
collect study outcomes is acceptable to the subject, then the subject will be 
deemed not to have withdrawn consent for follow-up. 
Early termination procedures should be conducted if the subject withdraws consent (see 
Section 9.7.15). 
The Investigator is encouraged to contact the Sponsor prior to discontinuing a subject from 
treatment.  The Investigator must notify the Sponsor study monitor by telephone or email as soon 
as possible if any subject prematurely withdraws from the study. 
8.4.2. 
Withdrawal of Consent 
If the subject 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 subjects volunteer for the study and that 
they may withdraw their consent to continue in the study at any time. 
Diligent efforts must be made to determine the reason(s) for subject discontinuation (such as 
initiation of commercial OCALIVA or underlying adverse events).  This information and date 
must be recorded in the appropriate case report form (CRF). 
8.4.3. 
Requirements to Re-Initiate Investigational Product or Re-Enter the Study 
Subjects who wish to re-initiate investigational product while participating in study follow-up or 
re-enter the study after having withdrawn consent more than 3 months since the last visit must 
confirm that they have not received any investigational product that is being evaluated for the 
treatment of PBC within 30 days or commercial OCALIVA for 3 months before restarting 
investigational product or within 5 half-lives of the compound (whichever was longer). Subjects 
are to be re-consented and new baseline visit procedures must be performed. 
8.4.4. 
Lost to Follow-up 
If a subject fails to return to the clinic for a study visit, and the Investigator ceases to have 
contact with the subject, he or she will be withdrawn from the study. 
Diligent efforts to determine the reason(s) why a subject failed to return for a study visit or is lost 
to follow-up must be made. If the subject has provided consent, the subject’s primary care 
physician or personal contacts who can provide information on behalf of the subject by the 
Investigator, must be contacted if the subject consistently fails to return for study visits. This 
information and date of contact must be recorded in the appropriate CRF. 
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8.4.5. 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by telephone or email as soon as 
possible if any subject prematurely withdraws from the study.  The date when the subject is 
withdrawn and the reason for discontinuation must be recorded in the CRF.  If a subject is “lost 
to follow up” (fails to return for a visit), diligent efforts should be made to contact the subject in 
order to determine why the subject failed to return (see Section 8.4.3).  This information must be 
documented in the CRF.  If a subject is withdrawn from the study early (regardless of the cause), 
all of the EOT/EOS evaluations should be performed at the time of withdrawal, as appropriate 
(See Section 9.7.15, Early Discontinuation and/or Early Termination Procedures). 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Investigational Product Treatment Regimen 
The term investigational product refers to either OCA (provided as part of this clinical study) or 
matching 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 5 mg OCA tablet or one 
10 mg OCA tablet, or matching placebo).   
Investigational product will be taken orally, up to once daily, for the duration of the study.   
All subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1) and 
to take investigational product at approximately the same time of day.  Subjects must be 
instructed to swallow the tablet whole; they must not chew, divide, or crush the tablet. 
At each study visit where the daily dose of investigational product is administered at the site, all 
assessments, except for the post-dose collection of blood samples for the subset of subjects 
participating in the Month 9 PK assessment, must be completed before administration of 
investigational product. 
9.2. 
Concomitant Medications 
Concomitant medications (other than prohibited concomitant medications listed in Section 9.2.1) 
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 CRF, as well as any dose or dose 
regimen changes that occur during the study.  Concomitant medications should be stable prior to 
Day 0.   
Drug Interactions 
Subjects 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 
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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 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 Investigator’s Brochure (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 with OCA that may be observed in study subjects. 
PBC-Specific Therapy 
In general, 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 subjects’ 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, subjects 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, subjects should be reminded to keep taking their blinded 
investigational product. 
9.2.1. 
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.  Subjects who initiate commercial OCA therapy must discontinue investigative 
product and are expected to continue through the end of the study (see Section 9.7.15).  The 
study will only terminate at the time when the needed number of adjudicated events has accrued 
or at the discretion of the Sponsor.  Subjects will need to complete EOT procedures but continue 
with regularly scheduled visits until the study is terminated (see Section 9.7.15). 
9.3. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product at 
each study visit, and confirm by conducting investigational product accountability (ie, count of 
returned tablets). 
Subjects should be instructed to complete a dosing diary to help monitor compliance to the 
prescribed dosing regimen.  Subjects should be instructed to retain all bottles of investigational 
product, even if empty, and to return them to the Investigator at the subsequent visit.  The 
Investigator or designee should perform investigational product accountability and, if applicable, 
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follow up with the subject to retrieve any investigational product bottles that have not been 
returned.  
If the Investigator has concerns about a subject’s dosing compliance s/he should discuss this with 
the subject, assess the reasons for noncompliance and the likelihood that the subject will remain 
noncompliant, and notify the Sponsor accordingly.   
9.4. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Allocation to one of 
two treatment groups (OCA or placebo) will occur on a 1:1 ratio across sites and will be 
stratified by UDCA treatment (yes/no) and mean baseline bilirubin categories (>ULN/≤ULN), as 
specified by the central laboratory.  The randomization will be based on a predefined 
randomization code (generated by the Sponsor or designee) using an interactive web response 
system (IWRS), which the Sponsor intends will serve as a computer-based subject registration 
system at Screening and Day 0.  The IWRS will also serve as an investigational product 
inventory and management system and may be integrated with the study database.  
The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide subject data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned (refer to Section 9.5.2 below) and 
investigational product dispensing information (ie, bottle number[s]) will be provided. 
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects 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 subject).  If it 
is not reasonable to inform the Medical Monitor in advance of the unblinding, the Investigator 
must promptly document in the subject’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 subject’s treatment will be provided separately to the 
Investigator.  Similarly, if the Medical Monitor breaks the blind for an individual subject for the 
purpose of evaluating an emergent safety issue, the Medical Monitor will document within trial 
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 subjects.  Refer to 
Section 13.3 for further details regarding DMC access to blinded and unblinded data.  The DMC 
will document details about any unblinded subject data reviews in the closed session DMC 
minutes, which will be made available to the Sponsor only after the database is locked and the 
trial 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. 
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9.5. 
Assignment of Site and Subject 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 subject data and to identify the site and or Investigator 
within study documents.  This number will be recorded in the CRF. 
9.5.2. 
Subject Numbers 
Subjects 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 trial is prohibited.   
9.7. 
Visit Procedures 
9.7.1. 
Visit Windows 
Visits should be based on Day 0 (not on the prior visit), eg, Month 3 should ideally occur 
3 calendar months (± 2 weeks) following Day 0.   
The visit windows are as follows: 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening Visit 1 interval is 3 to 8 weeks prior to Day 0.  Screening 
Visit 2 interval is 1 to 6 weeks prior to Day 0.  The visit window for 
Screening 2 visits allows for the repeat biochemistry tests to be 
collected at least two weeks after the initial biochemistry sample 
was collected and will ensure ample time to receive lab results.  
The overall Screening interval is up to 56 days, but screening 
procedures should not be performed during the last 7 days of the 
window.  
See Section 9.7.3 for scenario specific visit windows that may be 
applicable at Screening.  
Day 0 
This is the day of randomization.  On-treatment visit scheduling 
should be calculated from this point going forward. (The first dose 
of investigational product should be taken the next day, on Day 1.) 
Month 1  
±1 week (7 days)  
Titration Visit – Standard Dosing Regimen 
≥Month 3 
Titration Visit 1 – Modified Dosing 
Regimen 
≥Month 3 
Titration Visit 2 – Modified Dosing 
Regimen 
≥6 weeks after Titration Visit 1 
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Visit or Procedure 
Visit Window and/or Interval 
Titration Visit 3 – Modified Dosing 
Regimen (Child-Pugh B ONLY) 
≥6 weeks after Titration Visit 2 
Post-Titration Visit 
1 month and 2 months (±1 week [7 days]) from date of titration   
Month 3 to Month 12 
±2 weeks (14 days)  
Quarterly visits (Months 15 to EOS) 
±2 weeks (14 days) 
EOT 
(When subject discontinues investigational 
product) 
As soon as possible upon study discontinuation and as near as 
possible to last dose taken 
EOS 
(When subject terminates the study) 
The final study visit; EOS will occur concurrent with EOT if a 
subject discontinues investigative product at the time the subject’s 
participation in the study ends (eg, withdrawal of consent or study 
termination by the Sponsor); EOS will occur after the EOT if the 
subject discontinues investigative product but continues in the 
study. 
IP Re-Initiation/ Study Re-Entry 
(When a subject has previously 
discontinued treatment/ withdrawn consent 
and has chosen to return to study 
participation) 
Day 0 procedures should be conducted and the visit window will be 
relative to Day 0 from the original study entry. 
EOS = end of study; EOT = end of treatment; IP=investigational product 
9.7.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk and benefit of / study 
to the subject and will provide his/her with a copy of the written information and informed 
consent form (ICF).  The subject will be given sufficient time to consider the study before 
deciding whether or not to participate.  The subject 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 s/he can withdraw from the study at any time.  The subject must be willing and 
able to provide written informed consent before entering the study.  The Investigator or a 
medically qualified designee is responsible for administering and documenting the written 
informed consent of the subject.  The subject will be given a copy of the written information and 
his/her signed and dated consent form. 
Any change in a subject’s consent status (eg, semi-annual telephone contact or medical record 
review) must be documented in a signed informed consent form or addendum.  The subject will 
be given a signed and dated copy of the consent document. 
9.7.3. 
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 week to 8 weeks prior to Day 0 to 
determine whether the subject meets all the inclusion criteria and none of the exclusion criteria.  
Screening Visit 1 will occur 3 weeks to 8 weeks prior to Day 0; Screening Visit 2 will occur 
1 week to 6 weeks prior to Day 0, depending on the date that the first serum chemistry sample 
was collected. Subjects who do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects may be rescreened after 2 months have elapsed from the date of their most recent 
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screening visit procedure; however, all Screening procedures (including obtaining informed 
consent) should be repeated and a new three-digit Screening number assigned.   
Collection of 2 serum chemistry samples (collected at least 2 weeks apart) during Screening is 
required for confirmation of the pretreatment serum chemistry values, including ALP and total 
bilirubin used to determine eligibility: 
• All subjects will have 2 bilirubin and ALP assessments at least 2 weeks apart. 
• When the 2 bilirubin or ALP assessments collected at Screening Visit 1 and 
Screening Visit 2 differ by ≥30%, a third sample must be collected at an unscheduled 
visit as a confirmatory sample to include in the mean result(s) that will be used to 
determine eligibility.  
• The mean of all available (at least 2; including both scheduled and 
unscheduled) bilirubin and ALP assessments will be used to determine eligibility 
(total bilirubin >ULN and ≤5x ULN and/or an ALP >3x ULN).   
Screening Visit 1 procedures are as follows: 
• The subject is to review and sign the ICF.  Informed consent must be obtained from 
the subject 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  
• Assess for the presence/absence of cirrhosis. 
• Verify inclusion and exclusion criteria for eligibility. 
• Perform a physical examination.  
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Assess and record any pretreatment-emergent AEs. 
• Record prior (if within 30 days of Screening) and current concomitant medications. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
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Screening Visit 2 procedures are as follows: 
• Verify inclusion and exclusion criteria for eligibility. 
• Perform an ultrasound for HCC surveillance and gallbladder assessment (if 
equipment is unavailable, sites should make every attempt to use available 
community referral sites).  If an ultrasound has been done within 3 months of the 
planned Day 0 visit, and a report/adequate data are available, a pretreatment 
ultrasound is not required.  If the ultrasound cannot be performed at Screening Visit 2 
(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 must be reviewed to assess possible exclusion criteria prior to 
randomization. 
• Assess and record any pretreatment-emergent AEs. 
• Review and record prior and concomitant medications. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry tests. 
• The subject should be instructed to fast overnight (at least 8 hours) prior to next visit.  
Fasting is required prior to all study visits, but water is permitted. 
It is acceptable to repeat laboratory evaluations or other assessments or procedures within the 
Screening period (Weeks -8 to -1), as appropriate.  In the event that the 2 screening bilirubin or 
ALP assessments differ by ≥30%, and a third confirmatory sample is required to be collected, the 
Screening Visit window may be extended up to 3 additional weeks. 
9.7.4. 
Day 0 Procedures (Randomization) 
• Review inclusion and exclusion criteria for eligibility. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.5). 
• Perform TE at all study sites with access to Fibroscan® TE device.  If TE has been 
done within 3 months of Day 0 and a report/adequate data are available, a 
pretreatment TE at Day 0 is not required.  If the TE cannot be performed on Day 0 
(eg, device/technician unavailability, scheduling issues, TE data is needed to inform 
cirrhosis assessment, etc), the procedure may be completed within the screening visit 
window, at Screening Visit 1 (if data is needed for cirrhosis assessment) or as close as 
possible to the Day 0 visit, preferably, after subject eligibility has been confirmed. 
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• Perform an esophagogastroduodenoscopy (endoscopy; at study sites, where the 
device is available) to assess the presence or absence of oesophageal varix/varices.  
If an endoscopy has been done within 12 months of Day 0 and a report/adequate data 
are available, a pretreatment endoscopy at Day 0 is not required. If the endoscopy 
cannot be performed on Day 0 (eg, device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the screening visit window, as 
close as possible to the Day 0 visit, preferably, after subject eligibility has been 
confirmed. 
− Subsequent endoscopies should be performed annually or per standard of care and 
the Investigator’s clinical judgment throughout the course of the study.  
Endoscopies should also be performed when platelet counts are <150 × 109 /L. 
• Assess and record any pretreatment-emergent AEs. 
• Review and record prior concomitant medications. 
• Review and record any nonstudy 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 subject only if s/he meets all inclusion criteria and no exclusion 
criteria. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Perform a urine-based β-hCG pregnancy test in females of childbearing potential. 
• If hepatobiliary ultrasound for HCC screening and gallbladder assessment was not 
performed at Screening and the historic ultrasound is >3 months from Day 1, perform 
a hepatobiliary ultrasound. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and fibroblast growth factor-19 (FGF-19) 
− Markers of hepatic fibrosis and/or inflammation (including enhanced liver fibrosis 
[ELF]) 
− Genetics (see Section 11.1.2.3) 
• Perform assessments for calculation of Child-Pugh Score. 
• Access the IWRS and dispense investigational product. 
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• Instruct the subject to begin dosing on the day after the Day 0 visit (ie, on Day 1).  
Instruct the subject to swallow the tablet whole; s/he must not chew, divide, or crush 
the tablet. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
9.7.5. 
Months 1, 2 Procedures 
• Perform a physical examination.  
• Assess and record AEs 
• Review and record prior and concomitant medications. 
• Assess investigational product compliance, perform investigational product 
accountability, and review dosing diary with the subject. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm. 
• Provide the subject with a dosing diary to document his or her dosing. 
• In the event it is not feasible for the subject to return to the site for the above 
referenced procedures, the following alternative visit procedures are available to help 
ensure compliance with the Month 1 and Month 2 visit laboratory requirements: 
− At the Day 0 visit, the subject can be provided with the central laboratory 
collection kit and shipping materials associated with the Month 1 visit, and have 
the laboratory specimen collection performed at his or her local doctor’s office or 
designated laboratory collection center.  The subject must also be contacted via 
telephone at the visit timepoint to assess AEs, review concomitant medications, 
and assess investigational product compliance;  
− If all other options for the collection of the Month 1 and Month 2 laboratory 
samples have been exhausted, the use of a local laboratory for the Month 1 
samples would be accepted for this visit; although, any laboratory data obtained 
from a local laboratory will not be captured in the eCRF or included in the study 
analysis.  A copy of the local laboratory report would need to be provided to the 
Investigator for review and available in the source records.  The Investigator 
should contact the Medical Monitor as soon as possible to discuss any local 
laboratory values that may be of clinical concern.  The subject must also be 
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contacted via telephone at the visit timepoint to assess AEs, review concomitant 
medications, and assess investigational product compliance;  
− A physical examination should be performed at the Month 3 visit if an onsite 
Month 1 or Month 2 visit was not performed. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
Month 3 Procedures 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record AEs. 
• Review and record prior and concomitant medications. 
• 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests.  
• Obtain blood samples for: 
− OCA, C4, and FGF-19 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Provide the subject with a dosing diary to document his or her dosing. 
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• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
Post-Titration Visit Procedures 
• Perform a physical examination.  
• Assess and record AEs. 
• Review and record prior and concomitant medications 
• Assess investigational product compliance, perform investigational product 
accountability, and review dosing diary with the subject. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm  
• Provide the subject with a dosing diary to document his or her dosing. 
• In the event it is not feasible for the subject to return the site for the above referenced 
procedures, the following alternative visit procedures are available, to help ensure 
compliance with the Post-Titration laboratory requirements: 
− At the Up-titration Visit, the subject can be provided with the central laboratory 
collection kit and shipping materials associated with the Post-Titration Visit, and 
have the laboratory specimen collection performed at his or her local doctor’s 
office or designated laboratory collection center.  The subject must also be 
contacted via telephone at the Post-Titration Visit timepoint to assess AEs, review 
concomitant medications, and assess investigational product compliance;  
− If all other options for the collection of the Post-Titration laboratory samples have 
been exhausted, the use of a local laboratory for the Post-Titration samples would 
be accepted for this visit; although, any laboratory data obtained from a local 
laboratory will not be captured in the eCRF or included in the study analysis.  A 
copy of the local laboratory report would need to be provided to the Investigator 
for review and available in the source records.  The Investigator should contact 
the Medical Monitor as soon as possible to discuss any local laboratory values 
that may be of clinical concern.  The subject must also be contacted via telephone 
at the Post-Titration Visit timepoint to assess AEs, review concomitant 
medications, and assess investigational product compliance;  
− A physical examination should be performed at the next scheduled visit if an 
onsite Post-Titration Visit was not performed 
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• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
- 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. 
Month 6 Procedures  
• Perform a physical examination. 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.5) 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record prior and concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
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− Markers of hepatic fibrosis and/or inflammation (including ELF) 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
• For subjects who will participate in the PK assessment and are taking BAS or 
aluminum hydroxide- or smectite-containing antacids, they should be instructed to 
not take their regular dose on the morning of the study visit.   
9.7.9. 
Month 9 Procedures 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm. 
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate, 
and sitting blood pressure). 
• Assess and record AEs. 
• Review and record prior and concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits, but water is permitted. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• PK assessment in participating subjects at select study sites (see Section 9.7.10). 
• Provide the subject with a dosing diary to document his or her dosing. 
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• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic Assessment 
At selected investigational sites, subjects will have the option to consent to participate in an 
additional OCA PK assessment.  PK samples will be used to support further analysis of OCA 
exposure-response in subjects with PBC.  This is optional and subjects may decline to participate 
without affecting their involvement in the rest of the study.  Consent to participate in the 
assessment can be given at any point during study participation prior to the Month 9 visit.  
Subjects who are following the Child-Pugh B and Child-Pugh C modified dosing regimen may 
participate in the PK assessment and will dose in the clinic at this visit even if the previous dose 
was taken less than 3 days prior; however, every attempt should be made to schedule the 
Month 9 PK visit according to the subject’s established dosing schedule. 
Following collection of the Month 9 fasted samples (refer to Section 9.7.9, subjects who are 
participating in the PK assessment will each receive a single dose of investigational product 
(blinded OCA or placebo tablet) with approximately 240 mL of water.  Subjects taking BAS or 
aluminum hydroxide- or smectite-containing antacids should be instructed to stagger their dosing 
of investigative product and UDCA, ensuring at least 4 hours between doses of the BAS and/or 
these antacids and the investigative product (and UDCA).   
Serial blood samples will be obtained for measurement of OCA and its conjugates prior to 
dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours post dose.  Samples should be collected 
within a window of ±5 minutes of the scheduled sample time.  Subjects should not drink 
additional water for 1 hour after taking the dose of investigational product and will remain fasted 
until the 4-hour sample is collected.  Lunch will be provided following collection of the 4 hour 
PK sample; the lunch will be a meal replacement drink with no other food allowed until after the 
final 6-hour post-dose sample is collected.  Samples will be stored for up to 5 years after the end 
of the study and will be destroyed after 5 years if not analyzed. 
9.7.11. 
Month 12 Procedures 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Perform assessments for calculation of Child-Pugh Score 
• Review progression to cirrhosis algorithm  
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead electrocardiogram (ECG). 
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• Quality of Life and Subject questionnaires and (see Section 11.1.2.2 
and Section 12.2.5). 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
• Perform an endoscopy (at all study sites, where device is available) to assess the 
presence or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record prior and concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for: 
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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 
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− 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. 
Month 3 and Month 9 Continued Follow-Up Procedures (±2 weeks) 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm  
• Assess and record AEs. 
• Review and record prior and concomitant medications. 
• Review and record any nonstudy 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, and review dosing diary with the subject. 
• Assess for dose titration, if eligible (refer to Section 7.4). 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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. 
9.7.13. 
Month 6 Continued Follow-Up Procedures (Semi-annually [±2 weeks]) 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm  
• Assess and record vital signs (weight, temperature, sitting heart rate, respiratory rate 
and sitting blood pressure). 
• Subject questionnaires (see Section 12.2.5) 
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• Perform TE at all study sites with access to the Fibroscan® TE device. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record prior and concomitant medications 
• Review and record any nonstudy 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 (refer to Section 7.4). 
• Assess investigational product compliance, perform accountability, and review dosing 
diary with the subject. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− Markers of hepatic fibrosis and/or inflammation (including ELF). 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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 
9.7.14. 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Perform assessments for calculation of Child-Pugh Score. 
• Review progression to cirrhosis algorithm. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
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• Perform a standard 12-lead electrocardiogram (ECG). 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.5). 
• Perform TE at all study sites with access to the Fibroscan® TE device. 
• Perform an endoscopy (at all study sites, where device is available) to assess the 
presence or absence of oesophageal varix/varices. 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites). 
• Assess and record AEs. 
• Review and record prior and concomitant medications 
• Review and record any nonstudy 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 (refer to Section 7.4). 
• Assess investigational product compliance, perform accountability, and review dosing 
diary with the subject. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required prior to all study 
visits. 
• Obtain urine sample for urinalysis. 
• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
− Genetics (see Section 11.1.2.3) 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− 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 
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− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all study visits, but water is permitted. 
9.7.15. 
Early Discontinuation and/or Early Termination Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent 
Subjects who discontinue investigational product are expected to continue in the study until the 
end of the study, and the study will only terminate at the time when the needed number of 
adjudicated events has accrued or at the discretion of the Sponsor.  In general, subjects should be 
strongly encouraged to both stay on investigational product and remain in the study until study 
termination.  Even if a subject is no longer receiving investigational product, if the subject is 
attending study visits or participating in study follow-up (through telephone visits or electronic 
medical record review), their information will contribute to the study primary endpoint and the 
evaluation of clinical benefit of OCA.  All information collected in the study during regular 
study visits and through subjects participating in follow-up will contribute to the evaluation of 
safety of OCA and the scientific and medical understanding of PBC. 
EOT procedures will be required whenever subjects discontinue treatment with investigational 
product.  The EOT visit and procedures listed below must be performed as close as possible to 
the subject’s last dose of investigational product.  When a subject discontinues investigational 
product, but continues with regularly scheduled study visits, the EOS visit will be completed 
later in the study as the subject’s final study visit.  The actual investigational product 
discontinuation scenario (Table 8) will determine the sequence of the EOT and EOS visits and 
procedures.  In some cases, the EOT visit and procedures will precede the EOS visit; in others, 
the EOT and EOS visits will be combined and performed as close as possible to the subject’s last 
dose of investigational product.   
When a subject ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (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 subject 
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 and EOS procedures in the CRF.  
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Table 8: 
Early Discontinuation Scenarios 
 
Investigational 
Product 
Consent 
Study Visit 
Status 
EOT Visita 
EOS Visita 
Early 
Terminationb 
Discontinued 
Withdrawn 
No additional 
visits except 
EOT/EOS 
Combined Visit, Completed as 
close as possible to last dose IP 
Treatment 
Discontinuationb,c 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
Discontinued 
Semiannual 
contactd 
Telephone 
contact every 
6 months (±2 
weeks) 
Combined Visit, Completed as 
close as possible to last dose IP 
Discontinued 
Record review 
onlyd 
Record review 
only 
Combined visit 
Completed as close as possible 
to last dose IP 
Sponsor 
Termination 
Discontinued 
N/A 
No additional 
visits except 
EOT/EOS 
Combined visit 
Completed as close as possible 
to last dose IP 
 
Investigational 
Product 
Consent 
Study Visit 
Status 
EOT Visita 
EOS Visita 
Pregnancy 
Interrupted 
Retained 
Regular Visit 
Schedule 
Complete as 
close as 
possible to last 
dose IP 
Complete at 
Final study 
visit 
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; IP = investigational product 
a Refer to Section 7.1.1 Schedule of Study Procedures, Table 2 for all procedures and evaluations required at the 
End of Treatment and End of Study Visits.  
b Subjects may choose to re-consent, re-enter the study, and re-initiate IP at a later date.  Day 0 procedures will be 
repeated and the subject will resume in the visit window relative to the original Day 0. 
c   Includes initiation of commercially available OCA. 
d Outcomes data to be discussed or collected include data related to adjudicated hepatic and cardiovascular event-
related data.  Additional data such as information on concurrent medical conditions, co-morbidities, relevant 
adverse events, and concomitant medications may be collected to help facilitate adjudication of these post-study 
events.   
Some assessments noted below may be omitted if they have been completed within the 6 months 
(or the timeframe otherwise specified) and so long as safety issues do not warrant repeat testing. 
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Prior to the EOT/EOS Visit: 
If possible to do before the visit, when scheduling the EOT/EOS visit, reiterate dosing 
instructions and advise the subject: 
• If applicable, NOT to take investigational product on the morning of the next visit, 
and  
• To bring the investigational product bottle(s); if applicable, s/he will dose at the 
clinic, 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. 
During the EOT/EOS Visit: 
• Perform a physical examination (including smoking and alcohol consumption habits). 
• Review progression to cirrhosis algorithm  
• Perform assessments for calculation of Child-Pugh Score. 
• Assess and record vital signs (height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure). 
• Perform a standard 12-lead ECG. 
• Quality of Life and Subject questionnaires (see Section 11.1.2.2 and Section 12.2.5). 
• Perform TE at all study sites with access to the Fibroscan® TE device (not required at 
EOT/EOS if done within 6 months). 
• Perform an ultrasound for HCC surveillance (if equipment is unavailable, sites should 
make every attempt to use available community referral sites); not required at 
EOT/EOS if done within 6 months. 
• Assess and record AEs; all ongoing “related” AEs must be followed until stable or 
resolved. 
• Review and record concomitant medications. 
• Review and record any nonstudy 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 accountability, and review dosing 
diary with the subject; retrieve used bottles, accordingly, and document returns. 
• Verify that the subject has fasted for at least 8 hours. 
− Record fasting status in the source and CRF. 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and CRF. 
• Obtain urine sample for urinalysis. 
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• Obtain blood samples for serum chemistry, hematology, and coagulation tests. 
• Obtain blood samples for:  
− OCA, C4, and FGF-19 
− Markers of hepatic fibrosis and/or inflammation (including ELF) 
For subjects who prematurely terminate investigational product and/or the study, procedures 
outlined in Section 8.4.1 should be followed. 
Subjects who wish to re-initiate investigational product while participating in study follow-up or 
re-enter the study after having withdrawn consent or having discontinued treatment more than 
3 months since the last visit must confirm that they have not received any investigational product 
being evaluated for the treatment of PBC within 30 days or commercial OCALIVA for three 
months before restarting investigational product or within 5 half-lives of the compound 
(whichever was longer).  Subjects are to be re-consented and new Day 0 visit procedures must be 
performed.  The subject will resume the study in the visit window relative to their original 
Day 0 visit. 
9.7.16. 
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.   
In the event of an inexplicable and acute (for example not explained by natural progression of the 
chronic disease) increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
or total bilirubin is observed during the course of the study, refer to Section 7.5 to confirm 
whether an unscheduled safety visit is required. 
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 5 mg or 10 mg OCA 
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 
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may be dispensed to the subject at each visit to provide enough tablets for daily 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 trial sites in support of clinical study 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 Preparation 
The investigational product will be provided to the distribution center in bulk bottles and 
therefore may be repackaged in unit dose form for administration to subjects before shipping to 
the sites. 
10.5. 
Investigational Product Administration 
Refer to Section 9.1. 
10.6. 
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 subject 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. 
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11. 
ASSESSMENT OF EFFICACY  
11.1. 
Assessment of Efficacy  
11.1.1. 
Primary Assessments 
The following primary efficacy assessments will be measured: 
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• 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 or greater) 
− Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
11.1.2. 
Secondary Assessments 
The following secondary efficacy assessments will be measured: 
• Individual components of the primary endpoint 
• Liver-related death 
• Progression to cirrhosis as assessed by the presence of clinical, laboratory, or 
radiological evidence of cirrhosis and/or liver stiffness (Fibroscan® TE), confirmed 
by biopsy unless not medically indicated.  
− Histological assessment of disease progression or improvement using paired 
biopsies in a subset of subjects (defined in Addendum 2). 
• HCC confirmed by 2 complimentary imaging modalities, unless confirmed by biopsy. 
• Liver biochemistry (see Table 12 for list of analytes to be tested) 
• Biomarkers, including other markers of hepatic fibrosis and/or inflammation, to be 
tested will include:  IgM, c-reactive protein (CRP), tumor necrosis factor-α (TNF-α), 
FGF-19, cytokeratin-18 (CK-18) ELF, and Fibroscan (and others as determined 
during the course of the study). 
• Clinical outcomes, including individual component of the primary endpoint (where 
available), liver transplant, and death will be compared to historical controls. 
• PK of OCA and its conjugates. 
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• Data will be collected to inform quality of life and cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Quality of life will be 
assessed by questionnaires (PBC-40, EQ-5D-5L, and FIS) administered annually.  
Resource utilization information will be collected from the Medical and Surgical 
Treatment Procedures and Office Visit Log or other CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician visits (subject reported), 
and use of concomitant medications.  
• Endoscopy will be conducted at all study sites where the device is available to assess 
for the presence of oesophageal varix/varices at baseline.  Throughout the study, any 
endoscopy performed as part of the annual study assessments or standard of care will 
be collected in the case report form to assess for the development of varix/varices. 
11.1.2.1. Noninvasive Assessments of Liver Fibrosis 
• Blood samples for measurement of ELF test and other analytes will be collected.  The 
ELF test assesses: hyaluronic acid (HA), procollagen-3 N-terminal peptide (P3NP), 
and a tissue inhibitor of metalloproteinase 1 (TIMP-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.   
11.1.2.2. Other Secondary Assessments 
• OCA (OCA, tauro-OCA, glyco-OCA, total OCA, OCA-glucuronide) and C4 will be 
assayed to determine bioanalytical concentrations.  Additional analyses may include 
other conjugates or metabolites not yet identified.   
• Quality of Life questionnaires. 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 (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 respondent’s self-rate 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). 
− Fatigue Impact Scale (FIS):  The FIS is a validated 40 question questionnaire 
organized into 3 dimensions:  cognitive, physical, and social.  Each dimension has 
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5 levels:  no problem, small problem, moderate problem, big problem, and 
extreme problem (Fisk 1994). 
11.1.2.3. Other Exploratory Evaluations 
• A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved 
in PBC will be conducted for subjects and at study sites willing to provide samples at 
Day 0, Month 12, and every other year at the yearly visits thereafter.  RNA 
expression resulting from treatment with OCA will be assessed at indicated 
timepoints during the study.   Subjects will be permitted to decline to provide a blood 
sample for the genetics study, without affecting their involvement in the study.  
IRB/IEC review and approval will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will be stored for up to 1 year 
after the end of the study and destroyed after 1 year if not analyzed. 
11.1.2.4. Potential Clinical Outcome Events 
The events listed in Section 12.1.6 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 13.4) 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 suspected 
unexpected serious adverse reaction (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 13.4. 
12. 
ASSESSMENT OF SAFETY 
12.1. 
Adverse Events and Serious Adverse Events 
12.1.1. 
Definitions of Adverse Events 
12.1.1.1. Adverse Event  
An AE is 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) subject 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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Subjects should be questioned in a general way, without leading the subject 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. 
Subjects 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 whites of eyes, and bruising easily. 
12.1.1.2. 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-subject 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 subject 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. 
12.1.1.3. Treatment-Emergent Adverse Event  
A treatment-emergent AE (TEAE) is any event not present prior to the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
12.1.1.4. Adverse Events of Special Interest 
The following decompensation events are adverse events of special interest.  A subset of these 
events are also individual components of the primary endpoint (Section 11.1.1).   
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• 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, 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 
12.1.1.5. Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is defined as a suspected adverse 
reaction which is assessed as serious, causally related to the investigational product, and 
unexpected per the reference safety information (RSI) in the Investigator’s Brochure.  
SUSARs are subject to expedited reporting. The Sponsor shall ensure that all relevant 
information about SUSARs that are fatal or life-threatening are recorded and reported as soon as 
possible to the relevant competent authorities (either directly or through the Eudravigilance 
Clinical Trials Module, as applicable), and to the Ethics Committees, no later than 7 days after 
knowledge by the Sponsor of such a case. Relevant follow-up information is subsequently 
communicated within an additional 8 days. All other SUSARs shall be reported to the competent 
authorities concerned (either directly or through the Eudravigilance Clinical Trials Module) and 
to the Ethics Committees concerned, within a maximum of 15 days of first knowledge by the 
sponsor. Each competent authority shall ensure that all SUSARs to an investigational product 
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which are brought to its attention are recorded. The Sponsor shall also inform all participating 
Investigators, as applicable to the local regulations. 
12.1.2. 
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/serious adverse event (SAE) and the investigational product is 
determined to be “possible” or “probable” 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 subject’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 
A reaction 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 subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
12.1.3. 
Relationship of Adverse Events to Liver Biopsy 
The Investigator will document her/his opinion of the relationship of an AE to liver biopsy using 
the criteria outlined in Table 10.  
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Table 10: 
Relationship of Adverse Events to Liver Biopsy 
Relationship 
Description 
Related 
A reaction that follows a reasonable temporal sequence from the liver biopsy; that follows 
a known or expected response pattern to the liver biopsy. 
Not Related 
Any event that does not meet the above criteria. 
12.1.4. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 11, must be entered on the AE CRF.  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 11: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Causing no limitation of usual activities; the subject may experience slight discomfort. 
2 = Moderate 
Causing some limitation of usual activities; the subject may experience annoying 
discomfort. 
3 = Severe 
Causing inability to carry out usual activities; the subject may experience intolerable 
discomfort or pain. 
12.1.5. 
Reporting of Adverse Events and Serious Adverse Events 
12.1.5.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
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 subject’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.  
In addition, the Investigator should contact the study Medical Monitor upon awareness when any 
signs or symptoms of hepatic decompensation are observed in any subject. 
12.1.5.2. 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).   
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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 be reported by: 
• E-mail to the SAE email address:  sae@interceptpharma.com 
• Fax using a paper SAE report form:  +1 800 497 8521 
If an SAE is reported by email 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:   
• Subject 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 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 +1 800 497 8521 or 
emailed to sae@interceptpharma.com as soon as possible.  Redacted medical record source 
documentation will be requested for all SAEs and emergency room visits. 
The Investigator is responsible for submitting information on 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 IECs/IRBs must be retained in the appropriate study file(s).  
As instructed by the Sponsor, 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 12.1.6.  
12.1.6. 
Suspected Liver-Related Clinical Outcome Events 
Specified liver-related clinical outcome events may, by definition qualify as SAEs (see 
Section 12.1.1.2).  The Sponsor must be notified of any SAEs within 24 hours of the site 
becoming aware of the event (see Section 12.1.5.2).  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. 
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Given that the liver-related clinical outcome events may also meet the criteria of a SUSAR, but 
are considered in aggregate as part of the primary endpoint and the DMC reviews of all safety 
and efficacy data approximately quarterly, the Sponsor will not expeditiously report suspected 
liver-related 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 “study event” on the AE 
CRF and will be submitted for adjudication to the Hepatic Outcomes Committee as described in 
Section 13.4. 
The Sponsor will consider the following list of clinical outcome events (MedDRA preferred 
terms) to be disease related and exempt from expeditious regulatory reporting, but will continue 
to report them in a nonexpeditious 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 or oesophageal varices haemorrhage), hepatic encephalopathy (preferred term: 
hepatic encephalopathy),  spontaneous bacterial peritonitis (preferred term: peritonitis bacterial), 
ascites (preferred term: ascites), and histological or clinical progression to cirrhosis (preferred 
term: hepatic cirrhosis). 
12.1.7. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the CRF 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 subject’s AE CRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the Medical Monitor, 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 subject 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. 
12.1.8. 
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 12.1.5.2. 
SAEs that occur in subjects 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 12.1.5.2.  
12.1.9. 
Notification of Poststudy 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 12.1.5.2. 
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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 12.1.5.2. 
12.1.10. 
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 subject 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 subject 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. 
Drug-Induced Liver Injury or Disease Progression 
All subjects 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 from drug-induced liver injury 
follow-up 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 
At the time of consent for new subjects (or re-consent to the protocol amendments for ongoing 
subjects), subjects will 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.  Subjects will 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 will be instructed to 
promptly bring subjects 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 will be monitored monthly for 
3 months after onset of symptoms, irrespective of whether a diagnosis of cholecystitis and or 
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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. 
12.1.11. 
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 7.6 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 sae@interceptpharma.com or faxed to +1 800 497 8521.   The 
subject and neonate must be followed for outcome information and/or as considered appropriate 
by the Investigator and Sponsor. 
The subject 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 subject must have a negative pregnancy test before restarting investigational product.  If a 
subject’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 12.1.5 must also be followed. 
12.2. 
Other Safety Parameters 
12.2.1. 
Medical History/Demographics 
A complete medical history and PBC disease-specific history will be obtained from the subject at 
Screening.  Smoking and alcohol consumption history and current habits will be recorded.  
Demographic characteristics (age, gender, race, and ethnicity) will be recorded. 
12.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the timepoints specified in the Schedule of Study Procedures (Section 7.1.1).  A basic physical 
examination should be performed, including all body systems pertinent to the subject.  Any 
clinically significant abnormality should be reported on the AE CRF page for findings that 
appear after consent, and on the medical history CRF for any finding present prior to consent.  
Information about smoking and alcohol consumption habits will be collected at the same 
(follow-up) timepoints as the physical exam. 
12.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits: height, weight, temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure.  When taking heart rate, respiratory rate, and blood 
pressure readings, subjects should be seated quietly for a minimum of 3 minutes before the 
readings are taken.   
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12.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected at the Screening Visit 1, Month 12, and at EOT/EOS.  
The Investigator or designee will review the 12-lead ECG and findings will be recorded in the 
CRF as normal, abnormal but not clinically significant, or abnormal and clinically significant.  
Any clinically significant abnormality on ECGs should be reported on the AE CRF page.  
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 subject’s initials, Subject ID number, 
date, and time. 
12.2.5. 
Subject Questionnaires 
Information about the subject’s PBC disease history (ie, date of diagnosis, treatment history, 
pruritus history, signs and symptoms, and including smoking history) will be collected during 
Screening.  At subsequent study visits (see Section 7.1.1), subjects will be asked to complete the 
following questionnaires; they may be asked to initial and date to document confirmation of their 
responses, and the questionnaires should be filed in the subject’s study records.  These may 
require transcription to the CRF by study site staff. 
• 5-D Pruritus Questionnaire:  This is a questionnaire that has been validated in several 
different diseases.  It assesses symptoms in terms of 5 domains: degree, duration, 
direction, disability and distribution (Elman 2010). 
• Pruritus VAS:  A Visual Analogue Scale (VAS) will also be used to assess pruritus in 
individual subjects. 
12.2.6. 
Laboratory Assessments 
Subjects will be instructed to attend any study or unscheduled laboratory visits (except 
Screening) in a fasted state, and subjects should remain fasted until their blood samples have 
been collected.  At each visit, the Investigator or designee will verify that the subject has fasted 
for at least 8 hours and record fasting status in the source and CRF.  If the subject reports having 
eaten (water is permitted) within 8 hours, the Investigator or designee will document accordingly 
in the source and CRF and remind the subject that fasting is required prior to all study visits. 
Blood samples for serum chemistry and hematology will be collected at every visit as detailed in 
the Schedule of Study Procedures (Section 7.1.1).  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 by the central clinical laboratory in a study specific laboratory 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 subjects 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 12, and the normal reference ranges 
for liver biochemistries are shown in Appendix C. 
Table 12: 
List of Laboratory Analytes to be Tested 
Laboratory Assessment 
Analyte 
Serum Chemistry  
Albumin, blood urea nitrogen (BUN), 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 very low-density 
lipoprotein [VLDL] fractions and triglycerides[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 
Prothrombin time (PT), partial thromboplastin time 
(PTT), international normalized ratio (INR) 
Urinalysis 
pH, specific gravity, total protein, glucose, ketones, 
bilirubin, blood, microscopic exam, urobilinogen, 
albumin, creatine, leucocytes, nitrates, 
albumin/creatine ratio (if positive) 
Markers of Cholecystitis and Pancreatitis 
amylase and lipase 
Biomarkers of Hepatic Fibrosis and/or Inflammation  
IgM, C-reactive protein (CRP), TNF-α, FGF-19, CK-
18, ELF, and others as determined during course of 
study  
Genetics 
DNA including single-nucleotide polymorphisms 
(SNPs) that may be involved in PBC; RNA 
Other 
OCA (parent and conjugates [glyco and tauro], 
OCA-glucuronide) and C4 
The Investigator should manage subjects with clinically significant lipoprotein abnormalities 
using local standard of care procedures as appropriate after assessing the individual subject’s 
total cardiovascular risk profile. 
Urine-based β-hCG pregnancy tests will be performed in female subjects of childbearing 
potential per protocol specified visits.  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 
subject will be followed, as outlined in Section 12.1.11 through pregnancy outcome. 
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MELD scores and Child-Pugh score will be calculated at screening, and at all visits based on 
serum chemistry and coagulation. 
13. 
STATISTICAL METHODS 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
hypothesis tests, will be prepared and approved by the Sponsor and its designees prior to the first 
interim analysis, propensity score determination, and unblinding of the double-blind subject 
treatment assignments. 
13.1. 
Efficacy Analysis 
13.1.1. 
Analysis Populations 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
• The Intent-to-Treat (ITT) Population will include all randomized subjects who 
receive any amount of investigational product (OCA or placebo).  The ITT 
Population will be the primary population used for efficacy analyses.  Treatment 
assignment will be based on the randomized treatment. 
• The Per Protocol (PP) Population will include all ITT subjects who do not have any 
major protocol violations that potentially affect the efficacy conclusion.  Treatment 
assignment will be based on the randomized treatment. 
• The Safety Population will include all subjects who received any amount of 
investigational product (placebo or OCA).  The Safety Population will be the primary 
population used for safety analyses.  Treatment assignment will be based on the 
treatment actually received. 
• The PK Population will include all OCA subjects who have at least one confirmed 
fasted analyzable sample.  Subjects must have been fasting for approximately 8 hours 
prior to the visit and must not have any major protocol deviations that potentially 
affect exposure levels.  The PK population will be used for OCA PK analyses.  
• The Overall Historical Control Population will include subjects from the United 
Kingdom (UK) -PBC Group and Global PBC Study Group databases with 
demonstrated comparability to randomized subjects in this clinical study (747-302) 
with respect to both subject characteristics and disease progression. 
• The UK-PBC Historical Control Population will include subjects from the UK-PBC 
Group databases with demonstrated comparability to randomized subjects in this 
clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
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• The Global PBC Historical Control Population will include subjects from the Global 
PBC Study Group database with demonstrated comparability to randomized subjects 
in this clinical study (747-302) with respect to both subject characteristics and disease 
progression. 
13.1.1.1. Comparability of Historical Controls 
Utilization of both historical control/observational databases (UK-PBC and Global PBC Study 
Group), with more than 6000 subjects each, allow for a rigorous subject level meta-analysis.  The 
historical databases include long-term follow up, detailed subject-level information such as 
baseline clinical characteristics, longitudinal liver biochemistry, and long-term outcomes, and 
span a broad range of subject characteristics that may influence disease (disease state, age, 
gender, and regional differences in standard of care).  Historical controls from both databases 
will be chosen based on the same study inclusion/exclusion criteria.  Propensity score matching 
method will be utilized to select historical controls that match the treated subjects using available 
covariates. The adequacy of matching will be assessed by statistical methods described under 
Section 13.1.8.  
13.1.2. 
Determination of Sample Size 
The target population is subjects who are at higher risk of liver-related clinical complications. 
Eligible subjects will have a diagnosis of PBC with bilirubin levels >ULN and ≤5x ULN and/or 
ALP >3× ULN.  The following assumptions were used in sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.6 at 8 years with a hazard 
ratio of 0.60, and total study duration of 10 years (from first subject enrolled), 
allowing for 4 years of subject accrual and 6 years of follow up. 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 groups will be compared using a 2-sided log rank test at the 5% level of 
significance. 
• Two interim analyses and one final analysis are planned.  The first interim analysis 
will be performed when 50% of the target events are accrued and the second interim 
will be performed when 75% of the target events are accrued.  
• A dropout rate of 10% is assumed 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
13.1.2.1. Sample Size Monitoring 
Conducting a long-term outcomes study given the low disease prevalence, relatively slow 
disease progression, and ethical considerations, which in combination will impact recruitment 
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and event rates, is inherently difficult.  As stated in ICH E9, in long-term trials there is an 
opportunity to check the assumptions that underlay the original design and sample size 
calculations.  The power stated above depends on the total number of events.  Thus, the overall 
survival function can be estimated without unblinding. 
Therefore, the aggregate event rate and sample size based on recruitment and retention will be 
evaluated quarterly in a blinded manner.  This evaluation will determine if any increases in 
number of subjects are required in order to obtain a total of 127 adjudicated events for the final 
analysis in the combined groups.  Specifically, the pooled number of events will be available 
during the study in a blinded manner, without any knowledge of the comparative efficacy in the 
treatment groups.  This method for evaluating the sample size does not inflate the type I error 
rate.  Additional subjects may be enrolled as appropriate. 
13.1.3. 
Primary Efficacy Analysis 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
• Liver transplant 
• MELD score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month). 
The primary efficacy analysis will compare OCA to placebo with respect to the primary efficacy 
endpoint using the ITT population.  Only adjudicated events will be included in analyses.  The 
2 treatment groups will be compared 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 determined based on a Cox regression model stratified by 
randomization strata to estimate the magnitude of the effect.  The same analyses for primary 
efficacy endpoints will be performed for PP population as a sensitivity analysis.  
13.1.4. 
Key Secondary Efficacy Analyses 
The key secondary efficacy endpoints will compare OCA to placebo on the following: 
• Time to first occurrence of MELD score ≥15 
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• Time to liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The key secondary efficacy analyses will compare OCA to placebo in the ITT population with 
respect to the key secondary efficacy endpoints.  Only adjudicated events will be included in 
time-to-event analyses.  The comparison (hypothesis testing) will be conducted as specified in 
Section 13.1.10 in a sequential closed testing gate-keeping procedure, provided that the primary 
efficacy endpoint comparison is statistically significant in favor of the OCA treatment group.  If 
the primary comparison is not statistically significant then comparison of the secondary 
endpoints will be considered as descriptive and exploratory.  This procedure controls the 
study-wise type I error. 
The 2 treatment groups will be compared using the same methodology as specified for the 
primary efficacy analysis (Section 13.1.3).  The same analyses for key secondary efficacy 
endpoints will be performed for PP population as a sensitivity analysis. 
Analyses of change from Baseline to end of study in ALP and total bilirubin will be compared 
between treatment groups using analysis of covariance (ANCOVA) with change from Baseline 
as the dependent variable including treatment group and randomization stratification factor as 
fixed effects and the Baseline values as a covariate.  The same analysis will be carried out using 
percentage change from Baseline as the dependent variable. 
Descriptive statistics of the laboratory values will be summarized by treatment group.  The 
results, change from Baseline, and percentage change from Baseline values, as well as estimates 
of least-square means, standard errors, and 95% CIs, will be presented by treatment group.  
Estimates of the mean difference between treatment groups, the standard error of the difference, 
and 95% CI of the difference will be presented.  
13.1.5. 
Additional Secondary Efficacy Analyses 
The following time-to-event secondary efficacy analyses will compare OCA versus placebo 
using the ITT population: 
• Time to each component of the primary efficacy endpoint (except MELD score ≥15 
which is captured above) 
• Time to development of varix/varices 
• Progression to cirrhosis 
• Time to occurrence of HCC 
• Time to liver-related death 
• Time to liver-related death or liver transplant 
• Time to liver-related death, liver transplant, or MELD score ≥15 
The same analysis methodology as used for the primary efficacy analysis will be used for these 
secondary efficacy analyses.  Similar endpoints, where available, will be analyzed to compare 
OCA to historical controls as described below in Section 13.1.8. 
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Analyses of changes in liver biochemistry (GGT, ALT, AST, conjugated bilirubin, albumin, and 
INR) will be summarized and analyzed using the same methodology as specified in 
Section 13.1.4 for the key secondary analyses of change in ALP and total bilirubin. 
Progression to cirrhosis will be assessed in the subset of subjects considered noncirrhotic at 
Baseline using available medical history, clinical, and laboratory assessments as well as baseline 
TE, where available.  Specifically, subjects with no clinical, laboratory, or radiological evidence 
of cirrhosis at baseline and/or a TE liver stiffness of <16.9 kPa (Corpechot 2012) will be 
considered noncirrhotic (See Section 7.5.4).  Progression to cirrhosis will be assessed by the 
development of clinical, laboratory, or radiological evidence of cirrhosis and/or when liver 
stiffness increases to ≥16.9 kPa during the study in which case histological progression to 
cirrhosis should be confirmed by biopsy unless not medically indicated. Using this definition for 
progression to cirrhosis, the percentage of noncirrhotic subjects progressing to cirrhosis during 
the treatment period will be summarized by treatment group and compared using a 
Cochran-Mantel-Haenszel test stratified by the randomization stratification factor.  
For those subjects enrolled in the biopsy substudy (defined in Addendum 2) progression to 
cirrhosis identified by the above criteria and improvement in fibrosis/cirrhosis will be confirmed 
by paired biopsy.  Analyses for the histological assessment conducted as part of the biopsy 
substudy are defined in Addendum 2). 
Analyses of changes in MELD score, Child-Pugh score, MRS, IgM, CRP, TNF-α, FGF-19, 
CK-18, C4, and ELF score will be summarized and analyzed using the Wilcoxon Rank Sum Test 
to compare treatment groups.  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. 
13.1.5.1. Association of Biochemistry with Clinical Outcomes and Clinical Benefit  
The association between biochemistry including ALP and bilirubin with clinical outcomes will 
be assessed and the clinical benefit of OCA using biochemistry as a surrogate endpoint will be 
evaluated.  Detailed analysis will be described in the SAP.  
Based on the association between biochemical changes and clinical outcomes described above, 
clinical benefit of OCA using biochemistry as a surrogate endpoint for key subpopulations of 
interest will be evaluated. This analysis will be further described in the SAP. 
13.1.6. 
Exploratory Efficacy Analyses 
13.1.6.1. Responder Analyses 
The percentage of subjects with a decrease in ALP of ≥15% and ≥40% from Baseline will be 
summarized by treatment group.  In addition, the percentage of subjects with ALP ≤ULN will be 
summarized by treatment group. 
The percentage of subjects that meet the criteria of a responder based on each of the definitions 
below will be summarized by treatment group.  The response classification at baseline will also 
be included in the summary:  
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• ALP ≤3x ULN and AST ≤2x ULN and total bilirubin ≤ULN (Corpechot 2008) 
• ALP ≤1.5x ULN and AST ≤1.5x ULN and total bilirubin ≤ULN (Corpechot 2011) 
• ALP ≤1.67x ULN and total bilirubin ≤ULN (Momah 2012) 
• Normal bilirubin (values ≤ULN) and normal albumin (values ≥lower limit of normal) 
(Kuiper 2009) 
• ALP ≤1.76x ULN (Kumagi 2010) 
Responder analyses will compare treatment groups using a Cochran–Mantel–Haenszel test 
stratified by the randomization stratification factor.  Missing values will be considered as a 
non-responder.   
13.1.7. 
Pharmacoeconomic and Health Outcomes Endpoints 
Sufficient data will be collected on resource utilization and quality of life to undertake 
cost-effectiveness analyses that are relevant to the major countries taking part in this study.  
Resource utilization data on hospitalizations, healthcare provider visits, and medications will be 
combined with appropriate national unit costs to calculate a cost per patient per year in the study. 
Quality of life data from patient-reported outcomes measures will be combined with survival 
data to calculate quality adjusted time in the study per patient.  Cost-effectiveness analyses will 
report the incremental cost per major clinical outcome averted, liver-related death averted, 
life-year gained and quality-adjusted life year gained, including OCA as part of usual care versus 
usual care without OCA.  Analyses will be conducted within the study and using a lifetime 
perspective.  A separate economic analysis plan will be prepared and reported separately from 
this protocol. 
13.1.8. 
Supportive Analysis 
Per the International Conference on Harmonisation (ICH) E10 guidance, “where no obvious 
single optimal external control exists, it may be advisable to study multiple external controls”.  
In order to address the risks associated with the inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare clinical outcomes in the OCA treatment arm to 
historical controls, which serves as an external control for supportive analysis.   
In an attempt to avoid the inherent biases with historical controls and to maintain the integrity of 
this comparison, one can invoke matching methods to optimize comparability and find a 
historical control that is “similar” to a participating subject.  The historical database control 
should be as similar as possible to the study population and should have been exposed to a 
similar standard of care (see Section 5.5.2.3). 
A propensity score can be used to reduce bias through matching, stratification, regression 
adjustment, or some combination.  Propensity scores use information from a pool of patients who 
do not participate in the study (historical controls) to identify what would have happened to 
participating subjects in the absence of the treatment.  By comparing how outcomes differ for 
treated subjects relative to historical controls, it is possible to estimate the effects of the treatment 
between the treated subjects and the matched natural history subjects. 
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A full range of covariates across which the treatment and historical controls might differ will be 
considered to mitigate potential bias. Although the results of using matching controls are 
conditional only on the observed covariates, if one has the ability to measure many of the 
covariates that are believed to be related to the treatment assignment, then one can be fairly 
confident that approximately unbiased estimates for the treatment effect can be obtained.  Both 
UK-PBC Group and the Global PBC Study Group formally collect numerous covariates that 
could be used for propensity score estimation including standard of care, eg, UDCA. 
Historical controls will be chosen based on the same inclusion/exclusion criteria where possible. 
Propensity scores will be estimated using the available covariates that predict receiving the 
treatment.  Only covariates and not outcome variables will be included in the propensity score 
estimation, to avoid biased results that are in favor of one treatment.  
The covariates and factors collected in the historical databases will be specified in the SAP. 
Propensity scores will be estimated first through a logistic regression model with treatment group 
as the dependent variable and the above covariates/factors as independent variables.  Then the 
stratum boundaries are determined based on the propensity score values for both groups (OCA 
population and control [historical and randomized placebo]) combined or in the OCA population 
or historical control group alone.  Based on recommendations in the literature, quintiles of the 
estimated propensity score from the combined group will be used to determine the stratum 
boundary cut-offs for the different strata.  
The baseline characteristics between treated and natural history subjects in the matched dataset 
will be summarized and presented in a tabular format.  Statistical methods such as Wilcoxon 
Rank-Sum test will be used to assess the balance for baseline covariates.  The standardized 
difference and variance ratios for these covariates will also be calculated.  In addition, box plots 
of propensity scores for treated and natural history subjects will be separately presented, to 
further assess the adequacy of matching.  
A third-party statistician(s) will perform the propensity score modeling and matching.  This 
third-party statistician(s) will be separate and independent from the statistician(s) who will assess 
the success of matching and perform efficacy analyses.  Outcome events collected in the 
historical database are:  death (liver-related and all-cause), liver transplant, HCC, and other.  
Other is defined as cirrhosis or decompensation such as ascites, variceal bleed, and 
encephalopathy. 
The propensity score quintile will be then be used as the stratification factor in the stratified log 
rank test to compare randomized OCA-treated subjects in the ITT population and historical 
controls (Overall Historical Control Population: both the UK-PBC Group and Global PBC Study 
Group databases) on the following outcomes: 
• Time to death (all-cause) 
• Time to liver-related death 
• Time to liver transplant 
• Time to liver transplant or death (all-cause) 
• Time to liver transplant or liver-related death 
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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 determined based on a Cox regression 
model stratified by randomization strata to estimate the magnitude of the effect. 
Sensitivity analyses will be conducted limiting to the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms and factors may be considered. 
Although the study is designed as a placebo-controlled study, the DMC may recommend changes 
to study conduct based on the pre-specified interim analyses (see Section 13.1.12), including the 
potential use of a revised primary efficacy analysis.  This analysis would compare all subjects in 
the OCA population, to all control subjects (randomized placebo and historical controls) on time 
to liver transplant or death (all-cause), using similar statistical methodology as specified above. 
Notably, the planned primary analysis would not be revised without prior agreement with 
regulatory authorities. 
13.1.9. 
Handling of Dropouts or Missing Data 
Subjects who discontinue investigational product are expected to continue in the study until 
study termination. 
Missing data will be assumed to be missing at random.  In order to determine the effect of 
missing data on the analysis, efficacy endpoints will be analyzed using different methods of 
imputation as described below. In addition, the same analyses for primary and key secondary 
endpoints based on ITT and PP populations will be performed to assess robustness of analysis 
results.  During the conduct of the study, the DMC may recommend refining the missing data 
strategy to better address the observed pattern of missing data, based on blinded monitoring of 
the data. 
13.1.9.1. Time to Event Endpoints 
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 investigational product dosing). 
For analyses of the percentage of subjects with an event, subjects with no data after 
randomization will be considered to have an event. 
All time to event endpoints include only adjudicated events.  Sensitivity analyses may consider 
all events regardless of adjudication.  Events with discrepant adjudication will be analyzed using 
both results. 
13.1.9.2. Quantitative Endpoints 
For efficacy endpoints that utilize an ANCOVA model, observed cases will serve as the primary 
analysis.  Sensitivity analyses to assess the effect of missing data may be conducted where 
missing data is imputed using last observation carried forward. 
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Sensitivity analyses of ANCOVA models will also be evaluated using a restricted maximum 
likelihood based mixed-effect repeated measures model where no imputations will be made for 
missing values.   
13.1.9.3. Responder Endpoints 
In an efficacy analysis in which subjects are classified as either a responder or a non-responder 
(binary outcome) based on dichotomizing a continuous variable, any subject who does not 
provide an assessment at the specified timepoint for the defining of response will be considered 
to be a non-responder.  That is, for the percentage of responders, the subject will be included in 
the denominator and will not contribute to the numerator. 
For sensitivity analyses using only “observed cases,” subjects who do not provide an assessment 
at the specified timepoint for the defining of response will not be included.  That is, for the 
percentage of responders, the subject will not be included in the numerator or the denominator. 
13.1.10. 
Multiple Comparisons/Multiplicity 
The key secondary efficacy endpoints are as follows: 
• Time to MELD score ≥15 
• Time to first occurrence of liver transplant or death (all-cause) 
• Change from Baseline in total bilirubin at end of study 
• Change from Baseline in ALP at end of study 
The hypothesis testing of key secondary analyses will compare placebo and OCA and will be 
conducted in a sequential closed testing gate-keeping procedure (in the order in which the key 
secondary endpoints are stated above), provided that the primary efficacy endpoint comparison is 
statistically significant in favor of OCA.  If the primary comparison is not statistically significant 
then comparison of the secondary endpoints will be considered as descriptive and exploratory.  
This procedure controls the study-wise type I error.  
• First (step 1) placebo and OCA will be compared with respect to the primary efficacy 
endpoint.  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• The time to MELD score ≥15 will be compared between placebo and OCA (step 2).  
If the comparison achieves statistical significance at 2-sided 0.05 level in favor of 
OCA group, then 
• The time to liver transplant or death (all-cause) will be compared between placebo 
and OCA (step 3).  If the comparison achieves statistical significance at 2-sided 
0.05 level in favor of OCA group, then 
• Change from Baseline in total bilirubin will be compared between placebo and OCA 
(step 4).  If the comparison achieves statistical significance at 2-sided 0.05 level in 
favor of OCA group, then 
• Change from Baseline in ALP at the end of study will be compared between placebo 
and OCA (step 5). 
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If at any step defined above the comparison is not statistically significant at the 2-sided 
0.05 level then the remaining comparisons in the stated hierarchy will be considered descriptive 
and exploratory.  The study-wise type I error will be maintained with the above closed 
procedure. 
Additional efficacy endpoints will be analyzed; however, hypothesis tests will be applied for 
descriptive and exploratory purposes only.  
13.1.11. 
Examination of Subgroups 
The primary and secondary efficacy endpoints will be analyzed for subject subgroups based on 
the ITT population.  Subgroups will be assessed at Baseline and only if there are a sufficient 
number of subjects in each group (eg, >5 subjects per group). 
Baseline subgroups of interest are as follows:  age, age at PBC diagnosis, sex, race, body mass 
index, ALP level, bilirubin level, use of UDCA, years since diagnosis of PBC, and geographic 
region. 
The primary efficacy endpoint will also be assessed across the spectrum of PBC disease stage as 
defined by Rotterdam criteria (Kuiper 2009)  
• Early (normal albumin and normal bilirubin) 
• Moderate (abnormal albumin or abnormal bilirubin) 
• Advanced (abnormal albumin and abnormal bilirubin) 
The primary efficacy endpoint will also be assessed for the following clinically relevant 
subpopulations. 
• Monotherapy in patients who are intolerant or non-responsive to UDCA  
• Elderly patients 
Assuming a strong correlation between biochemistry and clinical outcomes using the total study 
population (Section 13.1.5.1) is observed, we will further assess the biochemical improvement in 
relevant subpopulations as applicable (eg, Rotterdam disease severity and monotherapy) and 
estimate the reduction in risk of clinical outcomes associated with the biochemical improvement. 
Additional details regarding statistical methods and subgroup definitions will be provided in the 
SAP. 
13.1.12. 
Continuous Monitoring and Interim Analyses 
Blinded safety reports including the accrual of events, drop outs, and/or loss of subjects to 
commercially available OCA will be reviewed by the DMC on a regular basis.  
Two planned interim analyses of the liver-related outcomes will be conducted using the 
Lan-DeMets O’Brien-Fleming boundaries (Reboussin 2000).  Both interim analyses will be 
pre-specified and will occur after accrual of 50% (64 events) and 75% (96 events) of clinical 
outcome events, respectively.  
The DMC will review the available efficacy data in conjunction with detailed safety data and 
other relevant information to recommend continuation, modification, or cessation (for efficacy) 
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of the study beyond each interim analysis.  Modification of the study would not take place 
without prior agreement with regulatory authorities. 
13.2. 
Safety Analysis 
Safety data, including AEs and clinical laboratory observations, will be summarized by treatment 
group using the Safety Population. 
13.2.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary of Regulatory Activities.  Summary tables of 
treatment-emergent AEs will be provided.  The incidence of TEAEs will be tabulated by system 
organ class and preferred term for each treatment group, and by severity and relationship to 
treatment.  Tables of TEAEs leading to investigational product discontinuation and SAEs will be 
provided. 
Adverse events of special interest as described in Section 12.1.1.4  will be summarized for each 
treatment group.  In addition, each event is a component of the primary endpoint, and will be 
summarized as secondary endpoints as described in Section 13.1.4. 
13.2.2. 
Clinical Laboratory Evaluations 
Descriptive statistics summarizing central laboratory data (hematology and chemistry) will be 
presented for all study visits.  Changes from pretreatment to each study visit will also be 
summarized by treatment group. 
13.2.3. 
Additional Safety Analysis 
Additional safety assessments include vital signs and ECGs.  Descriptive statistics of the vital 
sign and ECG parameters will be presented by treatment group and study visit, as well as the 
change from pretreatment at each visit. 
13.2.4. 
Cardiovascular Adjudication Committee 
In addition to potential clinical endpoint events, cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary endpoint in this study. Adjudicated cardiovascular events include core 
MACE (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) and expanded 
MACE (unstable angina requiring hospitalization, transient ischemic attack, peripheral or 
coronary revascularization procedures, hospitalization for congestive heart failure).  Other events 
potentially related to adverse cardiovascular outcomes may be included in the Cardiovascular 
Adjudication Committee (CAC) Charter for adjudication.  The adjudication of these events will 
be handled separately from the adjudication of events for assessment of the primary endpoint in 
this study (see Section 13.4). 
13.3. 
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 
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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 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 subjects.  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 subject treatment information; 
however, the DMC will have access to the database and may unblind individual subject data as 
appropriate.  Summary tables reviewed by the DMC during closed sessions will include an 
overall column containing information regarding all subjects 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, Medical Dictionary for Regulatory Activities (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 subject safety, which alter the 
conduct of this study.  The Investigators will inform the subjects of such actions and the 
protocol, patient information sheet (PIS), and consent will be revised, as appropriate. 
13.4. 
Adjudication Committees 
All suspected liver-related clinical outcomes, and MACE/Expanded MACE, 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 
2 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 
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 
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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 subject 
treatment or site-specific information.  The assessment of events will be conducted in 
compliance with study-specific procedures, manuals, good clinical practice (GCP), and all other 
applicable regulatory requirements, including the archiving of essential documents.    
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
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 subject’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 CRF.  The CRF 
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 
subject's medical records if these are deemed relevant to the performance, observations or 
conduct of this study. 
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14.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC 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.   
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the CRF 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 14.2 for more details regarding the audit 
process. 
16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF and/or other subject 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 the Sponsor before he or she can enroll 
any subject 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 subjects to the ethics committee 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 subjects for 
the study.  The protocol must be reapproved by the IRB or 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.  
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, at a minimum annually, and after the study is complete. 
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16.2. 
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. 
16.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated ICF 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 subject. 
16.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential and confidentiality of all subjects will be maintained.  Monitors 
(eg, CRA, Medical Monitor), auditors and inspectors will require access to a subject’s medical 
notes for the purpose of source document verification but the subject’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 subject’s names and identifying information (eg, subject’s 
hospital number, unique subject number).  This list will not be collected by the Sponsor. 
The written information sheet 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 subject 
number/randomization code/subject initials/site number, only. 
When personal data on subjects are stored or processed by computer, the data must be protected 
to prevent their disclosure to unauthorized third parties.  The pertinent sections of the data 
protection laws in which the country is being conducted will be complied with in full. 
The written ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IEC/IRB may require direct access to parts of the hospital 
or study site records relevant to the study, including subject’s medical history. 
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17. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the subjects 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 subjects, as applicable. 
17.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject 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 Medical Monitor. 
17.2. 
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 subject’s safety to be compromised if immediate action is not taken. 
17.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
• Approved ICF (all versions) 
• IRB/EC approvals (of protocol/amendments, subject questionnaires, etc) 
• Form FDA 1572 or equivalent form for the Investigator’s region 
• Current medical license 
• Curriculum vitae 
• Laboratory certification and reference ranges 
• Financial disclosure forms 
17.4. 
Ethics Review 
Please see Section 16.1 for the Investigator’s responsibilities regarding ethics review. 
17.5. 
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. 
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All documents relating to the study including the ISF itself, source documents and subject 
medical files (retained per country specific regulations), completed study subject log and 
confidential subject 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 prior to 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. 
18. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it sponsors consistent 
with the Declaration of Helsinki (Seoul Revision 2008, 
[http://www.wma.net/en/30publications/10policies/b3/index.html, accessed May 22, 2013]).  
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 Study Registries (eg, 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 (when available) 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 
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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:  The Sponsor, 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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19. 
LIST OF REFERENCES 
Banks O, Bollen T, Dervenis C, et al.  Classification of acute pancreatitis02012: revision of the 
Atlanta classification and definitions by international consensus.  Gut.2013;62:102-111. 
Beuers U, Gershwin M, Gish R, et al. Changing nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Digestive and Liver Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin M, Gish R, et al. Changing nomenclature for PBC: From ‘cirrhosis’ to 
‘cholangitis’. Gastroenterology. 2015b;149(6):1627-9. 
Beuers U, Gershwin M, Gish R, et al. Changing nomenclature for PBC: From 'cirrhosis' to 
'cholangitis'. Hepatology. 2015c;62(5):1620-2. 
Beuers U, Lindor KD. A major step towards effective treatment evaluation in primary biliary 
cirrhosis. J Hepatol. 2011;55(6):1178-80. 
Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and 
long term prognosis in primary biliary cirrhosis. Hepatology. 2008;48(3):871-877. 
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. 
Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: Biochemical response 
to treatment and prediction of long-term outcome. J Hepatol. 2011;55:1361–1367. 
Dickson ER, Grambsch PM, Fleming TR, et al.  Prognosis in primary biliary cirrhosis:  Model 
for decision making.  Hepatology. 1989;10(1):1-7. 
Elman S, Hynan L.S., Gabriel V, and Mayo M.J. The 5-D itch scale: a new measure of pruritus, 
British Journal of Dermatology. 2010;162,587–593. 
European Association for the Study of the Liver.  EASL Clinical Practice Guidelines: 
Management of cholestatic liver diseases.  J Hepatol. 2009;51:237-267. 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact of fatigue: initial validation of 
the fatigue impact scale. Clin Infect Dis. 1994 Jan;18 Suppl 1:S79-83.  
Greenburg J, Hsu J, Bawazeer M., et al.  Clinical Practice Guideline:  Management of acute 
pancreatitis.  Can J Surg. 2016;59 (2):128-140. 
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. 
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. 
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Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict 
long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol. 
2010;105(10):2186-94. 
Kumar A, Saraswat V.  Hepatitis E and Acute-on-Chronic Liver Failure.  J Clin Exp Hepatol. 
2013 Sep;3(3):225-30. doi: 10.1016/j.jceh.2013.08.013. Epub 2013 Sep 16. 
Lammers WJ, van Buuren HR, Hirschfield GM, et al. Alkaline phosphatase values are a 
surrogate marker in prediction of transplant-free-survival in patients with primary biliary 
cirrhosis - an international, collaborative analysis.  J Hepatol. 2013; 58(Suppl):S388. 
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. 
Momah N, Silveira MG, Jorgensen R, et al. Optimizing biochemical markers as endpoints for 
clinical trials in primary biliary cirrhosis. Liver Int. 2012;32(5):790-795. 
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. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-3572. 
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. 
Reboussin DM, DeMets, DL, Kim KM, et al.  Computations for Group Sequential Boundaries 
Using the Lan-DeMets Spending Function Method.  Controlled Clin Trials.  2000;21(3):190-207. 
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. 
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APPENDIX A. MODIFIED DOSING REGIMEN FOR SUBJECTS WITH 
CHILD-PUGH B/C HEPATIC IMPAIRMENT 
Subjects with cirrhosis and classified as Child-Pugh B or Child-Pugh C at Screening will follow 
a modified dosing schedule initiating 5 mg OCA or matching placebo once weekly as described 
in Figure 3.  After a minimum of 3 months dosing once weekly with 5 mg OCA or matching 
placebo, and following review of the pre-titration laboratory results to assess safety and 
tolerability, the dosing frequency of 5 mg OCA or matching placebo should be increased to twice 
weekly (at least three days apart).  Subjects who have maintained the twice weekly dosing 
frequency for a minimum of at least 6 weeks, and meet the dose titration criteria, should 
up-titrate to the maximum allowed dose of 10 mg OCA or matching placebo twice weekly 
(Table 13). 
Investigators may decrease the dosing frequency (back to once weekly) or dose for any subject at 
any time during the study, as considered clinically appropriate (eg, tolerability).   
Figure 3: 
Dosing by Cirrhosis Status and Child-Pugh Score 
 
a  Cirrhosis may be assessed by histology or non-histological methods as defined in Section 7.5.4. 
BIW = twice weekly; QW = once weekly 
Table 13: 
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Modified Dosing Regimen for  
Child-Pugh B or Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg once weekly 
 
Titration 1b  
(≥Month 3) 
5 mg twice weeklyc 
 
Titration 2b  
(≥6 weeks after Titration 1) 
10 mg twice weeklyc 
 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject 
tolerability and/or changes in cirrhosis status or Child-Pugh Score at any time during the study. 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
Dose Titration due to Change in Cirrhosis or Child-Pugh Score 
When subjects demonstrate a change in cirrhosis status (as assessed per Section 7.5.4) or 
Child-Pugh Score (Section 7.5.5 dosing should be reassessed and the dosing regimen modified 
appropriately.  Changes in Child-Pugh Score that result from a transient, explainable change in 
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laboratory parameters (eg, increase in INR due to vitamin K deficiency) should be documented 
appropriately and discussed with the Medical Monitor before any continuation or change to the 
dosing regimen.    
Possible scenarios for dosing modifications include: 
• Subjects who develop cirrhosis during the course of the trial with a classification of 
Child-Pugh B or C 
• Subjects with pre-existing cirrhosis who demonstrate a change in the Child-Pugh 
Score from A to B or C at any point in the study   
Subjects may titrate dose and dosing frequency up or down as appropriate, within the dosing 
regimen.  Up-titration should be done per Investigator discretion and be guided by the 
pre-titration tolerability assessments outlined in Section 7.4.1.  A 1-Month and 2-Month 
Post-Titration Assessment must be performed any time a subject’s dose or frequency is up-
titrated (see Section 7.1.1 and Section 9.7.7). 
Unscheduled Titration Visit, Optional Visit 
An unscheduled up-titration visit may be scheduled for as early as 6 weeks after the initial 
titration visit (or subsequent titration visit) occurs for subjects who are following the modified 
dosing regimen.  The visit procedures required for the unscheduled titration visit are outlined 
below.  Subjects who up titrate at an unscheduled visit will continue to follow the regular visit 
schedule for all other study visits.   
For subjects who up titrate at an unscheduled visit the following procedures will be performed: 
• Assess and record AEs. 
• Review and record concomitant medications. 
• Perform the pre-Titration Tolerability Assessment as outlined in Section 7.4.1. 
• Assess the subject’s supply of investigational product to ensure an adequate amount.  
Access the IWRS and dispense investigational product if necessary. 
• Provide the subject with a dosing diary to document his or her dosing. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
- 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. 
For subjects who up-titrate at an unscheduled visit:  The ±1-week window related to the 2-month 
Post-Titration Visit can be modified to occur 2 weeks earlier or 2 weeks outside of the allowed 
visit window to allow for the post-titration assessment to be performed during one of the 
subject’s regularly scheduled study visits.  If the 2-month Post-Titration Visit is performed 
during a regularly scheduled study visit, all scheduled procedures associated with that visit 
should be performed.  
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APPENDIX B. ETHICAL CONDUCT ACCORDING TO THE 
DECLARATION OF HELSINKI FOR COUNTRIES 
PARTICIPATING OUTSIDE THE US (DECLARATION 
OF HELSINKI, FORTELEZA, BRAZIL, 2013) 
 
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Copyright 2013 American Medical Association. All rights reserved.
World Medical Association Declaration of Helsinki
Ethical Principles for Medical Research
Involving Human Subjects
World Medical Association
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1. The World Medical Association (WMA) has developed the Dec-
larationofHelsinkiasastatementofethicalprinciplesformedi-
cal research involving human subjects, including research on
identifiable human material and data.
The Declaration is intended to be read as a whole and each of
its constituent paragraphs should be applied with consider-
ation of all other relevant paragraphs.
2. ConsistentwiththemandateoftheWMA,theDeclarationisad-
dressed primarily to physicians. The WMA encourages others
who are involved in medical research involving human subjects
to adopt these principles.
General Principles
3. TheDeclarationofGenevaoftheWMAbindsthephysicianwith
the words, “The health of my patient will be my first consider-
ation,”andtheInternationalCodeofMedicalEthicsdeclaresthat,
“A physician shall act in the patient's best interest when provid-
ing medical care.”
4. It is the duty of the physician to promote and safeguard the
health,well-beingandrightsofpatients,includingthosewhoare
involvedinmedicalresearch.Thephysician'sknowledgeandcon-
science are dedicated to the fulfilment of this duty.
5. Medical progress is based on research that ultimately must in-
clude studies involving human subjects.
6. Theprimarypurposeofmedicalresearchinvolvinghumansub-
jects is to understand the causes, development and effects of
diseasesandimprovepreventive,diagnosticandtherapeuticin-
terventions (methods, procedures and treatments). Even the
bestproveninterventionsmustbeevaluatedcontinuallythrough
research for their safety, effectiveness, efficiency, accessibility
and quality.
7. Medicalresearchissubjecttoethicalstandardsthatpromoteand
ensure respect for all human subjects and protect their health
and rights.
8. Whiletheprimarypurposeofmedicalresearchistogeneratenew
knowledge, this goal can never take precedence over the rights
and interests of individual research subjects.
9. Itisthedutyofphysicianswhoareinvolvedinmedicalresearch
to protect the life, health, dignity, integrity, right to self-
determination,privacy,andconfidentialityofpersonalinforma-
tion of research subjects. The responsibility for the protection
ofresearchsubjectsmustalwaysrestwiththephysicianorother
health care professionals and never with the research subjects,
even though they have given consent.
10. Physiciansmustconsidertheethical,legalandregulatorynorms
andstandardsforresearchinvolvinghumansubjectsintheirown
countries as well as applicable international norms and stan-
dards.Nonationalorinternationalethical,legalorregulatoryre-
quirementshouldreduceoreliminateanyoftheprotectionsfor
research subjects set forth in this Declaration.
11. Medical research should be conducted in a manner that mini-
mises possible harm to the environment.
12. Medicalresearchinvolvinghumansubjectsmustbeconducted
onlybyindividualswiththeappropriateethicsandscientificedu-
cation, training and qualifications. Research on patients or
healthyvolunteersrequiresthesupervisionofacompetentand
appropriately qualified physician or other health care profes-
sional.
Clinical Review & Education
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13. Groups that are underrepresented in medical research should
be provided appropriate access to participation in research.
14. Physicians who combine medical research with medical care
should involve their patients in research only to the extent that
this is justified by its potential preventive, diagnostic or thera-
peuticvalueandifthephysicianhasgoodreasontobelievethat
participation in the research study will not adversely affect the
health of the patients who serve as research subjects.
15. Appropriate compensation and treatment for subjects who are
harmed as a result of participating in research must be en-
sured.
Risks, Burdens and Benefits
16. Inmedicalpracticeandinmedicalresearch,mostinterventions
involve risks and burdens.
Medical research involving human subjects may only be con-
ductediftheimportanceoftheobjectiveoutweighstherisksand
burdens to the research subjects.
17. All medical research involving human subjects must be pre-
ceded by careful assessment of predictable risks and burdens
to the individuals and groups involved in the research in com-
parisonwithforeseeablebenefitstothemandtootherindividu-
als or groups affected by the condition under investigation.
Measurestominimisetherisksmustbeimplemented.Therisks
mustbecontinuouslymonitored,assessedanddocumentedby
the researcher.
18. Physiciansmaynotbeinvolvedinaresearchstudyinvolvinghu-
mansubjectsunlesstheyareconfidentthattheriskshavebeen
adequately assessed and can be satisfactorily managed.
When the risks are found to outweigh the potential benefits or
when there is conclusive proof of definitive outcomes, physi-
cians must assess whether to continue, modify or immediately
stop the study.
Vulnerable Groups and Individuals
19. Somegroupsandindividualsareparticularlyvulnerableandmay
haveanincreasedlikelihoodofbeingwrongedorofincurringad-
ditional harm.
All vulnerable groups and individuals should receive specifi-
cally considered protection.
20. Medical research with a vulnerable group is only justified if the
research is responsive to the health needs or priorities of this
group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to ben-
efit from the knowledge, practices or interventions that result
from the research.
Scientific Requirements and Research Protocols
21. Medicalresearchinvolvinghumansubjectsmustconformtogen-
erally accepted scientific principles, be based on a thorough
knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as appropriate, ani-
mal experimentation. The welfare of animals used for research
must be respected.
22. The design and performance of each research study involving
human subjects must be clearly described and justified in a re-
search protocol.
The protocol should contain a statement of the ethical consid-
erations involved and should indicate how the principles in this
Declaration have been addressed. The protocol should include
information regarding funding, sponsors, institutional affilia-
tions, potential conflicts of interest, incentives for subjects and
information regarding provisions for treating and/or compen-
sating subjects who are harmed as a consequence of participa-
tion in the research study.
In clinical trials, the protocol must also describe appropriate ar-
rangements for post-trial provisions.
Research Ethics Committees
23. Theresearchprotocolmustbesubmittedforconsideration,com-
ment, guidance and approval to the concerned research ethics
committee before the study begins. This committee must be
transparent in its functioning, must be independent of the re-
searcher, the sponsor and any other undue influence and must
be duly qualified. It must take into consideration the laws and
regulations of the country or countries in which the research is
to be performed as well as applicable international norms and
standardsbutthesemustnotbeallowedtoreduceoreliminate
anyoftheprotectionsforresearchsubjectssetforthinthisDec-
laration.
The committee must have the right to monitor ongoing stud-
ies.Theresearchermustprovidemonitoringinformationtothe
committee, especially information about any serious adverse
events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of
thestudy,theresearchersmustsubmitafinalreporttothecom-
mittee containing a summary of the study’s findings and con-
clusions.
Privacy and Confidentiality
24. Every precaution must be taken to protect the privacy of re-
search subjects and the confidentiality of their personal infor-
mation.
Informed Consent
25. Participation by individuals capable of giving informed consent
as subjects in medical research must be voluntary. Although it
Clinical Review & Education Special Communication
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2192
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may be appropriate to consult family members or community
leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26. In medical research involving human subjects capable of giving
informed consent, each potential subject must be adequately
informed of the aims, methods, sources of funding, any pos-
sible conflicts of interest, institutional affiliations of the re-
searcher,theanticipatedbenefitsandpotentialrisksofthestudy
and the discomfort it may entail, post-study provisions and any
other relevant aspects of the study. The potential subject must
be informed of the right to refuse to participate in the study or
to withdraw consent to participate at any time without repri-
sal. Special attention should be given to the specific informa-
tionneedsofindividualpotentialsubjectsaswellastothemeth-
ods used to deliver the information.
Afterensuringthatthepotentialsubjecthasunderstoodthein-
formation, the physician or another appropriately qualified in-
dividual must then seek the potential subject’s freely-given in-
formed consent, preferably in writing. If the consent cannot be
expressedinwriting,thenon-writtenconsentmustbeformally
documented and witnessed.
Allmedicalresearchsubjectsshouldbegiventheoptionofbeing
informed about the general outcome and results of the study.
27. When seeking informed consent for participation in a research
study the physician must be particularly cautious if the poten-
tial subject is in a dependent relationship with the physician or
mayconsentunderduress.Insuchsituationstheinformedcon-
sentmustbesoughtbyanappropriatelyqualifiedindividualwho
is completely independent of this relationship.
28. For a potential research subject who is incapable of giving in-
formedconsent,thephysicianmustseekinformedconsentfrom
thelegallyauthorisedrepresentative.Theseindividualsmustnot
be included in a research study that has no likelihood of benefit
forthemunlessitisintendedtopromotethehealthofthegroup
represented by the potential subject, the research cannot in-
stead be performed with persons capable of providing in-
formed consent, and the research entails only minimal risk and
minimal burden.
29. When a potential research subject who is deemed incapable of
givinginformedconsentisabletogiveassenttodecisionsabout
participationinresearch,thephysicianmustseekthatassentin
addition to the consent of the legally authorised representa-
tive. The potential subject’s dissent should be respected.
30. Research involving subjects who are physically or mentally in-
capable of giving consent, for example, unconscious patients,
may be done only if the physical or mental condition that pre-
ventsgivinginformedconsentisanecessarycharacteristicofthe
research group. In such circumstances the physician must seek
informedconsentfromthelegallyauthorisedrepresentative.If
nosuchrepresentativeisavailableandiftheresearchcannotbe
delayed,thestudymayproceedwithoutinformedconsentpro-
videdthatthespecificreasonsforinvolvingsubjectswithacon-
dition that renders them unable to give informed consent have
beenstatedintheresearchprotocolandthestudyhasbeenap-
provedbyaresearchethicscommittee.Consenttoremaininthe
researchmustbeobtainedassoonaspossiblefromthesubject
or a legally authorised representative.
31. Thephysicianmustfullyinformthepatientwhichaspectsoftheir
care are related to the research. The refusal of a patient to par-
ticipateinastudyorthepatient’sdecisiontowithdrawfromthe
study must never adversely affect the patient-physician rela-
tionship.
32. For medical research using identifiable human material or data,
such as research on material or data contained in biobanks or
similarrepositories,physiciansmustseekinformedconsentfor
its collection, storage and/or reuse. There may be exceptional
situations where consent would be impossible or impracti-
cable to obtain for such research. In such situations the re-
search may be done only after consideration and approval of a
research ethics committee.
Use of Placebo
33. The benefits, risks, burdens and effectiveness of a new inter-
vention must be tested against those of the best proven inter-
vention(s), except in the following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best
proven one, the use of placebo, or no intervention is necessary
to determine the efficacy or safety of an intervention
andthepatientswhoreceiveanyinterventionlesseffectivethan
thebestprovenone,placebo,ornointerventionwillnotbesub-
ject to additional risks of serious or irreversible harm as a result
of not receiving the best proven intervention.
Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34. Inadvanceofaclinicaltrial,sponsors,researchersandhostcoun-
trygovernmentsshouldmakeprovisionsforpost-trialaccessfor
all participants who still need an intervention identified as ben-
eficialinthetrial.Thisinformationmustalsobedisclosedtopar-
ticipants during the informed consent process.
Research Registration and Publication and Dissemination
of Results
35. Every research study involving human subjects must be regis-
teredinapubliclyaccessibledatabasebeforerecruitmentofthe
first subject.
World Medical Association Declaration of Helsinki
Special Communication Clinical Review & Education
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36. Researchers, authors, sponsors, editors and publishers all have
ethical obligations with regard to the publication and dissemi-
nationoftheresultsofresearch.Researchershaveadutytomake
publicly available the results of their research on human sub-
jectsandareaccountableforthecompletenessandaccuracyof
their reports. All parties should adhere to accepted guidelines
for ethical reporting. Negative and inconclusive as well as posi-
tiveresultsmustbepublishedorotherwisemadepubliclyavail-
able. Sources of funding, institutional affiliations and conflicts
of interest must be declared in the publication. Reports of re-
search not in accordance with the principles of this Declaration
should not be accepted for publication.
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven inter-
ventions do not exist or other known interventions have been
ineffective, the physician, after seeking expert advice, with in-
formed consent from the patient or a legally authorised repre-
sentative, may use an unproven intervention if in the physi-
cian's judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should subse-
quently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be re-
corded and, where appropriate, made publicly available.
ARTICLE INFORMATION
Corresponding Author: World Medical
Association, 13, ch. du Levant, CIB - Bâtiment A,
01210 Ferney-Voltaire, France; wma@wma.net.
Published Online: October 19, 2013.
doi:10.1001/jama.2013.281053.
Disclaimer: ©2013 World Medical Association, Inc.
All Rights Reserved. All intellectual property rights
in the Declaration of Helsinki are vested in the
World Medical Association. The WMA has granted
JAMA exclusive rights to publish the
English-language version of the Declaration
through December 31, 2013.
Online-Only Content: Audio podcast is available at
www.jama.com.
Clinical Review & Education Special Communication
World Medical Association Declaration of Helsinki
2194
JAMA
November 27, 2013
Volume 310, Number 20
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APPENDIX C. REFERENCE LABORATORY VALUES FROM CENTRAL LABORATORIES 
Covance Central Laboratories (Indianapolis, Indiana, US [for North America and Latin America regions]; Geneva, Switzerland [for 
Europe]; and Singapore [for Asia-Pacific region]) will serve as the central labs for analysis or specimen management for the analytes 
listed in the Table 12 of Protocol 747-302 Version 4.  The following in text table provides the Covance Laboratory reference ranges 
for the pertinent liver biochemistries analyzed by Covance.  These reference ranges are sex and/or age specific, and can change during 
the course of the clinical trial; therefore, investigative sites should always refer to the reference ranges available on the Covance issued 
laboratory reports. 
 
Covance Indianapolis 
Covance Geneva and Covance Singapore 
Analyte 
Sex 
Agea 
Reference Range 
Agea 
Reference Range 
Albumin 
Both 
18Y – 69Y 
SI Units: 33-49 g/L 
Conventional Units: 3.3-4.9 g/dL 
18Y – 69Y 
33-49 g/L 
69Y-80Y 
SI Units: 33-46 g/L 
Conventional Units: 3.3-4.6 g/dL 
69Y-80Y 
33-46 g/L 
80Y-150Y 
SI Units: 30-46 g/L 
Conventional Units: 3.0-4.6 g/dL 
80Y-150Y 
30-46 g/L 
ALP 
Female 
18Y - 50Y 
31-106 U/L 
18Y - 50Y 
31-106 U/L 
50Y - 60Y 
35-123 U/L 
50Y - 60Y 
35-123 U/L 
60Y - 70Y 
35-123 U/L 
60Y - 70Y 
35-123 U/L 
70Y - 80Y 
35-123 U/L 
70Y - 80Y 
35-123 U/L 
80Y - 90Y 
35–135 U/L 
80Y - 90Y 
35–135 U/L 
90Y – 150Y 
35-140 U/L 
90Y – 150Y 
35-140 U/L 
ALP 
Male 
18Y - 50Y 
31-129 U/L 
18Y - 50Y 
31-129 U/L 
50Y - 60Y 
35-131 U/L 
50Y - 60Y 
35-131 U/L 
60Y - 70Y 
35-125 U/L 
60Y - 70Y 
35-125 U/L 
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Covance Indianapolis 
Covance Geneva and Covance Singapore 
Analyte 
Sex 
Agea 
Reference Range 
Agea 
Reference Range 
70Y - 80Y 
35-130 U/L 
70Y - 80Y 
35-130 U/L 
80Y - 90Y 
35–125 U/L 
80Y - 90Y 
35–125 U/L 
90Y – 150Y 
35-125 U/L 
90Y – 150Y 
35-125 U/L 
ALT 
Female 
18Y – 69Y 
6-34 U/L 
18Y – 69Y 
6-34 U/L 
69Y – 150Y 
6-32 U/L 
69Y – 150Y 
6-32 U/L 
ALT 
Male 
18Y – 69Y 
6-43 U/L 
18Y – 69Y 
6-43 U/L 
69Y – 150Y 
6-35 U/L 
69Y – 150Y 
6-35 U/L 
AST 
Female 
18Y – 59Y 
9-34 U/L 
18Y – 59Y 
9-34 U/L 
59Y – 150Y 
9-34 U/L 
59Y – 150Y 
9-34 U/L 
AST 
Male 
18Y – 59Y 
11-36 U/L 
18Y – 59Y 
11-36 U/L 
59Y – 150Y 
11-36 U/L 
59Y – 150Y 
11-36 U/L 
Direct 
Bilirubin 
Both 
18Y – 150Y 
SI Units: 2-7 umol/L 
Conventional Units: 0.1-0.4 mg/dL 
18Y – 150Y 
2-7 umol/L 
Indirect 
Bilirubin 
Both 
0Y – 150Y 
SI Units: 0-21 umol/L 
Conventional Units: 0.0-1.2 mg/dL 
0Y – 150Y 
0-21 umol/L 
Total 
Bilirubin 
Both 
18Y – 150Y 
SI Units: 3-21 umol/L 
Conventional Units: 0.2-1.2 mg/dL 
18Y – 150Y 
3-21 umol/L 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; Y = years; SI=International System of Units 
a The unstated word “to” is implied by the “dash” appearing in age specific reference ranges. A range such as “0-59 years” and “59-150 years” means: “0 up to 
but not including 59 years” and “59 up to but not including 150 years”. 
Source: Covance Laboratory Services Manual Version 5.0.0. Dates vary by region: 10 Nov 2016 (North America), 22 Nov 2016 (Europe and Singapore) 
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APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1 (DATED 29 APR 2015) 
Rationale 
The changes to the Original Version of the protocol, detailed below, modify the dose titration schedule based on observed efficacy and 
tolerability of OCA, address advice provided by regulatory agencies, and clarify questions raised by study site personnel currently 
using Original protocol version 1 dated 03 October 2014. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.  (Note:  Differences are denoted in bold font; Minor 
formatting changes are not listed) 
Section 
Original Text 
Revised Text 
Title Page 
Original:  03 October 2014 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Procedures in 
Case of 
Emergency 
 
Procedures in Case of Emergency 
 
Study Personnel Contact Information 
 
Or if Not 
Available 
Contact:
 MD, 
 & 
 Development, Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
 
Contact:
 MD, Medical Director, Drug Safety, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
Synopsis 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
≤1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 
2 weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
Methodology 
This Phase 3b, double-blind, randomized, placebo-controlled, 
multicenter study will evaluate the effect of OCA on clinical 
outcomes in subjects with PBC.  Subjects will be screened during a 
1 to 8 week Screening period prior to entering the study to allow 
for the collection of repeat serum chemistry samples (at least 
2 weeks apart) to confirm pretreatment alkaline phosphatase (ALP) 
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and total bilirubin values (refer to Section 9.7.3).  Subjects who 
meet all inclusion criteria and none of the exclusion criteria will be 
randomized (1:1) to OCA or placebo treatment groups.  The 
randomization will be stratified by ursodeoxycholic acid (UDCA) 
treatment (yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 6 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 6-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
 
and total bilirubin values (refer to Section 9.7.3).  Mean values for 
ALP and total bilirubin will be calculated using all available 
screening values.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment (yes/no) and baseline 
bilirubin categories (>upper limit of normal [ULN]/ ≤ ULN). 
Investigational product (OCA or matched placebo) will be taken 
orally, once daily.  Investigational product will be initiated at 5 mg 
OCA or matched placebo.  After 3 months of treatment with 
investigational product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched placebo, in a blinded 
manner) at the 3-month visit or any subsequent study visit based on 
tolerability.   
 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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Synopsis 
Inclusion Criteria 
2.  A mean total  bilirubin >ULN and ≤3× ULN or an ALP 
>5×ULN  
4.  Either is not taking UDCA (UDCA naïve or  no UDCA dose in 
the past 3 months) or has been taking UDCA for at least 12 months 
with an approved, stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
contraception during the study and for 30 days after the end of 
treatment visit. 
 
Inclusion Criteria 
2. A mean total bilirubin >ULN and ≤3× ULN and/or a mean 
ALP >5× ULN 
4.  Either is not taking UDCA (no UDCA dose in the past 
3 months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
Synopsis 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
 
 
Exclusion Criteria 
2.  History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
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3. Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
4.  Other medical conditions that may diminish life expectancy to 
<2 years, including known cancers (except carcinomas in situ or 
other stable, relatively benign conditions such as chronic lymphatic 
leukemia) 
5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of screening (pretreatment) QT 
 
3.  Mean total bilirubin >3× ULN 
 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
5.  Deleted text 
Synopsis 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life 
 
 
Criteria for Evaluation: 
Health outcomes and 
economics research 
Including the following: 
Cost-effectiveness and 
resource utilization 
Quality of Life (Fatigue 
Impact Score and EQ-5D-
5L) 
 
Synopsis 
Statistical Methods: Other Efficacy Analyses 
• 
Added text 
Statistical Methods: Other Efficacy Analyses 
• 
Development of varix/varices 
4 
List of Abbreviations 
Added text 
 
List of Abbreviations 
EOS 
 end of study 
 
5.4 
As of 31 March 2014, OCA has been evaluated in the clinic in 
18 completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 March 2014, a total of 1023 subjects have 
received at least one dose of OCA and of these, 414 (40%) were 
subjects with PBC.   
As of 31 January 2015, OCA has been evaluated in the clinic in 
20 completed and ongoing studies, including subjects with other 
chronic liver diseases (eg, nonalcoholic steatohepatitis) and healthy 
subjects.  As of 31 January 2015, approximately 1650 subjects 
have received at least 1 dose of OCA and of these, 432 were 
subjects with PBC with ≤5 years of OCA treatment.   
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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 up to 4 years.  The LSTE phase of studies 
747-201 and 747-301 are ongoing; the LTSE phase of 
Study 747-202 is complete 
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.  The LTSE phase of studies 747-201 and 
747-301 are ongoing; the LTSE phase of Study 747-202 is 
complete 
5.5.2.1 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg and 10 mg; both treatment 
groups exhibited clinically meaningful improvements in liver 
biochemistry and were safe and generally well tolerated. 
 
Rationale for OCA Doses 
…  The Phase 3 PBC study subsequently evaluated the safety and 
efficacy of OCA at lower doses of 5 mg (titrated to 10 mg after 6 
months based on efficacy and tolerability in the double-blind 
phase and after 3 months in the open-label phase) and 10 mg; 
both treatment groups exhibited clinically meaningful 
improvements in liver biochemistry and were safe and generally 
well tolerated.  Based on these data, the intended commercial 
doses of OCA for the treatment of patients with PBC are 5 mg 
and 10 mg. 
The majority of efficacy results with OCA, in terms of change 
in alkaline phosphatase, was observed by 3 months and the 
time to treatment-emergent pruritus was typically 1 month or 
less in Study 747-301.  As such, Study 747-302 will evaluate the 
effect of OCA on clinical outcomes using the 5 mg OCA dose 
increasing to 10 mg OCA if tolerated. 
 
5.5.2.2. 
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons.   
Rationale for Control Groups; Historical Control Group 
Therefore, further evaluation of the effect of OCA will compare 
OCA treatment versus historical controls, and will be supportive to 
placebo comparisons (ie, comparisons to historical and placebo 
controls will be evaluated separately). 
 
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5.6 
Additionally, consistent with nonclinical findings and the 
chemical characteristics of OCA (bile acid and detergent), an 
increase in liver function tests and hepatic AEs, including 
jaundice, were observed in subjects with liver disease at doses 
between 10 mg and 50 mg and in healthy volunteers who were 
treated at doses greater than 100 mg in Phase 1 multiple dose 
studies. 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  The clinical 
significance of these lipid findings remains unclear and is being 
studied further.  Notably, despite the observed decrease, HDL 
levels have generally remained within normal limits in subjects 
treated with OCA. 
• 
Deleted text 
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 subjects with chronic liver disease such as PBC, hepatic 
findings including increased transaminases and bilirubin and 
signs or symptoms of hepatic decompensation such as 
development of jaundice were observed mainly at the highest 
dose of OCA (50mg daily). 
Lipoprotein changes have also been observed with OCA dosing, 
including a decrease in high density lipoprotein (HDL) and an 
increase in low density lipoprotein (LDL).  Notably, in subjects 
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 subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in OCA-treated 
subjects with the exception of a modest transient and early rise 
after initiation of treatment. 
7.1 
Overall Study Design 
…Subjects will be screened during a ≤1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to 
Section 9.7.3)….Following 6 months of treatment with 
investigational product, subjects should be titrated in a blinded 
manner (ie, subjects randomized to OCA will increase their dose to 
10 mg OCA) based on tolerability…. 
Overall Study Design 
…Subjects will be screened during a 1 to 8 week Screening period 
prior to entering the study to allow for the collection of repeat 
serum chemistry samples (at least 2 weeks apart) to confirm 
pretreatment ALP and total bilirubin values (refer to Section 9.7.3). 
….Following 3 months of treatment with investigational product, 
subjects should be titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose to 10 mg OCA) based 
on tolerability…. 
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7.1.1 
Study Design Diagram 
 
EOT = end of treatment; M = month; UDCA = ursodeoxycholic 
acid; ULN = upper limit of normal 
Study Design Diagram 
 
EOS = end of study; M = month; UDCA = ursodeoxycholic acid; 
ULN = upper limit of normal 
7.1.2 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
1st column heading was “Screening Visit  x2) 
 
Visit Window ≤1 to 8 wks … 
Visit window in 2nd column added new text 
Added text 
 
 
 
 
 
 
 
 
 
 
 
 
Footnote a:   All subjects will have two 2 bilirubin assessments at 
least 2 weeks apart including those subjects who qualify based 
on ALP criteria.  For subjects that do not qualify based on 
Schedule of Trial Procedures 
Table 1:  Schedule of Procedures 
Now 2 columns: 1st column now “Screening Visit 1” 
2nd column now Screening Visit 2 
3 to 8 wks… 
1 to 6 wks prior to Day 0 
 
Added Procedures: 
Quality of Life Questionnaires (PBC-40, EQ-5D-5L, and 
FIS) g (Day 0, Annually, EOT/EOS) 
Endoscopy I (Day 0, annually, per standard of care) 
Hepatic Ultrasound (Day 0, Annually, EOT/EOS) 
Physical Exam and Assessments for Mayo Risk Score and Child-
Pugh (every 6 months) 
Health Outcome Assessments (All visits) 
Added Dose Titration at M3 
Footnote a All subjects will have the chemistry panel retested 
to ensure subjects have 2 ALP and bilirubin assessments at 
least 2 weeks apart to calculate the mean result for both 
Entry:  Bilirubin >ULN and ≤3x ULN and/or ALP >5xULN
M12
0
5 mg OCA Titrated to 10 mg* at or after Month 3
Placebo
M9
M6
M3
Years 2 - end of study
Year 1
Standard of Care
Screening 
1 to 8 weeks
EOS
* Titration to 10 mg based on tolerability
Quarterly Visits
Continued
Follow-up
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ALP (ALP >5× ULN), the mean of the two 2 bilirubin 
assessments will be used to determine eligibility (total bilirubin 
>ULN and ≤3× ULN). 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2, and also 2 weeks post dose titration, to assess for AEs 
and concomitant medications and to verify that s/he is dosing as 
directed 
Footnote e:  Medical history at Screening will smoking and alcohol 
consumption history and current habits for both.   
 
Footnote g:  Subject Questionnaires include: Pruritus VAS, 5-D 
Pruritus Scale and Quality of Life questionnaires (See 
Section 11.1.2.2 and Section 12.2.5.1) 
 
 
 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.   
 
 
Footnote i: Added text 
 
 
Footnote j:  Added text 
 
 
 
 
Footnote k:  Added text 
analytes.   The mean of the all screening ALP and bilirubin 
assessments will be used to determine eligibility).  Samples for 
hematology and coagulation will not be collected at Screening 
visit 2. 
Footnote b:  The subject should be contacted by telephone on a 
monthly basis in between at-clinic study visits at Month 1 and 
Month 2 (± 1 week), and also 2 weeks post dose titration (up or 
down), to assess for AEs and concomitant medications and to 
verify that s/he is dosing as directed.   
Footnote e:  Medical history at Screening and the yearly physical 
exam will include an assessment of smoking and alcohol 
consumption history and current habits for both.   
Footnote g:  The EQ-5D-5L and FIS Quality of Life 
questionnaires are validated for use in multiple languages. If 
a validated translation is not available in the local language 
required for a specific study subject, the data from that 
questionnaire will not be collected.    (See Section 11.1.2.2 and 
Section 12.2.6) 
Footnote h:   Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device is available.  
Similarly, DEXA will be conducted at selected study sites where 
the DEXA device is available.  Please refer to Section 9.7.7 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote i: Endoscopy will be conducted at selected study sites 
where the device is available to assess for the presence of 
oesophageal varix/varices.  Please refer to Section 9.7.7 for 
additional information related to the allowed windows at Day 
0 for these specific procedures. 
Footnote j:  Ultrasound will be conducted to enhanced HCC 
surveillance.  If a lesion is found, a second confirmatory 
image (eg, MRI) should be obtained.  Please refer to 
Section 9.7.7 for additional information related to the allowed 
windows at Day 0 for these specific procedures. 
Footnote k:  Child-Pugh Score will be calculated based on 
ascites assessment, hepatic encephalopathy grade, and central 
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Footnote l:  Added text 
 
 
 
Footnote m:  After 6 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 6 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit.  Fasting is required prior to all 
study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at site.  If the blood 
test is also positive, the subject may not be enrolled in the study.  
(Additional testing may be conducted where required, 
regionally). 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
laboratory evaluations per the Child-Pugh scoring system 
noted in the case report form.  Mayo Risk Score will be 
calculated based on central laboratory evaluations, diuretic 
use data, and peripheral edema assessment data captured in 
the CRF.  
Footnote l:  Health Outcome Assessments: Data related to non-
study related medical or surgical treatment procedures that 
the subject underwent and any medically relevant health care 
provider (HCP) or non-HCP related office visits that the 
subject attended should be collected throughout the study. 
Footnote m:  After 3 months of treatment with investigational 
product, the dose should be increased (in a blinded manner) based 
on tolerability; this may occur at the Month 3 visit, or at any 
study visit thereafter.  Titration above 10 mg OCA is not allowed. 
Footnote o:  The subject should be instructed to fast overnight (at 
least 8 hours) prior to each visit (except Screening visit 1).  
Fasting is required prior to all study visits, but water is permitted. 
Footnote p: Urine β-hCG pregnancy tests must be performed in 
females of childbearing potential prior to entry.  If positive, a 
confirmatory blood test must be performed at the central 
laboratory.  If the blood test is also positive, the subject may not 
be enrolled in the study.  (Additional testing may be conducted 
where required, regionally). 
 
Other Footnotes may have changed symbols due to the additions 
above, but the content of the remaining footnotes did not change 
 
7.3 
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 6 month study visit or at 
any study visit thereafter depending on tolerability.   
Treatment Assignment 
Subjects will receive either placebo or 5 mg OCA and should titrate 
to 10 mg OCA (in a blinded manner) at the 3 month study visit or 
at any study visit thereafter depending on tolerability.   
7.4 
Dose Titration Criteria 
After 6 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
Dose Titration Criteria 
After 3 months of treatment at the 5 mg dose, the dose of OCA will 
be increased to the maximum dose of 10 mg OCA or matched 
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placebo (in a blinded manner) at the 6-month visit or any study visit 
following the 6-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
placebo (in a blinded manner) at the 3-month visit or any study visit 
following the 3-month visit based on tolerability of investigational 
product.  For those subjects that increased their dose to 10 mg, they 
may decrease his or her dose to 5 mg at any time during the study 
as considered appropriate (eg, tolerability), but should be titrated 
back to 10 mg based on tolerability and clinical judgment by the 
Investigator as soon as possible with the goal that all subjects 
remain on the 10-mg dose if tolerated. 
7.4.1 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, her or she should continue the regular 
visit schedule and continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination.  Early termination 
procedures should only be conducted if the subject withdraws 
consent. 
Safety Criteria for Adjustment or Stopping Doses 
If a subject reaches an event, he or she should continue the regular 
visit schedule and continue taking investigational product as long 
as the Investigator assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on investigational product and 
remain in the study until study termination. 
7.5 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all subjects have 
completed the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the Study/Early Termination Visit. 
Criteria for Study Termination 
As a result of such a review or a recommendation by the DSMC, it 
may be necessary to stop the study before all events have been 
accrued, and when subjects are still active on the study. 
 
Investigators will be informed by the Sponsor as to when the final 
study visit is to be completed, and should then schedule all subjects 
for the End of Study Visit. 
8.2 
Subject Inclusion Criteria  
2.  A mean total bilirubin >ULN and ≤3× ULN or an ALP >5× 
ULN 
4.  Either is not taking UDCA (UDCA naïve or no UDCA 
dose in the past 3 months) or has been taking UDCA for at 
least 12 months with an approved, stable dose for ≥3 months 
prior to Day 0 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
be prepared to use ≥1 effective (≤1% failure rate) method of 
Subject Inclusion Criteria 
2.  A mean total bilirubin >ULN and ≤3× ULN and/or a mean ALP 
>5× ULN  
4.  Either is not taking UDCA (no UDCA dose in the past 
3 months) or has been taking UDCA for at least 12 months with a 
stable dose for ≥3 months prior to Day 0 
 
5.  Contraception:  Female subjects must be postmenopausal, 
surgically sterile, or if premenopausal (and not surgically sterile), 
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contraception during the study and for 30 days after the end of 
treatment visit. 
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:   
• 
Double barrier method, ie, (a) condom (male or female) or 
(b) diaphragm, with spermicide; or  
• 
Intrauterine device (IUD); 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 subject)  
 
 
8.3 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.   
 
 
3.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
4.  Other medical conditions that may diminish life expectancy 
to <2 years, including known cancers (except carcinomas in 
situ or other stable, relatively benign conditions such as chronic 
lymphatic leukemia) 
 
Subject Exclusion Criteria 
2. History of liver transplant, current placement on a liver 
transplant list, or current MELD score >12.  Subjects who are 
placed on a transplant list despite a relatively early disease 
stage (for example, per regional guidelines) may be eligible as 
long as they do not meet any of the other exclusion criteria 
 
3.  Mean total bilirubin >3× ULN 
 
4.  Subjects who have undergone gastric bypass procedures 
(gastric lap band is acceptable) or ileal resection or plan to 
undergo either of these procedures 
 
 
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5.  History or presence of clinically concerning cardiac 
arrhythmias likely to affect survival during the study, or 
prolongation of Screening (pretreatment) QT 
 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test), or lactating 
 
5.  Other medical conditions that may diminish life expectancy, 
including known cancers (except carcinomas in situ or other stable, 
relatively benign conditions such as chronic lymphatic leukemia) 
 
5. Deleted text 
 
6.  If female:  plans to become pregnant, known pregnancy or a 
positive urine pregnancy test (confirmed by a positive serum 
pregnancy test by the central laboratory), or lactating 
 
8.4.1 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test. 
Reasons for Mandatory Discontinuation of Investigational Product 
… Subjects whose pregnancy is terminated early (planned or 
unplanned) may be permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a serum beta human 
chorionic gonadotropin (β-hCG) test performed at the central 
laboratory. 
8.4.2 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent. 
 
 
The following events are considered potential appropriate reasons 
for a subject to discontinue investigational product;…  
• 
Withdrawal of Consent 
- 
Added text 
 
 
 
 
 
 
Other Reasons for Discontinuations of Investigational Product 
…Early termination procedures should only be conducted if the 
subject withdraws consent (See Section 9.7.18 Early 
Discontinuation and/or Early Termination Procedures). 
 
The following events are considered appropriate reasons for a 
subject to discontinue investigational product; … 
• 
Withdrawal of Consent 
- 
Consent may be fully withdrawn 
- 
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 potential adjudicated hepatic and/or 
cardiovascular events 
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The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study.   
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study.   
8.4.3 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone as soon as possible if any subject prematurely withdraws 
from the study….This information must be documented in the CRF.  
If a subject is withdrawn from the study early (regardless of the 
cause), all of the end of treatment (EOT) evaluations should be 
performed at the time of withdrawal, as appropriate.  
Subject Discontinuation Notification 
The Investigator must notify the Sponsor study monitor by 
telephone or email as soon as possible if any subject prematurely 
withdraws from the study….This information must be documented 
in the CRF.  If a subject is withdrawn from the study early 
(regardless of the cause), all of the (EOT/EOS) evaluations should 
be performed at the time of withdrawal, as appropriate (See 
Section 9.7.18 Early Discontinuation and/or Early Termination 
Procedures). 
9.1.1 
Dose Adjustment Beginning at Month 6 
After 6 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 6 visit, or at 
any study visit thereafter.   
Dose Adjustment Beginning at Month 3 
After 3 months of treatment with investigational product, the dose 
of investigational product should be increased in a blinded manner 
and based on tolerability; this may occur at the Month 3 visit, or at 
any study visit thereafter.   
9.2 
Concomitant Medications 
Relevant information about all concomitant medications (including 
prescribed, over-the-counter, or herbal preparations) taken prior to 
(ie, within 30 days of Day 0) and during the study must be recorded 
in the source documents and CRF, as well as any dose or dose 
regimen changes that occur during the study.   
Concomitant Medications 
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 CRF, as well as any dose or 
dose regimen changes that occur during the study. 
9.2.1 
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.   
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 and encourage the discontinuation of open-label 
OCA therapy.  However, if commercial OCA therapy remains, then 
investigational product should be discontinued to avoid potential 
double dosing.  Subjects that discontinue investigational product 
but continue commercial OCA therapy are expected to 
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continue through the end of the study, and the study will only 
terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.  Subjects 
will need to complete EOT procedures but continue with 
regularly scheduled visits until the study is terminated (See 
Section 9.7.18 Early Discontinuation and/or Early Termination 
Procedures). 
 
9.4 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and baseline bilirubin categories (>ULN/≤ULN), 
as specified by the central laboratory.   
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled 
manner.  Allocation to 1 of 2 treatment groups (OCA or placebo) 
will occur on a 1:1 ratio across sites and will be stratified by UDCA 
treatment (yes/no) and mean baseline bilirubin categories 
(>ULN/≤ULN), as specified by the central laboratory.   
9.4.1. 
Unblinding Procedures – Emergency Unblinding Procedures 
• 
Added text - New section inserted. 
Unblinding Procedures – Emergency Unblinding Procedures 
Treatment assignment for individual subjects will be made 
available to the Investigator for emergency use only 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 is necessary for further medical management of the 
subject).  If it is not reasonable to inform the Medical Monitor 
in advance of unblinding the Investigator must promptly 
document in the subject’s source record and should 
subsequently contact the Medical Monitor to explain any 
premature unblinding of treatment assignment (such as 
unblinding which is necessary in order to treat an SAE). 
Procedures for unblinding a subject’s treatment will be 
provided separately to the Investigator.  Similarly, if the 
Medical Monitor breaks the blind for an individual subject for 
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the purpose of evaluating an emergent safety issue, the Medical 
Monitor will document within trial documentation the 
rationale, circumstances, and the person or persons being 
informed about the unblinding. 
The Data and Safety Monitoring Committee (DSMC) will have 
access to the IWRS and will be able to unblind individual 
subjects.  Refer to Section 13.3 for further details regarding 
DSMC access to blinded and unblinded data.  The DSMC will 
document details about any unblinded subject data reviews in 
the closed session DSMC minutes, which will be made available 
to the Sponsor only after the database is locked and the trial is 
unblinded.   Cases of premature unblinding, as noted above, 
will also be reviewed by the DSMC.  
Access to treatment assignments will also be made available 
through the IWRS system to the appropriate named 
individual(s) responsible for reporting SAEs and suspected 
unexpected serious adverse reactions (SUSARs) to the 
Regulatory Authorities. 
9.6 
Restrictions 
No additional restrictions. 
Restrictions 
Participation in another investigation product, biologic, or 
medical device study within 30 days prior to Screening and 
during the course of the trial is prohibited. 
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9.7.1 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Interval is ≤1 to 8 weeks prior to 
Day 0, allowing for 2 Screening 2 
visits to repeat biochemistry tests, 
and ensuring ample time to receive 
lab results.  The overall Screening 
interval is up to 56 days. 
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (7 days)  
Quarterly visits (Months 
15 – EOT) 
±2 weeks (14 days) 
EOT 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOT = end of treatment 
 
Visit or Procedure 
Visit Window and/or Interval 
Screening 
Screening visit 1 interval is 3 to 8 
weeks prior to Day 0 for screening 
visit 1.  Screening visit 2 interval is 
1 to 6 weeks prior to Day 0.   The 
visit window for Screening 2 visits 
allows for the repeat biochemistry 
tests to be collected at least two 
weeks after the initial biochemistry 
sample was collected, and will 
ensure ample time to receive lab 
results.  The overall Screening 
interval is up to 56 days, but 
screening procedures should not be 
performed during the last 7 days of 
the window.  
Day 0 
This is the day of randomization.  
On-treatment visit scheduling should 
be calculated from this point going 
forward. (The first dose of 
investigational product should be 
taken the next day, on Day 1.) 
Months 3-12 
±2  week (14 days)  
Quarterly visits 
(Months 15 – EOS) 
±2 weeks (14 days) 
EOT 
(When subject 
discontinues 
investigational 
product) 
As soon as possible upon study 
discontinuation and as near as 
possible to the last dose taken 
EOS 
(When subject 
terminates the study) 
The final study visit; EOS will 
occur concurrent with EOT if a 
subject discontinues investigative 
product at the time the subject’s 
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participation in the study ends (eg, 
withdrawal of consent or study 
termination by the Sponsor); EOS 
will occur after the EOT if the 
subject discontinues investigative 
product but continues in the study. 
EOT = end of treatment 
EOS = end of study 
 
9.7.2 
Informed Consent Procedures 
• 
Added text 
Informed Consent Procedures 
Any change in a subject’s consent status (eg, semi-annual 
telephone contact or medical record review) must be 
documented in a signed informed consent form or addendum.  
The subjects will be given a signed and dated copy of the 
consent document. 
9.7.3 
Screening Procedures (≤1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed ≤1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Subjects who 
do not fulfill all eligibility criteria will not be enrolled in the study.  
Subjects may be rescreened after 2 months; however, all Screening 
procedures should be repeated and a new 3-digit Screening number 
assigned.  
 
 
 
 
 
• 
All subjects will have 2 bilirubin and ALP 
assessments at least 2 weeks apart including those 
subjects who qualify based on ALP criteria. 
• 
For subjects that do not qualify based on ALP alone 
(ALP >5×  
Screening Procedures (1 to 8 Weeks prior to Day 0) 
Two Screening Visit assessments must be performed 1 to 8 weeks 
prior to Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria.  Screening 
Visit 1 will occur 3 to 8 weeks prior to Day 0; Screening Visit 2 
will occur 1 to 6 weeks prior to Day 0, depending on the date 
that the first serum chemistry sample was collected. Subjects 
who do not fulfill all eligibility criteria will not be enrolled in the 
study.  Subjects 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 3-digit Screening number 
assigned. 
 
• 
All subjects will have 2 bilirubin and ALP assessments at 
least 2 weeks apart 
 
• 
For subjects that do not qualify based on ALP alone (ALP 
>5× ULN), the mean of all available (at least 2; 
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ULN), the mean of the 2 bilirubin assessments will be 
used to determine eligibility (total bilirubin >ULN 
and ≤3× ULN). 
  
 
 
• 
Screening Visit procedures are as follows: 
• 
Record prior (if within 30 days of Day 0) and current 
concomitant medications 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual emission X ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
 
 
• 
Added text 
 
including both scheduled and unscheduled) bilirubin 
assessments will be used to determine eligibility (total 
bilirubin >ULN and ≤3× ULN).   
 
 
 
• 
Screening Visit 1 procedures are as follows: 
• 
Record prior (if within 30 days of Screening) and current 
concomitant medications 
• 
Deleted text  
 
• 
Deleted text 
 
 
 
 
 
 
Screening Visit 2 procedures are as follows: 
• 
Verify inclusion and exclusion criteria for eligibility 
• 
Assess and record any pretreatment-emergent AEs 
• 
Record current concomitant medications 
• 
Verify that the subject has fasted for at least 8 hours 
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- 
Record fasting status in the source and CRF 
- 
If the subject reports having eaten within 8 hours, 
document accordingly in the source and CRF and 
remind the subject that fasting is required prior to all 
study visits 
• 
Obtain blood samples for serum chemistry tests 
• 
The subject should be instructed to fast overnight (at 
least 8 hours) prior to next visit.  Fasting is required 
prior to all study visits, but water is permitted. 
• 
In preparation for the dual-emission X-ray 
absorptiometry (DEXA) bone density scan to be done 
at Day 0 (selected study sites only), subjects who are 
taking calcium supplements should stop taking them 
for 48 hours before the scan.  If the subject is taking 
any medications for osteoporosis or osteopenia, s/he 
should not take them on the day of the scan. 
9.7.4 
Day 0 Procedures (Randomization) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE has 
been done within 3 months of Day 0 and a report/adequate data 
are available, a pretreatment TE at Day 0 is not required.   
 
 
 
 
• 
Day 0 Procedures (Randomization) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6.) 
• 
Perform transient elastography (TE; at selected study sites, 
where available) using the Fibroscan® TE device.  If TE 
has been done within 6 months of Day 0 and a 
report/adequate data are available, a pretreatment TE at 
Day 0 is not required.  If the TE cannot be performed on 
Day 0 (e.g., device/technician unavailability, scheduling 
issues, etc), the procedure may be completed within the 
screening visit window, as close as possible to the Day 0 
visit, after subject eligibility has been confirmed.   
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• 
 Conduct a DEXA bone density scan (at selected study sites, 
where available); document whether the subject stopped taking 
her/his calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of the 
scan, if applicable.  
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 Conduct a DEXA bone density scan (at selected study 
sites, where available); document whether the subject 
stopped taking her/his calcium supplements for 48 hours 
before the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable.  If DEXA 
has been done within 12 months of Day 0 and a 
report/adequate data are available, a pretreatment 
DEXA at Day 0 is not required.  If DEXA cannot be 
performed on Day 0 (e.g., device/technician 
unavailability, scheduling issues, etc), the procedure 
may be completed within the screening visit window, as 
close as possible to the Day 0 visit, after subject 
eligibility has been confirmed. 
• 
Perform an esophagogastroduodenoscopy (endoscopy; 
at selected study sites, where available) to assess the 
presence or absence of oesophageal varix/varices. If an 
endoscopy has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment endoscopy at Day 0 is not required. If the 
endoscopy cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
- 
Subsequent endoscopies should be performed 
annually or per standard of care and the 
Investigator’s clinical judgment throughout 
the course of the study.  Endoscopies should 
also be performed when platelet counts are 
<150 × 109 /L. 
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• 
Added text 
 
 
 
 
 
 
 
 
• 
Added text 
 
 
 
 
 
 
• 
Added text 
 
• 
Record prior (within 30 days of Day 0) and current  
concomitant medications 
• 
Perform an ultrasound (if equipment is unavailable, 
sites should make every attempt to use available 
community referral sites) for HCC surveillance.  If an 
ultrasound has been done within 12 months of Day 0 
and a report/adequate data are available, a 
pretreatment ultrasound at Day 0 is not required. If 
the ultrasound cannot be performed on Day 0 (e.g., 
device/technician unavailability, scheduling issues, etc), 
the procedure may be completed within the screening 
visit window, as close as possible to the Day 0 visit, 
after subject eligibility has been confirmed. 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
 Review and record prior concomitant medications 
• 
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. 
9.7.6 
Month 3 Procedures 
• 
Added text 
• 
Added text 
Month 3 Procedures 
• 
Assess for dose titration, if eligible (refer to Section 7.4) 
• 
Obtain blood samples for: 
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- 
OCA, C4, and FGF-19 
9.7.7 
 
Month 6 Procedures 
• 
Added text 
 
Month 6 Procedures 
• 
 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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.8 
Month 9 Procedures 
• 
Added text 
Month 9 Procedures 
• 
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 
 
9.7.9 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.9), subjects who are participating in the PK assessment 
will each receive a single dose of investigational product (10 mg 
OCA tablet) with approximately 240 mL of water. 
Month 9 Procedures for Subjects Participating in Pharmacokinetic 
Assessment 
Following collection of the Month 9 fasted samples (refer to 
Section 9.7.12), subjects who are participating in the PK 
assessment will each receive a single dose of investigational 
product (blinded OCA or placebo tablet) with approximately 
240 mL of water. 
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Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours postdose.  Subjects should not drink additional water 
for 1 hour after taking the dose of investigational product and will 
remain fasted until the 4 hour sample is collected.  Lunch will be 
provided following collection of the 4 hour PK sample; the lunch 
will be a meal replacement drink. 
 
 
Serial blood samples will be obtained for measurement of OCA and 
its conjugates prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours post dose.  Samples should be collected within a 
window of ±5 minutes of the scheduled sample time.  Subjects 
should not drink additional water for 1 hour after taking the dose of 
investigational product and will remain fasted until the 4 hour 
sample is collected.  Lunch will be provided following collection of 
the 4 hour PK sample; the lunch will be a meal replacement drink.  
Samples will be stored for up to 5 years after the end of the 
study and will be destroyed after 5 years if not analyzed. 
9.7.10 
 
Month 12 Procedures 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Added text 
Month 12 Procedures 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
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9.7.11 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
Subjects should come to the study center for a quarterly study 
visit for a clinical laboratory evaluation to collect blood samples 
for calculation of MELD score.  If the subject is not able to 
come to the study center for a visit, home visits may be 
arranged on a per subject basis. 
Month 3 and Month 9 Continued Follow-up Procedures ([±2 
weeks]) 
• 
Deleted text 
• 
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 
• 
Mayo Clinic Score and Child-Pugh Assessment 
9.7.12 
Month 6 Continue Follow-up Procedures (Semi-annually 
[±2 weeks]) 
• 
Added text 
Month 6 Continue Follow-up Procedures (Semi-annually 
[±2 weeks]) 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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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9.7.13 
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject questionnaires (see Section 12.2.5.1) 
 
• 
Added text  
Month 12 Continued Follow-up Procedures (Annually [±2 weeks]) 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform an endoscopy (at selected study sites, where 
available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites)   
• 
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 physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
o 
Presence/absence of peripheral edema 
o 
Presence (degree)/absence of ascites 
o 
Presence (degree)/absence of hepatic 
encephalopathy 
9.7.14 
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw Consent 
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
Early Discontinuation and/or Early Termination Procedures for 
Subjects that Withdraw from Investigational Product or 
Withdraw Consent  
Subjects that discontinue investigational product are expected to 
continue in the study until the end of the study, and the study will 
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Added text 
 
 
 
 
 
 
 
 
When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination or 
discontinuation (withdrawal of consent), an EOT visit must be 
performed as near as possible to her/his last dose of investigational 
product and the procedures, listed below, performed.  …  In these 
cases, the data will be recorded as EOT procedures in the CRF.  
 
 
Added table 
 
 
 
only terminate at the time when the needed number of adjudicated 
events has accrued or at the discretion of the Sponsor.   
EOT procedures will be required whenever subjects 
discontinue treatment with investigational product.  The EOT 
visit and procedures listed below must be performed as close as 
possible to the subject’s last dose of investigational product.  
When a subject discontinues investigational product but 
continues with regularly scheduled study visits, the EOS visit 
will be completed later in the study as the subject’s final study 
visit.  The actual investigational product discontinuation 
scenario (Table 7) will determine the sequence of the EOT and 
EOS visits and procedures.  In some cases, the EOT visit and 
procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible 
to the subject’s last dose of investigational product.   
When a subject ends her/his participation in the study (eg, at a point 
between standard study visits) either due to early termination 
(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.  ….  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 and EOS procedures in the 
CRF.  
Table 2: 
Early Discontinuation Scenarios 
 
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Investiga
tional 
Product 
Conse
nt 
Study 
Visit 
Status 
EOT 
Visita 
EOS 
Visita 
Early 
Terminati
on 
Discontin
ued 
Withdr
awn 
No 
additi
onal 
visits 
excep
t 
EOT/E
OS 
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
Treatmen
t 
Discontin
uation 
Discontin
ued 
Active 
Regul
ar 
Visit 
Sched
ule 
Comp
lete 
as 
close 
as 
possi
ble to 
last 
dose 
IP 
Comp
lete 
at 
Final 
study 
visit 
Discontin
ued 
Semia
nnual 
contac
tb 
Telep
hone 
conta
ct 
every 
6 
mont
hs (±2 
weeks
Combined 
Visit, 
Completed as 
close as 
possible to 
last dose IP 
 
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Some assessments noted below may be omitted if they have been 
completed within the 3 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing. 
Prior to the EOT Visit: 
During the EOT Visit: 
• 
Subject questionnaires (see Section 12.2.6) 
• 
Conduct a DEXA bone density scan (selected study sites); 
document whether the subject stopped taking her/his calcium 
supplements for 48 hours before the scan and medications for 
osteoporosis or osteopenia on the day of the scan, if applicable 
 
 
• 
Added text 
 
• 
Added text 
 
• 
Added text 
 
a Refer to Section 7.1.2 Schedule of Study Procedures for all procedures 
and evaluations required at the End of Treatment and End of Study Visits. 
b Outcomes data to be discussed or collected include data related to 
adjudicated hepatic and cardiovascular event-related data.  No additional 
data (e.g. AE, concomitant medication, etc) data will be collected, except 
as indicated in Section 12.1.7. 
Some assessments noted below may be omitted if they have been 
completed within the 6 months (or the timeframe otherwise 
specified) and so long as safety issues do not warrant repeat testing 
Prior to the EOT/EOS Visit: 
During the EOT/EOS Visit 
• 
Subject and Quality of Life questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
 Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Subject and Quality of Life  questionnaires (see 
Section 11.1.2.2 and Section 12.2.6) 
• 
Perform TE (where available) using the Fibroscan® TE 
device (not required at EOT/EOS if done within 6 months) 
• 
Conduct a DEXA bone density scan (selected study sites; 
not required at EOT/EOS if done within 6 months); 
document whether the subject stopped taking her/his 
calcium supplements for 48 hours before the scan and 
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• 
Added text 
medications for osteoporosis or osteopenia on the day of 
the scan, if applicable 
• 
Perform an ultrasound for HCC surveillance (if 
equipment is unavailable, sites should make every 
attempt to use available community referral sites); not 
required at EOT/EOS if done within 6 months 
• 
Perform physical examination and overall status 
assessment for calculation of Mayo Risk Score and 
Child-Pugh Assessments 
- 
Presence/absence of peripheral edema 
- 
Presence (degree)/absence of ascites 
- 
Presence (degree)/absence of hepatic 
encephalopathy 
• 
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 
 
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.  [Added text]  As appropriate, the Medical 
Monitor should be contacted. 
 
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.   
In the event of an inexplicable and acute (for example not 
explained by natural progression of the chronic disease) 
increase in alanine aminotransferase (ALT) to >3× baseline 
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(and >upper limit of normal [ULN]) or total bilirubin >2× 
baseline (and >ULN), the subject should be followed by repeat 
testing within 48 to 72 hours of the serum chemistry to confirm 
the abnormalities and to determine if they are increasing or 
decreasing. AE information should also be collected.  If 
symptoms persist or repeat testing shows ALT >3× baseline 
(and >ULN) or total bilirubin >2× baseline (and >ULN), 
subjects should be followed until resolution of the abnormality 
and as clinically indicated depending on other laboratory and 
clinical signs and symptoms. 
 
As appropriate, the Medical Monitor should be contacted. 
10.4 
Investigational Product Preparation 
The investigational product will be provided in bulk bottles and 
therefore may be repackaged in unit dose form for administration to 
subjects. 
 
Investigational Product Preparation 
The investigational product will be provided to the distribution 
center in bulk bottles and therefore may be repackaged in unit dose 
form for administration to subjects before shipping to the sites. 
 
11.1.2 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Resource utilization information 
will be collected from CRFs such as number, type and 
duration of hospitalizations, number of outpatient physician 
visits (subject reported), and use of concomitant medications.  
 
 
Secondary Assessments 
• 
Data will be collected to inform quality of life and cost-
effectiveness analyses that are relevant to major health care 
systems around the world.  Quality of life will be assessed by 
questionnaires (PBC-40, EQ-5D-5L, and FIS) 
administered annually.  Resource utilization information will 
be collected from the Medical and Surgical Treatment 
Procedures and Office Visit Log or other CRFs such as 
number, type and duration of hospitalizations, number of 
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• 
Added text 
outpatient physician visits (subject reported), and use of 
concomitant medications.  
• 
Endoscopy will be conducted at selected study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices at baseline.  Throughout the 
study, any endoscopy performed as part of the annual 
study assessments or standard of care will be collected in 
the case report form to assess for the development of 
varix/varices 
11.1.2.2 
• 
Quality of Life questionnaires.   
• 
Quality of Life questionnaires.  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: 
a. PBC-40: The PBC-40 (Jacoby 2005) 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. 
b. EQ-5D-5L:  The Eq-5D-5L consists of 2 sections – the 
descriptive system and the visual analogue scales (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 
respondent’s self-rate 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). 
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c. 
Fatigue Impact Score (FIS):  The FIS is a validated 
40-question questionnaire organized into 3 dimensions:  
cognitive, physical, and social.  Each dimension has 5 
levels:  no problem, small problem, moderate problem, 
big problem, and extreme problem (Fisk 1994) 
11.1.2.3 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. The samples will be stored for up to 1 year after the 
end of the study and destroyed after 1 year if not analyzed. 
 
• Blood samples for future analysis of additional analytes, such 
as PBC autoantibodies and other cytokines and interleukins, 
may be assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease or 
investigational product characteristics.  Appropriate serum and 
plasma samples will be collected at selected time points during 
the study. Subjects will be permitted to decline future 
analysis of blood samples without affecting their 
involvement in the study.  IRB/IEC review and approval 
will be required and willing subjects must specifically 
consent to participate in this evaluation.  The samples will 
be stored for up to 1 year after the end of the study and 
destroyed after 1 year if not analyzed. 
 
12.1.1.2 
Serious Adverse Event 
• 
Added text 
Serious Adverse Event 
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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12.1.4.2 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
  
All SAEs (including Potential Clinical Outcome Events that qualify 
as serious) must be reported to the medical monitor immediately 
(ie, within 24 hours) after the Investigator identifies the SAE…. 
 
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 investigational 
new drug (IND) safety reports (SUSARs) that occur during the 
study within the time frames required by each regulatory agency.  
The Investigator is responsible for submitting information on IND 
safety reports received from the Sponsor to her/his local IRB.  
Documentation of the submissions to IRBs and health authorities 
must be retained in the appropriate study file(s). 
 
Reporting of Serious Adverse Events 
 MD 
Tel: 
 (Pacific time zone) 
Mobile: 
 
Email: 
 
All SAEs occurring while subjects are receiving investigational 
product or are on an investigational product holiday (including 
Potential Clinical Outcome Events that qualify as serious) must be 
reported to the medical monitor immediately (ie, within 24 hours) 
after the Investigator identifies the SAE….  
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.  A SAE assessed with a possible, probable, or definite 
causal relationship to the investigational product and 
unexpected according to IB Reference Safety Information 
(RSI), is known as a suspected unexpected serious adverse 
reaction (SUSAR).  The Sponsor will notify the appropriate 
regulatory agencies as well as all participating Investigators of 
investigational new drug (IND) safety reports (SUSARs) that occur 
during the study within the time frames required by each regulatory 
agency.  The Investigator is responsible for submitting information 
on IND safety reports/SUSARs received from the Sponsor or 
Sponsor designee to her/his local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities must be retained in the 
appropriate study file(s). 
 
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12.1.6 
Notification of Post-Study SAEs 
• 
Added text 
 Notification of Post-Study SAEs 
SAEs that occur more than 30 days after a subject has 
discontinued investigative product, and are not considered 
related to investigational product, must still be reported in the 
EDC system; however, these events are not required to be 
reported within 24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to investigational 
product, action taken with investigative product, treatment, 
outcome, and potential endpoint status need to be recorded in 
EDC for the SAE.  Additional information (e.g. event summary, 
SAE details) may also be required to be entered, when 
requested by the Sponsor. 
 
12.1.8 
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments.  
Pregnancy and Follow up 
Safety will be monitored and assessed by AEs/SAEs, medical 
history, physical examination, vital signs measurements, ECG 
results, and clinical laboratory assessments. The Sponsor may also 
follow the health of an infant born subsequent to use of 
investigational product. 
 
12.2.2 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page …. 
Physical Examination 
… Any clinically significant abnormality should be reported on the 
AE CRF page for findings that appear after consent, and on the 
medical history CRF for any finding present prior to consent…. 
12.2.5.1 
12.2.5.1  Subject Questionnaires 
 
12.2.6 Subject Questionnaires 
12.2.6/12.2.7 
12.2.6   Laboratory Assessments 
Subjects testing positive for urine drug screen will be excluded 
from the study. 
12.2.7 Laboratory Assessments 
Deleted text 
 
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Table 4  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids, thyroid hormones (T3, 
T4, TSH) 
 
Table 5  List of Laboratory Analytes to be Tested 
Laboratory 
Assessment 
Analyte 
Serum Chemistry 
Albumin, blood urea nitrogen (BUN), 
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 very low density lipoprotein 
[VLDL] fractions and 
triglycerides[TG]), magnesium, 
phosphorus, bicarbonate, 
unconjugated (indirect) bilirubin, 
conjugated (direct) bilirubin, free 
fatty acids 
 
12.2.6 
Laboratory Assessments 
• 
Added text 
 
 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly visits based on serum chemistry and coagulation. 
 
12.2.7  Laboratory Assessments 
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. 
MELD scores, Child-Pugh score and MRS will be calculated at 
quarterly (MELD scores only) and semi-annual visits based on 
serum chemistry and coagulation. 
 
13.1.5 
Additional Secondary Efficacy Analyses 
• 
Added text 
Additional Secondary Efficacy Analyses 
• 
Time to development of varix/varices 
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13.1.8 
Supportive Analysis 
Although the results of using matching are conditional only on the 
observed covariates, if one has the ability to measure many of the 
covariates that are believed to be related to the treatment 
assignment, then one can be fairly confident that approximately 
unbiased estimates for the treatment effect can be obtained. 
 
Supportive Analysis 
Although the results of using matching controls are conditional 
only on the observed covariates, if one has the ability to measure 
many of the covariates that are believed to be related to the 
treatment assignment, then one can be fairly confident that 
approximately unbiased estimates for the treatment effect can be 
obtained. 
13.3 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study. In addition, the DSMC statistician 
will evaluate the sample size as described in Section 13.1.2.1. 
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.   
 
Data and Safety Monitoring Committee 
The DSMC will review data on a periodic basis to ensure the safe 
and proper treatment of subjects.  Based on review of these data, 
the DSMC will advise the Sponsor on the validity and scientific 
merit of continuing the study.  
The DSMC operates under an appropriate charter (in compliance 
with relevant regulatory guidance) that defines its organization and 
operation and includes specific procedures for each study.  The 
DSMC will prepare written minutes of both its open and closed 
sessions for each study.  The DSMC will document details about 
any unblinded subject data reviews in the closed session DSMC 
minutes, which will be made available to the Sponsor only after 
the database is locked and the trial is unblinded.   Cases of 
premature unblinding, as noted above, will also be reviewed by 
the DSMC.  
 
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16.2, Ethical 
Conduct of the 
Study 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles 
that have their origin in the Declaration of Helsinki (Seoul 
Revision, 2008) and are consistent with ICH/GCP, applicable 
regulatory requirements and the Sponsor’s policies. 
Ethical Conduct of the Study 
 The study will be performed in accordance with ethical principles 
and are consistent with ICH/GCP, local applicable regulatory 
requirements (in addition to Appendix C) and the Sponsor’s 
policies. 
19 
List of References 
• 
Added text 
List of References 
Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact 
of fatigue: initial validation of the fatigue impact scale. Clin Infect 
Dis. 1994 Jan;18 Suppl 1:S79-83.  
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 Dec;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), 
1622-1629. 
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. 
Appendix C 
• 
Added document 
Ethical Conduct according to the Declaration of Helsinki for 
Countries Participating Outside the US 
 
 
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APPENDIX E.  SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 (DATED 12 NOV 2015) 
Rationale 
The changes to Amendment 1 of the protocol, detailed below, generated specifically for regulatory authority requests, include an 
additional exclusion criteria and changes to text precluding UDCA naïve subjects from entering the study and clarifying information 
showing that OCA may increase the exposure of narrow therapeutic index drugs that are substrates for CYP1A2, thus answering 
questions raised by regulatory authorities. 
Summary of Changes 
The following revisions were made to protocol 747-302 under Amendment 1.1.  (Note:  Revised text in Amendment 1.1 is indicated in 
bold font, and the text deleted from Protocol Amendment 1 is crossed out in the table below. Minor formatting changes are not listed.) 
Section 
Original Text (Amendment 1, 29 April 2015) 
Revised Text (Amendment 1.1, 12 November 2015) 
Title Page 
Original:  03 October 2014 
Amendment 1:  29 APRIL 2015 
Original:  03 October 2014 
Amendment 1:  29 April 2015 
Amendment 1.1:  12 November 2015 
Study Personnel 
Contact 
Information 
Mobile:      
 (Pacific time zone) 
Telephone: 
 
Telephone 
 
(deleted) 
Telephone: 
 
(deleted)   
Synopsis, 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
Synopsis, 
Statistical 
Methods:  
Sample Size 
Justification 
• 
5% of the subjects will have never been treated with UDCA; 
95% of the subjects will have been on UDCA for at least 1 
year 
(deleted) 
 
8.3 Subject 
Exclusion 
Criteria 
(insertion)  
14.  UDCA naïve (unless contraindicated) 
9.2 Concomitant 
Medications 
(insertion) 
The effect of OCA on drug metabolizing enzymes has been 
evaluated in both in vitro and clinical studies.  The PK profile 
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Revised Text (Amendment 1.1, 12 November 2015) 
of caffeine, a sensitive CYP1A2 substrate, 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. 
12.1.4.2 
Reporting of 
Serious Adverse 
Event 
Mobile:      
 (Pacific time zone) 
Telephone: +1 858 964 1571 
(deleted) 
Telephone: 
   
13.1.2 
Determination of 
Sample Size 
5% of the subjects will have never been treated with UDCA; 95% 
of the subjects will have been on UDCA for at least 1 year 
(deleted) 
 
 
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APPENDIX F. SUMMARY OF CHANGES:  PROTOCOL AMENDMENT 1.1 TO VERSION 3 
(DATED 07 SEP 2016) 
Rationale 
The changes to Version 3 of the protocol, include dosing adjustments based on Child-Pugh scoring, additional exclusion criteria, 
changes to text precluding UDCA-naïve subjects from entering the study.  
Please note that the Sponsor has renamed protocol “amendments” to “versions”, therefore all future revisions that require a revised 
protocol will have an associated “version” number. The table below includes substantial revisions made to Protocol 747-302 under 
Version 3, which encompass the revisions captured in Protocol Amendment 1.1. Revised text in Version 3 is indicated in bold font, 
and the text deleted from Protocol Amendment 1.1 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 (Amendment 1.1, 
12 November 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology 
...  Mean values for ALP and total bilirubin 
will be calculated using all available 
screening values.  Subjects who meet all 
inclusion criteria and none of the exclusion 
criteria will be randomized (1:1) to OCA or 
placebo treatment groups.  The 
randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment 
(yes/no) and baseline bilirubin categories 
(>upper limit of normal [ULN]/ ≤ULN). 
Investigational product (OCA or matched 
placebo) will be taken orally, once daily.  
Investigational product will be initiated at 5 
mg OCA or matched placebo.  After 3 
months of treatment with investigational 
product, the dose may be increased (to the 
maximum dose of 10 mg OCA or matched 
placebo, in a blinded manner) at the 3-
month visit or any subsequent study visit 
based on tolerability.  Subjects will be seen 
at quarterly visits for the duration of the 
study. 
...  Investigational product will be taken orally, once daily 
for the majority of subjects; dose and frequency will be 
modified for subjects with cirrhosis (including subjects 
progressing to cirrhosis during the study) and 
classified as Child-Pugh B or C.  The randomization will 
be stratified by ursodeoxycholic acid (UDCA) treatment 
(yes/no) and baseline bilirubin categories (>upper limit of 
normal [ULN]/ ≤ ULN). 
To incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores, 
to align with the 
recommended dosing 
regimen found in the 
Ocaliva US Package Insert 
for patients with hepatic 
impairment. 
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Original Text (Amendment 1.1, 
12 November 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology. 
7.1.1, Study 
Design Diagram, 
Figure 1 
Schematic diagram
 
Updated schematic diagram 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.  Subsequent dose titration(s) for subjects 
classified as Child Pugh B or Child-Pugh C and 
following a modified dosing schedule may occur no 
earlier than 6 weeks after the previous dose titration 
Incorporate updated dosing 
scheme to reflect addition of 
Child-Pugh scoring. 
g
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Original Text (Amendment 1.1, 
12 November 2015) 
Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Synopsis, 
Methodology 
(insertion) 
Dosing frequency will be determined by the presence 
or absence of cirrhosis and, if cirrhosis is present, by 
Child-Pugh Score as described below: 
• 
Non-cirrhotic subjects or subjects classified as 
Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects 
should titrate to a maximum dose of 10-mg OCA once 
daily (or matching placebo) at the Month 3 visit or at 
any study visit following the Month 3 visit based on 
tolerability of the product.    
• 
For those subjects that up-titrate to 10 mg, dosing 
may be decreased to 5 mg at any time during the study 
as considered clinically appropriate (eg, based on 
tolerability). Subjects may be titrated back to a 
maximum dose of 10 mg once daily based on 
tolerability and clinical judgment of the Investigator.    
• 
 Subjects who are cirrhotic and classified as Child-
Pugh Class B or Child-Pugh Class C will initiate a 
modified treatment regimen with 5-mg OCA or 
matching placebo once weekly for at least 3 months.  
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5-mg OCA or 
matching placebo once daily, based on tolerability.  
Subjects classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 10-mg 
OCA or matching placebo twice weekly, based on 
tolerability. 
Includes New Table: Planned Dosing Regimen by 
Cirrhosis and Child-Pugh Score 
Revised methodology to 
incorporate the changes in 
dosing for subjects based on 
the Child-Pugh Scores. 
 
5.1, Overview 
(insertion) 
The United States Food and Drug Administration 
(FDA) has granted accelerated approval for Ocaliva 
for the treatment of PBC.  Ocaliva is not yet approved 
outside the United States for use in any indication. 
Language updated as OCA 
is approved in the US with 
the trade name Ocaliva. 
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5.5.2.2, Rationale 
for Modified OCA 
Doses in Patients 
Classified with 
Child-Pugh B or 
Child-Pugh C 
Hepatic 
Impairment 
(Insertion) 
New section: Rationale for Modified OCA Doses in 
Patients Classified with Child-Pugh B or Child-Pugh C 
Hepatic Impairment 
Simulations using a physiologic PK model predicted 
changes in systemic and liver OCA concentrations 
associated with changes in the severity of hepatic 
impairment (Child-Pugh score).  Model simulations 
predicted that for mild (Child-Pugh A), moderate 
(Child-Pugh B), and severe (Child-Pugh C) hepatic 
impairment, total OCA plasma concentrations 
increase 1.4-, 8.0-, and 13-fold relative to subjects 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 (Child-Pugh B and C) 
subjects treated with OCA in phase 1 and 2 studies 
experienced plasma OCA exposures >10-fold higher 
than those in healthy subjects, 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.  Collectively, the 
results from these analyses and those from bile acids in 
the literature suggest that the doses of OCA 
administered to hepatically-impaired patients should 
be modestly lower than those for patients with normal 
hepatic function to achieve similar hepatic exposure.   
Per the approved FDA prescribing label, the 
recommended dosing regimen for OCA in subjects 
with moderate and severe hepatic impairment is a 
starting dose of 5-mg OCA once weekly.   Dosage 
adjustments in subjects with moderate (Child-Pugh B) 
or severe (Child-Pugh C) hepatic impairment may be 
made after establishing tolerability at the lower dose 
Provide the rationale to 
incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores 
into the protocol. 
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(full modified dosing regimen is described in 
Appendix A). 
5.6, Summary of 
Known Potential 
Risks with OCA 
(Insertion) 
…These findings were seen more frequently with doses 
above 10 mg OCA.  In addition, cholecystitis, including 
acute cholecystitis, was reported in association with 
treatment with OCA. 
Added two AE terms 
reported in the updated 
Investigator’s Brochure. 
7.1, Overall Study 
Design 
…Investigational product will be initiated 
at 5 mg OCA or matched placebo.   
Following 3 months of treatment with 
investigational product, subjects should be 
titrated in a blinded manner (ie, subjects 
randomized to OCA will increase their dose 
to 10 mg OCA) based on tolerability 
Investigational product will be taken orally, once daily.  
Subjects who are non-cirrhotic or classified as Child-
Pugh A at Screening will initiate investigational 
product once daily with 5-mg OCA or matching 
placebo. Following 3 months of once daily treatment with 
investigational product, the dose should be titrated to a 
maximum 10 mg OCA or matching placebo once daily, 
based on tolerability (see Section 7.3).  
Subjects with cirrhosis and classified as Child-Pugh 
Class B or Child-Pugh Class C will follow a modified 
dosing regimen, and will initiate investigational 
product once weekly with the 5-mg OCA or matching 
placebo dose.  In addition, these subjects will follow a 
modified titration plan, which is outlined in 
Appendix A.  
Amend the protocol to 
incorporate a dosing and 
titration regimen based on 
subject’s Child-Pugh Scores. 
7.1.2, Table 1, 
Schedule of Study 
Procedures – 
Screening to 
Month 12 (Table 1 
of 2), 9.3, 
Treatment 
compliance 
Safety Contact 
This visit has been deleted. 
Replaced with the 1 Month 
Post-Titration Visit. 
(Insertion) 
Added the following visits: 
• 
Month 1 
• 
1 Month Post-Titration Visit 
Visits were added to 
accommodate the updated 
dosing and titration regimen 
based on subject’s 
Child-Pugh Scores. 
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bThe subject should be contacted by 
telephone on a monthly basis in between at-
clinic study visits at Month 1 and Month 2 
(± 1 week), and also 2 weeks post dose 
titration (up or down), to assess for AEs and 
concomitant medications and to verify that 
s/he is dosing as directed. 
cAs soon as possible upon study 
discontinuation and as near as possible to 
last dose taken. 
nSubject to begin dosing on Day 1 
Deleted. 
Result of table being 
updated for the dosing and 
titration regimen based on 
subject’s Child-Pugh Scores. 
(Insertion) 
Added the following study procedures: 
• 
Cirrhosis Status Assessmente 
• 
Assessments for Child-Pugh Scoresg 
• 
Dose Titration: Standard Dosingn,o 
• 
Dose Titration: Modified Dosing n,o 
• 
Dosing Diary 
Study procedures were 
added to accommodate the 
updated dosing/titration 
regimen.  Dosing diary was 
added to improve 
compliance. 
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(Insertion) 
Added the following footnotes: 
• 
bSafety 
Post-Titration 
visits 
must 
be 
performed 1 month + 1 week after any up-
titration in dose and/or frequency in subjects 
following modified dosing due to Child-Pugh 
B and Child-Pugh C hepatic impairment.  In 
subjects following the standard dosing 
regimen, the post-titration visit must be 
performed only after the first up-titration to 
10 mg OCA or matching placebo, or after ≥3 
months at a decreased dose or frequency. 
• 
ePresence or absence of cirrhosis should be 
assessed per Section 9.7.3.  Cirrhosis status 
should be repeated as clinically indicated. 
• 
fMayo Risk Score will be calculated based on 
central laboratory evaluations, diuretic use 
data, and peripheral edema assessment data 
captured in the CRF. 
• 
gChild-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. 
• 
nPre-titration tolerability assessment, which 
include a review of AEs and a review of 
safety laboratory results (eg, chemistry, 
hematology, and coagulation), must be 
completed by the Investigator before any up-
titration 
can 
occur 
as 
defined 
in 
Section 7.4.1.  Lab results obtained within 2 
months prior to any up-titration may be used 
for assessment. 
• 
oDose Titration is based on cirrhosis status 
(Section 9.7.3) 
and 
Child-Pugh 
score 
(Section 7.3).  The initial dose titration of 
investigational product may occur at the 
Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.  Subsequent dose titration(s) for 
Added footnotes provide 
clarity regarding 
assessments and visits based 
on the evaluation of 
Child-Pugh scores.  
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subjects who are classified as Child-Pugh B 
or Child-Pugh C and following a modified 
dosing schedule may occur no earlier than 6 
weeks after the previous dose titration.  For 
complete modified dose titration criteria, 
refer to Appendix A. 
• 
pSubjects will be instructed to begin dosing 
on the day after the Day 0 visit (ie, on Day 1) 
and to take investigational product at 
approximately the same time of day.  
Subjects must be instructed to swallow the 
tablet whole; they must not chew, divide, or 
crush the tablet. 
7.1.2, Table 2, 
Schedule of Study 
Procedures – Year 
2 Through End of 
Study (Table 2 of 
2) 
 
New table- Schedule of Study Procedures – Year 2 
Through End of Study (Table 2 of 2) 
Divided Schedule of Study 
Procedures into 2 tables, 
updated to include visits 
added per updated 
dosing/titration information.   
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7.3, Planned 
Dosing Regimen 
7.3 Treatment Assignment 
Subjects will receive either placebo or 5 mg 
OCA and should titrate to 10 mg OCA (in a 
blinded manner) at the 3-month study visit 
or at any study visit thereafter depending on 
tolerability. 
7.3 Planned Dosing Regimen 
Subjects will be randomized to treatment with either 
OCA or matching placebo in a 1:1 ratio.  Subjects will 
be dosed according to their cirrhosis status (as defined 
in Section 9.7.3) and applicable Child-Pugh Score (see 
Section 9.7.4) as outlined in Table 3.  
Subjects who are non-cirrhotic or classified as 
Child-Pugh A at screening will receive 5-mg OCA or 
matching placebo once daily for 3 months.  Subjects 
should titrate to a maximum dose of 10-mg OCA once 
daily (or matching placebo) at the Month 3 visit or at 
any study visit following the Month 3 visit based on 
tolerability of the product.  A review of safety 
laboratory results (eg, chemistry, hematology, and 
coagulation) obtained no more than 2 months prior to 
the planned up-titration visit must be completed as 
part of the product tolerability assessment before up-
titration can occur (see Section 7.4.1).   
For those subjects that up-titrate to 10 mg, dose may 
be decreased to 5 mg at any time during the study as 
considered clinically appropriate (eg, tolerability). 
Subjects may be titrated back up to a maximum dose 
of 10 mg once daily based on tolerability and clinical 
judgment of the Investigator.  A review of safety 
laboratory results obtained within 2 months of the 
planned up-titration visit date is not required prior to 
re-challenging a subject up to 10 mg once daily dosing, 
as long as the decrease in dose/dosing frequency was 
less than 3 months in duration. 
Section renamed to reflect 
changes in titration and 
dosing for subjects with 
hepatic impairment. 
(Insertion) 
New:  Table 3: Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
Tables added to clarify 
changes in titration and 
dosing. 
New: Table 4: Determination of Dosing Regimen 
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7.4 Dose Titration 
Criteria 
After 3 months of treatment at the 5 mg 
dose, the dose of OCA will be increased to 
the maximum dose of 10 mg OCA or 
matched placebo (in a blinded manner) at 
the 3-month visit or any study visit 
following the 3 month visit based on 
tolerability of investigational product.   
 
For those subjects that increased their dose 
to 10 mg, they may decrease his or her dose 
to 5 mg at any time during the study as 
considered appropriate (eg, tolerability), but 
should be titrated back to 10 mg based on 
tolerability and clinical judgment by the 
Investigator as soon as possible with the 
goal that all subjects remain on the 10-mg 
dose if tolerated 
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 
subject’s cirrhosis status (using histology or 
non-histological methods as defined in Section 9.7.3 
and Section 9.7.4) or Child-Pugh Score.   
Scheduled Dose Titration - The first dose titration for 
any subject may occur no earlier than 3 months 
following initiation of OCA or matching placebo.  
Subsequent titrations in dose or dosing frequency for 
subjects following the Modified Dosing Regimens may 
occur no earlier than 6 weeks (via an unscheduled visit 
or regular visit- see Appendix A) following an 
up-titration. 
Tolerability Dose Titration - Investigators may 
decrease the dosing frequency or dose for any subject at 
any time during the study, as considered clinically 
appropriate (eg, tolerability; see Section 7.4.2).   
Dose Titration due to Change in Cirrhosis or 
Child-Pugh Score - When subjects demonstrate a 
change in cirrhosis status (as assessed per 
Section 9.7.3) or Child-Pugh Score (Section 9.7.4), 
dosing should be reassessed and the dosing regimen 
modified appropriately.  Changes to the dosing 
regimen are not mandatory and should be based on 
clinical judgment as well as change in cirrhosis status.  
Table 5 provides an overview of the possible changes in 
dosing regimen due to changes in cirrhosis or Child-
Pugh 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.  
Entire section revised to 
reflect changes in titration 
and dosing. 
7.4 Dose Titration 
Criteria 
(Insertion) 
New: Table 5:  Changes in Dosing Regimen Due to 
Changes in Cirrhosis Status or Child-Pugh Score 
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7.4 Dose Titration 
Criteria 
(Insertion) 
Subjects who exhibit development of cirrhosis at any 
point in the study should be assessed per Section 9.7.3.  
If the presence of cirrhosis is confirmed and the 
subject’s Child-Pugh score is either B or C, the 
appropriate modified dosing regimen should be 
followed.  The dose or frequency of investigational 
product should be down-titrated to the next lowest 
dosing frequency in the appropriate modified dosing 
regimen unless the subject is currently taking a dose 
and frequency also specified in the modified dosing 
regimen and the investigator determines that it is 
clinically appropriate for the subject to continue at 
that dose (Appendix A). 
Subjects with pre-existing cirrhosis who demonstrate a 
change in the Child-Pugh Score from A to B or C at 
any point in the study should also have their dosing 
modified per the appropriate dosing regimen 
(Appendix A).  
Subjects who demonstrate an improvement in 
cirrhosis status or in Child-Pugh Score from B to A, or 
from Child-Pugh C to B, may be eligible to transition 
to the standard dosing regimen or the modified dosing 
for Child-Pugh B, respectively, based on tolerability.  
Prior to any dosing change, subjects must meet 
pre-titration assessment requirements for dosing as 
described in Section 7.4.1. 
Child-Pugh Scores will be calculated at all quarterly 
study visits. All associated visit data (including central 
laboratory results) should be entered into the eCRF in 
a timely fashion to confirm that the subject’s Child 
Pugh Score has not changed.  If a change in cirrhosis 
status (as defined in Section 9.7.3) and/or Child-Pugh 
Score is observed independent of a study visit, the 
subject 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 and table added to 
provide dosing guidelines to 
investigators. 
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Subjects’ dose and dosing frequency may be titrated 
up or down within the appropriate dosing regimen 
based on the calculated Child-Pugh Scores.  Up-
titration should be done per Investigator discretion 
and be guided by the pre-titration tolerability 
assessments. 
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7.4.1, 
Pre-Titration 
Tolerability 
Assessment 
Requirements 
(Insertion) 
7.4.1  Pre-Titration Assessment Requirements 
Tolerability of investigational product must be 
assessed prior to titrating a subject to a higher dose.  A 
review of adverse events and safety laboratory results 
(eg, chemistry, hematology, and coagulation) obtained 
within 2 months of the up-titration visit must be 
performed as part of the investigational product 
tolerability assessment, prior to any planned up-
titration in investigative product (eg, Month 3, Month 
6).  Safety laboratory results obtained at the Month 1 
visit (for titration at Month 3) or at the 1 Month 
Post-Titration Assessment visit (for titration prior to 
or at the subsequent quarterly visit) are acceptable for 
review purposes; however, 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 subject to a higher dose.  
To be eligible for a dose up-titration: 
• 
Subjects 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.  
• 
There must be no clinically significant increase (as 
determined by the investigator) in the subject’s liver 
function tests.  Subjects whose total bilirubin is 
>2× baseline (and >ULN) cannot be up-titrated, and 
additional unscheduled safety visit procedures, 
outlined in Section 9.7.19, should be implemented, as 
required 
Section added to provide 
guidance for assessing 
subject tolerability prior to 
titration. 
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8.4.2, Other 
Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
(Insertion) 
• 
Subject begins treatment with commercially 
available OCA 
… safety concerns and related to study drug 
• 
Consent may be fully withdrawn (in which case the 
subject discontinues both investigational product and 
study visits and procedures) 
…Subjects who undergo a liver transplant during the 
course of the study must discontinue investigational 
product and discontinue the study visit schedule.  
However, these subjects 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. 
Added text as Ocaliva is 
commercially available in 
the US and therefore 
subjects may be 
discontinued if they began 
off-study treatment with 
Ocaliva.   
8.4.2.1, Elevated 
Liver Enzymes 
(Insertion) 
New Section:  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. 
Section added to incorporate 
monitoring of liver test 
results during the study. 
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9.1, 
Investigational 
Product Treatment 
Regimen 
9.1.1 Dose Adjustment Beginning at 
Month 3 
After 3 months of treatment with 
investigational product, the dose of 
investigational product should be increased 
in a blinded manner and based on 
tolerability; this may occur at the Month 3 
visit, or at any study visit thereafter.  
Titration above 10 mg OCA is not 
permitted. 
At each study visit where the daily dose of 
investigational product is administered at the site, all 
assessments, except for the post-dose collection of 
blood samples for the subset of subjects participating 
in the Month 9 PK assessment, must be completed 
before administration of investigational product. 
Section revised to reflect 
changes in titration and 
dosing. 
9.2, Concomitant 
Medications 
Subjects taking bile acid sequestrants 
(BAS) 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). 
 
New sub-heading:   
Drug Interactions 
Subjects 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 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.  
(…) Information related to additional drug-drug 
interaction (DDI) studies is available in the current 
version of the Investigator’s Brochure (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 with OCA that may 
be observed in study subjects. 
Section revised to provide 
additional information on 
drug-drug interactions with 
OCA. 
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9.2.1, Prohibited 
Medications 
… the Investigator should be cognizant of 
the possibility of double dosing and 
encourage the discontinuation of open-label 
OCA therapy.  However, if commercial 
OCA therapy remains, then investigational 
product should be discontinued to avoid 
potential double dosing.  Subjects that 
discontinue investigational product but 
continue commercial OCA therapy are 
expected to continue through the end of the 
study, and the … 
… the Investigator should be cognizant of the possibility 
of double dosing.  Subjects who continue with 
commercial OCA therapy must discontinue investigative 
product and are expected to continue through the end of 
the study.  … 
Ocaliva is commercially 
available in the US and, 
therefore, subjects wishing 
to take commercially 
available drug are not 
discouraged, but they must 
discontinue investigative 
product. 
9.7.1, Visit 
Windows 
(insertion) 
Added the following visit windows: 
• 
Month 1 (+1 week [7 days]) 
• 
Titration Visit – Standard Dosing Regimen 
(≥Month 3) 
• 
Titration Visit 1 – Modified Dosing Regimen 
(≥Month 3) 
• 
Titration Visit 2 – Modified Dosing Regimen 
(≥6 weeks after Titration Visit 1) 
• 
Titration Visit 3 – Modified Dosing Regimen 
(Child-Pugh B ONLY) (≥6 weeks after 
Titration Visit 2) 
• 
Post-Titration Visit, (+1week [7 days]) from 
date of titration or after ≥3 months at a 
decreased dose or frequency) 
Added visits to 
accommodate the updated 
dosing/titration scheme. 
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9.7.3, Assessing 
Cirrhosis 
(Insertion) 
New: 9.7.3. Assessing Cirrhosis 
To determine which dosing regimen subjects should 
follow, the presence or absence of 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 
is defined as a subject 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  
− 
elevation in prothrombin time /INR (not 
due to antithrombotic agent use), or 
− 
elevated bilirubin (2× ULN) 
Subjects who exhibit no evidence of cirrhosis by the 
above methods of assessment will be dosed using the 
Standard Dosing Regimen, while those who do exhibit 
evidence of cirrhosis by one or more of the above 
methods will be dosed using the Modified Dosing 
Regimen according to their Child-Pugh Score 
calculated in the electronic case report form (eCRF) 
(see Appendix A). 
Cirrhosis status should be reassessed as clinically 
indicated throughout the study.  Any change in 
Added section to assess 
cirrhosis as this assessment 
will determine the 
acceptable dosing regimen 
based on a subject’s 
Child-Pugh score.  
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cirrhosis status will necessitate re-evaluation of the 
dosing regimen. 
9.7.4, Child-Pugh 
Score 
(Insertion) 
9.7.4. 
Child-Pugh Score 
Child-Pugh Score (Pugh 1973, Lucey 1997) is 
calculated and reported within the electronic data 
capture (EDC) system based on data entered into the 
eCRF adding the scores from the 5 factors outlined in 
Table 6 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 
Child-Pugh 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.   
It is important to note that subjects must have 
confirmed cirrhosis as assessed by one or more of the 
above criteria (Section 9.7.3) prior to applying the 
calculated Child-Pugh score for dosing.  Investigators 
will be responsible for determining the appropriate 
dosing regimen based on both the cirrhosis status and 
the Child-Pugh score (Table 6).  Any change in 
cirrhosis status or Child-Pugh Score will necessitate 
re-evaluation of the dosing regimen 
Section added to provide 
Investigators with 
information on the 
Child-Pugh scoring system. 
9.7.4, Child-Pugh 
Score 
(Insertion) 
Table 6 (New) Child-Pugh Scoring System 
 
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9.7.6, Screening 
Procedures (1 to 8 
Weeks prior to 
Day 0) 
(Insertion) 
The following procedures were added: 
Screening Visit 1 procedures are as follows: 
• 
Provide the subject with a dosing diary to 
document his or her dosing 
• 
Assess for the presence/absence of cirrhosis 
• 
Perform status assessment for calculation of 
Mayo Risk Score 
Screening Visit 2 procedures are as follows: 
• 
Perform an ultrasound for hepatocellular 
carcinoma (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 Visit 2, and a report/adequate data are 
available, a pretreatment ultrasound at Screening 
Visit 2 is not required.  If the ultrasound cannot 
be performed at Screening Visit 2 (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. 
Procedures added to assess 
cirrhosis. 
 
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Pr ot oc ol 7 4 7 -3 0 2  
Versi o n 6: 0 5 N o v 2 0 1 9  
 
Pa ge 1 8 1  
 
C o nfi de ntial a n d Pr o prietar y   
Secti o n  
Ori gi n al Te xt ( A m e n d m e nt 1. 1, 
1 2  N o ve m ber  2 0 1 5)  
Re vise d Te xt ( Versi o n 3, 0 7  Se pte m ber  2 0 1 6)  
J ustific ati o n f or C h a n ge  
9. 7. 7, Da y 0 
Pr oce d ures 
( Ra n d o mizati o n) 
9. 7. 4. 
Da y 0 Pr oce d ures  
• 
Perf or m a n ultras o u n d f or 
he pat ocell ular carci n o ma ( H C C) 
s ur veilla nce (if e q ui p me nt is u na vaila ble, 
… 
• 
Perf or m p h ysical e xa mi nati o n a n d 
o verall stat us assess me nt f or calc ulati o n of 
Ma y o Ris k Sc ore a n d C hil d -P u g h 
Assess me nts.  
 Prese nce/a bse nc e of peri p heral e de ma 
 Prese nce ( de gree)/a bse nce of ascites  
 Prese nce ( de gree)/a bse nce of he patic 
e nce p hal o pat h y 
9. 7. 7 : Da y 0 Pr oce d ures ( Ra n d o mizati o n)  
• 
Pr o vi de t he s u bject wit h a d osi n g di ar y t o 
d oc u m e nt his or her d osi n g.  
 
U p date d visit t o 
acc o m m o date t he u p date d 
d osi n g/titrati o n sc he me.  
9. 7. 8, M o nt h 1 
Pr oce d ures  
9. 7. 5 Safet y C o ntact ( M o nt h 1, M o nt h 2, 
a n d 2 Wee ks P ost -Titrati o n [ b y tele p h o ne])  
9. 7. 8  M o nt h 1 Pr oce d ures  
• 
Pr o vi de t he s u bject wit h a d osi n g di ar y t o 
d oc u m e nt his or her d osi n g.  
• 
I n t he e ve nt it is n ot fe asi ble f or t he s u bject t o 
ret ur n t o t he site f or t he a b o ve refere nce d pr oce d ures, 
t he f oll o wi n g alter n ati ve visit pr oce d ures are a v ail a ble 
t o hel p e ns ure c o m pli a nce wit h t he M o nt h 1 visit 
re q uire m e nts:  
- 
At t he D a y 0 visit, t he s u bject c a n be pr o vi de d 
wit h t he ce ntr al l a b or at or y c ollecti o n kit a n d s hi p pi n g 
m ateri als ass oci ate d wit h t he M o nt h 1 visit, …  
- 
If all ot her o pti o ns f or t he c ollecti o n of t he M o nt h 
1 l a b or at or y s a m ples h a ve bee n e x h a uste d, t he use of a 
l oc al l a b or at or y f or t he M o nt h 1 s a m ples w o ul d be 
acce pte d f or t his visit alt h o u g h a n y l a b or at or y d at a 
o bt ai ne d fr o m a l oc al l a b or at or y will n ot be c a pt ure d 
i n t he e C R F or i ncl u de d i n t he st u d y a n al ysis.  … 
 
Re vise d secti o n t o i ncl u de 
t he ne w M o nt h 1 visit 
pr oce d ures.  
Pa ge 1 8 1 of 3 5 1
Pa ge 1 4 9 2 of 1 6 8 2


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9.7.9, Month 3 
procedures, 
9.7.11, Month 6 
Procedures, 
9.7.12, Month 9, 
9.7.14, Month 12 
Procedures  
(Insertion) 
• 
Perform assessments for calculation of Child-Pugh 
Score 
Added procedure to 
accommodate the updated 
dosing/titration scheme. 
9.7.9 thru 9.7.17 
(Insertion) 
If up-titration will occur at this visit, complete the pre-
titration visit and visit related assessments as outlined 
to ensure all procedures required for dose titration 
eligibility have been met, including the required review 
of the dose titration laboratory parameters. 
• 
Provide the subject with a dosing diary to 
document his or her dosing 
• 
… review dosing diary with the subject 
Text added to clarify 
procedures required before 
up-titration. 
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9.7.10, Post 
Titration Visit 
Procedures 
(Insertion) 
New: 9.7.10. Post Titration Visit Procedures 
• 
Assess and record AEs. 
• 
Review and record concomitant medications. 
• 
Assess investigational product compliance, 
perform investigational product accountability, and 
review dosing diary with the subject. 
• 
Obtain blood samples for serum chemistry, 
hematology, and coagulation tests. 
• 
Provide the subject with a dosing diary to 
document his or her dosing. 
• 
In the event it is not feasible for the subject to 
return the site for the above referenced procedures, 
the following alternative visit procedures are available, 
to help ensure compliance with the Post-Titration visit 
requirements: 
- 
At the Up-titration Visit, the subject can be 
provided with the central laboratory collection kit 
and shipping materials associated with the Post-
Titration visit, and have the laboratory specimen 
collection performed at his or her local doctor’s 
office or designated laboratory collection center.  
The subject must also be contacted via telephone 
at the Post-Titration Visit time point to assess 
AEs, review concomitant medications, and assess 
investigational product compliance. 
- 
If all other options for the collection of the 
Post-Titration laboratory samples have been 
exhausted, the use of a local laboratory for the 
Post Titration samples would be accepted for this 
visit although any laboratory data obtained from 
a local laboratory will not be captured in the 
eCRF or included in the study analysis.  A copy of 
the local laboratory report would need to be 
provided to the investigator for review and 
available in the source records.  The subject must 
also be contacted via telephone at the Post-
Titration Visit time point to assess AEs, review 
Added visit to accommodate 
the updated dosing/titration 
scheme. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
concomitant medications, and assess 
investigational product compliance. 
• 
Schedule the next visit, reiterate dosing 
instructions, and advise the subject: 
- 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… 
9.7.13, Month 9 
Procedures for 
Subjects 
Participating in 
Pharmacokinetic 
Assessment 
(Insertion) 
…Subjects who are following the Child-Pugh B and 
Child-Pugh C modified dosing regimen may 
participate in the PK assessment and will dose in the 
clinic at this visit even if the previous dose was taken 
less than 3 days prior; however, every attempt should 
be made to schedule the Month 9 PK visit according to 
the subject’s established dosing schedule. 
Clarify that subjects with 
hepatic impairment may 
continue to participate in the 
PK assessment. 
9.7.13, Month 9 
Procedures for 
Subjects 
Participating in 
Pharmacokinetic 
Assessment 
…Lunch will be provided following 
collection of the 4 hour PK sample; the 
lunch will be a meal replacement drink… 
…Lunch will be provided following collection of the 
4 hour PK sample; the lunch will be a meal replacement 
drink with no other food allowed until after the final 
6-hour post dose sample is collected… 
Clarify PK collection 
procedures. 
 
11.1.2.2, Other 
Secondary 
Assessments 
• 
OCA (and its conjugates) and C4 will 
be assayed 
• 
OCA (OCA, tauro-OCA, glyco-OCA, total OCA, 
OCA-glucuronide) and C4 will be assayed to determine 
bioanalytical concentrations.  Additional analyses may 
include other conjugates or metabolites not yet 
identified. 
Clarify the analytes to be 
measured for the PK 
analyses. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
11.1.2.4, Potential 
Clinical Outcome 
Events 
(Insertion) 
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 13.4. 
Revised to clarify that 
potential clinical outcome 
events meeting the criteria 
of a SUSAR will not be 
reported to regulatory 
authorities expeditiously.  
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12.1.4.2 Reporting 
of Serious 
Adverse Event 
In agreeing to the provisions of this 
protocol, the Investigator accepts all legal 
responsibilities for immediate reporting of 
SAEs to the medical monitor. 
All SAEs occurring while subjects are 
receiving investigational product or are on 
an investigational product holiday 
(including Potential Clinical Outcome 
Events that qualify as serious) must be 
reported to the medical monitor 
immediately (ie, within 24 hours) after the 
Investigator identifies the SAE.  SAEs are 
reported by entering the SAE data into the 
electronic data capture (EDC) system.  
Entering the SAE data into the EDC system 
will automatically notify the medical 
monitor of the event.  In the event that the 
EDC system is inaccessible, an SAE may 
be reported by telephone or fax using a 
paper SAE Report form.  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:   
subject number and initials, a description of 
the event, at least one criterion classifying 
the event as serious and the name and title 
of the reporting individual.  Additionally, 
judgment of causality by the Investigator 
must be provided as soon as possible to 
ensure timely reporting to regulatory 
authorities by the Sponsor or designee(s).  
Following the initial report, any additional 
information obtained by the Investigator 
about the SAE must be reported promptly 
to the medical monitor.  Any supporting 
source documentation should be faxed to 
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 be reported by: 
• 
E-mail to the SAE email address:  
sae@interceptpharma.com 
• 
Fax using a paper SAE report form:  
+1 800 497 8521 
• 
Telephone:  +1 858 964 1571  
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:   
• 
Subject 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 Sponsor will notify the appropriate regulatory 
agencies as well as all participating Investigators of 
investigational new drug (IND) 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 
Updated guidance for 
reporting SAEs. 
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+1 800 497 8521 or emailed to 
sae@interceptpharma.com as soon as 
possible. 
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.  A 
SAE assessed with a possible, probable, or 
definite causal relationship to the 
investigational product and unexpected 
according to IB Reference Safety 
Information (RSI), is known as a suspected 
unexpected serious adverse reaction 
(SUSAR).  The Sponsor will notify the 
appropriate regulatory agencies as well as 
all participating Investigators of 
investigational new drug (IND) safety 
reports (SUSARs) that occur during the 
study within the time frames required by 
each regulatory agency.  The Investigator is 
responsible for submitting information on 
IND safety reports/SUSARs received from 
the Sponsor or Sponsor designee to her/his 
local EC/IRB.  Documentation of the 
submissions to IRBs and health authorities 
must be retained in the appropriate study 
file(s). 
Potential Clinical Outcome Events 
(Appendix A) as well as Anticipated Events 
(Appendix B) will not undergo expeditious 
reporting to regulatory authorities 
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 
+1 800 497 8521 or emailed to 
sae@interceptpharma.com as soon as possible.   
The Investigator is responsible for submitting 
information on IND 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 
IECs/IRBs must be retained in the appropriate study 
file(s).  As instructed by the Sponsor, IND 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 12.1.5. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
Section 12.1.5, 
Suspected Liver-
related Clinical 
Outcome Events 
Clinical Outcome Events (Appendix A) as 
well as Anticipated Events (Appendix B) 
will not undergo expeditous reporting. 
12.1.5 Suspected Liver-Related Clinical Outcome 
Events 
Specified liver-related clinical outcome events may, by 
definition (see Section 12.1.1.2) qualify as SAEs.  The 
Sponsor must be notified of any SAEs within 24 hours 
of the site becoming aware of the event (see 
Section 12.1.4.2).  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. 
Given that the liver-related clinical outcome events 
could also meet the criteria of a SUSAR, please refer to 
Section 11.1.2.4. 
The Sponsor will consider the following list of clinical 
outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy), spontaneous bacterial 
and peritonitis (preferred term: peritonitis bacterial). 
Updated section to account 
for events related to hepatic 
impairment. 
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Justification for Change 
13.2.4, 
Cardiovascular 
Adjudication 
Committee 
13.2.3 
(…) 
In addition to potential clinical endpoint 
events, cardiovascular events will be 
adjudicated.  The adjudication of these 
events will be handled separately from the 
adjudication of events for assessment of the 
primary endpoint in this study and will be 
described separately. 
New Section: Cardiovascular Adjudication Committee 
In addition to potential clinical endpoint events, 
cardiovascular events will be adjudicated.  The 
adjudication of these events will be handled separately 
from the adjudication of events for assessment of the 
primary endpoint in this study. Adjudicated 
cardiovascular events include core major adverse 
cardiovascular events (MACE) (cardiovascular death, 
nonfatal myocardial infarction, and nonfatal stroke) 
and expanded MACE (unstable angina requiring 
hospitalization, transient ischemic attack, peripheral 
or coronary revascularization procedures, 
hospitalization for congestive heart failure).  Other 
events potentially related to adverse cardiovascular 
outcomes may be included in the Cardiovascular 
Adjudication Committee (CAC) Charter for 
adjudication.  The adjudication of these events will be 
handled separately from the adjudication of events for 
assessment of the primary endpoint in this study (see 
Section 13.4). 
Committee added to assess 
cardiovascular events in 
subjects during the study. 
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13.4, Adjudication 
Committee 
All potential endpoint events will be 
reviewed by an adjudication committee 
before inclusion in the any analysis.  The 
adjudication of potential clinical endpoint 
events will include, but is not limited to:  
available hospital reports, histology, 
discharge summaries, and death certificates.  
The assessment of events will be conducted 
in compliance with the protocol, study-
specific procedures, manuals, Good 
Clinical Practice (GCP), and all other 
applicable regulatory requirements, 
including the archiving of essential 
documents.  A separate adjudication 
committee charter will document the entire 
data flow and process from committee 
membership, the reporting of events by the 
study site, reporting of the final assessment, 
supply of source documentation to the 
committee, the review of the events by the 
committee, and the working procedures of 
the committee.  The adjudication committee 
members will be independent hepatologists 
not involved in the study as investigators, 
DSMC members, or consultants.  All 
adjudication committee members will 
remain blinded to treatment group 
throughout the study. 
In addition to potential clinical endpoint 
events, cardiovascular events will also be 
adjudicated.  The adjudication of these 
events will be handled separately from the 
adjudication of events for assessment of the 
primary endpoint in this study and will be 
described separately. 
All suspected liver-related clinical outcomes, 
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 subject treatment or site-
specific information.  The assessment of events will be 
conducted in compliance with study-specific 
Committees added to assess 
liver impairment in subjects 
during the study. 
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Revised Text (Version 3, 07 September 2016) 
Justification for Change 
procedures, manuals, good clinical practice (GCP), 
and all other applicable regulatory requirements, 
including the archiving of essential documents. 
Appendix A, 
Modified Dosing 
Regimen for 
Subjects with 
Child-Pugh B/C 
Hepatic 
Impairment 
(Insertion) 
New: APPENDIX A. MODIFIED DOSING 
REGIMEN FOR SUBJECTS WITH CHILD-PUGH 
B/C HEPATIC IMPAIRMENT 
Added section to describe 
changes in dosing and 
titration for subjects 
assessed as cirrhotic 
Child-Pugh B or 
Child-Pugh C. 
Appendix B, LIST 
OF STUDY 747-
302 OUTCOME 
EVENTS 
Was Appendix A 
Now Appendix B  
The hepatic dosing appendix 
became Appendix B  
Appendix C 
LIST OF STUDY 747-302 ANTICIPATED 
EVENTS 
Deleted 
Replaced by Appendix B, 
more comprehensive 
description of the outcome 
events. 
 
 
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APPENDIX G. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO PROTOCOL VERSION 3.1 
(DATED 23 DEC 2016) 
Please note that Protocol 747-302 Version 3.1 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.  This 
summary of changes is provided for completeness.  A full accounting of the changes from Protocol Version 3 to Protocol 
Version 4 is provided in Appendix I. 
Rationale and Summary of Changes 
Major revisions to Protocol 747-302 include the expansion of the spectrum of stages of PBC disease, the addition of progression to 
cirrhosis as a secondary endpoint, and the addition of two interim analyses.   Additional revisions include an increase in subject 
number and the number of required clinical outcome events, a change in the study phase, an update to the nomenclature for PBC, and 
various clarifications within the protocol.   
The following table includes revisions that were made to Protocol Version 3.1 with an associated reason or justification for the 
change.  Rationales (Justifications for Change) that impact multiple sections are provided below and referenced in the table with the 
appropriate rationale number.  
1. The phase of the study has been changed from ‘3b’ to ‘4’ to reflect that this is a post-marketing study. 
2. The term ‘primary biliary cirrhosis’ has been changed to ‘primary biliary cholangitis’ throughout the document to reflect 
recent changes in nomenclature for PBC. 
3. The increase in number of required events from 121 to 127 is due to the addition of two interim analyses (IA), which will 
allow an independent DMC to recommend continuation, modification, or cessation (for efficacy or futility) of the study.  One 
IA will occur at 50% information (after 64 events occur) and one at 75% information (after 96 events occur).  Inclusion of 
patients with earlier stage disease will also increase the time to event requiring more events in order to keep follow-up to 
approximately 6 years.   
4. The first-year study enrollment rate was lower than projected due to slower-than-anticipated activation of sites and required a 
re-estimation of the accrual duration.   Using observed accrual rates, the accrual duration was extended by two years.  The 
follow-up period was maintained at 6 years, thereby leading to a total trial duration of 10 years. 
5. ‘Encephalopathy’ has been modified to ‘Hepatic Encephalopathy’ to clarify that the relevant clinical outcome endpoint should 
be related to hepatic disease. 
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6. Histological confirmation (biopsy) has been added as an acceptable method of confirming a diagnosis of Hepatocellular 
Carcinoma. 
7. Broadening the Spectrum of Disease:  Lowering the minimum allowable baseline ALP to 3x ULN and raising the maximum 
allowable baseline total bilirubin to 5x ULN will increase the number of subjects enrolled with early and advanced disease 
facilitating the collection of safety and efficacy data in a population that covers the spectrum of PBC disease and overlaps with 
the subject population in the phase 3 protocol 747-301. 
8. The titration regimen has been updated to reflect assessment of both tolerability and biochemical response prior to up-titration 
per the USPI and SmPC.   
9. The increase in enrollment from 350 to 428 is due in part to the increased number of events, and in part due to the change in 
the estimated Placebo baseline hazard rate which resulted from changing the lower limit of ALP from 5× ULN to 3× ULN in 
the enrollment criteria #2. 
10. Progression to Cirrhosis has been added as a secondary endpoint:  Due to the chronic nature of PBC, outcomes require a very 
long time to accrue to evaluate the impact of potential therapies.  Despite the proven prognostic utility of ALP and bilirubin, 
there is a remaining need to evaluate noninvasive assessments of disease progression that can be linked to histological 
progression of the disease.  Therefore, it is important to evaluate potential non-invasive markers of fibrosis/cirrhosis and their 
relationship to clinical outcomes as part of 302. 
The text deleted from Protocol Version 3 is crossed out while revised text in Version 3.1 is indicated in bold font in the table below.  
Minor/editorial changes and non-substantial changes are not listed individually in the summary table below.  
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Section 
Original Text (Amendment 3, 
07 September 2016) 
Revised Text (Version 3.1, 23 December 2016) 
Justification for Change 
Title Page 
Synopsis, Title of 
Study 
A Phase 3b, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study Evaluating 
the Effect of Obeticholic Acid on Clinical 
Outcomes in Subjects with Primary Biliary 
Cirrhosis 
A Phase 4, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on 
Clinical Outcomes in Subjects with Primary 
Biliary Cholangitis 
 
Rationale 1 and 2  
Study Personnel 
Contact 
Information 
Or if Not Available: 
Contact: 
 MD, PhD, 
Executive Director, Clinical 
Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
 
 
Email: 
 
 (Pacific 
time zone) 
 
 
Or if Not Available: 
Contact: 
 MD, PhD 
Medical Director, Clinical 
Research, 
Intercept Pharmaceuticals, 
Inc. 
Telephone: 
Mobile: 
 
Email: 
 
 (Pacific 
time zone) 
 
Back-up medical monitor 
responsibilities were 
transferred to 
 
Synopsis, Studied 
Period (years) 
 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 and 4   
 
Synopsis, Phase of 
Development  
3b 
4 
Rationale 1 
Synopsis, 
Objectives, 
Primary, 
Statistical 
• 
Encephalopathy (as defined by a West Haven 
score of ≥2) 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities 
• 
Hepatic encephalopathy (as defined by a 
West Haven score of ≥2) 
Rationale 5   
 
 
Rationale 6 
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Methods – 
Efficacy Analyses 
Section 6.1 
Primary Objective 
Section 11.1.1 
Primary 
Assessments 
 
Section 13.1.3 
Primary Efficacy 
Analysis 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities unless 
confirmed by biopsy 
Synopsis, 
Objectives, 
Secondary  
Section 6.2 
Secondary 
Objectives 
 
Insertion 
 
To assess the pharmacokinetics of OCA and its 
conjugates in a subset of subjects 
To assess the effect of OCA compared to 
placebo on progression to cirrhosis 
To characterize the pharmacokinetics of OCA 
and its conjugates in a subset of subjects 
Rationale 6 
 
 
 
Synopsis, 
Methodology: 
Schematic 
Diagram 
 
Section 7.1.1 
Study Design 
Diagram, Figure 1 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.   
 
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability of the product. 
 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability and biochemical response.   
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability and biochemical response of the 
product. 
Rationale 7 
 
 
 
 
Rationale 8 
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• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability. Subjects 
classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 
10-mg OCA or matching placebo twice 
weekly, based on tolerability. 
 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the titration of 
dose and/or frequency is dependent on subject tolerability, 
and/or changes in cirrhosis status or Child-Pugh Score at any 
time during the study.  
 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability and biochemical 
response. Subjects classified as Child-Pugh 
Class C should titrate to a maximum dose 
and frequency of 10-mg OCA or matching 
placebo twice weekly, based on tolerability 
and biochemical response. 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the titration 
of dose and/or frequency is dependent on subject tolerability, 
biochemical response, and/or changes in cirrhosis status or 
Child-Pugh Score at any time during the study. 
Synopsis, Number 
of Subjects 
(planned)  
Approximately 350 subjects 
Approximately 428 subjects 
Rationale 9 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
2.  A mean total bilirubin >ULN and ≤3x ULN 
and/or a mean ALP >5x ULN 
2.  A mean total bilirubin >ULN and ≤5x ULN 
and/or a mean ALP >3x ULN 
Rationale 7 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
5.  Contraception:  Female subjects 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:   
5.  Contraception:  Female subjects of 
childbearing potential must use ≥1 effective 
method of contraception during the study and 
until 30 days following the last dose of 
investigational product.  Effective methods 
of contraception are considered to be those 
listed below:   
Standardizing language across 
protocols; removing double-
barrier terminology 
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• 
Double barrier method, ie, (a) condom 
(male or female) or (b) diaphragm, with 
spermicide; or  
• 
Intrauterine device (IUD); 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 subject   
• 
Barrier method, ie, (a) condom (male 
or female) or (b) diaphragm, with 
spermicide 
• 
Intrauterine device (IUD)  
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection) 
• 
Abstinence, if in line with the preferred 
and usual lifestyle of the subject   
Synopsis, 
Exclusion Criteria 
Section 8.3 
Subject Exclusion 
Criteria 
 
3.  Mean total bilirubin >3x ULN 
Mean total bilirubin >5x ULN 
Rationale 7 
Synopsis, Criteria 
for Evaluation 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Encephalopathy (as 
defined by a West 
Haven score of ≥2) 
 
• 
Hepatocellular 
carcinoma 
confirmed by 
2 complimentary 
imaging modalities 
 
Secondary Objectives 
 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Hepatic 
encephalopathy (as 
defined by a West 
Haven score of ≥2) 
• 
Hepatocellular 
carcinoma confirmed 
by 2 complimentary 
imaging modalities 
already confirmed by 
biopsy 
Secondary Objectives 
 
Rationale 5 
 
 
 
 
 
 
 
 
 
 
Rationale 10 
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Progression to 
cirrhosis 
Clinical, laboratory, 
or radiological 
evidence of cirrhosis 
and/or liver stiffness 
(i.e., Fibroscan® TE) 
confirmed by biopsy 
unless not medically 
indicated 
Synopsis, 
Statistical 
Methods 
Analysis 
Populations 
 
The following subject populations will be 
evaluated and used for presentation and analysis of 
the data:  Randomized, Intent-to-Treat (ITT), 
Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical 
Control.  Descriptions of subject populations are 
provided in Section 13.1.1. 
The following subject populations will be 
evaluated and used for presentation and analysis 
of the data:  Intent-to-Treat (ITT), Safety, PK, 
Overall Historical Control, UKPBC Historical 
Control, and the Global PBS Historical Control.  
Descriptions of subject populations are provided 
in Section 13.1.1. 
 
Randomized population 
includes patients on OCA who 
withdrew prior to receiving 
drug and this is already 
collected with the safety 
population. 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Analysis 
The primary efficacy analysis will compare 
randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the 
ITT population.   
The primary efficacy analysis will compare OCA 
to placebo with respect to the primary efficacy 
endpoint using the ITT population.   
 
Synopsis, 
Statistical 
Methods, Key 
Secondary 
Efficacy Analyses 
The key secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
in ITT population with respect to the key 
secondary efficacy endpoints.   
The key secondary efficacy analyses will 
compare OCA to placebo in the ITT population 
with respect to the key secondary efficacy 
endpoints.   
 
Synopsis, 
Statistical 
Methods, Other 
Efficacy Analyses 
 
Section 13.1.5 
Additional 
Insertion 
Progression to cirrhosis will be assessed in the 
subset of subjects considered non-cirrhotic at 
baseline using available medical history, 
clinical, and laboratory assessments as well as 
baseline transient elastography (TE), where 
available. Specifically, subjects with no 
clinical, laboratory, or radiological evidence of 
cirrhosis at baseline and/or a TE liver stiffness 
of <16.9 kPa (Corpechot 2012) will be 
Rationale 10 
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Secondary 
Efficacy Analyses 
considered non cirrhotic.  Progression to 
cirrhosis will be assessed by the development 
of clinical, laboratory, or radiological evidence 
of cirrhosis and/or when liver stiffness 
increases to ≥16.9 kPa during the trial in 
which case histological progression to cirrhosis 
should be confirmed by biopsy unless not 
medically indicated. Using this definition for 
progression to cirrhosis, the percentage of 
non-cirrhotic subjects progressing to cirrhosis 
during the treatment period will be 
summarized by treatment group and 
compared using a Cochran–Mantel–Haenszel 
test stratified by the randomization 
stratification factor. 
Analyses for the histological assessment 
conducted as part of the biopsy sub-study are 
defined in Appendix C. 
 
Synopsis, 
Statistical 
Methods, Safety 
Analyses 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will compare OCA and placebo using the Safety 
Population. 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
will be summarized by treatment group for the 
Safety Population. 
 
Clarification of summary 
analyses 
Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
Rationale 3 
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Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
 
Section 13.1.2. 
Determination of 
Sample Size 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, placebo 
survival estimate of 0.5 at 8 years 
with a hazard ratio of 0.60, and total 
study duration of 8 years, allowing 
for 2 years accrual and 6 years of 
follow up 
 
• 
Insertion 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, 
placebo survival estimate of 0.6 at 8 
years with a hazard ratio of 0.60, 
and total study duration of 10 years 
(from first subject enrolled), 
allowing for 4 years subject accrual 
and 6 years of follow up 
• 
Two interim analyses and one 
final analysis are planned 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
 
 
 
Rationale 4 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale 3 
 
 
 
 
 
 
Section 5.6 
Summary of 
Known Potential 
Risks with OCA 
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).  
An increase in liver enzymes and hepatic AEs, 
including jaundice, were observed in subjects 
with liver disease at OCA doses between 10 mg 
and 50 mg and in healthy subjects who were 
treated at doses ≥100 mg in Phase 1, multiple-
dose studies. 
Language has been updated to 
reflect Sponsor standards 
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Insertion 
Refer to the IB for additional information 
regarding the known potential risks with the 
investigational product. 
Section 7.1 
Overall Study 
Design 
This is a Phase 3b, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤3× ULN or ALP 
>5× ULN.   
 
Approximately 350 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 2-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
Investigational product will be taken orally, once 
daily….based on tolerability (see Section 7.3). 
 
 
 
The study will continue until approximately 121 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
This is a Phase 4, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤5× ULN or ALP 
>3× ULN.   
 
Approximately 428 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 4-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
Subjects will be dosed according to their 
cirrhosis status and Child-Pugh Score….based 
on tolerability and biochemical response (see 
Section 7.3)   
 
The study will continue until approximately 127 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
Rationale 1 
 
 
 
 
 
Rationale 9 
 
 
 
 
 
Clarification  
Rationale 7 
 
 
 
Rationale 3 
Section 7.1.2 
Schedule of Study 
Procedures, Table 
1  
Insertions 
 
 
 
 
 
 
Physical exams have been added at: 
• 
Month 1 
• 
1-Month Post Titration 
• 
Month 6 
Fibroscan® TE has been added at Month 6 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring. 
 
 
 
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j Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device 
is available.  Similarly, DEXA will be conducted at 
selected study sites where the DEXA device is 
available.    
 
 
Insertion (subsequent footnotes are renumbered 
accordingly) 
 
 
 
 
 
 
 
l Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be obtained to 
confirm if a study endpoint has been met. 
 
 
 
 
o … The initial dose titration of investigational product 
may occur at the Month 3 visit, or any study visit 
thereafter for subjects on all dosing regimens, based 
on tolerability. … 
 
u  A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of these 
samples.  Genetics samples will be collected at Day 0 
and every other year beginning at Month 12. 
 
j Transient elastography (TE) will be conducted at 6-
month intervals at all study sites where the 
Fibroscan® TE device is available.   
 
 
 
 
k DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available.  Please refer to Section 9.7.7 for 
additional information related to the allowed 
windows at Day 0 for this procedure. 
 
 
 
 
m Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: unless HCC has already confirmed 
by biopsy, a second confirmatory image (eg, MRI) 
should be obtained to confirm if a study endpoint 
has been met   
 
 
 
p … The initial dose titration of investigational product 
may occur at the Month 3 visit, or any study visit 
thereafter for subjects on all dosing regimens, based 
on tolerability and biochemical response. … 
 
v A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of these 
samples.  Genetics samples will be collected at Day 
0 and every other year beginning at Month 12.  If a 
baseline (e.g. Day 0) genetic sample is not 
obtained, subsequent genetic samples are not 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments at Day 0 
and Month 12) 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
 
 
Rationale 8 
 
 
 
 
Clarification 
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required to be collected during the course of the 
study. 
 
Section 7.1.2 
Schedule of Study 
Procedures, Table 
2 
Insertions 
 
 
 
 
 
i Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE device 
is available.  Similarly, DEXA will be conducted at 
selected study sites where the DEXA device is 
available.  Not required if done within 6 months of 
visit. 
   Insertion (subsequent footnotes are renumbered 
accordingly) 
  
 
j   Endoscopy will be conducted at selected study sites 
where the device is available to assess for the 
presence of oesophageal varix/varices. 
 
k  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be obtained to 
confirm if a study endpoint has been met. 
Fibroscan® TE has been added at Month 6 
continued follow up 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
continued follow up 
 
i Transient elastography (TE) will be conducted at 6-
month intervals at all study sites where the 
Fibroscan® TE device is available. Not required if 
done within 3 months of visit 
 
 
j  DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available.  Not required if done within 6 months 
of visit. 
k   Endoscopy will be conducted at all study sites where 
the device is available to assess for the presence of 
oesophageal varix/varices. 
 
l  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: unless HCC has already been 
confirmed by biopsy, a second confirmatory image 
(eg, MRI) should be obtained to confirm if a study 
endpoint has been met. 
 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
 
 
 
 
 
 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments) 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
Section 7.1.3 
Study Duration 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
Rationale 3 
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are expected to have a minimum follow-up time of 
approximately 6 years. 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Section 7.2 
Number of 
Subjects 
It is expected that approximately 350 subjects will 
be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
It is expected that approximately 428 subjects 
will be randomized in the study.   
Rationale 9 
 
 
Section 7.3 
Planned Dosing 
Regimen 
Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at 
the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the 
product.   
 
 
 
Table 3:  Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
Footnotes were re-ordered 
b   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is dependent 
on subject tolerability and/or changes in cirrhosis 
status or Child-Pugh score at any time during the 
study 
Subjects should titrate to a maximum dose of 10 
mg OCA once daily (or matching placebo) at the 
Month 3 visit or at any study visit following the 
Month 3 visit based on tolerability of the product 
and assessment of biochemical response.  Up-
titration should be considered if ALP and/or 
total bilirubin >ULN.   
 
Table 3:  Planned Dosing Regimen by Cirrhosis 
and Child-Pugh Score 
 
c   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is 
dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or 
Child-Pugh score at any time during the study 
Rationale 8 
Section 7.4 Dose 
Titration Criteria 
Insertion 
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) as 
well as biochemical response (as assessed by 
reductions in ALP and/or total bilirubin).  In 
general, down-titration will be done in 
response to tolerability concerns and can occur 
at any time while on-study.  Up-titration will 
be done per protocol when subjects have no 
tolerability concerns and have not achieved an 
adequate reduction in ALP and/or total 
Added language to clarify 
titrations (up or down) 
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bilirubin to within normal limits, or 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 for each dosing regimen as defined 
in Section 7.3. 
 
Section 8.4.1.1 
Severe Drug-
Induced Liver 
Injury 
Insertion 
If a subject develops signs and symptoms of a 
severe drug-induced liver injury, regardless of 
causality, investigational product should be 
interrupted until the event has resolved or 
returned to baseline, but the subject should 
continue with the study visit schedule.  
Subjects who develop significant drug-induced 
liver injury which is considered 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, evidence of 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. 
Severe drug induced-liver injury that is not 
considered related to investigational product 
must be discussed with the Sponsor before 
investigational product is reinitiated.  Follow-
up procedures for subjects resuming 
treatment, including laboratory evaluations 
and physical examinations, must be performed 
Added guidelines for subjects 
who develop severe Drug-
Induced Liver Injury  
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after a maximum of 2 weeks of re-treatment 
and may be conducted at a local clinic if the 
subject is unable to return to the site.  Results 
must be reported immediately to the site so the 
Investigator can determine if the subject is to 
be allowed to continue treatment.  Subjects 
should be encouraged to continue study visits 
despite stopping investigational product for 
continued study data collection but may 
withdraw consent at any time. 
All suspected drug-related hepatic injury 
events will be adjudicated by the Hepatic 
Safety Committee (see Section 13.4). 
Section 8.4.1.2 
Liver 
Transplantation 
Moved from Section 8.4.2 Other Reasons for 
Discontinuation of Study or Investigational 
Product 
8.4.1.2 Liver Transplantation 
Subjects must discontinue investigational 
product after undergoing liver transplantation 
surgery.  Subjects should be encouraged to 
continue study visits, despite stopping 
investigational product, for continued study 
data collection. 
The relocation of this 
statement from within 
Section 8.4.2 to 8.4.1.2 
clarifies directions to 
discontinue subjects who 
undergo a liver transplant 
from investigational product 
but not study visits 
Section 8.4.2 
Reasons for 
Mandatory 
Interruption of 
Investigational 
Product 
Insertion/Reorganization 
8.4.2 Reasons for Mandatory Interruption of 
Investigational Product 
Prior to re-starting investigational product 
after a prolonged interruption, the subject 
must be re-consented and new baseline visit 
procedures must be performed if the interval 
from the last visit was more than 3 months 
(+2 weeks) during the first 18 months of the 
study or more than 6 months prior (+2 weeks) 
during the remainder of the study.   
 
This clarifies what should be 
done when a subject 
experiences a prolonged 
interruption in investigational 
product such as in the event of 
pregnancy  
 
Section 8.4.2.1 
Pregnancy 
Modification of 8.4.1 Reasons for Mandatory 
Discontinuation of Investigational Product 
8.4.2.1 Pregnancy 
If a female subject becomes pregnant, she must 
interrupt treatment with investigational product 
Language simplified and 
aligned with Sponsor 
standards 
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Revised Text (Version 3.1, 23 December 2016) 
Justification for Change 
If a female subject becomes pregnant, she must 
discontinue taking investigational product, but 
should continue with the study visit schedule.  The 
subject must be followed as considered 
appropriate by the Investigator and the medical 
monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an 
AE.  The subject may reinstate investigational 
product after delivery and cessation of 
breastfeeding (if applicable) at the discretion of 
the Investigator.  Subjects whose pregnancy is 
terminated early (planned or unplanned) may be 
permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotropin (β-
hCG) test performed at the central laboratory. 
immediately, but should continue with the study 
visit schedule.  As described in Section 12.1.9 
pregnancy is not considered an AE for reporting 
purposes.  The subject may re-start 
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 12.1.9).  New baseline 
procedures should include pregnancy testing. 
Section 8.4.3 
Other Reasons for 
Discontinuation of 
Study of 
Investigational 
Product 
8.4.2 Other Reasons for Discontinuation of Study 
of Investigational Product 
Subjects that discontinue investigational product 
are expected to continue in the study until the end 
of the study, and the study will only terminate at 
the time when the needed number of adjudicated 
events has accrued or at the discretion of the 
Sponsor.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  Subjects who 
choose to discontinue investigational product prior 
to termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.   
The following events are considered appropriate 
reasons for a subject to discontinue investigational 
product; however, these subjects are expected to 
continue in the study until study termination and 
8.4.3 Other Reasons for Discontinuation of Study 
of Investigational Product 
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.  
With the exception of liver transplant, if a 
subject experiences a suspected or confirmed 
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.  Subjects who 
discontinue investigational product prior to 
termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.   
The following events are considered appropriate 
reasons for a subject to discontinue 
investigational product; however, these subjects 
are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
Discontinuation of 
investigational product 
language updated to clarify the 
process that is to be followed 
after discontinuation and 
instruct subjects to continue 
regular visit schedule. 
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the study will only terminate (or at the discretion 
of the Sponsor): 
− 
Consent may be modified to discontinue 
study visits or semi-annual telephone contact 
but allow continued access to medical 
records to assess for potential adjudicated 
hepatic and/or cardiovascular events. 
Subjects who undergo a liver transplant during the 
course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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. 
 
− 
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), liver-related clinical outcomes, 
and drug-related hepatic injury events. 
The Investigator is encouraged to contact the 
Sponsor prior to discontinuing a subject from 
treatment.   
Section 9.7.3.1 
Determination for 
Dosing Regimen 
Insertion 
To determine which dosing regimen subjects 
should follow, the presence or absence of 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 is defined as a 
subject who has documented evidence or presence 
of one or more of the following cirrhosis 
indicators: 
9.7.3.1 Determination for Dosing Regimen 
To determine which dosing regimen subjects 
should follow, the presence or absence of 
cirrhosis should be assessed by the Investigator at 
Screening Visit 1.  Acceptable methods of 
confirming (via medical history) or assessing 
cirrhosis for purposes of determining dosing is 
defined as a subject who has documented 
evidence or presence of one or more of the 
following cirrhosis indicators: 
Header added to differentiate 
the assessment of cirrhosis for 
determining dosing regimen 
versus progression to cirrhosis 
Section 9.7.3.2 
Progression to 
Cirrhosis 
Insertion 
9.7.3.2 Progression to Cirrhosis  
When a subject identified as non-cirrhotic at 
baseline per the criteria listed in 
Section  9.7.3.1 exhibits any of those same 
criteria (excluding biopsy results consistent 
with PBC Stage 4), the subject should also be 
assessed by Fibroscan® TE where available 
and progression to cirrhosis confirmed by 
biopsy unless not medically indicated.  Sites 
Provides detail around the 
assessment of Progression to 
Cirrhosis as a secondary 
endpoint 
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participating in the paired biopsy sub-study 
(see Appendix C) must confirm progression to 
cirrhosis by biopsy.  All suspected cases of 
progression to cirrhosis should be submitted 
for adjudication regardless of the availability 
of transient elastography or biopsy results. 
Section 9.7.6 
Screening 
Procedures 
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments 
will be used to determine eligibility (total 
bilirubin >ULN and ≤3× ULN and/or an ALP 
>5× ULN).   
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments 
will be used to determine eligibility (total 
bilirubin >ULN and ≤5× ULN and/or an ALP 
>3× ULN).   
Reflects new inclusion criteria 
Section 9.7.7 Day 
0 Procedures 
• 
Perform transient elastography (TE; at 
selected study sites, where available) using 
the Fibroscan® TE device. If TE has been 
done within 6 months of Day 0 and a 
report/adequate data are available, a 
pretreatment TE at Day 0 is not required.   
• 
Perform transient elastography at all study 
sites with access to Fibroscan® TE device. 
If TE has been done within 3 months of Day 
0 and a report/adequate data are available, a 
pretreatment TE at Day 0 is not required.   
Clarifies use of TE and 
modifies the time during 
which an historic TE report 
remains valid 
Section 9.7.8 
Month 1 
Procedures 
 
Section 9.7.10 
Post-titration visit 
Procedures 
Insertion 
 
 
• 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit 
requirements: 
• 
Perform a physical examination.  
 
− 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit 
laboratory requirements: 
Physical examinations 1 
month after initiating dosing 
with investigational product 
will enhance safety 
monitoring 
Returning to the site for 
monthly laboratory 
assessments can present a 
significant burden on subjects, 
thus alternatives are provided 
for collecting lab samples; 
with the addition of the 
physical exam as well the 
requirement for these exams is 
provided in the context of the 
alternatives for laboratory 
specimen collection 
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Section 9.7.11 
Month 6 
Procedures 
 
Section 9.7.16 
Month 6 
Continued 
Follow-Up 
Procedures 
Insertion 
• 
Perform a physical examination 
• 
Perform TE at all study sites with access 
to Fibroscan® TE device. 
• 
Perform an ultrasound for HCC 
surveillance (if equipment is unavailable, 
sites should make every attempt to use 
available community referral sites). 
TE assessment has been added 
as biannual assessment at all 
study sites with access to 
Fibroscan® TE device 
 
Hepatic ultrasound should be 
performed biannually per 
AASLD and EASL guidelines 
for subjects with PBC 
Section 11.1.2 
Secondary 
Assessments 
Insertion 
• 
Progression to cirrhosis as assessed by the 
presence of clinical, laboratory, or 
radiological evidence of cirrhosis and/or 
liver stiffness (Fibroscan® TE), confirmed 
by biopsy unless not medically indicated. 
• 
Histological assessment of disease 
progression or improvement using paired 
biopsies in a subset of subjects (see 
Appendix C) 
Rationale  
Section 11.1.2.4 
Potential Clinical 
Outcome Events 
The events listed in Appendix A will be initially 
assessed by the Investigator to determine if they 
are Potential Clinical Outcome Events.   
The events listed in Section 12.1.5 will be 
initially assessed by the Investigator to determine 
if they are Potential Clinical Outcome Events.   
Appendix referencing clinical 
outcomes events was removed 
due to redundancy 
Section 12.1.4.2 
Reporting of 
Serious Adverse 
Events 
Insertion 
Redacted medical record source 
documentation will be requested for all SAEs 
and emergency room visits. 
 
 
Added sentence regarding 
redacted medical records to 
align with Sponsor safety 
standards 
Section 12.1.5 
Suspected Liver-
Related Clinical 
Outcome Events 
For liver-related clinical outcome events could 
also meet the criteria of a SUSAR, which would 
necessitate unblinding for expedited reporting, 
please refer to Section 11.1.2.4. 
 
 
Given that the liver-related 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 liver-related clinical outcome 
events in order to retain the study blind and 
preserve the integrity of the clinical outcomes 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language 
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The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy),  and spontaneous 
bacterial peritonitis (preferred term: peritonitis 
bacterial). 
 
endpoint.  These events will be selected as a 
“study event” on the Adverse Event CRF and 
will be submitted for adjudication to the 
Hepatic Outcomes Committee as described in 
Section 13.4. 
 
The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy 
(preferred term: hepatic encephalopathy),  
spontaneous bacterial peritonitis (preferred term: 
peritonitis bacterial), ascites (preferred term: 
ascites), and histological progression to 
cirrhosis (preferred term: hepatic cirrhosis). 
Section 12.1.7 
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 SAE 
must be reported to the Sponsor immediately (ie, 
within 24 hours). 
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 12.1.4.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language 
Section 12.1.8 
Follow-up of AEs 
and SAEs 
Insertion 
All subjects 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 CRF. Note that longer follow-
up can sometimes reveal an off-drug repetition 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language 
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of what had appeared to be drug-induced liver 
injury, indicating that liver injury was related 
to underlying liver disease. 
Section 12.1.9 
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 investigational 
product and the Sponsor must be notified within 
24 hours of the Investigator’s learning of the 
pregnancy by completing the Pregnancy 
Notification Form and faxing or emailing to the 
Sponsor at +1 800 497 8521 or 
sae@interceptpharma.com.  
Safety will be monitored and assessed by 
AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and 
clinical laboratory assessments. The Sponsor may 
also follow the health of an infant born subsequent 
to use of investigational product. 
The subject may reinstate investigational product 
after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  
Subjects whose pregnancy is terminated early 
(planned or unplanned) may be permitted to 
resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test 
(see Section 8.4.1). 
 
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 8.4.2.1) 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 
sae@interceptpharma.com or faxed to 
+1 800 497 8521.   The subject and neonate 
must be followed for outcome information 
and/or as considered appropriate by the 
Investigator and Sponsor. 
The subject may re-start 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 subject must have a 
negative pregnancy test before restarting 
investigational product.  If a subject’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 
Updated to align with 
modified standard safety 
procedures and Sponsor 
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reporting procedures described in 
Section 12.1.4 must also be followed. 
 
Table 10 List of 
Laboratory 
Analytes 
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Other 
Insertion 
 
 
Deletion 
 
Other 
OCA-glucuronide 
 
Measurements of liver fibrosis 
are captured in a different 
section 
 
OCA-glucuronide was listed 
in the text but missing from 
the table 
Section 13.1.1 
Analysis 
Populations 
• 
The Randomized Population will include all 
randomized subjects 
Deletion 
 
Section 13.1.2.1 
Sample Size 
Monitoring 
9.1.2.1 Sample Size Re-Estimation Plan 
Therefore, starting approximately 2 years after the 
first subject is randomized, the aggregate event 
rate and sample size based on recruitment and 
retention will be evaluated in a blinded manner 
quarterly.  This evaluation will determine if any 
increases in number of subjects are required in 
order to obtain a total of 121 adjudicated events 
for the final analysis in the combined groups. 
If after 4 years of accruing subjects, despite 
increases in the number of subjects, it is 
determined that at least an additional 2 years (ie, 
total study duration of at least 10 years) are needed 
to randomize sufficient subjects to achieve a total 
of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label 
OCA.  Previously randomized subjects will 
continue to be treated in a blinded manner with 
either OCA or matching placebo.  If this 
modification is implemented, the alternative 
9.1.2.1 Sample Size Monitoring 
Therefore, the aggregate event rate and sample 
size based on recruitment and retention will be 
evaluated in a blinded manner quarterly.  This 
evaluation will determine if any increases in 
number of subjects are required in order to obtain 
a total of 127 adjudicated events for the final 
analysis in the combined groups. 
Deletion 
 
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primary efficacy analysis is specified is Section 
13.1.9. 
Any revised sample size or changes to treatment 
allocation will be justified and documented in a 
protocol amendment and in the CSR. 
Section 13.1.5.1 
Association of 
Biochemistry with 
Clinical Outcomes 
and Clinical 
Benefit 
Insertion 
13.1.5.1 Association of Biochemistry with 
Clinical Outcomes and Clinical Benefit  
The association between the effect of OCA on 
ALP and bilirubin and the clinical benefit of 
OCA will be evaluated by estimating the 
proportion of net treatment effect on the 
primary composite endpoint that is explained 
by each biochemical marker.  For each 
biochemical endpoint, this proportion will be 
estimated by applying the partial likelihood 
function to two Cox models that use the same 
failure time variable, as described in Lin 1997. 
This analysis will be based on the ITT 
population.  
Based on the association between biochemical 
changes and clinical outcomes described 
above, clinical benefit of OCA for key 
subpopulations of interest will be evaluated. 
This analysis will be further described in the 
SAP. 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
13.1.8 Supportive 
Analysis 
Insertion 
Although the study is designed as a placebo-
controlled study, the DMC may recommend 
changes to study conduct based on the pre-
specified interim analyses (see Section 13.1.12), 
including the potential use of a revised 
primary efficacy analysis.  This analysis would 
compare all subjects in the OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant 
or death (all-cause) (see Section 13.1.2.1), using 
As a placebo-controlled study, 
the alternative primary 
analysis section has been 
removed.   
Upon review of blinded data, 
the DMC may recommend 
changes to study conduct.  
However, such 
recommendations will not be 
implemented unless the 
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similar statistical methodology as specified 
above. 
Notably, the planned primary analysis would 
not be revised without prior agreement with 
regulatory authorities. 
Sponsor has received 
agreement from regulatory 
authorities. 
Section 13.1.9 
Alternative 
Primary Analysis 
13.1.9 Alternative Primary Analysis 
Based on sample size re-estimations, it may be 
determined that subjects will be enrolled to receive 
open-label OCA from that point forward, and the 
new primary efficacy analysis will become the 
comparison of all subjects in OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant or 
death (all-cause) (see Section 13.1.2.1).  Similar 
statistical methodology as specified above in 
Section 13.1.8 for supportive analyses will be 
utilized. 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare groups.  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 determined based 
on a Cox regression model stratified by 
randomization strata to estimate the magnitude of 
the effect. 
 In addition, the outcome events specified above in 
Section 13.1.8 will also be evaluated to compare 
all subjects in OCA population to all control 
subjects (randomized placebo and historical 
controls). 
Deletion 
 
As a placebo-controlled study, 
the alternative primary 
analysis section has been 
removed.   
 Upon review of blinded data, 
the DMC may recommend 
changes to study conduct.  
However, such 
recommendations will not be 
implemented unless the 
Sponsor has received 
agreement from regulatory 
authorities 
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Sensitivity analyses will be conducted limiting to 
the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC 
Study Group.  To evaluate the robustness of the 
propensity score estimations, additional 
algorithms and factors may be considered. 
 
13.1.12 
Continuous 
Monitoring and 
Interim Analyses 
Insertion 
13.1.12 Continuous Monitoring and Interim 
Analyses  
Blinded safety reports including the accrual of 
events, drop outs and/or loss of patients to 
commercially available OCA will be reviewed 
by the DMC on a regular basis.  
Two planned interim analyses of the liver-
related outcomes will be conducted using the 
Lan-DeMets O’Brien-Fleming boundaries 
(Reboussin 2000).  Both interim analyses will 
be pre-specified and will occur after accrual of 
50% and 75% of clinical outcome events, 
respectively.  
The DMC will review the available efficacy 
data in conjunction with detailed safety data 
and other relevant information to recommend 
continuation, modification, or cessation (for 
efficacy or futility) of the study beyond each 
interim analysis.  Modification of the study 
would not take place without prior agreement 
with regulatory authorities. 
Explanation of the type of 
review that will be ongoing by 
the DMC during study 
conduct. 
Section 19 List of 
References  
Insertion 
Lin DY, Fleming TR, De Gruttola V.  
Estimating the proportion of treatment effect 
explained by a surrogate marker.  Statistics in 
Medicine.  1997;16(13):1515-1527. 
 
Reboussin DM, DeMets, DL, Kim KM, et al.  
Computations for Group Sequential 
Additional relevant references 
were added. 
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Boundaries Using the Lan-DeMets Spending 
Function Method.  Controlled Clin Trials.  
2000;21(3):190-207. 
Appendix B  
List of Study 747-
302 Outcome 
Events 
Several of the specified clinical endpoints will 
also by definition (see 12.1) 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 12.1.4).  
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 
Deleted 
Redundant; Information is 
contained within the protocol 
Appendix C 
Biopsy Sub-Study 
of Protocol 
747.302: A Phase 
4, Double-Blind, 
Randomized, 
Placebo-
Controlled, 
Insertion 
See Appendix C 
The purpose of this sub-study 
is to assess the effect of OCA 
versus placebo on the 
histological severity of disease 
(fibrosis/cirrhosis) in subjects 
with PBC.  In addition, this 
sub-study will demonstrate the 
relationship between 
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Multicenter Study 
Evaluating the 
Effect of 
Obeticholic Acid 
on Clinical 
Outcomes in 
subjects with 
Primary Biliary 
Cholangitis 
histological changes and 
clinical, laboratory, and non-
invasive measures indicative 
of progression to cirrhosis in 
patients with PBC. 
 
 
 
 
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APPENDIX H. SUMMARY OF CHANGES:  PROTOCOL VERSION 3.1 TO PROTOCOL VERSION 4 
(DATED 10 MAY 2017) 
Please note that Protocol 747-302 Version 3.1 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.  A full 
accounting of the changes from Protocol Version 3 to Protocol Version 4 is provided in Appendix I. 
Rationale and Summary of Changes 
Major revisions to Protocol 747-302 Version 3.1 include: 
• Hepatocellular carcinoma (HCC) has been redefined as a secondary endpoint; 
• Following the broadening of the spectrum of disease, a commitment to enroll a minimum of 30% of subjects with abnormal 
bilirubin has been added to the protocol; 
• Clarifications have been incorporated throughout the protocol based on the addition of a biopsy substudy in Addendum 2; 
• Statistical language has been modified and added to clarify statistical assumptions and analyses including the addition of a 
Per Protocol (PP) Population;  
• Background rationale has been updated to reflect the current approval status of Ocaliva; and 
• Safety language has been updated throughout the protocol to reflect the updating of Sponsor standards. 
Minor revisions include editorial changes such as removal of hyphens and capitalization of words.  Minor revisions may be included 
in the following table when they are also part of major revisions; however, most minor/editorial changes and nonsubstantial changes 
are not listed individually. 
The text deleted from Protocol Version 3.1 is crossed out while revised text in Version 4 is indicated in bold font in the table below. 
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Revised Text  
(Version 4, 10 May 2017) 
Justification for Change 
Study Personnel 
Contact 
Information 
Or if Not Available: 
Contact: 
 MD, PhD Medical 
Director, Clinical Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
 
Email: 
 
 (Pacific 
time zone) 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical 
Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 (Pacific time 
zone) 
 
 
 
 
Updating emergency medical 
monitor contact information. 
 
 
 
 
 
 
 
The contact information for 
clinical operations and project 
management personnel is no 
longer required in the protocol 
per Sponsor’s procedures. 
Synopsis, 
Objectives, 
Primary, 
Statistical 
Methods – 
Efficacy Analyses 
To assess the effect of OCA compared to placebo, 
in conjunction with established local standard of 
care, on clinical outcomes in subjects with primary 
biliary cirrhosis (PBC) as measured by time to first 
occurrence of any of the following adjudicated 
events, derived as a composite event endpoint: 
To assess the effect of OCA compared to 
placebo, in conjunction with established local 
standard of care, on clinical outcomes in subjects 
with primary biliary cholangitis (PBC) as 
measured by time to first occurrence of any of the 
following adjudicated events, derived as a 
composite event endpoint: 
Editorial correction 
 
 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Section 6.1 
Primary Objective 
Section 11.1.1 
Primary 
Assessments 
Section 13.1.3 
Primary Efficacy 
Analysis 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities unless 
confirmed by biopsy 
composite-event endpoint per 
Regulatory Authority request. 
Synopsis, 
Objectives, 
Secondary  
Section 6.2 
Secondary 
Objectives 
 
 
 
 
In Section 6.2 
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
component of the primary endpoint as listed above 
and also to include liver related death. 
 
 
To characterize the effect of OCA compared to 
placebo on progression to cirrhosis. 
To assess the PK of OCA and its conjugates in a 
subset of subjects. 
To assess the effect of OCA compared to 
placebo on time to occurrence of 
hepatocellular carcinoma (HCC). 
 
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
component of the primary endpoint as listed 
above. 
To assess the effect of OCA compared to 
placebo on time to occurrence of liver-related 
death.  
To assess the effect of OCA compared to placebo 
on progression to cirrhosis. 
To characterize the PK of OCA and its 
conjugates in a subset of subjects. 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request.  
 
 
Editorial change 
 
Editorial change 
 
Editorial change 
Synopsis, 
Methodology  
Section 7.1, 
Overall Study 
Design.  
 
A minimum of 30% of subjects will have 
elevated bilirubin (>ULN) at Screening. 
To ensure enrollment of an 
adequate number of subjects 
with abnormal total bilirubin. 
 
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Section 7.1.1 
Study Design 
Diagram,  
Fig 1 (Footnote) 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on tolerability 
and biochemical response.   
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability and biochemical response (up-titration 
should be considered when ALP and/or total 
bilirubin are >ULN).   
Clarification of biochemical 
response 
Synopsis, Number 
of Subjects 
(Planned)  
Section 7.2 
Number of 
Subjects 
Insertion in both, Synopsis and Section 7.2 
 
 
Change in Synopsis section 
Approximately 428 subjects 
In the event additional subjects are needed for 
the enrollment in the biopsy substudy (N = 45 
subjects, as defined in Addendum 2), subjects 
who agree to participate in the substudy may 
be added to the target subject enrollment 
number currently planned. 
Approximately 428 subjects are planned to be 
enrolled in the study.  
Language added to allow for 
continued enrollment into the 
biopsy substudy; additional 
subjects are not anticipated to 
prolong the duration of the 
study. 
Synopsis, Criteria 
for Evaluation 
 
Primary Objectives 
Assessments 
 
• 
Hepatocellular 
carcinoma 
confirmed by 
2 complimentary 
imaging modalities 
unless confirmed 
by biopsy. 
 
Secondary Objectives 
 
 
Primary 
Objectives 
Assessments 
 
 
 
 
 
 
 
Secondary 
Objectives 
 
HCC 
Confirmed by 
2 complimentary imaging 
modalities unless confirmed 
by biopsy 
 
 
 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request. 
Synopsis, 
Statistical 
Methods 
Analysis 
Populations 
 
The following subject populations will be 
evaluated and used for presentation and analysis of 
the data: Intent-to-Treat (ITT), Safety, PK, Overall 
Historical Control, UKPBC Historical Control, 
and the Global PBC Historical Control.  
The following subject populations will be 
evaluated and used for presentation and analysis 
of the data: Intent-to-Treat (ITT), Per Protocol 
(PP), Safety, PK, Overall Historical Control, 
UK-PBC Historical Control, and the Global PBC 
Historical Control.   
The randomized population is 
included within the Safety 
population. 
The PP population will be 
used to conduct sensitivity 
analyses for primary and key 
efficacy endpoints. 
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Synopsis, 
Statistical 
Methods, Primary 
Efficacy Endpoint 
 
Section 11.1.1  
Primary 
Assessments 
Section 13.1.3  
Primary Efficacy 
Analysis  
• 
Hepatocellular carcinoma confirmed 
by 2 complimentary imaging modalities 
 
 
 
Section 13.1.3 
• 
Hepatocellular carcinoma confirmed 
by 2 complimentary imaging modalities 
unless confirmed by biopsy 
The primary efficacy analysis will compare 
randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the 
ITT population.   
 
 
 
 
 
 
Section 13.1.3 
 
The primary efficacy analysis will compare OCA 
to placebo with respect to the primary efficacy 
endpoint using the ITT population.   
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request. 
 
 
 
Editorial change 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Analysis 
Section 13.1.3  
Primary Efficacy 
Analysis 
Insertion 
 
The same analyses for primary efficacy 
endpoints will be performed for PP population 
as a sensitivity analysis.   
The PP population will be 
used to conduct sensitivity 
analyses for primary and key 
efficacy endpoints. 
Synopsis, 
Statistical 
Methods, Key 
Secondary 
Efficacy Analyses 
Section 13.1.4  
Secondary 
Efficacy Analysis 
Insertion 
 
 
Section 13.1.4 
The key secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
in the ITT population with respect to the key 
secondary efficacy endpoints.   
 
The same analyses for key secondary efficacy 
endpoints will be performed for PP 
population as a sensitivity analysis.   
 
 
Section 13.1.4 
The key secondary efficacy analyses will 
compare OCA to placebo in the ITT population 
with respect to the key secondary efficacy 
endpoints.   
 
 
The PP population will be 
used to conduct sensitivity 
analyses for primary and key 
efficacy endpoints. 
 
 
Editorial change 
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Synopsis, 
Statistical 
Methods, 
Additional 
Secondary 
Efficacy Analyses 
Other Efficacy Analyses 
The following secondary efficacy analyses will 
compare OCA to placebo on time to the following 
events: 
• 
Each component of the primary efficacy 
endpoint (except MELD score ≥15 which 
is listed above) 
• 
Development of varix/varices 
• 
Liver-related death 
• 
Liver-related death or liver transplant 
Liver-related death, liver transplant, or MELD 
score ≥15 
Additional Secondary Efficacy Analyses 
The following time-to-event secondary efficacy 
analyses will compare OCA versus placebo using 
the ITT population: 
• 
Time to each component of the primary 
efficacy endpoint (except MELD score 
≥15 which is listed above) 
• 
Time to development of varix/varices 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
• 
Time to liver-related death 
• 
Time to liver-related death or liver 
transplant 
Time to liver-related death or liver transplant, or 
MELD score ≥15 
Editorial Change 
 
 
 
 
Progression to cirrhosis added 
as secondary endpoint in 
Version 3.1. 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite event endpoint per 
Regulatory Authority request. 
Synopsis, 
Statistical 
Methods, 
Additional 
Secondary 
Efficacy Analyses 
 
Section 13.1.5 
Additional 
Secondary 
Efficacy Analyses 
Insertion 
 
 
Analyses for the histological assessment 
conducted as part of the biopsy substudy are 
defined in Appendix C. 
For those subjects enrolled in the biopsy 
substudy (defined in Addendum 2) progression 
to cirrhosis identified by the above criteria and 
improvement in fibrosis/cirrhosis will be 
confirmed by paired biopsy.  Analyses for the 
histological assessment conducted as part of the 
biopsy substudy are defined in Addendum 2.  
Provides further details of 
progression to cirrhosis as 
outlined in the biopsy 
substudy defined in 
Addendum 2. 
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Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
 
Section 13.1.2. 
Determination of 
Sample Size 
Insertion 
 
 
 
 
The following assumptions were used in sample 
size calculations:  
• Two interim analyses and one final analysis 
are planned.   
 
 
Insertion 
 
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
 
The target population is subjects who are at 
higher risk of liver-related clinical 
complications. Eligible subjects will have a 
diagnosis of PBC with bilirubin levels >ULN 
and ≤5x ULN and/or ALP >3x ULN.  The 
following assumptions were used in sample size 
calculations:  
 
• Two interim analyses and one final analysis 
are planned.  The first interim analysis will be 
performed when 50% of the target events are 
accrued and the second interim will be 
performed when 75% of the target events are 
accrued.  
•  A dropout rate of 10% is assumed.  
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to liver-related outcomes, including all-
cause mortality. 
 
Incorporation of the 
broadened spectrum of disease 
into the sample size 
justification. 
 
 
Clarification of interim 
analyses. 
 
 
Clarification of the assumed 
dropout rate. 
 
 
Clarification of outcomes 
being assessed in power 
calculations. 
Section 5.1 
Overview of PBC 
and OCA 
5.1. Overview of Primary Biliary Cirrhosis and 
Obeticholic Acid 
Primary biliary cholangitis, (PBC, also known as 
primary biliary cirrhosis) 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 
5.1. Overview of Primary Biliary Cholangitis 
and Obeticholic Acid 
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 
Updating language to include 
accelerated and conditional 
approvals of OCA in the US 
and EU.  
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necessitates liver transplantation or results in 
death.   
 
Ursodeoxycholic acid (UDCA), a physiological 
constituent of human bile , is currently the only 
treatment approved for PBC (Lindor 2009).  While 
UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a 
suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of 
a poor clinical outcome due to PBC disease 
progression.  There is a clear unmet medical need 
for better therapies for patients with PBC that have 
an inadequate response to UDCA, or those who 
cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  
Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have 
an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and 
effective. 
OCA is a modified bile acid and farnesoid X 
receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid 
(CDCA).  OCA is currently being developed in the 
United States (US) and Europe for the treatment of 
PBC and other chronic liver diseases.  OCA has 
been granted Orphan Drug Designation in the US 
(09 Apr 2008) and Orphan Medicinal Product 
Designation in the European Union (EU) 
(27 Jul 2010) for the treatment of PBC.  The 
United States Food and Drug Administration 
necessitates liver transplantation or results in 
death.   
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), 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 
(Pellicciari 2002).  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. 
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(FDA) has granted accelerated approval for 
Ocaliva for the treatment of PBC.  Ocaliva is not 
yet approved outside the United States for use in 
any indication. 
Section 5.4 
Overview of PBC 
and OCA 
As of 31 Jan 2016, approximately 1726 subjects 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 458 subjects had 
PBC, 330 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver disease 
(NAFLD), 33 subjects had alcoholic 
cirrhosis/portal hypertension, and 20 subjects had 
primary sclerosing cholangitis (PSC). 
As of 31 Jan 2017, approximately 2186 subjects1 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 525 subjects had 
PBC, 686 subjects had NASH, 41 subjects had 
diabetes mellitus/nonalcoholic fatty liver disease, 
33 subjects had alcoholic cirrhosis/portal 
hypertension, and 52 subjects had primary 
sclerosing cholangitis, and 5 subjects had 
biliary atresia. 
------------------------ 
1Includes estimated numbers from ongoing 
blinded studies. 
Language updated to include 
data from current IB. 
Section 5.5.2.1  
Rationale for 
OCA Dose 
The Phase 3 PBC study subsequently evaluated 
the safety and efficacy of OCA at lower doses of 
5 mg (titrated to 10 mg after 6 months based on 
efficacy and tolerability in the double-blind phase 
and after 3 months in the open-label phase) and 
10 mg;  
 
Insertion 
 
 
 
 
Based on these data, the indicated commercial 
doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
 As such, Study 747-302 will evaluate the effect of 
OCA on clinical outcomes using the 5 mg OCA 
dose increasing to 10 mg OCA, if tolerated. 
The Phase 3 PBC study (Study 747-301) 
subsequently evaluated the safety and efficacy of 
OCA at lower doses of 5 mg (titrated to 10 mg 
after 6 months based on efficacy and tolerability 
in the double-blind phase and after 3 months in 
the open-label phase) and 10 mg;  
Study 747-301 demonstrated that titration of 
OCA from a starting dose of 5 mg to 10 mg 
improved tolerance to pruritus relative to 
10 mg (56% versus 69% of subjects who 
experienced pruritus) and minimized dropouts 
due to pruritus.   
Based on these data, the approved dosing 
regimens for OCA for the treatment of patients 
with PBC are 5 mg and 10 mg. 
Study 747-302 will evaluate the effect of OCA on 
clinical outcomes using the 5 mg OCA dose for 
at least 3 months, increasing to 10 mg OCA, if 
tolerated. 
Provides rationale for the 
dosing in alignment with 
commercial labeling. 
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Section 5.6 
Summary of 
Known Potential 
Risks with OCA 
An increase in liver enzymes and hepatic AEs, 
including jaundice, were observed in subjects with 
liver disease at OCA doses between 10 mg and 
50 mg and in healthy subjects who were treated at 
doses ≥100 mg in Phase 1, multiple-dose studies. 
 
 
These findings were seen more frequently with 
doses above 10 mg OCA. 
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).  
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). 
Language has been updated to 
reflect Sponsor standards. 
Section 7.1.2 
Schedule of Study 
Procedures,  
Table 1  
 a All subjects will have the chemistry panel 
retested to ensure subjects have two ALP and 
bilirubin assessments 2 weeks apart to calculate 
the mean result for both analytes.  The mean of 
all screening ALP and bilirubin assessments 
will be used to determine eligibility.  
 
 
 
l 
Endoscopy will be conducted at selected 
study sites where the device is available. 
 
m Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: Unless HCC has already confirmed 
by biopsy, a second confirmatory image (eg, 
MRI) should be obtained to confirm if a study 
endpoint has been met. 
 a All subjects will have the chemistry panel 
retested to ensure subjects have at least two 
ALP and bilirubin assessments at least 2 weeks 
apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and 
bilirubin assessments will be used to determine 
eligibility. Refer to Section 9.7.6 for guidance 
on when an additional ALP or bilirubin 
sample may be needed to confirm eligibility. 
 
l 
Endoscopy will be conducted at all study 
sites where the device is available. 
 
m 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.   
Editorial changes 
Section 7.1.2 
Schedule of Study 
Procedures, Table 
2 
i Transient elastography (TE) will be conducted at 
6-month intervals at all study sites where the 
Fibroscan® TE device is available.  Not 
required if done within 3 months of visit. 
i Transient elastography (TE) will be conducted 
at 6-month intervals at all study sites where the 
Fibroscan® TE device is available. 
 
Editorial changes 
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j DEXA will be conducted at 12-month intervals 
at all study sites where the DEXA device is 
available.  Not required if done within 6 months 
of visit. 
 
k  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: unless HCC has already been 
confirmed by biopsy, a second confirmatory 
image (eg, MRI) should be obtained to confirm 
if a  study endpoint has been met. 
 
 
j  DEXA will be conducted at 12-month intervals 
at all study sites where the DEXA device is 
available. 
 
 
l  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, postday 0) 
ultrasounds: unless HCC has already been 
confirmed by biopsy, a second confirmatory 
image (eg, MRI) should be obtained to confirm 
suspected HCC. 
 
Section 7.4  
Dose Titration 
Criteria 
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. 
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, biochemical response, and 
clinical judgment. 
Changes in Child-Pugh Score that result from 
a transient, explainable change in laboratory 
parameters should be documented 
appropriately and should not necessarily 
result in a change to the dosing regimen 
(Appendix A). 
Editorial changes 
Section 7.4.1  
Pre-Titration 
Tolerability 
Assessment 
Requirements 
• 
There must be no clinically significant 
increase (as determined by the investigator) in the 
subject’s liver function tests.  Subjects whose total 
bilirubin is >2× baseline (and >ULN) cannot be 
up-titrated, and additional unscheduled safety visit 
procedures, outlined in Section 9.7.19 should be 
implemented, as required. 
• 
There must be no clinically significant 
increase (as determined by the Investigator) in 
the subject’s liver function tests.  
Clarification 
Section 7.4.2   
The text in this section is moved to Section 8.4.  
 
To avoid redundancy 
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Safety Criteria for 
Adjustment or 
Stopping Doses 
Section 8.4  
Dose Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
[Moved from Section 7.4.2 of Version 3] 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or 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 that 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 
when the needed number of adjudicated events has 
accrued.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, 
subjects should be strongly encouraged to both 
stay on investigational product and remain in the 
study until study termination.   
 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or by 
decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability 
concerns.  The dose of investigational product 
should be adjusted back to the maintenance dose 
in a blinded manner once the issues relating to the 
lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated 
events has accrued.  If a subject reaches an 
outcome event, he or she should continue the 
regular visit schedule and continue taking 
investigational product as long as the subject has 
not met any of the criteria for mandatory 
interruption of investigational product 
outlined in Section 8.4.1, and the Investigator 
assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on 
investigational product and remain in the study 
until study termination.   
 
Clarification 
Section 8.4.1.1   
Reasons for 
Additional 
Monitoring 
Related to Liver 
Chemistries 
Modification of 8.4.3.1 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 
 
Subjects 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.  Subjects with 
persistent elevations (eg, additional lab testing 
per Investigator discretion) should be closely 
monitored.  Concomitant elevations in total 
 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries.  
Language related to 
interruption of investigational 
product is now located in 
Section 8.4.1.2. 
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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. 
 
bilirubin or international normalized ratio 
(INR) with persistent increases in ALT or AST 
should also be closely monitored. 
Section 8.4.1.2   
Reasons for 
Investigational 
Product 
Interruption 
Related to 
Elevated Liver 
Chemistries 
Insertion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Development of any of the following clinical 
laboratory values, without explanation, during 
the study mandates investigational product 
interruption: 
• 
AST and/or ALT >3x baseline (and 
>ULN) 
• 
Total bilirubin >2x 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 AE information should also be 
collected and the subject 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 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries. 
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medications should be identified and 
discontinued if advisable.  
If symptoms persist or repeat testing shows 
AST or ALT >3x baseline (and >ULN) or total 
bilirubin >2x baseline (and >ULN), subjects 
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 investigative product 
and no other cause for the elevation is 
identified, it may be assumed that the 
elevations were due to disease progression and 
the subject 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 
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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 subject 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.  
 
Subjects who develop evidence of severe drug-
induced liver injury, which 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. 
 
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 
subjects 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 
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Section 8.4.1.1:   
Subjects who develop significant drug-induced 
liver injury which is considered 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, 
evidence of functional hepatic impairment as 
indicated by rising bilirubin or INR that cannot be 
explained by progression of disease.  
 
Insertion  
appropriate for the subject to continue 
treatment.  In the event the investigational 
product is required to be discontinued, 
subjects should be encouraged to continue 
study visits for continued data collection but 
may withdraw consent at any time.  
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 13.4). 
Section 8.4.1.3   
Pregnancy 
8.4.2.1 Pregnancy 
As described in Section 12.1.9 pregnancy is not 
considered an AE for reporting purposes.  The 
subject may re-start 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 12.1.9).  New baseline 
procedures should include pregnancy testing. 
8.4.1.3 Pregnancy 
As described in Section 12.1.11 pregnancy is not 
considered an AE for reporting purposes.  The 
subject may re-start 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 12.1.11. 
Revised section number. 
 
Section 8.4.2.1  
Liver 
Transplantation 
8.4.1.2 Liver Transplantation 
Subjects must discontinue investigational product 
after undergoing liver transplantation surgery.  
Subjects should be encouraged to continue study 
visits, despite stopping investigational product, for 
continued study data collection. 
8.4.2.1 Liver Transplantation 
Subjects who undergo a liver transplant during 
the course of the study must discontinue 
investigational product and discontinue the 
study visit schedule.  However, these subjects 
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. 
Clarification on process for 
subjects who undergo a liver 
transplant. 
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Section 8.4.3 
Other Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
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.  
With the exception of liver transplant, if a subject 
experiences a suspected or confirmed 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.  Subjects who discontinue 
investigational product prior to termination of the 
study need to also continue to follow the regular 
visit schedule through to study closure.  In 
general, subjects should be strongly encouraged to 
both stay on investigational product and remain in 
the study until study termination.  Early 
termination procedures should only be conducted 
if the subject withdraws consent (See 
Section 9.7.18). 
 
− 
Consent may be modified to discontinue study 
visits or semi-annual telephone contact but 
allow continued access to medical records to 
assess suspected major adverse cardiovascular 
events (MAC), liver-related clinical 
outcomes, and drug-related hepatic injury 
events. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
− 
Consent may be modified to discontinue 
study visits or semi-annual telephone contact 
but allow continued access to medical 
records to assess suspected major adverse 
cardiovascular events (MACE) and liver-
related clinical outcomes. 
− 
Early termination procedures should be 
conducted if the subject withdraws 
consent (See Section 9.7.18). 
 
Clarification of process 
Section 9.7.1  
Visit Windows 
Screening 
 
 
Screening 
See Section 9.7.6 for 
scenario specific visit 
windows that may be 
applicable at Screening.  
 
Section 9.7.3.2  
Progression to 
Cirrhosis 
When a subject identified as non-cirrhotic at 
Baseline per the criteria listed in Section 9.7.3.1 
exhibits any of those same criteria (excluding 
biopsy results consistent with PBC Stage 4), the 
When a subject identified as noncirrhotic at 
Baseline per the criteria listed in Section 9.7.3.1 
exhibits any signs or symptoms associated with 
progression to cirrhosis, as defined by the same 
Details the assessment of 
progression to cirrhosis. 
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subject should also be assessed by Fibroscan® TE 
where available and progression to cirrhosis 
confirmed by biopsy unless not medically 
indicated.  Sites participating in the paired biopsy 
sub-study (see Appendix C) must confirm 
progression to cirrhosis by biopsy.   
criteria, the subject should also be assessed by 
Fibroscan® TE where available and progression 
to cirrhosis confirmed by biopsy (centrally read) 
unless not medically indicated.  Laboratory 
samples needed to obtain noninvasive scores of 
liver fibrosis (ELF, and aspartate 
aminotransferase to platelet ratio index 
[APRI]) will also be collected when a subject 
develops evidence of progression to cirrhosis. 
Full instructions concerning the sample 
collection methods, processing, labeling, and 
shipping will be provided by the Sponsor in a 
study-specific histology manual.  Collection 
supplies will be provided by the central 
laboratory. 
Sites participating in the paired biopsy substudy 
must confirm progression to cirrhosis by biopsy 
as per the information outlined in protocol 
Addendum 2. 
Section 9.7.6  
Screening 
Procedures 
Two Screening visits will occur from 1 to 8 weeks 
prior to Day 0 (as outlined below) allowing for the 
collection of repeated serum chemistry samples (at 
least 2 weeks apart) to confirm pretreatment ALP 
and total bilirubin values: 
 
 
Insertion 
 
 
 
 
Collection of 2 serum chemistry samples 
(collected at least 2 weeks apart) during 
Screening is required for confirmation of the 
pretreatment serum chemistry values, including 
the ALP and total bilirubin used to determine 
eligibility: 
 
• 
When the 2 bilirubin or ALP assessments 
collected at Screening Visit 1 and Screening 
Visit 2 differ by ≥30%, a third sample must be 
collected at an unscheduled visit as a 
confirmatory sample to include in the mean 
result(s) that will be used to determine 
eligibility.  
Allows repeat assessments 
when baseline laboratory 
values are discrepant between 
Screening Visit 1 and 
Screening Visit 2. 
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• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(selected study sites only), 
 
 
Insertion 
• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(at all study sites where the device is available),   
 
In the event that the 2 screening bilirubin or 
ALP assessments differ by ≥30%, and a third 
confirmatory sample is required to be 
collected, the Screening Visit window may be 
extended up to 3 additional weeks. 
Section 9.7.8  
Month 1 
Procedures 
 
Section 9.7.10  
1-Month Post-
Titration visit 
Procedures 
Insertion (9.7.8) 
 
 
Insertion (9.7.10) 
 
- 
A physical examination should be 
performed at the Month 3 visit if an onsite 
Month 1 visit was not performed. 
- 
A physical examination should be 
performed at the next scheduled visit if an 
onsite post-titration visit was not performed. 
Clarification  
Section 9.7.12  
Month 9 
Procedures 
Section 9.7.14 
Month 12 
Procedures 
Section 9.7.16 
Month 16 
Continued 
Follow-Up 
Procedures 
Section 9.7.17  
Month 12 Follow-
up Procedures 
Section 9.7.18  
EOS/EOT 
Section 9.7.12, 9.7.14, 9.7.16, 9.7.17, and 9.7.18 
 
…DEXA procedure to be done at 
selected study sites only, 
 
 
Section 9.7.14, and 9.7.17 
 
 
• 
Perform an endoscopy (at selected study 
sites, where available) 
 
Section 9.7.12, 9.7.14, 9.7.16, 9.7.17, and 9.7.18 
 
…DEXA procedure to be done at 
all study sites where the device is available  
 
 
Section 9.7.14, and 9.7.17 
 
• 
Perform an endoscopy (at all study sites, 
where device is available) 
 
Clarification 
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Section 9.7.18  
EOS/EOT 
If the subject reports having eaten within 8 hours, 
document accordingly in the source and CRF and 
remind the subject that fasting is required prior to 
all study visits. 
If the subject reports having eaten within 8 
hours, document accordingly in the source and 
CRF. 
Clarification 
Section 10.3  
Investigational 
Product Storage 
The investigational product should be stored in the 
containers in which they are received from the 
Sponsor’s supplier, at 15°C to 25°C. 
All OCA tablet strengths provided to clinical 
trial sites in support of clinical study 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. 
Updating temperature 
excursions language per 
Sponsor stability studies. 
Section 11.1.2 
Secondary 
Assessments 
Insertion 
 
• 
Histological assessment of disease 
progression or improvement using paired biopsies 
in a subset of subjects (defined in Appendix C). 
 
 
 
 
• 
Biomarkers, including other markers of 
hepatic fibrosis and/or inflammation, to be 
tested will include:  IgM, c reactive protein 
(CRP), tumor necrosis factor α (TNF-α), 
FGF 19, cytokeratin-18 (CK-18) and ELF, 
(and others as determined during the course of 
the study). 
  
• 
Individual components of the primary 
endpoint. 
• 
Histological assessment of disease 
progression or improvement using paired 
biopsies in a subset of subjects (defined in 
Addendum 2). 
• 
HCC confirmed by 2 complimentary 
imaging modalities, unless confirmed by 
biopsy. 
• 
Biomarkers, including other markers of 
hepatic fibrosis and/or inflammation, to be 
tested will include:  IgM, c reactive protein 
(CRP), tumor necrosis factor α (TNF-α), 
FGF 19, cytokeratin-18 (CK-18) ELF, and 
Fibroscan (and others as determined during 
the course of the study). 
• 
 Clinical outcomes, including individual 
component of the primary endpoint 
Clarified and re-ordered 
bullets for consistency 
throughout document. 
 
Addition of Addendum 2.  
Reflects addition of a biopsy 
substudy available to 
interested sites in 
Addendum 2. 
 
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• 
Endoscopy will be conducted at selected 
study sites where the device is available to assess 
for the presence of oesophageal varix/varices at 
baseline.  
(where available), liver transplant, and 
death will be compared to historical 
controls. 
• 
PK of OCA and its conjugates. 
• 
Endoscopy will be conducted at all study 
sites where the device is available to assess for 
the presence of oesophageal varix/varices at 
baseline.  
Section 12.1.3  
Relationship of 
Adverse Events to 
Liver Biopsy 
 
Insertion (new section) 
The Investigator will document her/his opinion 
of relationship of an AE to liver biopsy using 
the criteria outlined in Table 9.  
Table 9: Relationship of Adverse Events to 
Liver Biopsy 
Relation
ship 
Description 
Related 
A reaction that follows a 
reasonable temporal sequence 
from the liver biopsy; that 
follows a known or expected 
response pattern to the liver 
biopsy. 
Not 
Related 
Any event that does not meet the 
above criteria. 
Added with the addition of 
liver biopsies for the 
confirmation of progression to 
cirrhosis. 
Section 12.1.5.2 
Reporting of 
Serious Adverse 
Events 
•Telephone:  +1 858 964 1571 
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. 
 
If an SAE is reported by email or fax, an SAE 
Report form must also be completed in the EDC 
system as soon as the EDC system is accessible. 
Updated to align with 
modified standard safety 
procedures. 
Section 12.1.6 
Suspected Liver-
Related Clinical 
Outcome Events 
Section 12.1.5 
Given that the liver-related 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 liver-related 
clinical outcome events in order to retain the study 
Section 12.1.6 
Given that the liver-related clinical outcome 
events may also meet the criteria of a SUSAR, 
but are considered in aggregate as part of the 
primary endpoint and the DMC reviews of all 
safety and efficacy data at least quarterly, the 
Sponsor will not expeditiously report suspected 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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blind and preserve the integrity of the clinical 
outcomes endpoint. 
 
The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy (preferred 
term: hepatic encephalopathy),  spontaneous 
bacterial peritonitis (preferred term: peritonitis 
bacterial), ascites (preferred term: ascites), and 
histological progression to cirrhosis (preferred 
term: hepatic cirrhosis). 
liver related clinical outcome events in order to 
retain the study blind and preserve the integrity of 
the clinical outcomes endpoint. 
 
The Sponsor will consider the following list of 
clinical outcome events (MedDRA preferred 
terms) to be disease related and exempt from 
expeditious regulatory reporting, but will 
continue to report them in a nonexpeditious 
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 or oesophageal varices 
haemorrhage), hepatic encephalopathy 
(preferred term: hepatic encephalopathy),  
spontaneous bacterial peritonitis (preferred term: 
peritonitis bacterial), ascites (preferred term: 
ascites), and histological or clinical progression 
to cirrhosis (preferred term: hepatic cirrhosis). 
Section 12.1.8 
Notification of 
Post-Treatment 
SAEs for Subjects 
Who Continue in 
the Study 
Insertion (new section) 
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 
12.1.5.2. 
SAEs that occur in subjects 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 12.1.5.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language. 
Section 12.1.9 
Notification of 
Poststudy SAEs 
Section 12.1.7 
All SAEs that occur within 30 days following the 
cessation of investigational product, whether or 
Section 12.1.9 
All SAEs that occur within 30 days following 
discontinuation from the study, whether or not 
Updated to align with 
modified safety procedures 
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not they are related to the investigational product, 
must be reported to the Sponsor within 24 hours 
by following the instructions provided in Section 
12.1.4.2. 
SAEs that occur more than 30 days after a subject 
has discontinued investigative product, and are not 
considered related to investigational product, must 
still be reported in the EDC system; however, 
these events are not required to be reported within 
24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to 
investigational product, action taken with 
investigative product, treatment, outcome, and 
potential endpoint status need to be recorded in 
EDC for the SAE.  Additional information (e.g. 
event summary, SAE details) may also be required 
to be entered, when requested by the Sponsor. 
they are related to the investigational product, 
must be reported to the Sponsor within 24 hours 
by following the instructions provided in Section 
12.1.5.2. 
and Sponsor standard 
language. 
Section 12.2.7  
Laboratory 
Assessments 
The list of laboratory analytes to be tested is 
shown in Table 10. 
The list of laboratory analytes to be tested is 
shown in Table 11, and the normal reference 
ranges for liver biochemistries are shown in 
Appendix C. 
Added per Regulatory 
Authority request. 
Section 13  
Statistical 
Methods 
A statistical analysis plan (SAP), providing details 
about the specific planned analyses and hypothesis 
tests, will be prepared and approved by the 
Sponsor and its designees prior to study database 
lock, propensity score determination, and 
unblinding of the double-blind subject treatment 
assignments. 
A statistical analysis plan (SAP), providing 
details about the specific planned analyses and 
hypothesis tests, will be prepared and approved 
by the Sponsor and its designees prior to the first 
interim analysis, propensity score determination, 
and unblinding of the double-blind subject 
treatment assignments. 
Reflects addition of interim 
analyses to the study protocol. 
Section 13.1.1 
Analysis 
Populations 
Insertion 
• 
The Per Protocol (PP) Population will 
include all ITT subjects who do not have any 
major protocol violations that potentially 
affect the efficacy conclusion.  Treatment 
assignment will be based on the randomized 
treatment. 
The Per Protocol Population 
will be used to conduct 
sensitivity analyses for 
primary and key efficacy 
endpoints. 
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Section 13.1.1.1  
Comparability of 
Historical 
Controls 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria where possible. 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria.  Propensity score 
matching method will be utilized to select 
historical controls that match the treated 
subjects using available covariates. The 
adequacy of matching will be assessed by 
statistical methods described under 
Section 13.1.8. 
Clarifies the use of propensity 
scores in the assessment of the 
historical control population. 
Section 13.1.5 
Additional 
Secondary 
Efficacy Analyses 
The following secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
on using the ITT population: 
The following time-to-event secondary efficacy 
analyses will compare OCA versus placebo using 
the ITT population: 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
 
Editorial Change 
Progression to cirrhosis added 
as secondary endpoint in 
Version 3.1. 
HCC has been redefined as a 
secondary endpoint instead of 
a component of the primary 
composite-event endpoint per 
Regulatory Authority request. 
Section 13.1.5.1  
Association of 
Biochemistry with 
Clinical Outcomes 
and Clinical 
Benefit 
The association between the effect of OCA on 
ALP and bilirubin and the clinical benefit of OCA 
will be evaluated by estimating the proportion of 
net treatment effect on the primary composite 
endpoint that is explained by each biochemical 
marker.  For each biochemical endpoint, this 
proportion will be estimated by applying the 
partial likelihood function to two Cox models that 
use the same failure time variable, as described in 
Lin 1997. This analysis will be based on the ITT 
population.  
Based on the association between biochemical 
changes and clinical outcomes described above, 
clinical benefit of OCA for key subpopulations of 
interest will be evaluated. This analysis will be 
further described in the SAP. 
The association between biochemistry including 
ALP and bilirubin with clinical outcomes will be 
assessed and the clinical benefit of OCA using 
biochemistry as a surrogate endpoint will be 
evaluated.  Detailed analysis will be described in 
the SAP.  
Based on the association between biochemical 
changes and clinical outcomes described above, 
clinical benefit of OCA using biochemistry as a 
surrogate endpoint for key subpopulations of 
interest will be evaluated. This analysis will be 
further described in the SAP. 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
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Section 13.1.8  
Supportive 
Analysis 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls. 
 
 
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment. 
 
Although it might be relatively simple to assign a 
historical control based on a single observable 
characteristic, in practice, if the matching process 
is to successfully mitigate potential bias, it has to 
be done considering a full range of covariates 
across which the treatment and historical controls 
might differ. 
Only covariates and not outcome variables will be 
included in the propensity score estimation.  
Therefore, there is no chance of biasing, to avoid 
biased results that are in favor of one treatment. 
 
 
 
 
 
 
 
 
 
 
 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls, which serves as an external 
control for supportive analysis.  
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment 
between the treated subjects and the matched 
natural history subjects. 
A full range of covariates across which the 
treatment and historical controls might differ will 
be considered to mitigate potential bias. 
 
 
Only covariates and not outcome variables will 
be included in the propensity score estimation to 
avoid biased results that are in favor of one 
treatment. 
 
The baseline characteristics between treated 
and natural history subjects in the matched 
dataset will be summarized and presented in a 
tabular format.  Statistical methods such as 
Wilcoxon Rank-Sum test will be used to assess 
the balance for baseline covariates.  The 
standardized difference and variance ratios 
for these covariates will also be calculated.  In 
addition, box plots of propensity scores for 
treated and natural history subjects will be 
separately presented, to further assess the 
adequacy of matching.  
A third-party statistician(s) will perform the 
propensity score modeling and matching.  This 
Clarifies the use of the 
historical controls as an 
external control in supportive 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
 
 
Clarifies the use of the 
historical controls as an 
external control in supportive 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
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Revised Text  
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Justification for Change 
 
 
 
 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
• 
Time to hepatocellular carcinoma 
 
third-party statistician(s) will be separate and 
independent from the statistician(s) who will 
assess the success of matching and perform 
efficacy analyses. 
 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
 
 
 
Section 13.1.9  
Handling of 
Dropouts or 
Missing Data 
Insertion 
In addition, the same analyses for primary and 
key secondary endpoints based on ITT and PP 
populations will be performed to assess 
robustness of analysis results. During the 
conduct of the study, the DMC may 
recommend refining the missing data strategy 
to better address the observed pattern of 
missing data, based on blinded monitoring of 
the data. 
Clarification of statistical 
analyses to address missing 
data. 
Section 13.1.11  
Examination of 
Subgroups 
The primary and secondary efficacy endpoints will 
be analyzed for subject subgroups (eg, age, sex, 
and race) based on the ITT population.  
 
Insertion 
The primary and secondary efficacy endpoints 
will be analyzed for subject subgroups based on 
the ITT population.  
 
The primary efficacy endpoint will also be 
assessed across the spectrum of PBC disease 
stage as defined by Rotterdam criteria 
(Kuiper 2009)  
• 
Early (normal albumin and normal 
bilirubin) 
 
 
 
 
 
Added per Regulatory 
Authority request. 
 
 
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• 
Moderate (abnormal albumin or 
abnormal bilirubin) 
• 
Advanced (abnormal albumin and 
abnormal bilirubin) 
The primary efficacy endpoint will also be 
assessed for the following clinically relevant 
subpopulations. 
• 
Monotherapy in patients who are 
intolerant or non-responsive to UDCA  
• 
Elderly patients 
Assuming a strong correlation between 
biochemistry and clinical outcomes using the 
total study population (Section 13.1.5.1) is 
observed, we will further assess the 
biochemical improvement in relevant 
subpopulations as applicable (eg, Rotterdam 
disease severity and monotherapy) and 
estimate the reduction in risk of clinical 
outcomes associated with the biochemical 
improvement. 
Additional details regarding statistical 
methods and subgroup definitions will be 
provided in the SAP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
Section 13.1.12  
Continuous 
Monitoring and 
Interim Analyses 
Both interim analyses will be pre-specified and 
will occur after accrual of 50% and 75% of 
clinical outcome events, respectively. 
 
The DMC will review the available efficacy data 
in conjunction with detailed safety data and other 
relevant information to recommend continuation, 
modification, or cessation (for efficacy or futility) 
of the study beyond each interim analysis.  
Both interim analyses will be pre-specified and 
will occur after accrual of 50% (64 events) and 
75% (96 events) of clinical outcome events, 
respectively. 
 
The DMC will review the available efficacy data 
in conjunction with detailed safety data and other 
relevant information to recommend continuation, 
Added number of anticipated 
events. 
 
 
 
Clarification 
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Justification for Change 
modification, or cessation (for efficacy) of the 
study beyond each interim analysis 
Section 19  
List of References  
Lin DY, Fleming TR, De Gruttola V.  Estimating 
the proportion of treatment effect explained by a 
surrogate marker.  Statistics in Medicine.  
1997;16(13):1515-1527. 
 
Insertion 
 
 
 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Digestive and Liver 
Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Gastroenterology. 
2015b;149(6):1627-9. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
'cirrhosis' to 'cholangitis'. Hepatology. 
2015c;62(5):1620-2. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-
ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed 
with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-3572. 
Reboussin DM, DeMets, DL, Kim KM, et al.  
Computations for Group Sequential 
Boundaries Using the Lan-DeMets Spending 
Function Method.  Controlled Clin Trials.  
2000;21(3):190-207. 
 
 
Additional relevant references 
were added. 
Appendix C 
Reference 
Laboratory Values 
from Central 
Laboratories 
Insertion (new appendix) 
 
 
Deletion:  
Appendix C in Version 3.1 has been deleted.  It is 
now published as Protocol Addendum 2. 
Appendix containing reference laboratory 
values from central laboratories added. 
Added per Regulatory 
Authority request. 
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APPENDIX I. SUMMARY OF CHANGES:  PROTOCOL VERSION 3 TO PROTOCOL VERSION 4 
(DATED 10 MAY 2017) 
Please note that Protocol 747-302 Version 3.1 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. Therefore, a 
full accounting of the changes from Protocol Version 3 to Protocol Version 4 is provided below. 
Rationale and Summary of Changes 
Major revisions to Protocol 747-302 include the modification of inclusion/exclusion criteria to expand the PBC disease spectrum, the 
addition of progression to cirrhosis as a secondary endpoint, and the addition of 2 interim analyses.  Additional revisions include an 
increase in subject number and the number of required clinical outcome events, a change in the study phase, an update to the 
nomenclature for PBC, and various clarifications within the protocol.  
The text deleted from Protocol Version 3 is crossed out while revised text in Version 4 is indicated in bold font.  Minor/editorial 
changes and non-substantial changes are not listed individually. For efficiency, rationales that impact multiple sections are provided 
below and referenced in the table with the corresponding rationale number.  
1. The phase of the study has been changed from “3b” to “4” to reflect that this is a post-marketing study.  Protocol 747-302 
is considered a Phase 4 study in regions where OCA has received regulatory approval for PBC, ie, in the US and the EU.  In all 
other regions, this study is considered Phase 3b.  In May 2016, the FDA granted accelerated approval for OCA (Ocaliva) for 
the treatment of PBC.  In December 2016, Ocaliva received Conditional Approval from the European Medicines Agency’s 
Committee for Medicinal Products for Human Use. 
2. The term “primary biliary cirrhosis” has been changed to “primary biliary cholangitis” to reflect recent changes in the 
nomenclature for PBC. 
3. The number of required adjudicated events for the final analysis has increased from 121 to 127 due to the addition of two 
interim analyses, which will allow an independent DMC to recommend continuation, modification, or cessation (for efficacy) 
of the study.  One interim analysis will occur at 50% information (after 64 events occur) and one at 75% information (after 
96 events occur).  In addition, inclusion of PBC subjects with earlier stage disease will increase the time to event, thereby 
requiring more events to maintain follow-up to approximately 6 years.   
4. The first-year study enrollment rate was lower than projected due to slower-than-anticipated activation of sites and required a 
re-estimation of the accrual duration.  Using observed accrual rates, the accrual duration was extended by 2 years.  The 
follow-up period was maintained at 6 years, thereby leading to a total trial duration of 10 years. 
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5.  “Encephalopathy” has been modified to “Hepatic Encephalopathy” to clarify that the relevant Clinical Outcome Event 
should be related to hepatic disease. 
6. Hepatocellular carcinoma (HCC) has been redefined as a secondary endpoint instead of a component of the primary 
composite-event endpoint per Regulatory Authority request.  
7. Histological confirmation (biopsy) has been added as an acceptable method of confirming a diagnosis of HCC. 
8. Broadening the Spectrum of Disease:  Lowering the minimum allowable baseline ALP from >5x ULN to >3x ULN and 
raising the maximum allowable baseline total bilirubin to ≤5x ULN will increase the number of subjects enrolled with early 
and advanced disease facilitating the collection of safety and efficacy data in a population that covers the spectrum of PBC 
disease and overlaps with the subject population in the Phase 3 protocol 747-301.  However, to ensure enrollment of an 
adequate number of subjects with abnormal total bilirubin, a minimum of 30% of the subjects enrolled in the study will have 
elevated bilirubin (>ULN) at Screening. 
9. The titration regimen has been updated to reflect assessment of both tolerability and biochemical response prior to up-titration 
per the USPI and SmPC.   
10. The increase in enrollment from 350 to 428 subjects is due in part to the increased number of events from two additional 
interim analyses, and in part due to the change in the estimated placebo baseline hazard rate, which resulted from changing the 
lower limit of ALP from >5x ULN to >3x ULN in the enrollment criteria #2.  
11. Progression to Cirrhosis has been added as a secondary endpoint:  Due to the chronic nature of PBC, outcomes require a very 
long time to accrue to evaluate the impact of potential therapies.  Despite the proven prognostic utility of ALP and bilirubin, 
there is a remaining need to evaluate noninvasive assessments of disease progression that can be linked to histological 
progression of the disease.  Therefore, it is important to evaluate potential noninvasive markers of fibrosis/cirrhosis and their 
relationship to clinical outcomes as part of Study 747-302. 
12. A Per Protocol (PP) population has been added to the statistical analysis section.  Sensitivity analysis for primary efficacy 
endpoints and key secondary efficacy endpoints will be performed using PP population. 
 
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Title Page 
Synopsis, Title of 
Study 
A Phase 3b, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study Evaluating 
the Effect of Obeticholic Acid on Clinical 
Outcomes in Subjects with Primary Biliary 
Cirrhosis 
A Phase 4, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on 
Clinical Outcomes in Subjects with Primary 
Biliary Cholangitis 
 
Rationale 1 and 2  
Study Personnel 
Contact 
Information 
Or if Not Available: 
Contact: 
 MD, PhD, 
Executive Director, Clinical 
Research, 
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
 
Email: 
 
 (Pacific 
time zone) 
 
 
Clinical Operations and Project Management 
Contact: 
 
 Clinical 
Operations,  
Intercept Pharmaceuticals, Inc. 
Telephone: 
Mobile: 
Fax: 
Email: 
 (Pacific time 
zone) 
 
 
 
O 
 
 
 
 
 
 
 
 
 
 
 
The contact information of 
clinical operations and project 
managements personnel is no 
longer required per Sponsor’s 
procedures. 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Synopsis, Studied 
Period (Years) 
 
The study is event driven and total duration will be 
determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 and 4   
 
Synopsis,  
Phase of 
Development 
Phase 3b 
Phase 4 
Rationale 1 
Synopsis, 
Objectives, 
Primary, 
Statistical 
Methods – 
Efficacy Analyses 
Section 6.1 
Primary Objective 
Section 11.1.1 
Primary 
Assessments 
Section 13.1.3 
Primary Efficacy 
Analysis 
• 
Encephalopathy (as defined by a West Haven 
score of ≥2) 
• 
Hepatocellular carcinoma confirmed by 2 
complimentary imaging modalities 
• 
Hepatic encephalopathy (as defined by a 
West Haven score of ≥2) 
 
Rationale 5   
 
Rationale 6 
Synopsis, 
Objectives, 
Secondary  
Section 6.2 
Secondary 
Objectives 
 
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
component of the primary endpoint as listed above 
and also to include liver related death. 
 
 
To assess the effect of OCA compared to placebo 
on time to first occurrence of each individual 
component of the primary endpoint as listed 
above.  
To assess the effect of OCA compared to 
placebo on time to occurrence of liver-related 
death. 
Rephrasing the objective 
 
 
 
 
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Insertion 
 
 
 
To assess the pharmacokinetics of OCA and its 
conjugates in a subset of subjects 
To assess the effect of OCA compared to 
placebo on progression to cirrhosis. 
To assess the effect of OCA compared to 
placebo on time to occurrence of 
hepatocellular carcinoma (HCC). 
To characterize the pharmacokinetics of OCA 
and its conjugates in a subset of subjects 
 
 
Rationale 11 
 
Rationale 6 
 
Synopsis, 
Methodology: 
 
A minimum of 30% of subjects will have 
elevated bilirubin (>ULN) at Screening. 
Rationale 8 
 
Schematic 
Diagram 
 
Section 7.1.1 
Study Design 
Diagram, Figure 1 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability.   
 
 
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability of the product. 
 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
 
Initial dose titration of investigational product should 
occur at the Month 3 visit, or any study visit thereafter 
for subjects on all dosing regimens, based on 
tolerability and biochemical response (up-titration 
should be considered when ALP and/or total 
bilirubin are >ULN).   
• 
Subjects should titrate to a maximum dose of 
10-mg OCA once daily (or matching 
placebo) at the Month 3 visit or at any study 
visit following the Month 3 visit based on 
tolerability and biochemical response of the 
product. 
• 
Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose 
of 5-mg OCA or matching placebo once 
daily, based on tolerability and biochemical 
 
Rationale 8 
 
 
 
Rationale 9 
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daily, based on tolerability. Subjects 
classified as Child-Pugh Class C should 
titrate to a maximum dose and frequency of 
10-mg OCA or matching placebo twice 
weekly, based on tolerability. 
 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
subject tolerability, and/or changes in cirrhosis status or 
Child-Pugh Score at any time during the study. 
 
response. Subjects classified as Child-Pugh 
Class C should titrate to a maximum dose 
and frequency of 10-mg OCA or matching 
placebo twice weekly, based on tolerability 
and biochemical response. 
 
Planned Dosing Regimen by Cirrhosis and Child-
Pugh Score (Table) 
b  Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
subject tolerability, biochemical response, and/or 
changes in cirrhosis status or Child-Pugh Score at any 
time during the study. 
Synopsis, Number 
of Subjects 
(Planned)  
Section 7.2 
Number of 
Subjects 
Insertion 
 
 
Change in Synopsis section 
Approximately 350 subjects 
 
Change in Section 7.2 section 
It is expected that approximately 350 subjects will 
be randomized in the study to achieve 121 
adjudicated primary endpoint events. 
In the event additional subjects are needed for 
the enrollment in the biopsy substudy (N = 45 
subjects, as defined in Addendum 2), subjects 
who agree to participate in the sub study may 
be added to the target subject enrollment 
number currently planned. 
Approximately 428 subjects are planned to be 
enrolled in the study.   
 
It is expected that approximately 428 subjects 
will be randomized in the study to achieve 127 
adjudicated primary endpoint events.  
Rationale 10 and 
Addendum 2 
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Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
2.  A mean total bilirubin >ULN and ≤3x ULN 
and/or a mean ALP >5x ULN 
2.  A mean total bilirubin >ULN and ≤5x ULN 
and/or a mean ALP >3x ULN 
Rationale 8 
Synopsis, 
Inclusion Criteria 
Section 8.2 
Subject Inclusion 
Criteria 
5.  Contraception:  Female subjects 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:   
• 
Double barrier method, ie, (a) condom 
(male or female) or (b) diaphragm, with 
spermicide; or  
• 
Intrauterine device (IUD); 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 subject   
5.  Contraception:  Female subjects of 
childbearing potential must use ≥1 effective 
method of contraception during the study and 
until 30 days following the last dose of 
investigational product.  Effective methods 
of contraception are considered to be those 
listed below:   
• 
Barrier method, ie, (a) condom (male 
or female) or (b) diaphragm, with 
spermicide 
• 
Intrauterine device (IUD)  
• 
Vasectomy (partner) 
• 
Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection) 
• 
Abstinence, if in line with the preferred 
and usual lifestyle of the subject   
Standardizing language across 
protocols; removing double-
barrier terminology. 
Synopsis, 
Exclusion Criteria 
Section 8.3 
Subject Exclusion 
Criteria 
 
2.  Presence of clinical complications of PBC or 
clinically significant hepatic decompensation, 
including: 
 
 
 
2.  Presence of clinical complications of PBC or 
clinically significant hepatic decompensation, 
including: 
•History of liver transplant, current 
placement on a liver transplant list, or 
current MELD score >12.  Subjects who 
are placed on a transplant list despite a 
relatively early disease stage (for example 
per regional guidelines) may be eligible as 
 
 
 
This criterion (sub-bullet) is 
already included in Version 3 
of the protocol.  In the 
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3.  Mean total bilirubin >3x ULN 
long as they do not meet any of the other 
exclusion criteria 
3.  Mean total bilirubin >5x ULN 
Version 4, it is added to the 
synopsis for consistency. 
 
Rationale 8 
Synopsis, 
Duration of 
Treatment 
It is estimated that subjects will be followed up for 
a minimum of 6 years.  The study is event driven 
and total duration of treatment will be determined 
by the time to accrue 121 total primary endpoint 
events. 
It is expected that subjects will be followed up 
for a minimum of 6 years.  The study is event 
driven and total duration of treatment will be 
determined by the time to accrue 127 total 
primary endpoint events. 
Rationale 3 
Synopsis, Criteria 
for Evaluation 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Encephalopathy (as 
defined by a West 
Haven score of ≥2) 
 
• 
Hepatocellular 
carcinoma 
confirmed by 
2 complimentary 
imaging modalities 
 
Secondary Objectives 
 
 
Primary Objectives 
Assessments 
Clinical outcomes 
− 
Hepatic 
encephalopathy (as 
defined by a West 
Haven score of ≥2) 
Secondary Objectives 
 
Progression to 
cirrhosis 
Clinical, laboratory, or 
radiological evidence of 
cirrhosis and/or liver 
stiffness (i.e., Fibroscan® 
TE) confirmed by biopsy 
unless not medically 
indicated 
Hepatocellular 
carcinoma 
Confirmed by 
2 complimentary imaging 
modalities unless 
confirmed by biopsy 
Rationale 5 
 
 
 
 
 
Rationale 11 
 
 
 
 
 
Rationale 6 
Synopsis, 
Statistical 
Methods 
Analysis 
Populations 
 
The following subject populations will be 
evaluated and used for presentation and analysis of 
the data:  Randomized, Intent-to-Treat (ITT), 
Safety, PK, Overall Historical Control, UKPBC 
Historical Control, and the Global PBS Historical 
Control.  Descriptions of subject populations are 
provided in Section 13.1.1. 
The following subject populations will be 
evaluated and used for presentation and analysis 
of the data:  Intent-to-Treat (ITT), Per Protocol 
(PP) Safety, PK, Overall Historical Control, 
UK-PBC Historical Control, and the Global PBS 
Historical Control.  Descriptions of subject 
populations are provided in Section 13.1.1. 
 
Randomized population 
includes patients on OCA who 
withdrew prior to receiving 
drug and this is already 
collected with the safety 
population. 
 
Rationale 12 (for PP 
Population) 
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Synopsis, 
Statistical 
Methods, Primary 
Efficacy Endpoint 
 
Section 11.1.1  
Primary 
Assessments 
The primary efficacy endpoint will be the time to 
first occurrence of one of the following post 
randomization:  
• 
Encephalopathy (as defined by a 
West Haven score of ≥2) 
• 
Hepatocellular carcinoma confirmed 
by 2 complimentary imaging modalities 
 
Change in Synopsis section 
Every event for enrolled subjects will be 
adjudicated by an independent committee. 
The primary efficacy endpoint will be the time to 
first occurrence of one of the following:  
• 
Hepatic encephalopathy (as defined 
by a West Haven score of ≥2) 
 
 
 
 
All events will be adjudicated by an independent 
committee. 
Rationale 5 
Synopsis, 
Statistical 
Methods, Primary 
Efficacy Analysis 
Section 13.1.3  
Primary Efficacy 
Analysis 
The primary efficacy analysis will compare 
randomized OCA to randomized placebo with 
respect to the primary efficacy endpoint using the 
ITT population.   
 
Insertion 
 
The primary efficacy analysis will compare OCA 
to placebo with respect to the primary efficacy 
endpoint using the ITT population.   
 
The same analyses for primary efficacy 
endpoints will be performed for PP population 
as a sensitivity analysis.   
 
 
 
 
Rationale 12 
Synopsis, 
Statistical 
Methods, Key 
Secondary 
Efficacy Analyses 
Section 13.1.4  
Secondary 
Efficacy Analysis 
The key secondary efficacy analyses will 
compare randomized OCA to randomized placebo 
in ITT population with respect to the key 
secondary efficacy endpoints.   
 
Insertion 
 
The key secondary efficacy analyses will 
compare OCA to placebo in the ITT population 
with respect to the key secondary efficacy 
endpoints.   
 
The same analyses for key secondary efficacy 
endpoints will be performed for PP 
population as a sensitivity analysis.   
 
 
 
 
 
Rationale 12 
Synopsis, 
Statistical 
Methods, 
Additional 
Efficacy Analyses 
 
Other Efficacy Analyses 
The following secondary efficacy analyses will 
compare OCA to placebo on time to the following 
events: 
 
 
Additional Efficacy Analyses 
The following time-to-event secondary efficacy 
analyses will compare OCA to placebo using the 
ITT population: 
• 
Progression to cirrhosis 
• 
Time to occurrence of HCC 
Rationale 6 and 
Rationale 11 
 
 
 
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Section 13.1.5 
Additional 
Secondary 
Efficacy Analyses 
Insertion 
 
Progression to cirrhosis will be assessed in the 
subset of subjects considered noncirrhotic at 
Baseline using available medical history, 
clinical, and laboratory assessments as well as 
Baseline transient elastography (TE), where 
available. Specifically, subjects with no 
clinical, laboratory, or radiological evidence of 
cirrhosis at baseline and/or a TE liver stiffness 
of <16.9 kPa (Corpechot 2012) will be 
considered noncirrhotic.  Progression to 
cirrhosis will be assessed by the development 
of clinical, laboratory, or radiological evidence 
of cirrhosis and/or when liver stiffness 
increases to ≥16.9 kPa during the study in 
which case histological progression to cirrhosis 
should be confirmed by biopsy unless not 
medically indicated. Using this definition for 
progression to cirrhosis, the percentage of 
noncirrhotic subjects progressing to cirrhosis 
during the treatment period will be 
summarized by treatment group and 
compared using a Cochran–Mantel–Haenszel 
test stratified by the randomization 
stratification factor. 
For those subjects enrolled in the biopsy 
substudy (defined in Addendum 2) progression 
to cirrhosis identified by the above criteria and 
improvement in fibrosis/cirrhosis will be 
confirmed by paired biopsy.  Analyses for the 
histological assessment conducted as part of 
the biopsy substudy are defined in 
Addendum 2.  
 
 
 
 
 
Rationale 11 
Synopsis, 
Statistical 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
Safety data, including AEs, vitals, 
electrocardiogram, and clinical laboratory results 
Clarification of summary 
analyses. 
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Methods, Safety 
Analyses 
will compare OCA and placebo using the Safety 
Population. 
will be summarized by treatment group for the 
Safety Population. 
 
Synopsis, 
Statistical 
Methods, Sample 
Size Justification 
 
Section 13.1.2. 
Determination of 
Sample Size 
 
 
 
The following assumptions were used in sample 
size calculations:  
• 
Exponential survival curves, 
placebo survival estimate of 0.5 at 
8 years with a hazard ratio of 0.60, 
and total study duration of 8 years, 
allowing for 2 years accrual and 
6 years of follow up 
 
 
 
 
Insertion 
 
 
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
121 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to clinical outcomes. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
350 subjects will be enrolled to attain 121 events. 
The target population is subjects who are at 
higher risk of liver-related clinical 
complications. Eligible subjects will have a 
diagnosis of PBC with bilirubin levels >ULN 
and ≤5x ULN and/or ALP >3x ULN.   
The following assumptions were used in sample 
size calculations:  
• Exponential survival curves, placebo survival 
estimate of 0.6 at 8 years with a hazard ratio of 
0.60, and total study duration of 10 years (from 
first subject enrolled), allowing for 4 years of 
subject accrual and 6 years of follow up.  
• Two interim analyses and one final 
analysis are planned.   The first interim 
analysis will be performed when 50% of the 
target events are accrued and the second 
interim will be performed when 75% of the 
target events are accrued.  
•  A dropout rate of 10% is assumed  
Based on the randomization ratio, significance 
level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 
80% power to demonstrate a statistically 
significant difference between OCA and placebo 
on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions 
stated above, it is estimated that approximately 
428 subjects will be enrolled to attain 127 events. 
 
Rationale 8 
 
 
Rationale 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale 3 
 
 
 
 
 
 
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Section 5.1 
Overview of PBC 
and OCA 
5.1. Overview of Primary Biliary Cirrhosis and 
Obeticholic Acid 
 
Primary biliary cholangitis, (PBC, also known as 
primary biliary cirrhosis) 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. 
ursodeoxycholic acid (UDCA), a physiological 
constituent of human bile, is currently the only 
treatment approved for PBC (Lindor 2009).  While 
UDCA therapy has a marked effect on the 
treatment of PBC, up to 50% of patients show a 
suboptimal response or no response to UDCA.  
Such patients are at significantly increased risk of 
a poor clinical outcome due to PBC disease 
progression.   
There is a clear unmet medical need for better 
therapies for patients with PBC that have an 
inadequate response to UDCA, or those who 
cannot tolerate UDCA (typically due to 
gastrointestinal adverse events [AEs]).  
Obeticholic acid (OCA) is being developed for the 
treatment of PBC and to provide patients that have 
an inadequate response to or poor tolerance of 
UDCA a novel treatment option that is safe and 
effective. 
OCA is a modified bile acid and farnesoid X 
receptor (FXR) agonist that is derived from the 
primary human bile acid chenodeoxycholic acid 
(CDCA).  OCA is currently being developed in the 
United States (US) and Europe for the treatment of 
PBC and other chronic liver diseases.  OCA has 
5.1. Overview of Primary Biliary Cholangitis 
and Obeticholic Acid 
 
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. 
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), 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 
(Pellicciari 2002).  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 
Updating language to include 
accelerated and conditional 
approvals of OCA in the US 
and EU.  
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been granted Orphan Drug Designation in the US 
(09 Apr 2008) and Orphan Medicinal Product 
Designation in the European Union (EU) (27 Jul 
2010) for the treatment of PBC.  The United States 
Food and Drug Administration (FDA) has granted 
accelerated approval for Ocaliva for the treatment 
of PBC.  Ocaliva is not yet approved outside the 
United States for use in any indication. 
UDCA.  In December 2016, the European 
Commission granted conditional approval for 
Ocaliva for the same indication. 
Section 5.4 
Overview of PBC 
and OCA 
As of 31 Jan 2016, approximately 1726 subjects 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 458 subjects had 
PBC, 330 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver disease 
(NAFLD), 33 subjects had alcoholic 
cirrhosis/portal hypertension, and 20 subjects had 
primary sclerosing cholangitis (PSC). 
As of 31 Jan 2017, approximately 2186 subjects1 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 525 subjects had 
PBC, 686 subjects had NASH, 41 subjects had 
diabetes mellitus/non-alcoholic fatty liver 
disease, 33 subjects had alcoholic cirrhosis/portal 
hypertension, and 52 subjects had primary 
sclerosing cholangitis, and 5 subjects had 
biliary atresia. 
------------------------ 
1Includes estimated numbers from ongoing 
blinded studies. 
Language updated to include 
data from current IB. 
Section 5.5.2.1  
Rationale for 
OCA Dose 
The Phase 3 PBC study subsequently evaluated 
the safety and efficacy of OCA at lower doses of 
5 mg (titrated to 10 mg after 6 months based on 
efficacy and tolerability in the double-blind phase 
and after 3 months in the open-label phase) and 
10 mg;  
 
Insertion 
 
 
 
 
The Phase 3 PBC study (Study 747-301) 
subsequently evaluated the safety and efficacy of 
OCA at lower doses of 5 mg (titrated to 10 mg 
after 6 months based on efficacy and tolerability 
in the double-blind phase and after 3 months in 
the open-label phase) and 10 mg;  
Study 747-301 demonstrated that titration of 
OCA from a starting dose of 5 mg to 10 mg 
improved tolerance to pruritus relative to 
10 mg (56% versus 69% of subjects who 
experienced pruritus) and minimized dropouts 
due to pruritus.   
Based on these data, the approved dosing 
regimen for OCA for the treatment of patients 
with PBC are 5 mg and 10 mg. 
Provides rationale for the 
dosing in alignment with 
commercial labeling. 
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Based on these data, the indicated commercial 
doses of OCA for the treatment of patients with 
PBC are 5 mg and 10 mg. 
 As such, Study 747-302 will evaluate the effect of 
OCA on clinical outcomes using the 5 mg OCA 
dose increasing to 10 mg OCA, if tolerated. 
Study 747-302 will evaluate the effect of OCA on 
clinical outcomes using the 5 mg OCA dose for 
at least 3 months, increasing to 10 mg OCA, if 
tolerated. 
Section 5.6 
Summary of 
Known Potential 
Risks with OCA 
These findings were seen more frequently with 
doses above 10 mg OCA. 
 
Insertion 
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).   
Refer to the Investigator’s Brochure (IB) for 
additional information regarding the known 
potential risks with the investigational 
product. 
Language has been updated to 
reflect Sponsor standards. 
Section 7.1 
Overall Study 
Design 
This is a Phase 3b, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤3× ULN or ALP 
>5× ULN.   
 
Approximately 350 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 2-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1).   
 
 
Investigational product will be taken orally, once 
daily….based on tolerability (see Section 7.3). 
 
 
 
This is a Phase 4, double-blind, randomized, 
placebo-controlled, multicenter study.  Eligible 
subjects will have a diagnosis of PBC with 
bilirubin levels of >ULN and ≤5x ULN and/or 
ALP >3x ULN.   
 
Approximately 428 subjects meeting all 
enrollment criteria will be recruited into the study 
over an approximate 4-year period, randomly 
allocated to treatment with either OCA or 
matching placebo in a 1:1 ratio (Figure 1). . . A 
minimum of 30% of subjects will have 
elevated bilirubin (>ULN) at Screening. 
 
Subjects will be dosed according to their 
cirrhosis status and Child-Pugh Score…based 
on tolerability and biochemical response (see 
Section 7.3)   
 
Rationale 1 and Rationale 8 
 
 
 
 
Rationale 10 
 
 
 
Rationale 8 
 
 
Clarification  
Rationale 9 
 
 
 
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The study will continue until approximately 121 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
The study will continue until approximately 127 
adjudicated primary endpoint events have been 
accrued in unique subjects, or until the Sponsor 
(eg, based on advisement by the Data Monitoring 
Committee; DMC) terminates the study. 
Rationale 3 
Section 7.1.2 
Schedule of Study 
Procedures,  
Table 1  
Insertions 
 
 
 
 
 
 
 
 a All subjects will have the chemistry panel 
retested to ensure subjects have at least two 
ALP and bilirubin assessments 2 weeks apart to 
calculate the mean result for both analytes.  The 
mean of all screening ALP and bilirubin 
assessments will be used to determine 
eligibility.  
 
 
 
j Transient elastography (TE) will be conducted 
at selected study sites where the Fibroscan® TE 
device is available.  Similarly, DEXA will be 
conducted at selected study sites where the 
DEXA device is available.    
 
 
Insertion (subsequent footnotes are renumbered 
accordingly) 
Physical exams have been added at: 
• 
Month 1 
• 
1-Month Post Titration 
• 
Month 6 
Fibroscan® TE has been added at Month 6 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
 
 a All subjects will have the chemistry panel 
retested to ensure subjects have at least two 
ALP and bilirubin assessments at least 2 weeks 
apart to calculate the mean result for both 
analytes.  The mean of all screening ALP and 
bilirubin assessments will be used to determine 
eligibility. Refer to Section 9.7.6 for guidance 
on when an additional ALP or bilirubin 
sample may be needed to confirm eligibility. 
 
j Transient elastography (TE) will be conducted 
at 6-month intervals at all study sites where 
the Fibroscan® TE device is available.   
 
 
k DEXA will be conducted at 12-month 
intervals at all study sites where the DEXA 
device is available.  Please refer to 
Section 9.7.7 for additional information 
related to the allowed windows at Day 0 for 
this procedure. 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
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k 
Endoscopy will be conducted at selected 
study sites where the device is available. 
 
l Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (eg, post-Day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be 
obtained to confirm if a study endpoint has been 
met. 
 
 
o … The initial dose titration of investigational 
product may occur at the Month 3 visit, or any 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability. … 
 
 
u  A genetics study will be conducted in a subset of 
subjects who provide consent for analyses of 
these samples.  Genetics samples will be 
collected at Day 0 and every other year 
beginning at Month 12. 
 
m 
Endoscopy will be conducted at all study 
sites where the device is available. 
 
m 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.   
 
p … The initial dose titration of investigational 
product may occur at the Month 3 visit, or any 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability and 
biochemical response. … 
 
v A genetics study will be conducted in a subset 
of subjects who provide consent for analyses of 
these samples.  Genetics samples will be 
collected at Day 0 and every other year 
beginning at Month 12.  If a Baseline (eg, 
Day 0) genetic sample is not obtained, 
subsequent genetic samples are not required 
to be collected during the course of the 
study. 
 
annual assessments at Day 0 
and Month 12). 
 
Hepatic ultrasound monitoring 
has been increased to every 6 
months to conform to AALSD 
and EASL practice guidelines 
for PBC patients with 
cirrhosis. 
 
 
 
 
Rationale 9 
 
 
 
 
Clarification 
Section 7.1.2 
Schedule of Study 
Procedures, Table 
2 
Insertions 
 
 
 
 
 
Physical exams have been added at 1-Month 
Post Titration 
Fibroscan® TE has been added at Month 6 
continued follow up 
DEXA has been moved to its own line 
Hepatic Ultrasound has been added at Month 6 
continued follow up 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring. 
 
 
 
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i Transient elastography (TE) will be conducted at 
selected study sites where the Fibroscan® TE 
device is available.  Similarly, DEXA will be 
conducted at selected study sites where the 
DEXA device is available.  Not required if done 
within 6 months of visit. 
   Insertion (subsequent footnotes are renumbered 
accordingly) 
  
 
j   Endoscopy will be conducted at selected study 
sites where the device is available to assess for 
the presence of oesophageal varix/varices. 
 
k  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. post-day 0) 
ultrasounds: If a lesion is found, a second 
confirmatory image (eg, MRI) should be 
obtained to confirm if a study endpoint has been 
met. 
 
o … The initial dose titration of investigational 
products may occur at the Month 3 visit, or any 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability. 
 
i Transient elastography (TE) will be conducted 
at 6-month intervals at all study sites where 
the Fibroscan® TE device is available. 
 
 
j  DEXA will be conducted at 12-month 
intervals at all study sites where the DEXA 
device is available. 
k   Endoscopy will be conducted at all study sites 
where the device is available to assess for the 
presence of oesophageal varix/varices. 
 
l  Ultrasound will be conducted to enhance HCC 
surveillance.  For all on study (e.g. 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. 
 
o … The initial dose titration of investigational 
products may occur at the Month 3 visit, or any 
study visit thereafter for subjects on all dosing 
regimens, based on tolerability and 
biochemical response. 
 
Fibroscan® TE monitoring 
has been increased to every 
6 months to facilitate 
monitoring for progression to 
cirrhosis. 
 
DEXA has been separated 
from Fibroscan® TE to allow 
additional monitoring of the 
latter (the schedule for DEXA 
exams has not changed from 
annual assessments). 
 
 
Hepatic ultrasound monitoring 
has been increased to every 
6 months to conform to 
AALSD and EASL practice 
guidelines for PBC patients 
with cirrhosis. 
 
Rationale 9 
Section 7.1.3 
Study Duration 
The study is event driven and total duration will be 
determined by the time required to accrue 
approximately 121 primary endpoint events, 
estimated to be approximately 8 years.  Subjects 
are expected to have a minimum follow-up time of 
approximately 6 years. 
The study is event driven and total duration will 
be determined by the time required to accrue 
approximately 127 primary endpoint events, 
estimated to be approximately 10 years.  Subjects 
are expected to have a minimum follow-up time 
of approximately 6 years. 
Rationale 3 
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Section 7.2 
Number of 
Subjects 
It is expected that approximately 350 subjects will 
be randomized in the study to achieve 
121 adjudicated primary endpoint events.   
It is expected that approximately 428 subjects 
will be randomized in the study to achieve 127 
adjudicated primary endpoint events.  In the 
event additional subjects are needed to 
complete enrollment in the biopsy substudy 
(N = 45 subjects, as defined in Addendum 2), 
subjects who agree to participate in the 
substudy may be added to the target subject 
enrollment number currently planned. 
Rationale 10 
Language added to allow for 
continued enrollment into the 
biopsy substudy; additional 
subjects are not anticipated to 
prolong the duration of the 
study. 
 
Section 7.3 
Planned Dosing 
Regimen, and 
Table 3 
Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at 
the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the 
product.   
 
 
Footnotes of Table 3 were re-ordered 
b   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is dependent 
on subject tolerability and/or changes in cirrhosis 
status or Child-Pugh score at any time during the 
study 
Subjects should titrate to a maximum dose of 
10 mg OCA once daily (or matching placebo) at 
the Month 3 visit or at any study visit following 
the Month 3 visit based on tolerability of the 
product and assessment of biochemical 
response.  Up-titration should be considered if 
ALP and/or total bilirubin are >ULN.   
 
c   Planned titration regimen is shown; however, 
the titration of dose and/or frequency is 
dependent on subject tolerability, biochemical 
response, and/or changes in cirrhosis status or 
Child-Pugh score at any time during the study 
Rationale 9 
Section 7.4  
Dose Titration 
Criteria 
Insertion 
 
 
 
 
 
 
 
 
 
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) as 
well as biochemical response (as assessed by 
reductions in ALP and/or total bilirubin).  In 
general, down-titration will be done in 
response to tolerability concerns and can occur 
at any time while on-study.  Up-titration will 
be done per protocol when subjects have no 
tolerability concerns and have not achieved an 
adequate reduction in ALP and/or total 
bilirubin to within normal limits, or as 
Added language to clarify 
titrations (up or down). 
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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. 
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 for each dosing regimen as defined 
in Section 7.3. 
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, biochemical response, and 
clinical judgment. 
Changes in Child-Pugh Score that result from 
a transient, explainable change in laboratory 
parameters should be documented 
appropriately and should not necessarily 
result in a change to the dosing regimen 
(Appendix A). 
Section 7.4.1  
Pre-Titration 
Tolerability 
Assessment 
Requirements 
• 
There must be no clinically significant 
increase (as determined by the investigator) in the 
subject’s liver function tests.  Subjects whose total 
bilirubin is >2× baseline (and >ULN) cannot be 
up-titrated, and additional unscheduled safety visit 
procedures, outlined in Section 9.7.19 should be 
implemented, as required. 
• 
There must be no clinically significant 
increase (as determined by the Investigator) in 
the subject’s liver function tests.  
Clarification 
Section 7.4.2   
Safety Criteria for 
Adjustment or 
Stopping Doses 
The text in this section is moved to Section 8.4.  
 
To avoid redundancy 
Section 7.5   
Criteria for Study 
Termination 
The window of time for scheduling the visit will 
be based on a final projection of when the 
requisite 121 adjudicated events will have been 
accrued. 
The window of time for scheduling the visit will 
be based on a final projection of when the 
requisite 127 adjudicated events will have been 
accrued. 
Rationale 3 
Section 8.4  
[Moved from Section 7.4.2 of Version 3] 
 
 
Clarification 
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Dose Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or 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 that 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 
when the needed number of adjudicated events has 
accrued.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  In general, 
subjects should be strongly encouraged to both 
stay on investigational product and remain in the 
study until study termination.   
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or by 
decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability 
concerns.  The dose of investigational product 
should be adjusted back to the maintenance dose 
in a blinded manner once the issues relating to the 
lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated 
events has accrued.  If a subject reaches an 
outcome event, he or she should continue the 
regular visit schedule and continue taking 
investigational product as long as the subject has 
not met any of the criteria for mandatory 
interruption of investigational product 
outlined in Section 8.4.1, and the Investigator 
assesses it as safe.  In general, subjects should be 
strongly encouraged to both stay on 
investigational product and remain in the study 
until study termination.   
Section 8.4.1.1   
Reasons for 
Additional 
Monitoring 
Related to Liver 
Chemistries 
Modification of 8.4.2.1 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 
 
Subjects 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.  Subjects with 
persistent elevations (eg, additional lab testing 
per Investigator discretion) should be closely 
monitored.  Concomitant elevations in total 
bilirubin or international normalized ratio 
(INR) with persistent increases in ALT or AST 
should also be closely monitored. 
 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries.  
Language related to 
interruption of investigational 
product is now located in 
Section 8.4.1.2. 
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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. 
 
Section 8.4.1.2   
Reasons for 
Investigational 
Product 
Interruption 
Related to 
Elevated Liver 
Chemistries 
Insertion 
Development of any of the following clinical 
laboratory values, without explanation, during 
the study mandates investigational product 
interruption: 
• 
AST and/or ALT >3x baseline (and 
>ULN) 
• 
Total bilirubin >2x 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 AE information should also be 
collected and the subject 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 >3x baseline (and >ULN) or total 
Clarified guidelines for 
subjects who develop 
elevations in liver chemistries. 
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Justification for Change 
bilirubin >2x baseline (and >ULN), subjects 
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 investigative product 
and no other cause for the elevation is 
identified, it may be assumed that the 
elevations were due to disease progression and 
the subject 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 subject 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.  
Subjects who develop evidence of severe drug-
induced liver injury, which 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 
subjects 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 
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appropriate for the subject to continue 
treatment.  In the event the investigational 
product is required to be discontinued, 
subjects should be encouraged to continue 
study visits for continued data collection but 
may withdraw consent at any time.  
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 13.4). 
Section 8.4.1.3   
Pregnancy 
Modification of 8.4.1 Reasons for Mandatory 
Discontinuation of Investigational Product 
If a female subject becomes pregnant, she must 
discontinue taking investigational product, but 
should continue with the study visit schedule.  The 
subject must be followed as considered 
appropriate by the Investigator and the medical 
monitor through pregnancy outcome.  For 
reporting purposes pregnancy is not considered an 
AE.  The subject may reinstate investigational 
product after delivery and cessation of 
breastfeeding (if applicable) at the discretion of 
the Investigator.  Subjects whose pregnancy is 
terminated early (planned or unplanned) may be 
permitted to resume participation in the study if 
termination of the pregnancy is confirmed by a 
serum beta human chorionic gonadotropin (β-
hCG) test performed at the central laboratory. 
8.4.1.3 Pregnancy 
If a female subject becomes pregnant, she must 
interrupt treatment with investigational product 
immediately, but should continue with the study 
visit schedule.  As described in Section 12.1.11 
pregnancy is not considered an AE for reporting 
purposes.  The subject may re-start 
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 12.1.11. 
Clarification regarding 
prolonged interruption in 
investigational product such as 
in the event of pregnancy.  
 
Section 8.4.2.1  
Liver 
Transplantation 
Text Moved from Section 8.4.2 Other Reasons 
for Discontinuation of Study or Investigational 
Product 
8.4.2.1 Liver Transplantation 
 
Subjects who undergo a liver transplant during 
the course of the study must discontinue 
The relocation of this 
statement from within 
Section 8.4.2 to 8.4.2.1 
clarifies procedure to 
discontinue subjects who 
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Subjects who undergo a liver transplant during the 
course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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. 
investigational product and discontinue the study 
visit schedule. However, these subjects 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. 
undergo a liver transplant, 
from investigational product 
but not study visits. 
Section 8.4.3 
Other Reasons for 
Discontinuation of 
Study or 
Investigational 
Product 
8.4.2 Other Reasons for Discontinuation of Study 
or Investigational Product 
Subjects that discontinue investigational product 
are expected to continue in the study until the end 
of the study, and the study will only terminate at 
the time when the needed number of adjudicated 
events has accrued or at the discretion of the 
Sponsor.  If a subject reaches an event, he or she 
should continue the regular visit schedule and 
continue taking investigational product as long as 
the Investigator assesses it as safe.  Subjects who 
choose to discontinue investigational product prior 
to termination of the study need to also continue to 
follow the regular visit schedule through to study 
closure.  In general, subjects should be strongly 
encouraged to both stay on investigational product 
and remain in the study until study termination.  
Early termination procedures should only be 
conducted if the subject withdraws consent (See 
Section 9.7.18 Early Discontinuation and/or Early 
Termination Procedures). 
The following events are considered appropriate 
reasons for a subject to discontinue investigational 
product; however, these subjects are expected to 
continue in the study until study termination and 
the study will only terminate at the time when the 
needed number of adjudicated events has accrued 
(or at the discretion of the Sponsor): 
8.4.3 Other Reasons for Discontinuation of Study 
or Investigational Product 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following events are considered appropriate 
reasons for a subject to discontinue 
investigational product; however, these subjects 
are expected to continue in the study until study 
termination (or at the discretion of the Sponsor): 
Clarification of process 
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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 potential adjudicated hepatic and/or 
cardiovascular events. 
 
 
Subjects who undergo a liver transplant during the 
course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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. 
 
 
− 
Consent may be modified to discontinue 
study visits or semi-annual telephone contact 
but allow continued access to medical 
records to assess suspected major adverse 
cardiovascular events (MACE) and liver-
related clinical outcomes. 
− 
Early termination procedures should be 
conducted if the subject withdraws 
consent (See Section 9.7.18). 
The Investigator is encouraged to contact the 
Sponsor prior to discontinuing a subject from 
treatment.   
Section 9.7.1  
Visit Windows 
Screening 
 
 
Screening 
See Section 9.7.6 for 
scenario specific visit 
windows that may be 
applicable at Screening.  
 
Section 9.7.3.1  
Determination for 
Dosing Regimen 
Insertion 
Acceptable methods of confirming (via medical 
history) or assessing cirrhosis for purposes of the 
study is defined as a subject who has documented 
evidence or presence of one or more of the 
following cirrhosis indicators: 
9.7.3.1 Determination for Dosing Regimen 
Acceptable methods of confirming (via medical 
history) or assessing cirrhosis for purposes of 
determining dosing is defined as a subject who 
has documented evidence or presence of one or 
more of the following cirrhosis indicators: 
Header added to differentiate 
the assessment of cirrhosis for 
determining dosing regimen 
versus progression to 
cirrhosis. 
Section 9.7.3.2  
Progression to 
Cirrhosis 
Insertion 
9.7.3.2 Progression to Cirrhosis  
When a subject identified as noncirrhotic at 
Baseline per the criteria listed in Section 
9.7.3.1 exhibits any signs or symptoms 
associated with progression to cirrhosis, as 
defined by the same criteria, the subject 
should also be assessed by Fibroscan® TE 
where available and progression to cirrhosis 
Details the assessment of 
progression to cirrhosis. 
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confirmed by biopsy (centrally read) unless 
not medically indicated.  Laboratory samples 
needed to obtain noninvasive scores of liver 
fibrosis (ELF, and aspartate aminotransferase 
to platelet ratio index [APRI]) will also be 
collected when a subject develops evidence of 
progression to cirrhosis. 
Full instructions concerning the sample 
collection methods, processing, labeling, and 
shipping will be provided by the Sponsor in a 
study-specific histology manual.  Collection 
supplies will be provided by the central 
laboratory. 
Sites participating in the paired biopsy 
substudy must confirm progression to 
cirrhosis by biopsy as per the information 
outlined in protocol Addendum 2. 
All suspected cases of progression to cirrhosis 
should be submitted for adjudication 
regardless of the availability of transient 
elastography or biopsy results. 
Section 9.7.6  
Screening 
Procedures 
Two Screening visits will occur from 1 to 8 weeks 
prior to Day 0 (as outlined below) allowing for the 
collection of repeated serum chemistry samples (at 
least 2 weeks apart) to confirm pretreatment ALP 
and total bilirubin values: 
 
 
Insertion 
 
 
 
 
Collection of 2 serum chemistry samples 
(collected at least 2 weeks apart) during 
Screening is required for confirmation of the 
pretreatment serum chemistry values, including 
the ALP and total bilirubin used to determine 
eligibility: 
 
• 
When the 2 bilirubin or ALP assessments 
collected at Screening Visit 1 and Screening 
Visit 2 differ by ≥30%, a third sample must be 
collected at an unscheduled visit as a 
confirmatory sample to include in the mean 
result(s) that will be used to determine 
eligibility.  
Allows repeat assessments 
when baseline laboratory 
values are discrepant between 
Screening Visit 1 and 
Screening Visit 2. 
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• 
The mean of all available (at least 2; including 
both scheduled and unscheduled) bilirubin and 
ALP assessments will be used to determine 
eligibility (total bilirubin >ULN and ≤3× ULN 
and/or an ALP >5× ULN).   
• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(selected study sites only), 
 
 
 
Insertion 
 
 
• 
The mean of all available (at least 2; 
including both scheduled and 
unscheduled) bilirubin and ALP assessments will 
be used to determine eligibility (total bilirubin 
>ULN and ≤5x ULN and/or an ALP >3x ULN).  
• 
…the dual-emission X-ray absorptiometry 
(DEXA) bone density scan to be done at Day 0 
(at all study sites where the device is available),   
 
In the event that the 2 screening bilirubin or 
ALP assessments differ by ≥30%, and a third 
confirmatory sample is required to be 
collected, the Screening Visit window may be 
extended up to 3 additional weeks. 
Section 9.7.7  
Day 0 Procedures 
• 
Perform transient elastography (TE; at 
selected study sites, where available) using the 
Fibroscan® TE device. If TE has been done within 
6 months of Day 0 and a report/adequate data are 
available, a pretreatment TE at Day 0 is not 
required.   
• 
Conduct a DEXA bone density scan (at 
selected study sites, where device is available); 
• 
Perform an esophagogastroduodenoscopy 
(endoscopy; at selected study sites, where device 
is available) to assess the presence or absence of 
oesophageal varix/varices. 
• 
Perform TE at all study sites with access to 
Fibroscan® TE device. If TE has been done 
within 3 months of Day 0 and a report/adequate 
data are available, a pretreatment TE at Day 0 is 
not required.   
• 
Conduct a DEXA bone density scan (at all 
study sites where the device is available); 
• 
Perform an esophagogastroduodenoscopy 
(endoscopy; at study sites, where device is 
available) to assess the presence or absence of 
oesophageal varix/varices. 
Clarifies use of TE and 
modifies the time during 
which an historic TE report 
remains valid.  
Clarifies the use of DEXA and 
endoscopy. 
Section 9.7.8  
Month 1 
Procedures 
 
Section 9.7.10  
9.7.10   Post-Titration visit Procedures 
Insertion 
 
• 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
9.7.10  1-Month Post-Titration visit Procedures 
• 
Perform a physical examination.  
 
• 
In the event it is not feasible for the subject 
to return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
Physical Exams have been 
added one month after each 
dose adjustment for added 
safety monitoring.  Options 
for safety monitoring 
assessments are provided 
when returning to the site 
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1-Month Post-
Titration visit 
Procedures 
procedures are available to help ensure 
compliance with the Month 1 visit requirements: 
 
 
Insertion (9.7.8) 
 
Insertion (9.7.10) 
 
compliance with the Month 1 visit laboratory 
requirements: 
 
- 
A physical examination should be 
performed at the Month 3 visit if an onsite 
Month 1 visit was not performed. 
- 
A physical examination should be 
performed at the next scheduled visit if an 
onsite post-titration visit was not performed. 
presents significant burden on 
the subject.  
Section 9.7.11  
Month 6 
Procedures 
 
Section 9.7.16  
Month 6 
Continued 
Follow-Up 
Procedures 
Insertion 
 
 
 
 
 
 
Insertion in 9.7.11 (not 9.7.16) 
• 
Perform TE at all study sites with access 
to Fibroscan® TE device. 
• 
Perform an ultrasound for HCC 
surveillance (if equipment is unavailable, 
sites should make every attempt to use 
available community referral sites).  
 
 
• 
Perform a physical examination 
Fibroscan® TE monitoring 
has been increased to every 6 
months to facilitate 
monitoring for progression to 
cirrhosis. 
  
Hepatic ultrasound has been 
increased to every 6 months to 
conform to AASLD and 
EASL guidelines for PBC 
patients with cirrhosis. 
Section 9.7.12  
Month 9 
Procedures 
Section 9.7.14 
Month 12 
Procedures 
Section 9.7.16 
Month 16 
Continued 
Follow-Up 
Procedures 
 
…DEXA procedure to be done at 
selected study sites only, 
 
…DEXA procedure to be done at 
all study sites where the device is available  
 
Clarification 
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Section 9.7.14  
Month 12 
Procedures 
Section 9.7.17  
Month 12 Follow-
up Procedures 
Section 9.7.18  
EOS/EOT 
• 
Perform TE (at selected study sites, where 
available) using the Fibroscan® TE device. 
 
Additional edit in Section 9.7.18 
- If the subject reports having eaten within 8 
hours, document accordingly in the source and 
CRF and remind the subject that fasting is 
required prior to all study visits. 
• 
Perform TE at all study sites with access to 
the Fibroscan® TE device. 
 
 
- If the subject reports having eaten within 8 
hours, document accordingly in the source and 
CRF. 
Clarification 
Section 10.3  
Investigational 
Product Storage 
The investigational product should be stored in the 
containers in which they are received from the 
Sponsor’s supplier, at 15°C to 25°C. 
All OCA tablet strengths provided to clinical 
trial sites in support of clinical study 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. 
Updating temperature 
excursions language per 
Sponsor stability studies. 
Section 11.1.2 
Secondary 
Assessments 
Insertion 
 
 
 
 
 
 
 
 
 
 
 
• 
Individual components of the primary 
endpoint. 
• 
Progression to cirrhosis as assessed by the 
presence of clinical, laboratory, or radiological 
evidence of cirrhosis and/or liver stiffness 
(Fibroscan® TE), confirmed by biopsy unless 
not medically indicated.  
• 
Histological assessment of disease 
progression or improvement using paired 
biopsies in a subset of subjects (defined in 
Addendum 2). 
- 
HCC confirmed by 2 complimentary 
imaging modalities, unless confirmed 
by biopsy. 
 
Rationale 11 
 
 
 
 
Reflects addition of a biopsy 
substudy available to 
interested sites in 
Addendum 2. 
 
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• 
Biomarkers, including markers of hepatic 
fibrosis and/or inflammation, to be tested will 
include:  IgM, c-reactive protein (CRP), tumor 
necrosis factor-α (TNF-α), FGF-19, cytokeratin-18 
(CK-18) and ELF, Fibroscan (and others as 
determined during the course of the study). 
 
 
 
 
 
• 
Endoscopy will be conducted at all study sites 
where the device is available to assess for the 
presence of oesophageal varix/varices at baseline.  
• 
Biomarkers, including other markers of 
hepatic fibrosis and/or inflammation, to be tested 
will include:  IgM, c-reactive protein (CRP), 
tumor necrosis factor-α (TNF-α), FGF-19, 
cytokeratin-18 (CK-18) ELF, and Fibroscan (and 
others as determined during the course of the 
study).  
• 
Clinical outcomes, including individual 
component of the primary endpoint (where 
available), liver transplant, and death will be 
compared to historical controls. 
• 
PK of OCA and its conjugates. 
• 
Endoscopy will be conducted at all study 
sites where the device is available to assess for 
the presence of oesophageal varix/varices at 
baseline.  
Section 12.1.3  
Relationship of 
AEs to Liver 
Biopsy 
 
Insertion (new section) 
The Investigator will document her/his opinion 
of relationship of an AE to liver biopsy using 
the criteria outlined in Table 9.  
Table 9: Relationship of Adverse Events to 
Liver Biopsy 
Relatio
nship 
Description 
Relate
d 
A reaction that follows a 
reasonable temporal sequence 
from the liver biopsy; that follows 
a known or expected response 
pattern to the liver biopsy. 
Not 
Relate
d 
Any event that does not meet the 
above criteria. 
Added with the addition of 
liver biopsies for the 
confirmation of progression to 
cirrhosis. 
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Section 12.1.5.2 
Reporting of 
Serious Adverse 
Events 
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 
•Telephone:  +1 858 964 1571 
Investigational new drug (IND) Safety Reports 
 
Insertion 
If an SAE is reported by email or fax, an SAE 
Report form must also be completed in the EDC 
system as soon as the EDC system is accessible 
 
Redacted medical record source 
documentation will be requested for all SAEs 
and emergency room visits. 
 
Updated to align with 
modified standard safety 
procedures. 
 
 
 
Added sentence regarding 
redacted medical records to 
align with Sponsor safety 
standards. 
Section 12.1.6 
Suspected Liver-
Related Clinical 
Outcome Events 
For liver-related clinical outcome events could 
also meet the criteria of a SUSAR, which would 
necessitate unblinding for expedited reporting, 
please refer to Section 11.1.2.4. 
 
 
 
 
 
 
 
 
The Sponsor will consider the following list of 
clinical outcome events (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), hepatic encephalopathy (preferred 
Given that the liver-related clinical outcome 
events may also meet the criteria of a SUSAR, 
but are considered in aggregate as part of the 
primary endpoint and the DMC reviews of all 
safety and efficacy data at least quarterly, the 
Sponsor will not expeditiously report 
suspected liver‑related 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 “study event” 
on the AE CRF and will be submitted for 
adjudication to the Hepatic Outcomes 
Committee as described in Section 13.4. 
 
The Sponsor will consider the following list of 
clinical outcome events (MedDRA preferred 
terms) to be disease related and exempt from 
expeditious regulatory reporting, but will 
continue to report them in a nonexpeditious 
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 or oesophageal varices 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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term: hepatic encephalopathy), and spontaneous 
bacterial peritonitis (preferred term: peritonitis 
bacterial). 
 
haemorrhage), hepatic encephalopathy 
(preferred term: hepatic encephalopathy), 
spontaneous bacterial peritonitis (preferred term: 
peritonitis bacterial), ascites (preferred term: 
ascites), and histological or clinical progression 
to cirrhosis (preferred term: hepatic cirrhosis). 
Section 12.1.8 
Notification of 
Post-Treatment 
SAEs for Subjects 
Who Continue in 
the Study 
Insertion (new section) 
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 12.1.5.2. 
SAEs that occur in subjects 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 12.1.5.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language. 
Section 12.1.9 
Notification of 
Poststudy SAEs 
All SAEs that occur within 30 days following the 
cessation of investigational product, 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 12.1.4.2. 
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 SAE 
must be reported to the Sponsor immediately (ie, 
within 24 hours). 
SAEs that occur more than 30 days after a subject 
has discontinued investigative product, and are not 
considered related to investigational product, must 
still be reported in the EDC system; however, 
these events are not required to be reported within 
24 hours.  At a minimum, the SAE term, event 
start and end date, severity, relationship to 
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 12.1.5.2. 
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 12.1.5.2. 
Updated to align with 
modified safety procedures 
and Sponsor standard 
language. 
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investigational product, action taken with 
investigative product, treatment, outcome, and 
potential endpoint status need to be recorded in 
EDC for the SAE.  Additional information (e.g. 
event summary, SAE details) may also be required 
to be entered, when requested by the sponsor.  
Section 12.1.10  
Follow-up of AEs 
and SAEs 
Insertion 
All subjects 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 CRF. 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. 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
Section 12.1.11  
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 8.4.1.3and the Sponsor must be notified 
within 24 hours of the Investigator’s learning of 
the pregnancy by completing the Pregnancy 
Notification Form and faxing or emailing to the 
Sponsor at +1 800 497 8521 or 
sae@interceptpharma.com.  
Safety will be monitored and assessed by 
AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and 
clinical laboratory assessments. The Sponsor may 
also follow the health of an infant born subsequent 
to use of investigational product. 
The subject may reinstate investigational product 
after delivery and cessation of breastfeeding (if 
applicable) at the discretion of the Investigator.  
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 
sae@interceptpharma.com or faxed to 
+1 800 497 8521.   The subject and neonate 
must be followed for outcome information 
and/or as considered appropriate by the 
Investigator and Sponsor. 
The subject may restart investigational product 
when she is no longer pregnant or 
Updated to align with 
modified standard safety 
procedures and Sponsor 
standard language. 
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Subjects whose pregnancy is terminated early 
(planned or unplanned) may be permitted to 
resume participation in the study if termination of 
the pregnancy is confirmed by a serum β-hCG test 
(see Section 8.4.1). 
breastfeeding (if applicable) at the discretion of 
the Investigator and after discussion with the 
Medical Monitor.  The subject must have a 
negative pregnancy test before restarting 
investigational product.  If a subject’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 12.1.5 must also be followed. 
Section 12.2.7  
Laboratory 
Assessments 
The list of laboratory analytes to be tested is 
shown in Table 10. 
The list of laboratory analytes to be tested is 
shown in Table 11, and the normal reference 
ranges for liver biochemistries are shown in 
Appendix C. 
Added per Regulatory 
Authority request. 
Section 12.2.7  
Table 10 List of 
Laboratory 
Analytes 
Measurement of Liver Fibrosis 
Fibroscan 
Bone Density Assessment 
DEXA 
Other 
Insertion 
 
 
Deletion 
 
Other 
OCA-glucuronide 
 
Measurements of liver fibrosis 
are captured in a different 
section. 
 
OCA-glucuronide was listed 
in the text but missing from 
the table. 
Section 13  
Statistical 
Methods 
A statistical analysis plan (SAP), providing details 
about the specific planned analyses and hypothesis 
tests, will be prepared and approved by the 
Sponsor and its designees prior to study database 
lock, propensity score determination, and 
unblinding of the double-blind subject treatment 
assignments. 
A statistical analysis plan (SAP), providing 
details about the specific planned analyses and 
hypothesis tests, will be prepared and approved 
by the Sponsor and its designees prior to the first 
interim analysis, propensity score determination, 
and unblinding of the double-blind subject 
treatment assignments. 
Reflects addition of interim 
analyses to the study protocol. 
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Section 13.1.1 
Analysis 
Populations 
• 
The Randomized Population will include all 
randomized subjects 
 
Insertion 
Deletion 
 
• 
The Per Protocol (PP) Population will 
include all ITT subjects who do not have any 
major protocol violations that potentially 
affect the efficacy conclusion.  Treatment 
assignment will be based on the randomized 
treatment. 
 
 
 
 
Rationale 12 
Section 13.1.1.1  
Comparability of 
Historical 
Controls 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria where possible. 
Historical controls from both databases will be 
chosen based on the same study 
inclusion/exclusion criteria.  Propensity score 
matching method will be utilized to select 
historical controls that match the treated 
subjects using available covariates. The 
adequacy of matching will be assessed by 
statistical methods described under 
Section 13.1.8. 
Clarifies the use of propensity 
scores in the assessment of the 
historical control population. 
Section 13.1.2.1 
Sample Size 
Monitoring 
13.1.2.1 Sample Size Re-Estimation Plan 
Therefore, starting approximately 2 years after the 
first subject is randomized, the aggregate event 
rate and sample size based on recruitment and 
retention will be evaluated in a blinded manner 
quarterly.  This evaluation will determine if any 
increases in number of subjects are required in 
order to obtain a total of 121 adjudicated events 
for the final analysis in the combined groups. 
If after 4 years of accruing subjects, despite 
increases in the number of subjects, it is 
determined that at least an additional 2 years (ie, 
total study duration of at least 10 years) are needed 
to randomize sufficient subjects to achieve a total 
of 121 adjudicated events, all subjects enrolled 
from that point forward will receive open-label 
OCA.  Previously randomized subjects will 
13.1.2.1 Sample Size Monitoring 
Therefore, the aggregate event rate and sample 
size based on recruitment and retention will be 
evaluated in a blinded manner quarterly.  This 
evaluation will determine if any increases in 
number of subjects are required in order to obtain 
a total of 127 adjudicated events for the final 
analysis in the combined groups. 
Deletion 
Clarifies the ongoing 
monitoring of event rate and 
sample size. 
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continue to be treated in a blinded manner with 
either OCA or matching placebo.  If this 
modification is implemented, the alternative 
primary efficacy analysis is specified is 
Section 13.1.9. 
Any revised sample size or changes to treatment 
allocation will be justified and documented in a 
protocol amendment and in the CSR. 
Section 13.1.5.1  
Association of 
Biochemistry with 
Clinical Outcomes 
and Clinical 
Benefit 
Insertion (new subsection) 
13.1.5.1 Association of Biochemistry with 
Clinical Outcomes and Clinical Benefit  
The association between biochemistry 
including ALP and bilirubin with clinical 
outcomes will be assessed and the clinical 
benefit of OCA using biochemistry as a 
surrogate endpoint will be evaluated.  Detailed 
analysis will be described in the SAP.  
Based on the association between biochemical 
changes and clinical outcomes described 
above, clinical benefit of OCA using 
biochemistry as a surrogate endpoint for key 
subpopulations of interest will be evaluated. 
This analysis will be further described in the 
SAP. 
This analysis will provide 
additional insight into the 
connection between surrogate 
endpoints and clinical 
outcome events allowing for 
evaluation of benefit in 
subpopulations for which the 
study is not powered. 
Section 13.1.8  
Supportive 
Analysis 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls. 
 
 
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment. 
 
In order to address the risks associated with the 
inclusion of a long-term placebo arm, supportive 
analyses of the primary endpoint will compare 
clinical outcomes in the OCA treatment arm to 
historical controls, which serves as an external 
control for supportive analysis.  
By comparing how outcomes differ for treated 
subjects relative to historical controls, it is 
possible to estimate the effects of the treatment 
between the treated subjects and the matched 
natural history subjects. 
Clarifies the use of the 
historical controls as an 
external control in supportive 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
 
 
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Although it might be relatively simple to assign a 
historical control based on a single observable 
characteristic, in practice, if the matching process 
is to successfully mitigate potential bias, it has to 
be done considering a full range of covariates 
across which the treatment and historical controls 
might differ. 
Only covariates and not outcome variables will be 
included in the propensity score estimation.  
Therefore, there is no chance of biasing, to avoid 
biased results that are in favor of one treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
A full range of covariates across which the 
treatment and historical controls might differ will 
be considered to mitigate potential bias. 
 
 
Only covariates and not outcome variables will 
be included in the propensity score estimation to 
avoid biased results that are in favor of one 
treatment. 
 
The baseline characteristics between treated 
and natural history subjects in the matched 
dataset will be summarized and presented in a 
tabular format.  Statistical methods such as 
Wilcoxon Rank-Sum test will be used to assess 
the balance for baseline covariates.  The 
standardized difference and variance ratios 
for these covariates will also be calculated.  In 
addition, box plots of propensity scores for 
treated and natural history subjects will be 
separately presented, to further assess the 
adequacy of matching.  
A third-party statistician(s) will perform the 
propensity score modeling and matching.  This 
third-party statistician(s) will be   separate and 
independent from the statistician(s) who will 
assess the success of matching and perform 
efficacy analyses. 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare randomized OCA-treated subjects 
in the ITT population and historical controls 
(Overall Historical Control Population: both the 
UK-PBC Group and Global PBC Study Group 
databases) on the following outcomes: 
Clarifies the use of the 
historical controls as an 
external control in supportive 
analyses of the primary 
endpoint and clarify the 
process for selecting the 
comparator group for the 
primary efficacy analysis 
using propensity score 
analysis. 
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• 
Time to hepatocellular carcinoma 
 
(Text from Section 13.1.9 [Alternative Primary 
Analysis] modified and included in this section) 
Based on sample size re-estimations, it may be 
determined that subjects will be enrolled to receive 
open-label OCA from that point forward, and the 
new primary efficacy analysis will become the 
comparison of all subjects in OCA population, to 
all control subjects (randomized placebo and 
historical controls) on time to liver transplant or 
death (all-cause) (see Section 13.1.2.1).  similar 
statistical methodology as specified above in 
Section 13.1.8 for supportive analyses will be 
utilized. 
The propensity score quintile will be then be used 
as the stratification factor in the stratified log rank 
test to compare groups.  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 determined based 
on a Cox regression model stratified by 
randomization strata to estimate the magnitude of 
the effect. 
In addition, the outcome events specified above in 
Section 13.1.8 will also be evaluated to compare 
all subjects in OCA population to all control 
subjects (randomized placebo and historical 
controls). 
Sensitivity analyses will be conducted limiting to 
the separate individual historical control 
databases, ie, UK-PBC Group and Global PBC 
 
 
 
Although the study is designed as a placebo-
controlled study, the DMC may recommend 
changes to study conduct based on the pre-
specified interim analyses (see Section 13.1.12), 
including the potential use of a revised primary 
efficacy analysis.  This analysis would compare 
all subjects in the OCA population, to all control 
subjects (randomized placebo and historical 
controls) on time to liver transplant or death (all-
cause), using similar statistical methodology as 
specified above. 
Notably, the planned primary analysis would 
not be revised without prior agreement with 
regulatory authorities. 
 
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Study Group.  To evaluate the robustness of the 
propensity score estimations, additional algorithms 
and factors may be considered. 
Section 13.1.9  
Handling of 
Dropouts or 
Missing Data 
Insertion 
In addition, the same analyses for primary and 
key secondary endpoints based on ITT and PP 
populations will be performed to assess 
robustness of analysis results. During the 
conduct of the study, the DMC may 
recommend refining the missing data strategy 
to better address the observed pattern of 
missing data, based on blinded monitoring of 
the data. 
Clarification of statistical 
analyses to address missing 
data. 
Section 13.1.11  
Examination of 
Subgroups 
The primary and secondary efficacy endpoints will 
be analyzed for subject subgroups (eg, age, sex, 
and race) based on the ITT population.  
 
Insertion 
The primary and secondary efficacy endpoints 
will be analyzed for subject subgroups based on 
the ITT population.  
 
The primary efficacy endpoint will also be 
assessed across the spectrum of PBC disease 
stage as defined by Rotterdam criteria 
(Kuiper 2009)  
• 
Early (normal albumin and normal 
bilirubin) 
• 
Moderate (abnormal albumin or 
abnormal bilirubin) 
• 
Advanced (abnormal albumin and 
abnormal bilirubin) 
The primary efficacy endpoint will also be 
assessed for the following clinically relevant 
subpopulations. 
• 
Monotherapy in patients who are 
intolerant or non-responsive to UDCA  
• 
Elderly patients 
Assuming a strong correlation between 
biochemistry and clinical outcomes using the 
 
 
 
Added per Regulatory 
Authority request. 
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total study population (Section 13.1.5.1) is 
observed, we will further assess the 
biochemical improvement in relevant 
subpopulations as applicable (eg, Rotterdam 
disease severity and monotherapy) and 
estimate the reduction in risk of clinical 
outcomes associated with the biochemical 
improvement. 
Additional details regarding statistical 
methods and subgroup definitions will be 
provided in the SAP. 
Section 13.1.12  
Continuous 
Monitoring and 
Interim Analyses 
Insertion 
13.1.12 Continuous Monitoring and Interim 
Analyses  
Blinded safety reports including the accrual of 
events, drop outs, and/or loss of subjects to 
commercially available OCA will be reviewed 
by the DMC on a regular basis.  
Two planned interim analyses of the liver-
related outcomes will be conducted using the 
Lan-DeMets O’Brien-Fleming boundaries 
(Reboussin 2000).  Both interim analyses will 
be pre-specified and will occur after accrual of 
50% (64 events) and 75% (96 events) of 
clinical outcome events, respectively.  
The DMC will review the available efficacy 
data in conjunction with detailed safety data 
and other relevant information to recommend 
continuation, modification, or cessation (for 
efficacy) of the study beyond each interim 
analysis.  Modification of the study would not 
take place without prior agreement with 
regulatory authorities. 
Two Interim Analyses have 
been added to the protocol. 
Section 19  
List of References  
Insertion 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
Additional relevant references 
were added. 
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Revised Text (Version 4, 10 May 2017) 
Justification for Change 
‘cirrhosis’ to ‘cholangitis’. Digestive and Liver 
Disease. 2015a;47(11):924-6. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
‘cirrhosis’ to ‘cholangitis’. Gastroenterology. 
2015b;149(6):1627-9. 
Beuers U, Gershwin M, Gish R, et al. 
Changing nomenclature for PBC: From 
'cirrhosis' to 'cholangitis'. Hepatology. 
2015c;62(5):1620-2. 
Lin DY, Fleming TR, De Gruttola V.  
Estimating the proportion of treatment effect 
explained by a surrogate marker.  Statistics in 
Medicine.  1997;16(13):1515-1527. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-
ethyl-chenodeoxycholic acid (6-ECDCA), a 
potent and selective FXR agonist endowed 
with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-3572. 
Reboussin DM, DeMets, DL, Kim KM, et al.  
Computations for Group Sequential 
Boundaries Using the Lan-DeMets Spending 
Function Method.  Controlled Clin Trials.  
2000;21(3):190-207. 
Appendix A 
Modified Dosing 
Regimen for 
Subjects with 
Child-Pugh B or C 
Hepatic 
Impairment 
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5 mg 
OCA or matching placebo once daily, based on 
tolerability. 
Subjects classified as Child-Pugh Class B should 
eventually titrate to a maximum dose of 5 mg 
OCA or matching placebo once daily, based on 
tolerability and biochemical response. 
Rationale 9 
Appendix B  
This Appendix with the following information 
has been deleted. 
 
 
Redundant; Information is 
contained within the protocol. 
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List of Study 747-
302 Outcome 
Events 
Several of the specified clinical endpoints will also 
by definition (see 12.1) 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 12.1.4).  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 
Appendix C 
Reference 
Laboratory Values 
from Central 
Laboratories 
Insertion (new appendix) 
Appendix containing reference laboratory 
values from central laboratories added. 
Added per Regulatory 
Authority request. 
 
 
 
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APPENDIX J. SUMMARY OF CHANGES:  PROTOCOL VERSION 4 TO PROTOCOL VERSION 5 
(DATED 04 JAN 2018) 
Rationale 
Protocol 747-302 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 United States Package Insert dosing 
guidelines.  Titration is now only based on tolerability and not CP score. 
• 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 diagnosed 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 5.  Revised and new text in Version 5 is indicated in bold 
font, and the text deleted from Protocol Version 4 is crossed out in the table below.  Minor/editorial changes are not listed 
individually in the summary table below.  Section numbers and names in column 1 refer to protocol Version 5 unless otherwise 
noted. 
Section 
Original Text (Amendment 4, 10 May 2017) 
Revised Text (Version 5, 04 Jan 2018) 
Justification for Change 
Sponsor’s 
approval 
 PhD 
 Clinical Development 
Intercept Pharmaceuticals, Inc. 
 PhD 
 Clinical Development 
Intercept Pharmaceuticals, Inc. 
Change in title 
Study Personnel 
Contact 
Information 
Contact: 
 MD, Medical Director, 
Drug Safety,  
Intercept Pharmaceuticals 
Mobile: 
 (Pacific time zone) 
Telephone: 
 
Email: 
 
Primary Contact: 
 MD, MPH| 
Senior Medical Director / Medical Affairs 
Syneos Health | Chapel Hill, NC 27514 |U.S.A. 
Tel: 
 Mobile: 
 
 
 
Secondary Contact: 
 DO, MSPH  
Senior Medical Director  
Intercept Pharmaceuticals, Inc. (Intercept) 
 
Updated medical monitoring 
contact information 
Synopsis, Phase 
of Development  
 
Phase 4:   
 
Phase 4:  US, Canada, and the EU 
Phase 3b:  All other regions 
Clarified that the phase of 
the study has been changed 
from “3b” to “4” to reflect 
that this is a post-marketing 
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. 
Synopsis, 
Methodology,  
 
…Subjects classified as Child-Pugh Class B 
should eventually titrate to a maximum dose of 5-
mg OCA or matching placebo once daily, based 
on tolerability and biochemical response.  
Subjects classified as Child-Pugh Class C should 
Subjects classified as Child-Pugh Class B or Child-
Pugh Class C should titrate to a maximum dose and 
frequency of 10 mg OCA or matching placebo twice 
weekly (at least 3 days apart), based on tolerability 
and biochemical response. 
To align with label, 
maximum dose for Child-
Pugh B or C subjects is 10 
mg OCA twice weekly. 
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PPD
PPD
PPD
PPD
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PPD
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titrate to a maximum dose and frequency of 10 
mg OCA or matching placebo twice weekly, 
based on tolerability and biochemical response 
Synopsis, 
Methodology, 
Table -Planned 
Dosing Regimen 
by Cirrhosis and 
Child-Pugh Score, 
Section 7.3, 
Planned Dosing 
Regimen, Table 3 
 
 
 
a Starting dose based on subject’s cirrhosis status 
and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the 
titration of dose and/or frequency is dependent on 
subject tolerability, biochemical response, and/or 
changes in cirrhosis status or Child-Pugh Score at 
any time during the study 
c Dosing per the twice weekly schedule must be at 
least 3 days apart 
Titration #3 is no longer 
applicable to study.  To 
align with label, maximum 
dose for Child-Pugh B or C 
subjects is 10 mg OCA 
twice weekly. 
Synopsis, Criteria 
for Evaluation; 
Secondary 
Objectives 
Safety and tolerability 
Including the 
following: 
Treatment-emergent 
adverse events Clinical 
laboratory values 
Safety and tolerability 
Including the following: 
Treatment-emergent 
adverse events including 
adverse events of special 
interest 
Clinical laboratory values 
Per FDA request 
Synopsis, 
Statistical 
Methods, Safety 
Analysis,  
Safety data, including AEs, vitals, 
electrocardiogram 
Safety data, including AEs, AEs of special interest 
including pruritus and hepatic safety, vitals, 
electrocardiogram… 
Per FDA request 
Section 5.1, 
Overview of 
Primary Biliary 
Cholangitis and 
Obeticholic Acid 
In December 2016, the European Commission 
granted conditional approval for Ocaliva for the 
same indication 
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 747-302 is 
considered a Phase 4 study in regions where OCA 
has received regulatory approval for PBC (ie, in 
Clarified that the phase of 
the study has been changed 
from “3b” to “4” to reflect 
that this is a post-marketing 
study in regions where OCA 
has received regulatory 
approval for PBC, ie, in the 
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the US, Canada, and the EU).  In all other 
regions, this study is considered Phase 3b 
US, Canada, and the EU.  In 
all other regions, this study 
is considered Phase 3b 
Section 5.4, 
Clinical 
Experience with 
Obeticholic Acid 
As of 31 Jan 2017, approximately 2186 subjects 
have received at least 1 dose of OCA.  Of these, 
844 were healthy volunteers, 525 subjects had 
PBC, 686 subjects had NASH, 41 subjects had 
diabetes mellitus/nonalcoholic fatty liver disease, 
33 subjects had alcoholic cirrhosis/portal 
hypertension, and 52 subjects had primary 
sclerosing cholangitis, and 5 subjects 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 subjects had PBC, 1141 
subjects had NASH, 41 subjects had diabetes 
mellitus/nonalcoholic fatty liver disease, 33 subjects 
had alcoholic cirrhosis/portal hypertension, and 73 
subjects had primary sclerosing cholangitis, and 6 
subjects had biliary atresia 
Updated number of subjects 
exposed to OCA 
Section 5.6, 
Importance of 
Monitoring of 
Disease 
Progression 
 
Insertion 
Given PBC is a chronic, progressive liver disease, 
it is important that subjects with PBC are closely 
monitored to ensure early identification of 
potential disease progression to cirrhosis, 
decompensation and/or liver injury.  More 
extensive safety monitoring and appropriate 
dosing adjustments, interruptions, and 
discontinuations will be implemented to improve 
subject oversight and safety.  Investigators, 
together with the Sponsor’s Medical Monitor, will 
consistently and frequently assess individual 
subjects to determine on an ongoing basis the 
totality of a subject’s clinical profile, which 
includes careful evaluation of signs and symptoms 
of potential hepatic injury and/or decompensation 
coupled with rules based laboratory monitoring. 
Subjects will be monitored for potential hepatic 
injury and/or decompensation and progression to 
cirrhosis (Section 7.5).  Criteria for implementing 
dosing adjustments, interruptions, or 
discontinuations, and close monitoring 
procedures postdose-adjustment are described in 
Section 7.6 and Section 7.7.  The more extensive 
monitoring is important given the elevated risk of 
Per FDA response 
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decompensation and potential for higher hepatic 
exposure to OCA in this population. 
Section 5.7, 
Summary of 
Known Potential 
Risks with OCA 
 
…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, but with a much lower 
frequency than that observed in subjects 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 subjects 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 (HDL) and an increase in low 
density lipoprotein (LDL).  Notably, in subjects 
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, 
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.  
One case was reported in a subject with no 
evidence of cirrhosis at baseline, while the second 
case was reported in a subject with cirrhosis and 
hepatic impairment at baseline.  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) 
Per FDA Response 
Updated section to include 
SUSARS 
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decreases in total cholesterol were observed in 
subjects with PBC, while LDLc concentrations 
remained comparable to baseline and placebo in 
OCA treated subjects with the exception of a 
modest transient and early rise after initiation of 
treatment.   
Refer to the Investigator’s Brochure (IB) for 
additional information regarding the known 
potential risks with the investigational product. 
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 
providing further support for the lack of safety 
concern and positive benefit-risk profile of OCA. 
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. 
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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 
Table 1, Schedule 
of Procedures, 
Screening to 
Month 12 
Insertion 
Added column for M2 and following procedures 
at the visit 
• 
Physical Exam 
• 
Child-Pugh Assessment  
• 
Adverse Events 
• 
Prior/Concomitant Medications 
• 
IP accountability/Compliance 
• 
Dosing Diary 
• 
Chemistry/Hematology/Coagulation 
• 
Review Progression to Cirrhosis 
Algorithm 
Added to satisfy 
requirement for monthly 
visits following any titration 
1-Month Post-Titration Visit 
Post-Titration Visits 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12; and 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study 
Insertions 
Added the following procedures 
• 
Gallbladder Assessment (Table 1 only) 
• 
Amylase and Lipase (if subject 
experiences acute pancreatitis or 
cholecystitis) 
• 
Review Progression to Cirrhosis 
Algorithm   
Added per FDA request 
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Table 1, Schedule 
of Events, 
Screening to 
Month 12; and 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study 
• 
Assessments for Mayo Risk Score 
• 
DEXA 
• 
Blood samples for future analysis 
 
Central lab will calculate 
value 
 
Procedures deleted to 
streamline collection of 
laboratory samples 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
footnote b 
Post-Titration visits must be performed 1 month 
(+ 1 week) after any up-titration in dose and/or 
frequency in subjects following modified dosing 
due to Child Pugh B and Child-Pugh C hepatic 
impairment.  In subjects following the standard 
dosing regimen, the post-titration visit must be 
performed only after the first up titration to 10 
mg OCA or matching placebo, or after ≥3 months 
at a decreased dose or frequency. 
Post-Titration visits must be performed 1 month (+ 1 
week) and 2 months (+1 week) after any up-titration 
in dose and/or frequency in subjects following 
modified dosing due to Child Pugh B and Child-
Pugh C hepatic impairment.  See Appendix A for 
additional guidance.  In subjects following the 
standard dosing regimen, the post-titration visit must 
be performed 1 month (+ 1 week) and 2 months 
(+1 week) only after the first up titration to 10 mg 
OCA or matching placebo. 
Added to satisfy 
requirement for monthly 
visits following any titration 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
previous footnote 
f 
Mayo Risk Score will be calculated based on 
central laboratory evaluations, diuretic use data, 
and peripheral edema assessment data captured in 
the eCRF. 
Deletion 
MRS score will be 
calculated by central lab. 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
footnote k 
DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available.  Please refer to Section 9.7.7 for 
additional information related to the allowed 
windows at Day 0 for this procedure 
Deleted 
Procedures deleted to 
streamline collection of 
laboratory samples 
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Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
footnote k 
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. 
Ultrasound will be conducted to enhance HCC 
surveillance and for gallbladder assessment at 
Screening.  If ultrasound was not performed at 
Screening and the historic ultrasound is >3 
months from Day 0, perform a hepatobiliary 
ultrasound at the Day 0 visit. 
Agreement with FDA to 
perform gallbladder 
assessments at screening. 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
footnote p 
The subject 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. 
The subject 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.  MELD and MRS values will be 
calculated based on serum chemistry and 
coagulation values at each visit. 
MELD and MRS removed 
as line items.   Central lab 
will calculate these values. 
Table 1, Schedule 
of Study 
Procedures, 
Screening to 
Month 12, 
footnote l, Table 
1, footnote w 
Please refer to Section 11.1.2.3 for description of 
the blood sample to be collected for future 
analysis 
Deletion 
Procedures deleted to 
streamline collection of 
laboratory samples 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study 
Column header: 
1-Month Post-Titration Visita,  
 
Post-Titration Visitsa 
Added to satisfy 
requirement for monthly 
visits following any 
titration, requirement to 
assess Child-Pugh at every 
visit. 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study 
Assessment for Mayo Risk Scoree 
DEXA 
Blood Sample for Future Analysis 
Deletion 
MRS score will be 
calculated by central lab. 
Table 2, Schedule 
of Study 
Visit Windows (+/-)c 
Year 2 Through End of 
Study 
Visit Windows (+/-)c 
Year 2 Through End of 
Study 
Added per FDA  
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Procedures Year 2 
Through End of 
Study 
Insertion 
 
Amylase and Lipase 
Sample to be collected if 
the subject experiences 
acute pancreatitis or 
cholecystitis 
Review Progression to 
Cirrhosis Algorithm   
 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote a 
In subjects following the standard dosing 
regimen, the post-titration visit must be 
performed only after the first up-titration to 10 
mg OCA or matching placebo, or after ≥3 months 
at a decreased dose or frequency.  Post-titration 
visits must be performed 1 month ± 1 week after 
any up-titration in dose and/or frequency in 
subjects following modified dosing due to Child-
Pugh B and Child-Pugh C hepatic impairment.   
Post-Titration Visits must be performed 1 month 
(±1 week) and 2 months (±1 week) after any up-
titration in dose and/or frequency in subjects 
following modified dosing due to Child-Pugh B and 
Child-Pugh C hepatic impairment.  See Appendix A 
for additional guidance.  In subjects following the 
standard dosing regimen, the Post-Titration visit 
must only be performed 1 month (±1 week) and 2 
months (±1 week) after the first up-titration to 10 
mg OCA or matching placebo. 
Added to satisfy 
requirement for monthly 
visits following any 
titration, requirement to 
assess Child-Pugh at every 
visit. 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote e 
Mayo Risk Score will be calculated based on 
central laboratory evaluations, diuretic use data, 
and peripheral edema assessment data captured in 
the CRF 
 
MRS score will be 
calculated by central lab 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote g 
Height will be collected at this visit 
 
 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote j 
DEXA will be conducted at 12-month intervals at 
all study sites where the DEXA device is 
available 
 
Procedure deleted 
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Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote m 
The subject 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. 
The subject 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.  MELD and MRS values will be 
calculated based on serum chemistry values at 
each visit. 
MELD and MRS removed 
as line items.   Central lab 
will calculate these values. 
Table 2, Schedule 
of Study 
Procedures Year 2 
Through End of 
Study, footnote s 
Please refer to Section  for description of the 
blood sample to be collected for future analysis 
 
Procedure deleted 
Section 7.3, 
Planned Dosing 
Regimen 
Insertion 
Non-Cirrhotic or Child-Pugh A 
… 
Cirrhotic or Child-Pugh B or C 
Subjects with cirrhosis (see Section 7.5.4 ) and 
classified as Child-Pugh Class B or Child-Pugh 
Class C will follow a modified dosing regimen, 
initiating 5 mg OCA or matching placebo once 
weekly.  After a minimum of 3 months dosing 
once weekly with 5 mg OCA or matching placebo, 
and following review of the pre-titration 
laboratory results to assess safety and tolerability, 
the dosing frequency of 5 mg OCA or matching 
placebo should be increased to twice weekly (at 
least 3 days apart).  Subjects who have 
maintained the twice weekly dosing frequency for 
a minimum of at least 6 weeks, and meet the dose 
titration criteria should up-titrate to the 
maximum allowed dose of 10 mg OCA or 
matching placebo twice weekly. 
Investigators may decrease the dosing frequency 
(back to once weekly) or dose for any subject at 
any time during the study, as considered clinically 
appropriate (eg, tolerability).     
The dosing regimen should be determined as 
described shown in Table 13  Appendix A.  
Heading and text added for 
additional clarity. 
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Investigators should follow the dosing/titration 
schedule as shown described in Section 7.4 and 
Appendix A. 
Section 7.3, 
Planned Dosing 
Regimen, Table 3 
 
 
To align with label, 
maximum dose for Child-
Pugh B or C subjects is 10 
mg OCA twice weekly. 
Section 7.3, 
Planned Dosing 
Regimen, Table 4 
 
Table deleted 
To align with label, 
maximum dose for Child-
Pugh B or C subjects is 10 
mg OCA twice weekly. 
Section 7.4, Dose 
Titration Criteria 
...  Up-titrations may only occur to the maximum 
dose and frequency for each dosing regimen as 
defined in Section 7.3.   
...  Up-titrations may only occur to the maximum 
dose and frequency for each dosing regimen as 
defined in Section 7.3.  A 1-Month and 2 Month 
Post-Titration Assessment must be performed 
any time a subject’s dose or frequency is up-
titrated (see Section 7.1.2 and Section 9.7.7). 
Clarify dosing assessments. 
Section 7.4, Dose 
Titration Criteria, 
Dose Titration 
due to Change in 
Cirrhosis or 
Child-Pugh Score 
Changes to the dosing regimen are not 
mandatory and should be based on clinical 
judgment as well as change in cirrhosis status.   
provides an overview of the possible changes in 
dosing regimen due to changes in cirrhosis or 
Child-Pugh Score. 
...  Changes in Child-Pugh Score that result from 
a transient, explainable change in laboratory 
parameters should be documented appropriately 
…Changes in Child-Pugh Score that result from a 
transient, explainable change in laboratory 
parameters should be documented 
appropriately, and should not necessarily result 
in a change to the dosing regimen 
 
...  Changes in Child-Pugh Score that result from a 
transient, explainable change in laboratory 
parameters (eg, increase in vitamin K resulting in 
Clarify that changes in CP 
scores should be discussed 
with medical monitor. 
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and should not necessarily result in a change to 
the dosing regimen 
 
 
Subjects who demonstrate an improvement in 
cirrhosis status or in Child-Pugh Score from B to 
A, or from Child-Pugh C to B, may be eligible to 
transition to the standard dosing regimen or the 
modified dosing for Child-Pugh B, respectively, 
based on tolerability.  Prior to any dosing 
change, subjects must meet pre-titration 
assessment requirements for dosing as described 
in Section . 
Child-Pugh Scores will be calculated at all 
quarterly study visits 
 
change in INR) should be documented 
appropriately and discussed with the Medical 
Monitor before any continuation or change to the 
dosing regimen 
 
 
 
 
 
 
Child-Pugh Scores will be calculated during 
screening, at each scheduled study visits, and at 
unscheduled visits in the event of signs or 
symptoms of suspected hepatic injury or 
decompensation are present. 
Section 7.4.1, Pre-
Titration 
Tolerability 
Assessment 
Requirements 
Safety laboratory results obtained at the Month 1 
visit (for titration at Month 3) or at the 1 Month 
Post- Titration Assessment visit (for titration 
prior to or at the subsequent quarterly visit) are… 
Safety laboratory results obtained at the visit (for 
titration at Month 3) or at the Post- Titration 
Assessment visits (for titration prior to or at the 
subsequent quarterly visit) are… 
Added to satisfy 
requirement for monthly 
visits following any titration 
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Section 7.5, 
Monitoring and 
Management of 
Potential Hepatic 
Injury and/or 
Disease 
Progression 
Insertion 
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 (Table 1).  Child Pugh Scores should 
only be applied in patients who demonstrate 
progression to cirrhosis based on criteria 
presented in Section 7.5.4.  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 the 
assessments of signs and symptoms of hepatic 
injury and liver biochemistry, the investigational 
product may be interrupted or discontinued per 
criteria discussed in Section 7.5.2 and Section 
7.5.3, and close monitoring procedures will be 
implemented (Section 7.7). 
Per FDA response, language 
added to provide guidance 
for monitoring disease 
progression due to potential 
hepatic decompensation. 
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Section 7.5.1, 
Signs and 
Symptoms of 
Hepatic Injury or 
Decompensation 
Insertion 
7.5.1. 
Signs and Symptoms of Hepatic Injury or 
Decompensation 
Subjects 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 subject 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 
 
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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 7.5.2), (2) 
assessment of clinical events for potential hepatic 
decompensation (Section 7.5 (3) triggering of 
investigational product interruption or 
discontinuation per criteria (Section 8.4 ), (4) 
documentation in the AE eCRF or the SAE 
eCRFs (Section 12.1.5.1 and Section 12.1.5.2), and 
(5) contact with the Medical Monitor. 
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Section 7.5.2, 
Liver 
Biochemistry 
Assessments for 
Suspected Hepatic 
Injury or Potential 
Hepatic 
Decompensation 
Insertion 
Liver biochemistry will be assessed to evaluate 
biochemical triggers that will prompt an 
immediate reevaluation of subjects for potential 
hepatic injury or hepatic decompensation.  These 
assessments will be performed at: 
• Each protocol-specified visit 
• 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 subject 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 subject 
evaluation (depending on the repeat result) are 
summarized in Table 5. 
Figure 2:  DILI Management Algorithm. 
Table 5: Liver Laboratory Criteria for 
Monitoring of Suspected Hepatic Injury or 
Potential Hepatic Decompensation and Criteria 
for Interruption or Discontinuation of 
Investigational Product. 
It should be noted that it is difficult to recognize 
every potential marker of hepatic or renal 
deterioration.  There is no substitute for good 
Per FDA response, added to 
provide guidance for 
monitoring disease 
progression due to potential 
hepatic decompensation 
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medical judgment.  Investigators will be reminded 
to be cautious and mindful in their evaluation of 
subjects’ 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. 
Section 7.5.3, 
Clinical Criteria 
for Monitoring for 
Potential Hepatic 
Decompensation 
Events 
Insertion 
Subjects will be monitored for potential hepatic 
decompensation events throughout the study.  
Clinical criteria for the monitoring these events 
and the interruption/discontinuation of 
investigational product is summarized in Table 6. 
Investigational product should be discontinued 
permanently if the subject received a liver 
transplant or experiences multi-organ failure as 
defined in Table 6, Part A).  Subjects should 
continue to return for scheduled study visits for 
safety follow up.  
Subjects who experience other potential hepatic 
decompensation events defined in Table 6, Part B 
should be closely monitored until normalization 
or stabilization.  Subjects may be rechallenged 
after a minimum of 30 days if fully resolved OR 
stable and approved by the Medical Monitor and 
Investigator. 
Table 6: Criteria for Monitoring Potential Hepatic 
Decompensation Events and Interruption / 
Discontinuation of Investigational Product 
Per FDA response, added to 
provide guidance for 
monitoring disease 
progression due to potential 
hepatic decompensation 
Section 7.5.4, 
Assessing 
Cirrhosis 
  
Section and subsections were moved from previous 
Section 9.7.3 and subsections. 
Content moved as it 
supports new content 
described above. 
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Revised Text (Version 5, 04 Jan 2018) 
Justification for Change 
Section 7.5.5, 
Child-Pugh Score 
 
Section was moved from previous Section 9.7.4. 
Section 7.5.5.1, 
Mayo Risk Score 
 
Section was moved from previous Section 9.7.5. 
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Section 7.6, Dose 
Adjustment, 
Interruption, and 
Withdrawal from 
Investigational 
Product or Study 
Insertion 
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 8), investigational 
product should be initiated at a lower dose and 
subjects 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 
8.  Subjects that 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 terminate at 
the time when the needed number of adjudicated 
events has accrued.  If a subject reaches an 
outcome event, he or she should continue the 
regular visit schedule and continue taking 
investigational product as long as the subject has 
not met any of the criteria for mandatory 
interruption of investigational product outlined in 
Table 8, and the Investigator assesses it as safe.  
In general, subjects should be strongly 
encouraged to both stay on investigational 
product and remain in the study until study 
termination. 
Table 8: Criteria for Dose Adjustment, 
Interruption, Discontinuation and Rechallenge. 
Per FDA response, added to 
provide guidance for 
monitoring disease 
progression due to potential 
hepatic decompensation 
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Section 7.7, Close 
Observation 
Insertion 
If investigational product is interrupted or 
discontinued as described in Section 7.6, subjects 
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 subject 
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 subject 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 
subject 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 7.5.1, Section 7.5.2, and 
Section 7.5.3.  These cases need to be discussed 
with the Sponsor's medical monitor: 
• 
Repeating liver enzyme and serum bilirubin 
tests as described in Section 7.5.2.  Frequency 
of retesting can decrease to once a week or 
less if abnormalities stabilize or the study 
drug has been discontinued and the subject is 
asymptomatic, as clinically indicated.  
Per FDA response, added to 
provide guidance for 
monitoring disease 
progression due to potential 
hepatic decompensation 
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• 
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 product should be discussed 
with the Sponsor's medical monitor.  The 
subject 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 (HEV) when assessing for 
hepatic decompensation as infection with 
HEV 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 
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Section 8.4. 
Subject 
Withdrawal 
Criteria 
Investigational product may be temporarily 
decreased (eg, from 10 mg to 5 mg daily, or by 
decreasing dosing frequency) or temporarily or 
permanently stopped based on tolerability 
concerns.  The dose of investigational product 
should be adjusted back to the maintenance dose 
in a blinded manner once the issues relating to the 
lack of tolerability are resolved.   
Subjects that 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 when the needed number of adjudicated 
events has accrued.  If a subject reaches an 
outcome event, he or she should continue the 
regular visit schedule and continue taking 
investigational product as long as the subject has 
not met any of the criteria for mandatory 
interruption of investigational product outlined in 
Section 8.4.1, and the Investigator assesses it as 
safe.  In general, subjects should be strongly 
encouraged to both stay on investigational 
product and remain in the study until study 
termination. 
Subjects can be discontinued from investigational 
product by the Investigator at any time for 
clinical safety concerns.  Subjects who are 
discontinued from investigational product are 
expected to continue in the study and should follow 
the regular visit schedule for the duration of the 
study.  See Section 7.6 for withdrawal criteria 
related to potential hepatic injury and/or 
decompensation; including liver transplantation 
or multi-organ failure.  Other reasons, including 
withdrawal of consent or lost to follow-up, are 
described in Section 8.4.1 below. 
 
Section updated to conform 
with FDA response. 
Previous Section 
8.4.1.1, Reasons 
for Additional 
Monitoring 
Related to Liver 
Chemistries 
(Version 4) 
Subjects 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.  Subjects with persistent 
elevations (eg, additional lab testing per 
Investigator discretion) should be closely 
monitored.  Concomitant elevations in total 
bilirubin or international normalized ratio (INR) 
with persistent increases in ALT or AST should 
also be closely monitored 
 
Replaced with updated DILI 
text in Section 7.5. 
Previous Section 
8.4.1.2, Reasons 
for Investigational 
Development of any of the following clinical 
laboratory values, without explanation, during the 
 
Replaced with updated DILI 
text in Section 7.5. 
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Product 
Interruption 
Related to 
Elevated Liver 
Chemistries 
(Version 4) 
study mandates investigational product 
interruption: 
• 
AST and/or ALT >3x baseline (and >ULN) 
• 
Total bilirubin >2x 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 AE information should also be collected 
and the subject 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 >3x baseline (and >ULN) or total 
bilirubin >2x baseline (and >ULN), subjects 
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 
study medication and no other cause for the 
elevation is identified, it may be assumed that the 
elevations were due to disease progression and 
the subject may be re-challenged following a 
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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. 
If at any time a subject 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.  
Subjects who develop evidence of severe drug-
induced liver injury, which 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, 
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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 subjects 
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 subject to 
continue treatment.  In the event the 
investigational product is required to be 
discontinued, subjects should be encouraged to 
continue study visits for continued data collection 
but may withdraw consent at any time.  
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 13.4) 
Previous Section 
8.4.1.3,Pregnancy 
(Version 4) 
If a female subject becomes pregnant, she must 
interrupt treatment with investigational product 
immediately, but should continue with the study 
visit schedule.  As described in Section 12.1.11 
pregnancy is not considered an AE for reporting 
purposes.  The subject may re-start 
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 
12.1.11. 
 
Addressed in Table 8 in 
Section 7.6. 
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Previous Section 
8.4.2.1, Liver 
Transplantation 
(Version 4) 
Subjects who undergo a liver transplant during 
the course of the study must discontinue 
investigational product and discontinue the study 
visit schedule.  However, these subjects 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 discussed in Table 8 in 
Section 7.6 
Section 9.7.1, 
Visit Windows 
Post-Titration Visit: 1 month (+1week [7 days]) 
from date of titration or after ≥3 months at a 
decreased dose or frequency   
Post-Titration Visit: 1 month and 2 months 
(±1week [7 days]) from date of titration   
Added to satisfy 
requirement for monthly 
visits following any titration 
Previous 9.7.3, 
Assessing 
Cirrhosis (Version 
4) 
 
Section and subsections were moved to earlier in the 
document (7.5.4 and subsections). 
Content moved. 
Section 9.7.3, 
Screening 
Procedures (1 to 8 
Weeks prior to 
Day 0) 
… 
• 
Perform assessment for calculation of 
Mayo Risk Score 
• 
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 
Visit 2, and a report/adequate data are 
available, a pretreatment ultrasound at 
Screening Visit 2 is not required.  …  
Results from the screening ultrasound 
should be reviewed to assess possible 
exclusion criteria prior to 
randomization. 
• 
Record current concomitant 
medications 
• 
In preparation for the dual-emission X-
ray absorptiometry (DEXA) bone 
… 
• 
Perform an ultrasound for HCC surveillance and 
gallbladder assessment (if equipment is 
unavailable, sites should make every attempt to 
use available community referral sites).  If an 
ultrasound has been done within 3 months of the 
planned Day 0 visit, and a report/adequate data 
are available, a pretreatment ultrasound is not 
required.  …  Results from the screening 
ultrasound must be reviewed to assess possible 
exclusion criteria, prior to randomization. 
• 
Review and record prior and concomitant 
medications 
Agreement with FDA to 
perform gallbladder 
assessments at screening.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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density scan to be done at Day 0 (at all 
study sites where the device is 
available), subjects who are taking 
calcium supplements should stop taking 
them for 48 hours before the scan.  If 
the subject is taking any medications for 
osteoporosis or osteopenia, s/he should 
not take them on the day of the scan. 
DEXA removed to 
streamline laboratory 
procedures. 
Previous Section 
9.7.4, Child-Pugh 
Score (Version 4) 
 
Section was moved to earlier in the document (7.5.5). 
Content moved. 
Section 9.7.4, Day 
0 Procedures 
(Randomization) 
…  
Conduct a DEXA bone density scan (at all study 
sites where the device is available); document 
whether the subject stopped taking her/his 
calcium supplements for 48 hours before the 
scan and medications for osteoporosis or 
osteopenia on the day of the scan, if 
applicable.  If DEXA has been done within 12 
months of Day 0 and a report/adequate data 
are available, a pretreatment DEXA at Day 0 is 
not required. If the DEXA cannot be 
performed on Day 0 (eg, device/technician 
unavailability, scheduling issues, etc), the 
procedure may be completed within the 
screening visit window, as close as possible to 
the Day 0 visit, preferably, after subject 
eligibility has been confirmed. 
… 
• 
Obtain blood samples for:  
− 
OCA, C4, and fibroblast growth factor-
19 (FGF-19) 
… 
• If hepatobiliary ultrasound for HCC screening 
and gallbladder assessment was not performed 
at Screening and the historic ultrasound is >3 
months from Day 1, perform a hepatobiliary 
ultrasound. 
… 
 
 
 
 
 
 
 
 
 
Obtain blood samples for:  
− 
OCA, C4, and fibroblast growth factor-19 
(FGF-19) 
Per FDA request 
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− 
Markers of hepatic fibrosis and/or 
inflammation (including enhanced liver 
fibrosis [ELF]) 
− 
Genetics (see Section 11.1.2.3) 
− 
Blood sample for future analysis (refer 
to Section 11.1.2.3)  
 
− 
Markers of hepatic fibrosis and/or 
inflammation (including enhanced liver 
fibrosis [ELF]) 
− 
Genetics (see Section 11.1.2.3) 
• Perform assessments for calculation of 
Child-Pugh Score 
Previous Section 
9.7.5, Mayo Risk 
Score (Version 4) 
 
Section was moved to earlier in the document 
(7.5.5.1). 
Content moved. 
Section 9.7.5, 
Months 1, 2 
Procedures 
... 
• 
Review and record concomitant medications. 
… 
 
 
 
 
 
In the event it is not feasible for the subject to 
return to the site for the above referenced 
procedures, the following alternative visit 
procedures are available to help ensure 
compliance with the Month 1 visit laboratory 
requirements: 
-At the Day 0 visit, the subject can be provided 
with the central laboratory collection kit and 
shipping materials associated with the Month 1 
visit, and have the laboratory specimen collection 
performed at his or her local doctor’s office or 
designated laboratory collection center.  The 
subject must also be contacted via telephone at 
the Month 1 visit timepoint to assess AEs, review 
concomitant medications, and assess 
investigational product compliance;  
... 
• 
Review and record prior and concomitant 
medications. 
… 
• 
Perform assessments for calculation of Child-
Pugh Score. 
• 
Review progression to cirrhosis algorithm. 
… 
In the event it is not feasible for the subject to return 
to the site for the above referenced procedures, the 
following alternative visit procedures are available to 
help ensure compliance with the Month 1 and 
Month 2 visit laboratory requirements: 
-At the Day 0 visit, the subject can be provided with 
the central laboratory collection kit and shipping 
materials associated with the Month 1 visit, and have 
the laboratory specimen collection performed at his 
or her local doctor’s office or designated laboratory 
collection center.  The subject must also be contacted 
via telephone at the visit timepoint to assess AEs, 
review concomitant medications, and assess 
investigational product compliance;  
-If all other options for the collection of the Month 1 
and Month 2 laboratory samples have been 
Month 2 added to section 
satisfy requirement for 
monthly visits following 
any titration and assess CP 
score per FDA request. 
 
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-If all other options for the collection of the 
Month 1 laboratory samples have been exhausted, 
the use of a local laboratory for the Month 1 
samples would be accepted for this visit; 
although, any laboratory data obtained from a 
local laboratory will not be captured in the eCRF 
or included in the study analysis.  A copy of the 
local laboratory report would need to be provided 
to the Investigator for review and available in the 
source records.  The subject must also be 
contacted via telephone at the Month 1 visit 
timepoint to assess AEs, review concomitant 
medications, and assess investigational product 
compliance;  
-A physical examination should be performed at 
the Month 3 visit if an onsite Month 1 visit was 
not performed. 
 
exhausted, the use of a local laboratory for the 
Month 1 samples would be accepted for this visit; 
although, any laboratory data obtained from a local 
laboratory will not be captured in the eCRF or 
included in the study analysis.  A copy of the local 
laboratory report would need to be provided to the 
Investigator for review and available in the source 
records.  The Investigator should contact the 
Medical Monitor as soon as possible to discuss 
any local laboratory values that may be of clinical 
concern.  The subject must also be contacted via 
telephone at the visit timepoint to assess AEs, review 
concomitant medications, and assess investigational 
product compliance;  
-A physical examination should be performed at the 
Month 3 visit if an onsite Month 1 or Month 2 visit 
was not performed. 
Section 9.7.6 
Month 3 
Procedures;  
Insertions. 
… 
• 
Review progression to cirrhosis algorithm 
… 
• 
Review and record prior and concomitant 
medications. 
Per FDA request 
 
Section 9.7.7, 
Post-Titration 
Visit Procedures 
… 
• 
Review and record concomitant medications. 
… 
 
 
 
 
 
If all other options for the collection of the Post-
Titration laboratory samples have been 
exhausted, the use of a local laboratory for the 
… 
• 
Review and record prior and concomitant 
medications. 
… 
• 
Perform assessments for calculation of Child-
Pugh Score. 
• 
Review progression to cirrhosis algorithm. 
… 
If all other options for the collection of the Post-
Titration laboratory samples have been exhausted, 
the use of a local laboratory for the Post-Titration 
samples would be accepted for this visit; although, 
per FDA request 
 
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Post-Titration samples would be accepted for this 
visit although any laboratory data obtained from a 
local laboratory will not be captured in the eCRF 
or included in the study analysis.  A copy of the 
local laboratory report would need to be provided 
to the investigator for review and available in the 
source records.  The subject must also be 
contacted via telephone at the Post-Titration Visit 
time point to assess AEs, review concomitant 
medications, and assess investigational product 
compliance; 
any laboratory data obtained from a local laboratory 
will not be captured in the eCRF or included in the 
study analysis.  A copy of the local laboratory report 
would need to be provided to the Investigator for 
review and available in the source records.  The 
Investigator should contact the Medical Monitor 
as soon as possible to discuss any local laboratory 
values that may be of clinical concern.  The subject 
must also be contacted via telephone at the Post-
Titration Visit timepoint to assess AEs, review 
concomitant medications, and assess investigational 
product compliance; 
Section 9.7.8, 
Month 6 
Procedures 
… 
• 
Perform assessment for calculation 
of Mayo Risk Score. 
 
… 
• 
Review and record concomitant medications. 
… 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis 
and/or inflammation (including 
ELF) 
− 
Blood sample for future 
analysis (refer to 
Section 11.1.2.2)  
… 
• 
Review progression to cirrhosis algorithm. 
… 
• 
Review and record prior and concomitant 
medications. 
… 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or 
inflammation (including ELF) 
 
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Section 9.7.9 
Month 9 
Procedures 
 
… 
 
• 
Review and record concomitant medications 
… 
• 
In preparation for the DEXA bone density 
scan to be done at the Month 12 visit (at all 
study sites where the device is available), 
subjects who are taking calcium supplements 
should stop taking them for 48 hours before 
the scan.  If the subject is taking any 
medications for osteoporosis or osteopenia, 
s/he should not take them on the day of the 
scan 
… 
• 
Review progression to cirrhosis algorithm  
• 
Review and record prior and concomitant 
medications 
… 
per FDA request. 
 
 
 
Procedure deleted. 
Section 9.7.11 
Month 12 
Procedures 
… 
Perform assessment for calculation of Mayo Risk 
Score. 
… 
• 
Conduct a DEXA bone density scan (at all 
study sites, where the device is available); 
document whether the subject stopped taking 
her/his calcium supplements for 48 hours before 
the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable 
… 
• 
Review and record concomitant medications 
… 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or 
inflammation (including ELF) 
− 
Genetics (see Section 11.1.2.3) 
Blood sample for future analysis (refer to 
Section 11.1.2.3) 
… 
• 
Perform assessments for calculation of Child-
Pugh Score 
• 
Review progression to cirrhosis algorithm 
… 
 
 
 
• 
Review and record prior and concomitant 
medications 
… 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or inflammation 
(including ELF) 
− 
Genetics (see Section 11.1.2.3) 
 
Per FDA request. 
 
Procedures deleted. 
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Section 9.7.12, 
Month 3 and 
Month 9 
Continued 
Follow-Up 
Procedures (±2 
weeks) 
Insertions 
… 
• 
Review progression to cirrhosis algorithm 
… 
• 
Review and record prior and concomitant 
medications 
 
 
Section 9.7.13, 
Month 6 
Continued 
Follow-Up 
Procedures (Semi-
annually [±2 
weeks]) 
• 
Perform assessment for calculation of Mayo 
Risk Score. 
• 
Perform assessments for calculation of 
Child-Pugh Score. 
 
 
 
… 
• 
Review and record concomitant medications 
… 
• 
Obtain blood samples for:  
− 
Markers of hepatic fibrosis 
and/or inflammation (including 
ELF). 
− 
Blood sample for future 
analysis (refer to 
Section 11.1.2.3). 
• 
At the semi-annual visit, in 
preparation for the DEXA bone 
density scan to be done at the 
annual visit (at all study sites where 
the device is available), subjects 
 
 
• 
Perform assessments for calculation of Child-
Pugh Score. 
• 
Review progression to cirrhosis algorithm  
… 
 
• 
Review and record prior and concomitant 
medications 
… 
• 
Obtain blood samples for:  
− 
Markers of hepatic fibrosis and/or 
inflammation (including ELF). 
 
per FDA request. 
 
 
Procedures deleted 
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who are taking calcium supplements 
should stop taking them for 48 
hours before the scan.  If the subject 
is taking any medications for 
osteoporosis or osteopenia, s/he 
should not take them on the day of 
the scan. 
 
Section 9.7.14, 
Month 12 
Continued 
Follow-up 
Procedures 
(Annually [±2 
weeks]) 
• 
Perform assessment for calculation of Mayo 
Risk Score 
… 
• 
Conduct a DEXA bone density scan (at all 
study sites where the device is available); 
document whether the subject stopped taking 
her/his calcium supplements for 48 hours before 
the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable. 
… 
• 
Review and record concomitant medications 
… 
• Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or 
inflammation (including ELF) 
− 
Genetics (see Section 11.1.2.3) 
− 
Blood sample for future analysis (refer to 
Section 11.1.2.3 
 
… 
• 
Review progression to cirrhosis algorithm 
… 
 
 
 
• 
Review and record prior and concomitant 
medications 
… 
• Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or inflammation 
(including ELF) 
− 
Genetics (see Section 11.1.2.3) 
 
 
per FDA request. 
 
 
Procedures deleted 
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Section 9.7.15, 
Early 
Discontinuation 
and/or Early 
Termination 
Procedures for 
Subjects that 
Withdraw from 
Investigational 
Product or 
Withdraw 
Consent 
Table 9, footnote c 
… No Additional data (e.g. AE, concomitant 
medication, etc) data will be collected, except as 
indicated in Section . 
Some assessments noted below may be omitted if 
they have been completed within the 6 months (or 
the timeframe otherwise specified) and so long as 
safety issues do not warrant repeat testing. 
… 
 
 
• 
Perform assessment for calculation of Mayo 
Risk Score 
… 
• 
Conduct a DEXA bone density scan (at all 
study sites where the device is available); 
document whether the subject stopped taking 
her/his calcium supplements for 48 hours before 
the scan and medications for osteoporosis or 
osteopenia on the day of the scan, if applicable. 
 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or 
inflammation (including ELF) 
− 
Blood sample for future analysis (refer to 
Section 11.1.2.3 
Table 9, footnote c 
…  Additional data such information on 
concurrent medical conditions, co-morbidities, 
relevant and concomitant medications may be 
collected to help facilitate adjudication of these 
post-study events.  Some assessments noted below 
may be omitted if they have been completed within 
the 6 months (or the timeframe otherwise specified) 
and so long as safety issues do not warrant repeat 
testing.   
… 
 
• 
Review progression to cirrhosis algorithm  
… 
 
 
 
 
 
 
• 
Obtain blood samples for:  
− 
OCA, C4, and FGF-19 
− 
Markers of hepatic fibrosis and/or inflammation 
(including ELF) 
 
Section 11.1.2.3, 
Other Exploratory 
Evaluations 
• 
Blood samples for future analysis of 
additional analytes, such as PBC autoantibodies 
and other cytokines and interleukins, may be 
assayed on an exploratory research basis.  Blood 
samples may also be used to assess other disease 
or investigational product characteristics.  
Appropriate serum and plasma samples will be 
collected at selected time points during the study. 
Subjects will be permitted to decline future 
Deleted 
Procedure deleted 
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analysis of blood samples without affecting their 
involvement in the study.  IRB/IEC review and 
approval will be required and willing subjects 
must specifically consent to participate in this 
evaluation.  The samples will be stored for up to 
1 year after the end of the study and destroyed 
after 1 year if not analyzed. 
Section 12.1.1.1, 
Adverse Event 
Insertions 
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) 
subject deterioration due to primary illness; (3) 
intercurrent illness; and (4) drug interaction.  For 
reporting purposes, pregnancy is not considered 
an AE 
 
Subjects 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 the or whites of 
eyes, and bruising easily. 
Per FDA request 
Section 12.1.1.4, 
Adverse Events of 
Special Interest 
Insertion 
The following decompensation events are adverse 
events of special interest.  A subset of these events 
are also individual components of the primary 
endpoint (Section 11.1.1).   
• 
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, 
irrespective of hospitalization or 
requirement of blood transfusion.  
Per FDA request 
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• 
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 
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Section 12.1.5.1, 
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 subject. 
Per FDA request 
Section 12.1.10, 
Follow-up of AEs 
and SAEs 
…  Drug-induced liver injury may develop or 
progress even after the causative drug has been 
stopped.  Results should be recorded in the CRF. 
Note that longer follow-up can sometimes reveal 
an off-drug repetition. 
Drug-Induced Liver Injury or Disease 
Progression 
…  Drug-induced liver injury may develop or 
progress even after the causative drug has been 
stopped.  Results from drug induced liver injury 
follow-up should be recorded in the eCRF. Note that 
longer follow-up can sometimes reveal an off-drug 
repetition… 
 
Cholecystitis or Pancreatitis 
At the time of consent for new subjects (or re-
consent to the protocol amendments for ongoing 
subjects), subjects will 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.  
Subjects will 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 will be instructed to 
promptly bring subjects 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)  
 
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• 
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 will be monitored monthly for 
3 months after onset of symptoms, irrespective of 
whether a diagnosis of cholecystitis and or 
pancreatitis is confirmed.  Results should be 
recorded promptly in the eCRF. 
Section 12.2.5, 
Dual Emission X-
Ray 
Absorptiometry 
12.2.5. Dual Emission X-Ray Absorptiometry 
A bone density assessment will be done using the 
DEXA scan. 
Deleted 
Procedure deleted 
Section 12.2.6, 
Laboratory 
Assessments 
Subjects will be instructed to attend each of their 
study visits (except Screening) in a fasted state, 
Subjects will be instructed to attend any study or 
unscheduled laboratory visits (except Screening) in 
a fasted state, 
Clarify subject should fast 
for all lab visits. 
Section 12.2.6, 
Laboratory 
Assessments, 
Table 13 
Laboratory 
Assessment 
Analyte 
Laboratory Assessment 
Analyte 
 
Labs added per FDA request 
 
 
 
 
Procedure deleted 
 
 
Markers of 
Cholecystitis and 
Pancreatitis 
amylase and lipase 
Blood Sample for 
Future Analysis 
PBC autoantibodies and 
other cytokines and 
interleukins TBD 
 
 
Section 12.2.6, 
Laboratory 
Assessments, 
MELD scores, Child-Pugh score, and MRS will 
be calculated at screening, and at quarterly 
(MELD and Child-Pugh scores) or semi-annual 
(MRS) visits based on serum chemistry and 
coagulation. 
MELD scores and Child-Pugh score will be 
calculated at screening, and at all visits based on 
serum chemistry and coagulation. 
Clarify subject should fast 
for all lab visits 
Section 13.2.1, 
Safety Analyses, 
Adverse Events 
Insertion 
Adverse events of special interest as described in 
Section 12.1.1.4 will be summarized for each 
treatment group.  In addition, each event is a 
Per FDA request. 
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component of the primary endpoint, and will be 
summarized as secondary endpoints as described 
in Section 13.1.4. 
Section 13.4, 
Adjudication 
Committees 
All suspected liver-related clinical outcomes, 
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, 
All suspected liver-related clinical outcomes and 
MACE/Expanded MACE 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 2 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 
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, 
There is no longer a need for 
the Hepatic Safety Committee 
given the updated guidance for 
the Investigator. 
References 
 
Kumar A, Saraswat V.  Hepatitis E and Acute-on-
Chronic Liver Failure.  J Clin Exp Hepatol. 2013 
Sep;3(3):225-30. doi: 10.1016/j.jceh.2013.08.013. 
Epub 2013 Sep 16 
Banks O, Bollen T, Dervenis C, et al.  
Classification of acute pancreatitis02012: revision 
of the Atlanta classification and definitions by 
international consensus.  Gut.2013;62:102-111. 
 
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Greenburg J, Hsu J, Bawazeer M., et al.  Clinical 
Practice Guideline:  Management of acute 
pancreatitis.  Can J Surg. 2016;59 (2):128-140. 
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. 
Appendix A, 
Overview of 
Modified Dosing 
Regimen for 
Subjects with 
Child-Pugh B or 
C Hepatic 
Impairment 
… Overview of Modified Dosing Regimen for 
Subjects with Child-Pugh B or C Hepatic 
Impairment 
An overview of the modified dosing regimen for 
subjects with Child-Pugh Class B or Child Pugh 
Class C is presented in  and . 
Subjects who are cirrhotic and classified as 
Child-Pugh Class B or Child-Pugh Class C will 
initiate a modified treatment regimen with 5 mg 
OCA or matching placebo once weekly for at 
least 3 months.  Subjects classified as Child-Pugh 
Class B should eventually titrate to a maximum 
dose of 5 mg OCA or matching placebo once 
daily, based on tolerability and biochemical 
response.  Subjects classified as Child-Pugh Class 
C should titrate to a maximum dose and 
frequency of 10 mg OCA or matching placebo 
twice weekly. 
Subjects with cirrhosis and classified as Child-
Pugh B or Child-Pugh C at Screening will follow 
a modified dosing schedule initiating 5 mg OCA 
or matching placebo once weekly as described in 
Figure 3.  After a minimum of 3 months dosing 
once weekly with 5 mg OCA or matching placebo, 
and following review of the pre-titration 
laboratory results to assess safety and tolerability, 
the dosing frequency of 5 mg OCA or matching 
placebo should be increased to twice weekly (at 
least three days apart).  Subjects who have 
maintained the twice weekly dosing frequency for 
a minimum of at least 6 weeks, and meet the dose 
titration criteria, should up titrate to the 
maximum allowed dose of 10 mg OCA or 
matching placebo twice weekly (Table 14). 
Investigators may decrease the dosing frequency 
(back to once weekly) or dose for any subject at 
any time during the study, as considered clinically 
appropriate (eg, tolerability). 
Deleted overview section 
and replaced with text  
Appendix A, 
Figure 3 
 
 
Same dosing scheme for 
CP-B and CP-C subjects. 
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Appendix A, 
Table 14 
 
 
Titration #3 is no longer 
applicable to study.  To 
align with label, maximum 
dose for Child-Pugh B or C 
subjects is 10 mg OCA 
twice weekly. 
Appendix A 
Modified Dosing Regimen for Subjects with 
Child-Pugh B Hepatic Impairment 
Subjects with cirrhosis and classified as Child-
Pugh BC at Screening will follow a modified 
dosing schedule receiving 5 mg OCA or 
matching placebo once weekly as described in .  
After a minimum of 3 months dosing once 
weekly with 5 mg OCA or matching placebo, and 
following review of the pre-titration laboratory 
results to assess safety and tolerability, the dosing 
frequency of 5 mg OCA or matching placebo 
should be increased to twice weekly (at least 3 
days apart).  Subjects who have maintained the 
twice weekly dosing frequency for a minimum of 
at least 6 weeks, and meet the dose titration 
criteria, should up-titrate to twice weekly dosing 
with 10 mg OCA or matching placebo.  Subjects 
with at least 6 weeks of twice weekly dosing at 
10 mg OCA or matching placebo, and meeting 
dose titration criteria, should up-titrate to the 
maximum allowed dose of 5 mg OCA or 
matching placebo once daily.  
Investigators may decrease the dosing frequency 
(back to once or twice weekly) or dose for any 
subject at any time during the study, as 
considered clinically appropriate (eg, 
tolerability). 
 
 
Appendix A, 
Dose Titration 
due to Change in 
Subjects on a modified dosing regimen who 
demonstrate a change in cirrhosis status 7.5.4 
and/or Child-Pugh Score7.5.5 should have their 
dose of investigational product modified to match 
When subjects demonstrate a change in cirrhosis 
status (as assessed per Section 7.5.4) or Child-Pugh 
Score (Section 7.5.5 dosing should be reassessed 
and the dosing regimen modified appropriately.  
 
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Cirrhosis or 
Child-Pugh Score 
their current status per the appropriate dosing 
regimen (see Section , ); however, changes to the 
dosing regimen are not mandatory and should be 
based on clinical judgment as well as changes in 
status. Changes in Child-Pugh Score that result 
from a transient, explainable change in laboratory 
parameters should be documented appropriately, 
and should not necessarily result in a change to 
the dosing regimen.  Investigators may contact 
the Medical Monitor at any time to discuss 
potential changes to dosing.   
Possible scenarios for dosing modifications 
include: 
• Subjects who develop cirrhosis during the 
course of the trial with a classification of 
Child-Pugh B or C 
• Subjects with pre-existing cirrhosis who 
demonstrate a change in the Child-Pugh 
Score from A to B or C at any point in the 
study   
• Improvement in classification of Child-
Pugh Score from C to B  
• Improvement in classification of Child-
Pugh Score from B to A; these subjects 
may be eligible to transition to the standard 
dosing regimen 
Subjects may titrate dose and dosing frequency 
up or down as appropriate, within the appropriate 
dosing regimen.  Up-titration should be done per 
Investigator discretion and be guided by the pre-
titration tolerability assessments outlined in 
Section 7.4.1.  A 1-Month Post-Titration 
Assessment must be performed any time a 
subject’s dose or frequency is up-titrated (see 
Section 7.1.2 and Section 9.7.10). 
Changes in Child-Pugh Score that result from a 
transient, explainable change in laboratory 
parameters (eg, increase in INR due to vitamin K 
deficiency) should be documented appropriately and 
discussed with the Medical Monitor before any 
continuation or change to the dosing regimen.    
Possible scenarios for dosing modifications include: 
• 
Subjects who develop cirrhosis during the 
course of the trial with a classification of 
Child-Pugh B or C 
• 
Subjects with pre-existing cirrhosis who 
demonstrate a change in the Child-Pugh Score 
from A to B or C at any point in the study   
Subjects may titrate dose and dosing frequency up or 
down as appropriate, within the dosing regimen.  Up-
titration should be done per Investigator discretion 
and be guided by the pre-titration tolerability 
assessments outlined in Section 7.4.1.  A 1-Month 
and 2-Month Post-Titration Assessment must be 
performed any time a subject’s dose or frequency is 
up-titrated (see Section 7.1.2 and Section 9.7.7). 
Appendix A, 
Unscheduled 
…:  The + 1 week window week related to the 1 
month Post-Titration Visit can be extended for up 
to an additional 5 weeks to allow for the post-
…:  The ±1 week window related to the 2-month 
Post-Titration Visit can be modified to occur 2 
weeks earlier or 2 weeks outside of the allowed 
 
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Titration Visit, 
Optional Visit 
titration assessment to be performed during one 
of the subject’s regularly scheduled study visits.  
If the window is extended past +1 week allowed 
visit window, at a minimum, a telephone safety 
contact should then be performed 1-month post-
titration. 
visit window to allow for the post-titration 
assessment to be performed during one of the 
subject’s regularly scheduled study visits.  If the 2-
month Post-Titration Visit is performed during a 
regularly scheduled study visit, all scheduled 
procedures associated with that visit should be 
performed. 
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APPENDIX K. SUMMARY OF CHANGES:  PROTOCOL VERSION 5 TO PROTOCOL VERSION 6 
(DATED 05 NOV 2019) 
Rationale 
Protocol 747-302 was revised as follows: 
• Updated contraception language to align with CTFG guidelines for highly effective methods 
• Updated the section on the total number of subjects exposed to OCA as of 26 May 2019 
• Update the section on known potential risks of OCA 
• Updated the section on reporting of adverse events to include instructions for reporting SUSARs 
• Included various options for retaining subjects in the study and emphasized the critical importance of collecting clinical 
outcomes data 
• Provided guidance for Investigators on the importance of documenting specific reasons in the EDC for subjects who 
discontinue treatment and/or the study, especially for subjects who discontinue due to adverse events 
• Provided guidance for Investigators on study procedures for subjects who reconsent to participate in the study 
Summary of Changes 
The following revisions were made to the protocol in Protocol Version 6.  Revised and new text in Version 6 is indicated in bold font, 
and the text deleted from Protocol Version 5 is crossed out in the table below.  Minor/editorial changes are not listed individually in 
the summary table below.  Section numbers and names in column 1 refer to protocol Version 6 unless otherwise noted. 
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Revised Text (Version 6, 05 Nov 2019) 
Justification 
for Change 
STUDY 
PERSONNEL 
CONTACT 
INFORMATION, 
Secondary 
Contact 
 DO, MSPH  
Senior Medical Director  
Intercept Pharmaceuticals, Inc. 
(Intercept) 
 
 MD| Executive Director, Clinical Research 
Intercept Pharmaceuticals, Inc. (Intercept)| New York, NY 10001 
Tel: 
 Mobile: 
 
 
Change in the 
Sponsor’s 
medical 
director. 
Synopsis, 
Methodology 
This Phase 4, double-blind, randomized, 
placebo-controlled, multicenter study 
will evaluate the effect of OCA on 
clinical outcomes in subjects with PBC.   
This Phase 3b/4, double-blind, randomized, placebo-controlled, multicenter 
study will evaluate the effect of OCA on clinical outcomes in subjects with 
PBC.   
Revision was 
made to 
clarify that in 
the US, 
Canada and 
Europe, this 
study is being 
conducted as 
a phase 4 
study. In all 
other regions, 
it is a 
phase 3b 
study. 
Synopsis, 
Methodology 
New language added. 
With the exception of liver transplant, if a subject experiences a suspected 
or confirmed clinical outcomes event, the subject should continue the 
regular visit schedule and continue taking investigational product as long 
as the subject has not met any of the criteria for discontinuation outlined 
in the protocol.  Subjects who discontinue investigational product are 
expected to be followed through to study closure (or at the discretion of the 
Sponsor).  Additional information regarding subject follow-up and 
different options available to subjects is provided in Section 7.9 and 
Section 8.4. 
Clarification 
of study 
procedures 
for subjects 
who 
discontinue 
treatment. 
Synopsis, 
Diagnosis and 
Main Criteria for 
Inclusion, 
Inclusion Criteria 
5. Contraception:  Female subjects of 
childbearing potential must use 
≥1 effective method of contraception 
during the study and until 30 days 
following the last dose of 
investigational product.  Effective 
5. 
Contraception:  Female subjects must be postmenopausal, surgically 
sterile, or, if premenopausal (and not surgically sterile), be prepared 
to use ≥1 highly effective method of contraception during the study and 
for 30 days after the end of treatment. Highly effective methods of 
contraception per the CTFG guidelines are those that alone or in 
combination results in a failure rate of less than 1% per year when 
Inclusion 
criterion #5 
was updated 
per CTFG 
guidelines for 
highly 
effective 
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PPD
PPD
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for Change 
methods of contraception are 
considered to be those listed below: 
• Barrier method, ie, (a) condom 
(male or female) or (b) 
diaphragm, with spermicide 
• Intrauterine device (IUD) 
• Vasectomy (partner) 
• Hormonal (eg, contraceptive 
pill, patch, intramuscular 
implant or injection) 
• Abstinence, if in line with the 
preferred and usual lifestyle of 
the subject 
used consistently and correctly. Highly effective methods of 
contraception are as follows: 
• 
Intrauterine device 
- 
Intrauterine device (IUD) 
- 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomy (partner) 
• Combined (estrogen and progestogen containing) hormonal 
contraception (eg, oral, intravaginal or transdermal) 
associated with inhibition of ovulation. If oral contraceptives 
are used, they must be used in combination with a male or 
female condom. Female subjects should have been on the 
hormone contraception for at least 8 days prior to Day 1. 
• 
Progestogen-only hormonal contraception (eg oral, injectable or 
implantable) associated with inhibition of ovulation. If oral 
contraceptives are used, they must be used in combination with a 
male or female condom. Female subjects should have been on the 
hormone contraception for at least 8 days prior to Day 1. 
• 
Sexual abstinence, if in line with the preferred and usual lifestyle of the 
subject (where abstinence is defined as refraining from heterosexual 
intercourse during the entire period of risk associated with study 
treatments). 
methods of 
contraception 
within a 
clinical 
study. 
Synopsis, 
Exclusion 
Criteria 
5. Other medical conditions that may 
diminish life expectancy, including 
known cancers (except carcinomas in 
situ or other stable, relatively benign 
conditions such as chronic 
lymphocytic leukemia) 
5.  
Other medical conditions that may diminish life expectancy, including 
known cancers (except carcinomas in situ or other stable, relatively 
benign conditions) 
Revised to 
remove 
chronic 
lymphocytic 
leukemia as a 
benign 
medical 
condition. 
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Synopsis, 
Duration of 
Treatment 
It is expected that subjects will be 
followed up for a minimum of 6 years.  
The study is event driven and total 
duration of treatment will be determined 
by the time to accrue 127 total primary 
endpoint events. 
The study is event driven and total duration will be determined by the time 
required to accrue approximately 127 primary endpoint   events, estimated 
to be approximately 10 years.  Subjects are expected to have a minimum 
follow-up time of approximately 6 years. 
Updated the 
estimated 
study 
duration. 
5.4, Clinical 
Experience with 
Obeticholic Acid 
As of 13 Oct 2017, approximately 
2690 subjects1 have received at least 
1 dose of OCA.  Of these, 844 were 
healthy volunteers, 552 subjects had 
PBC, 1141 subjects had NASH, 
41 subjects had diabetes 
mellitus/nonalcoholic fatty liver disease, 
33 subjects had alcoholic cirrhosis/portal 
hypertension, and 73 subjects had 
primary sclerosing cholangitis, and 
6 subjects had biliary atresia. 
1 Includes estimated numbers from 
ongoing blinded studies 
As of 26 May 2019, approximately 5386 subjects have been enrolled in the 
clinical development program for OCA.  Approximately 3926 subjects have 
received at least 1 dose of OCA in completed and ongoing clinical trials. 
Updated the 
number of 
subjects 
exposed to 
OCA as of 
26 May 2019. 
5.4, Clinical 
Experience with 
Obeticholic Acid 
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.  The LTSE 
phase of studies 747-201 and 747-301 
are ongoing; the LTSE phase of Study 
747-202 is complete. 
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.  The 
LTSE phase of Study 747-301 is ongoing; (a final CSR is pending); the 
LTSE phases of Study 747-201 and Study 747-202 are complete. 
Updated the 
status of 
clinical 
studies in 
PBC. 
5.5.1 Rationale 
for Study Design 
Study 747-302 is a clinical outcomes 
study, supportive of Phase 3 Study 
747-301 which was based on a surrogate 
biochemical endpoint, designed to 
confirm the clinical benefit of OCA 
treatment in patients with PBC.  A 
retrospective observational database 
(Global PBC Study Group [Lammers 
2013]) of patients with PBC allowed for 
a rigorous patient-level meta-analysis 
Study 747-302 is a clinical outcomes study, supportive of Phase 3 Study 
747-301 which was based on a surrogate biochemical endpoint, designed to 
confirm the clinical benefit of OCA treatment in patients with PBC.  A 
retrospective observational database (Global PBC Study Group [Lammers 
2013]) of patients with PBC allowed for a rigorous patient-level meta-analysis 
and provided an opportunity for a robust assessment of ALP and bilirubin as 
viable surrogate biochemical parameters and a comprehensive understanding of 
the natural history of the PBC disease process.  Data from the Global PBC 
Study Group was also utilized to inform the design of the confirmatory 
outcomes study. Despite the observational evidence that links ALP and 
Added 
language to 
stress the 
importance of 
collecting 
clinical 
outcomes 
data. 
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and provided an opportunity for a robust 
assessment of ALP and bilirubin as 
viable surrogate biochemical parameters 
and a comprehensive understanding of 
the natural history of the PBC disease 
process.  Data from the Global PBC 
Study Group was also utilized to inform 
the design of the confirmatory outcomes 
study. 
bilirubin to clinical outcomes in PBC, it is necessary to prospectively 
validate these surrogate endpoints.  As such collecting outcome 
information in Study 747-302 is of the utmost importance. 
5.7. Summary of 
Known Potential 
Risks with OCA 
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 
Clinical Data 
In two Phase 2 studies and a Phase 3 study evaluating OCA in the treatment of 
subjects with PBC, hepatic adverse events, including jaundice, worsening 
ascites and primary biliary cholangitis flare, 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), as early as one 
month after starting treatment with OCA. 
In addition, 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. 
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 individual subject and aggregate data from both the Phase 3 clinical 
outcomes study in subjects with PBC (Study 747-302) and the Phase 3 pivotal 
studies in subjects with NASH fibrosis (Study 747-303) and NASH cirrhosis 
(Study 747-304) on a quarterly basis, in an unblinded fashion, and in 
Updated the 
known 
potential 
risks of OCA. 
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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 
closed sessions (without the Sponsor’s participation).  In the quarterly 
DMC meetings to date, the DMC has recommended the studies continue 
without modification. 
Following a request from the FDA to provide an up to date DMC report 
analyzing unblinded data on respective incidence of cholecystitis, 
cholelithiasis, and pancreatitis by treatment group across all ongoing 
clinical studies, an ad hoc DMC review was held and the DMC 
recommended that: 
• 
As it concerned pancreatitis, all studies continue without changes. 
• 
For subjects in Study 747-303, investigational product should be 
uninterrupted in subjects who experience symptomatic 
cholelithiasis and/or cholecystitis. 
The Sponsor implemented the DMC recommendations across the NASH 
program but not the PBC program. 
Post-Marketing Cases in PBC 
As of 26 May 2019, the estimated cumulative patient exposure from 
marketing experience is 7694 patient-years.  
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. 
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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. 
Refer to the current version of the OCA Investigator’s Brochure for 
additional information regarding the known potential risks with the 
investigational product. 
7.1, Overall 
Study Design 
This is a Phase 4, double-blind, 
randomized, placebo-controlled, 
multicenter study 
This is a Phase 3b/4, double-blind, randomized, placebo-controlled, multicenter 
study 
Please refer 
to the 
previous 
explanation 
for this 
change. 
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7.1, Overall 
Study Design 
New language added. 
With the exception of liver transplant, if a subject experiences a suspected 
or confirmed clinical outcomes event, the subject should continue the 
regular visit schedule and continue taking investigational product as long 
as the subject has not met any of the criteria for discontinuation outlined 
in the protocol.  Subjects who discontinue investigational product are 
expected to be followed through to study closure (or at the discretion of the 
Sponsor).  Additional information regarding subject follow-up and 
different options available to subjects is provided in Section 7.9 and 
Section 8.4. 
Please refer 
to the 
previous 
explanation 
for this 
change. 
7.6, 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 7), investigational product 
should be initiated at a lower dose and 
subjects 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 7.  Subjects that 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 terminate at 
the time when the needed number of 
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 safety and/or 
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 7), investigational product should be initiated at a 
lower dose and subjects 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 
7.  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 terminate at the time when the needed number of adjudicated 
events has accrued.  If a subject reaches an outcome event, he or she should 
continue the regular visit schedule and continue taking investigational product 
as long as the subject has not met any of the criteria for mandatory interruption 
of investigational product outlined in Table 7, and the Investigator assesses it 
as safe to continue.  In general, subjects should be strongly encouraged to both 
stay on investigational product and remain in the study until study termination. 
If a subject discontinues investigational product and cannot continue to 
attend regularly scheduled study visits, the subject should be strongly 
encouraged to participate in study follow-up via phone calls or electronic 
medical record review as described in Section 7.9. 
Section was 
revised to 
reiterate the 
importance of 
collecting 
follow-up 
information 
for subjects 
who 
discontinue 
treatment 
and/or the 
study  
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adjudicated events has accrued.  If a 
subject reaches an outcome event, he or 
she should continue the regular visit 
schedule and continue taking 
investigational product as long as the 
subject has not met any of the criteria for 
mandatory interruption of investigational 
product outlined in Table 7, and the 
Investigator assesses it as safe.  In 
general, subjects should be strongly 
encouraged to both stay on 
investigational product and remain in the 
study until study termination 
7.9, Subject 
Retention 
A new section was created. 
The primary objectives for the end of study analysis are to evaluate the 
effects of OCA compared with placebo on all-cause mortality and liver-
related clinical outcomes.  The overall study duration is event driven and 
will be determined by the time required to observe the prespecified 
adjudicated events for the clinical outcomes’ composite endpoint (Section 
7.1).  Therefore, it is critical that subjects continue to participate for the 
duration of the study to enable assessment of clinical outcomes and 
confirmation of the clinical benefit of OCA in PBC.  
Subjects may discontinue investigational product during the study; 
however, these subjects are expected to continue in the study until study 
termination and every effort will be made by the investigator to discuss 
subjects’ continuation in the study.  Even if a subject is no longer receiving 
investigational product, if the subject is attending study visits or 
participating in study follow-up, their information will contribute to the 
study primary endpoint and the evaluation of clinical benefit of OCA.  All 
information collected in the study during regular study visits and through 
subjects participating in follow-up will contribute to the evaluation of 
safety of OCA and the scientific and medical understanding PBC. 
Investigators should emphasize to subjects the importance of their 
continuation in the study even after withdrawal of investigational product 
and discuss with subjects the various options for continued participation in 
the study: 
• 
Continuing to attend regularly scheduled visits, or 
A new 
section was 
created to 
provide 
guidance on 
the 
importance of 
retaining 
subjects in 
the study. 
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• 
Allowing semi-annual telephone visits by the investigator, or  
• 
Allowing the investigator to have continued access to the 
subjects’ medical records to assess suspected major adverse 
cardiovascular events (MACE) and liver-related clinical 
outcomes 
Subjects will be asked to provide both personal and primary physician(s) 
contact information who can provide information to the investigator about 
the clinical/medical status on the subjects’ behalf. 
Should subjects choose to discontinue treatment or withdraw consent and 
fully leave the study, it will be made clear to them that they may return to 
their randomized treatment group should they so choose. 
Additional information is described in Section 8.4. 
Given the importance of subject retention, clinical site personnel should 
refer to specific strategies and procedures as described in a separate 
Subject Retention Plan that will provide additional information to 
facilitate subject retention. 
8.2, Subject 
Inclusion Criteria 
5. Contraception:  Female subjects of 
childbearing potential must use 
≥1 effective method of contraception 
during the study and until 30 days 
following the last dose of 
investigational product.  Effective 
methods of contraception are 
considered to be those listed below: 
• Barrier method, ie, (a) condom 
(male or female) or (b) 
diaphragm, with spermicide 
• Intrauterine device (IUD) 
• Vasectomy (partner) 
• Hormonal (eg, contraceptive 
pill, patch, intramuscular 
implant or injection) 
5. 
Contraception:  Female subjects must be postmenopausal, surgically 
sterile, or, if premenopausal (and not surgically sterile), be prepared 
to use ≥1 highly effective method of contraception during the study and 
for 30 days after the end of treatment. Highly effective methods of 
contraception per the CTFG guidelines are those that alone or in 
combination results in a failure rate of less than 1% per year when 
used consistently and correctly. Highly effective methods of 
contraception are as follows: 
• 
Intrauterine device 
- 
intrauterine device (IUD) 
- 
intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomy (partner) 
• Combined (estrogen and progestogen containing) hormonal 
contraception (eg, oral, intravaginal or transdermal) 
associated with inhibition of ovulation. If oral contraceptives 
are used, they must be used in combination with a male or 
Please refer 
to previous 
reason for 
this change. 
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Abstinence, if in line with the preferred 
and usual lifestyle of the subject 
female condom. Female subjects should have been on the 
hormone contraception for at least 8 days prior to Day 1. 
• 
Progestogen-only hormonal contraception (eg oral, injectable or 
implantable) associated with inhibition of ovulation. If oral 
contraceptives are used, they must be used in combination with a 
male or female condom. Female subjects should have been on the 
hormone contraception for at least 8 days prior to Day 1. 
• 
Sexual abstinence, if in line with the preferred and usual lifestyle of the 
subject (where abstinence is defined as refraining from heterosexual 
intercourse during the entire period of risk associated with study 
treatments). 
8.3, Subject 
Exclusion 
Criteria 
5.Other medical conditions that may 
diminish life expectancy, including 
known cancers (except carcinomas in 
situ or other stable, relatively benign 
conditions such as chronic lymphocytic 
leukemia) 
5.  Other medical conditions that may diminish life expectancy, including 
known cancers (except carcinomas in situ or other stable, relatively benign 
conditions) 
Please refer 
to the 
previous 
reason for 
this change. 
8.4, Subject 
Withdrawal 
Criteria 
Subjects can be discontinued from 
investigational product by the 
Investigator at any time for clinical 
safety concerns.  Subjects who are 
discontinued from investigational 
product are expected to continue in the 
study and should follow the regular visit 
schedule for the duration of the study.  
See Section 7.6 for withdrawal criteria 
related to potential hepatic injury and/or 
decompensation including liver 
transplantation or multi-organ failure.  
Other reasons, including withdrawal of 
consent or lost to follow-up, are 
described in Section 8.4.1 below. 
Subjects can be discontinued from investigational product by the Investigator at 
any time for clinical safety concerns.  Subjects who are discontinued from 
investigational product are expected to continue in the study and should follow 
the regular visit schedule for the duration of the study.  See Section 7.6 for 
withdrawal criteria related to potential hepatic injury and/or decompensation 
including liver transplantation or multi-organ failure.  Other reasons, including 
withdrawal of consent or lost to follow-up, are described in Section 8.4.1. The 
specific reason(s) for discontinuation from investigational product and/or 
withdrawal of consent should be recorded on the appropriate CRF. 
Revisions 
were made to 
underscore 
the 
importance of 
providing the 
specific 
reason(s) 
why a subject 
discontinued 
treatment 
and/or 
withdrew 
consent. 
8.4.1, Other 
Reasons for 
The following events are considered 
appropriate reasons for a subject to 
In general, the site should counsel the subject on the importance of 
maintaining the regular visit schedule and remaining on investigational 
Please refer 
to the earlier 
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Discontinuation 
of Study or 
Investigational 
Product 
discontinue investigational product; 
however, these subjects are expected to 
continue in the study until study 
termination (or at the discretion of the 
Sponsor): 
• Subject begins treatment with 
commercially available OCA 
• The Investigator or Sponsor 
considers that it is advisable or in 
the best interest of the subject. 
• 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 
subject 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 outcomes. 
product.  Subjects should be strongly encouraged to both stay on 
investigational product and remain in the study until study termination.   
Subjects who discontinue investigational product prior to termination of 
the study need to also continue to follow the regular visit schedule through 
to study closure.  With the exception of liver transplant, if a subject 
experiences a suspected or confirmed 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.  
Specific strategies to encourage continued subject participation in the 
study will be outlined in a Subject Retention Plan.  Subjects who 
discontinue investigational product but agree to follow up either through 
phone calls or review of electronic medical records are expected to 
continue to provide information regarding clinical outcomes or new 
interventions for PBC (such as initiating commercial OCALIVA).  Early 
termination procedures should only be conducted if the subject withdraws 
consent (see Section 9.7.15). 
The following events are considered appropriate reasons for a subject to 
discontinue investigational product; however, these subjects are expected to 
continue in the study until study termination (or at the discretion of the 
Sponsor): 
• 
Subject begins treatment with commercially available OCALIVA. 
- 
If a subject begins treatment with commercially available 
OCALIVA, they must interrupt IP immediately and this must be 
reported in the treatment discontinuation eCRF to prevent double 
dosing and for notification of the sponsor and medical monitor. 
• The Investigator or Sponsor considers that it is advisable or in the best 
interest of the subject. 
• 
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 subject 
discontinues both investigational product and study visits and 
procedures). 
response for 
the reason for 
change. 
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− Early termination procedures 
should be conducted if the 
subject withdraws consent 
(See Section 9.7.15). 
The Investigator is encouraged to contact 
the Sponsor prior to discontinuing a 
subject from treatment.  The Investigator 
must notify the Sponsor study monitor 
by telephone or email as soon as possible 
if any subject prematurely withdraws 
from the study. 
− 
Consent may be modified to discontinue study visits, but allow 
semi-annual telephone contact of subject, subject’s primary 
care physician, or personal contacts who can provide 
information on behalf of the subject by the investigator 
− 
Consent may be modified to discontinue study visits or semi-
annual telephone contact, but may allow for continued access to 
medical records to assess for suspected major adverse 
cardiovascular events (MACE), liver-related clinical outcomes, 
and new interventions and medications for treatment of PBC. 
− 
Other subject follow-up options to collect study outcomes 
should be pursued according to local laws and regulations. If 
one of these alternate methods to collect study outcomes is 
acceptable to the subject, then the subject will be deemed not 
to have withdrawn consent for follow-up. 
Early termination procedures should be conducted if the subject withdraws 
consent (see Section 9.7.15). 
The Investigator is encouraged to contact the Sponsor prior to discontinuing a 
subject from treatment.  The Investigator must notify the Sponsor study 
monitor by telephone or email as soon as possible if any subject prematurely 
withdraws from the study. 
8.4.2, Withdrawal 
of Consent 
If the subject 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 subjects 
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 subject 
discontinuation.  This information and 
date must be recorded in the appropriate 
case report form (CRF). 
If the subject 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 subjects 
volunteer for the study and that they may withdraw their consent to continue in 
the study at any time. 
Diligent efforts must be made to determine the reason(s) for subject 
discontinuation (such as initiation of commercial OCALIVA or underlying 
adverse events).  This information and date must be recorded in the 
appropriate case report form (CRF). 
Revisions 
were made to 
provide 
guidance to 
Investigators 
on how to 
document the 
specific 
reasons why 
a subject 
withdrew 
consent. 
8.4.3, 
Requirements to 
New section added 
Subjects who wish to re-initiate investigational product while participating 
in study follow-up or re-enter the study after having withdrawn consent 
Revisions 
were made to 
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Re-Initiate 
Investigational 
Product or Re-
Enter the Study 
more than 3 months since the last visit must confirm that they have not 
received any investigational product that is being evaluated for the 
treatment of PBC within 30 days or Commercial OCALIVA for three 
months before restarting investigational product or within 5 half-lives of 
the compound (whichever was longer).  Subjects are to be re-consented 
and new baseline visit procedures must be performed. 
provide 
guidance to 
Investigators 
on study 
procedures 
for subjects 
who re-enter 
the study 
after having 
withdrawn 
consent. 
8.4.3, Lost to 
Follow Up 
If a subject fails to return to the clinic for 
a study visit, and the Investigator ceases 
to have contact with the subject, he or 
she will be withdrawn from the study. 
A reasonable effort must be made to 
contact the subject and determine the 
reason(s) why a subject 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 CRF. 
If a subject fails to return to the clinic for a study visit, and the Investigator 
ceases to have contact with the subject, he or she will be withdrawn from the 
study. 
Diligent efforts to determine the reason(s) why a subject failed to return for a 
study visit or is lost to follow-up must be made. If the subject has provided 
consent, the subject’s primary care physician or personal contacts who can 
provide information on behalf of the subject by the investigator, must be 
contacted if the subject consistently fails to return for study visits. This 
information and date of contact must be recorded in the appropriate CRF. 
Revisions 
were made to 
provide 
options for 
follow up of 
subjects who 
discontinue. 
8.4.4, Subject 
Discontinuation 
Notification 
The Investigator must notify the Sponsor 
study monitor by telephone or email as 
soon as possible if any subject 
prematurely withdraws from the study.  
The date when the subject is withdrawn 
and the reason for discontinuation must 
be recorded in the CRF.  If a subject is 
“lost to follow up” (fails to return for a 
visit), a reasonable effort should be made 
to contact the subject in order to 
determine why the subject failed to 
return.  This information must be 
documented in the CRF.  If a subject is 
withdrawn from the study early 
(regardless of the cause), all of the 
The Investigator must notify the Sponsor study monitor by telephone or email 
as soon as possible if any subject prematurely withdraws from the study.  The 
date when the subject is withdrawn and the reason for discontinuation must be 
recorded in the CRF.  If a subject is “lost to follow up” (fails to return for a 
visit), diligent efforts should be made to contact the subject in order to 
determine why the subject failed to return (see Section 8.4.3).  This 
information must be documented in the CRF.  If a subject is withdrawn from 
the study early (regardless of the cause), all of the EOT/EOS evaluations 
should be performed at the time of withdrawal, as appropriate 
(See Section 9.7.15, Early Discontinuation and/or Early Termination 
Procedures). 
Please refer 
to earlier 
reason for 
this change. 
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Section 
Original Text (Amendment 5, 
04 Jan 2018) 
Revised Text (Version 6, 05 Nov 2019) 
Justification 
for Change 
EOT/EOS evaluations should be 
performed at the time of withdrawal, as 
appropriate (See Section 9.7.15, Early 
Discontinuation and/or Early 
Termination Procedures). 
9.7.1, Visit 
Windows 
New row for study re-entry was added. 
Visit or Procedure 
Visit Window and/or Interval 
IP Re-Initiation/ Study Re-
Entry 
(When a subject has 
previously discontinued 
treatment/ withdrawn 
consent and has chosen to 
return to study 
participation) 
Day 0 procedures should be conducted 
and the visit window will be relative to 
Day 0 from the original study entry. 
Clarification 
of study 
procedures 
for subjects 
who re-enter 
the study. 
9.7.15. Early 
Discontinuation 
and/or Early 
Termination 
Procedures for 
Subjects that 
Withdraw from 
Investigational 
Product or 
Withdraw 
Consent 
Subjects that discontinue investigational 
product are expected to continue in the 
study until the end of the study, and the 
study will only terminate at the time 
when the needed number of adjudicated 
events has accrued or at the discretion of 
the Sponsor.   
Subjects who discontinue investigational product are expected to continue in 
the study until the end of the study, and the study will only terminate at the 
time when the needed number of adjudicated events has accrued or at the 
discretion of the Sponsor.  In general, subjects should be strongly 
encouraged to both stay on investigational product and remain in the 
study until study termination.  Even if a subject is no longer receiving 
investigational product, if the subject is attending study visits or 
participating in study follow-up (through telephone visits or electronic 
medical record review), their information will contribute to the study 
primary endpoint and the evaluation of clinical benefit of OCA.  All 
information collected in the study during regular study visits and through 
subjects participating in follow-up will contribute to the evaluation of 
safety of OCA and the scientific and medical understanding of PBC. 
Please refer 
to earlier 
justification 
for this 
change. 
 
A new footnote (footnote b) was to Table 
8. 
Table 8: 
Early Discontinuation Scenarios 
 
Investigational 
Product 
Consent 
Study 
Visit 
Status 
EOT 
Visita 
EOS 
Visita 
Early 
Terminationb 
Discontinued 
Withdrawn 
No 
additional 
visits 
except 
EOT/EOS 
Combined Visit, 
Completed as close as 
possible to last dose 
IP 
Please refer 
to earlier 
justification 
for this 
change. 
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Section 
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04 Jan 2018) 
Revised Text (Version 6, 05 Nov 2019) 
Justification 
for Change 
Treatment 
Discontinuationb,c 
Discontinued 
Active 
Regular 
Visit 
Schedule 
Complete 
as close 
as 
possible 
to last 
dose IP 
Complete 
at Final 
study 
visit 
Discontinued 
Semiannual 
contactd 
Telephone 
contact 
every 6 
months 
(±2 
weeks) 
Combined Visit, 
Completed as close as 
possible to last dose 
IP 
Discontinued 
Record 
review 
onlyd 
Record 
review 
only 
Combined visit 
Completed as close as 
possible to last dose 
IP 
Sponsor 
Termination 
Discontinued 
N/A 
No 
additional 
visits 
except 
EOT/EOS 
Combined visit 
Completed as close as 
possible to last dose 
IP 
Pregnancy 
Interrupted 
Retained 
Regular 
Visit 
Schedule 
Complete 
as close 
as 
possible 
to last 
dose IP 
Complete 
at Final 
study 
visit 
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; IP = investigational product 
a Refer to Section 7.1.1 Schedule of Study Procedures, Table 2 for all procedures and 
evaluations required at the End of Treatment and End of Study Visits.  
b Subjects may choose to re-consent, re-enter the study, and re-initiate IP at a later 
date.  Day 0 procedures will be repeated and the subject will resume in the visit 
window relative to the original Day 0. 
c   Includes initiation of commercially available OCA. 
d Outcomes data to be discussed or collected include data related to adjudicated hepatic and 
cardiovascular event-related data.  Additional data such as information on concurrent 
medical conditions, co-morbidities, relevant adverse events, and concomitant medications 
may be collected to help facilitate adjudication of these post-study events.   
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Section 
Original Text (Amendment 5, 
04 Jan 2018) 
Revised Text (Version 6, 05 Nov 2019) 
Justification 
for Change 
9.7.15, Early 
Discontinuation 
and/or Early 
Termination 
Procedures for 
Subjects that 
Withdraw from 
Investigational 
Product or 
Withdraw 
Consent 
New language added. 
During the EOT/EOS Visit: 
For subjects who prematurely terminate investigational product and/or 
the study, procedures outlined in Section 8.4.1 should be followed. 
Subjects who wish to re-initiate investigational product while participating 
in study follow-up or re-enter the study after having withdrawn consent or 
having discontinued treatment more than 3 months since the last visit 
must confirm that they have not received any investigational product 
being evaluated for the treatment of PBC within 30 days or commercial 
OCALIVA for three months before restarting investigational product or 
within 5 half-lives of the compound (whichever was longer).  Subjects are 
to be re-consented and new Day 0 visit procedures must be performed.  
The subject will resume the study in the visit window relative to their 
original Day 0 visit. 
Please refer 
to earlier 
justification 
for this 
change. 
12.1.1.5, 
Suspected 
Unexpected 
Serious Adverse 
Reactions 
New section was added.  
A suspected unexpected serious adverse reaction (SUSAR) is defined as a 
suspected adverse reaction which is assessed as serious, causally related to 
the investigational product, and unexpected per the reference safety 
information (RSI) in the Investigator’s Brochure.  
SUSARs are subject to expedited reporting. The Sponsor shall ensure that 
all relevant information about SUSARs that are fatal or life-threatening 
are recorded and reported as soon as possible to the relevant competent 
authorities (either directly or through the Eudravigilance Clinical Trials 
Module, as applicable), and to the Ethics Committees, no later than 7days 
after knowledge by the Sponsor of such a case. Relevant follow-up 
information is subsequently communicated within an additional 8 days. All 
other SUSARs shall be reported to the competent authorities concerned 
(either directly or through the Eudravigilance Clinical Trials Module) and 
to the Ethics Committees concerned, within a maximum of 15 days of first 
knowledge by the Sponsor. Each competent authority shall ensure that all 
SUSARs to an investigational product which are brought to its attention 
are recorded. The Sponsor shall also inform all participating Investigators, 
as applicable to the local regulations. 
Updated AE 
reporting 
requirements 
for SUSARs 
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Section 
Original Text (Amendment 5, 
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Revised Text (Version 6, 05 Nov 2019) 
Justification 
for Change 
14.1, Study 
Monitoring 
The Investigator may exercise judgment 
in allowing the CRA access to particular 
sections of the subject's medical records 
if these are deemed irrelevant to the 
performance, observations or conduct of 
this study. 
The Investigator may exercise judgment in allowing the CRA access to 
particular sections of the subject's medical records if these are deemed relevant 
to the performance, observations or conduct of this study. 
Revision was 
made to 
correct a 
typographical 
error 
17.3, Regulatory 
Documentation 
• 
Form FDA 1572 
• 
Form FDA 1572 or equivalent form for the Investigator’s region 
Revision was 
made for 
clarification 
purposes. 
 
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ADDENDUM 1 TO PROTOCOL 747-302 
Netherlands-specific monitoring of subjects receiving CYP2D6 substrates with a 
narrow therapeutic index 
PURPOSE 
To implement additional monitoring by investigators for subjects in the Netherlands 
receiving CYP2D6 substrates with a narrow therapeutic index, such as tricyclic 
antidepressants (TCAs), concomitantly with investigational product (obeticholic acid; 
OCA).  
OVERVIEW AND RATIONALE 
The following guidance is being provided based on feedback from the Medical Ethics 
Review Committee overseeing the 747-302 study in the Netherlands.  The Committee 
noted that specific data on drug interactions in subjects receiving CYP2D6 substrates 
with a narrow therapeutic index, such as TCAs, concomitantly with investigational 
product (OCA) are limited and recommended the implementation of additional 
monitoring in subjects who fall into this category. 
Currently there is no evidence of clinically meaningful interactions between OCA and 
CYP2D6 substrates.  The current United States Package Insert and European Union  
Summary of Product Characteristics for Ocaliva®, in Section 7 and Section 4.5, 
respectively, include potential interactions with warfarin, CYP1A2 substrates with a 
narrow therapeutic index, and bile acid binding resins but do not include specific mention 
of a potential interaction with CYP2D6 substrates with a narrow therapeutic index, 
consistent with the lack of evidence, at present, of clinically meaningful interactions 
between OCA and CYP2D6 substrates.  However, as data are limited, the Sponsor has 
agreed to incorporate the requested additional monitoring for subjects in the Netherlands 
concomitantly receiving TCAs.  
All information including, but not limited to, inclusion/exclusion criteria and study 
procedures provided in the current approved version of the study protocol should 
continue to be followed, in addition to the guidance provided below as a supplement to 
protocol Section 9.2 Concomitant Medications. 
9.2 CONCOMITANT MEDICATIONS 
9.2.2 Additional Guidance to the Investigator 
Subjects that receive CYP2D6 substrates with a narrow therapeutic index, such as TCAs, 
concomitantly with investigational product will require additional oversight by the 
Investigator.  Oversight should include close review of potential adverse events (AEs) 
associated with CYP2D6 substrates with a narrow therapeutic index and evaluation of 
untoward events including worsening of psychiatric symptoms.  Dose adjustments to 
concomitant CYP2D6 substrate and/or investigational product should be made based 
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upon the Investigator’s clinical judgement and on the safety, tolerability, and efficacy of 
the substrate.  
The Sponsor will continue to evaluate and discuss Investigator concerns regarding AEs 
associated with the use or discontinuation of CYP2D6 substrates to ensure protection of 
subjects enrolled in the 747-302 study. 
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Investigator’s Signature: 
I have received and read the current version of the Investigator’s Brochure (IB) for 
INT-747 (OCA/Obeticholic acid) and this Protocol 747-302 Addendum 1.  Having fully 
considered all the information available, I agree that it is ethically justifiable to give 
INT-747 to selected subjects/patients according to this protocol. 
I understand that all information concerning INT-747 supplied to me by the Sponsor, 
Intercept Pharmaceuticals, Inc., and/or its agents in connection with this trial and not 
previously published is confidential information.  This includes the IB, Clinical Trial 
Protocol, CRFs, 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 747-302 and its 
addendum and in accordance with Good Clinical Practice (CPMP/ICH/135/95), 
21CFR Part 312, and all applicable regulatory requirements. 
I acknowledge that the Sponsor of the trial has the right to discontinue the trial at any 
time. 
 
 
_________________________________________________ 
_____________ 
Investigator 
 
 
 
 
 
 
 
Date 
 
 
_________________________________________________ 
Print Name 
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1. 
TITLE PAGE 
 
 
Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cholangitis 
 
THE COBALT STUDY 
Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) 
 
Addendum 2:  27 April 2017 
 
EudraCT Number: 2014-005012-42 
 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA  92121 
USA 
 
TEL:  858-650-6398 
 
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 167 of 1682


Addendum 2: 27 Apr 2017
SPONSOR'S APPROVAL OF THE PROTOCOL ADDEI\DI]M
Reviewed and Approved by:
PhD
4l&l tT
 Clinical Development
Intercept Pharmaceuticals, Inc.
Confidential and Proprietary
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Protocol 747-302  
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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 747-302, 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 
addendum. 
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 (CRFs), 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 747-302 and this addendum, 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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PROCEDURES IN CASE OF EMERGENCY 
 
Sponsor Contact Information 
Medical Monitor – 24-hour Emergency Reporting 
Primary Contact:   
 MD, Medical Director, Drug Safety,  
Intercept Pharmaceuticals, Inc. 
Mobile: 
 
Telephone: 
 (Pacific time zone) 
Email: 
 
SAE Fax: 
+1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
 
Or if Not Available: 
Contact: 
 MD, PhD, Medical Director, Clinical Research, 
Intercept Pharmaceuticals, Inc. 
Mobile: 
 
Telephone: 
 (Pacific time zone) 
Email: 
 
 
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Protocol 747-302  
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2. 
TABLE OF CONTENTS  
 
1. 
TITLE PAGE ................................................................................................................1 
2. 
TABLE OF CONTENTS .............................................................................................5 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...............................6 
4. 
OVERVIEW AND RATIONALE ...............................................................................7 
5. 
OBJECTIVES ...............................................................................................................7 
6. 
DETAILS OF THE ADDIONAL PROCEDURES ......................................................8 
 
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this protocol. 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
APRI 
aspartate aminotransferase to platelet ratio index 
CRF 
case report form 
ELF 
enhanced liver fibrosis 
EOS 
end of study 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
IB 
Investigator’s Brochure 
OCA 
obeticholic acid 
PBC 
primary biliary cholangitis (also known as primary biliary 
cirrhosis) 
TE 
transient elastography 
 
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4. 
OVERVIEW AND RATIONALE 
Study 747-302 is a Phase 41, double-blind, placebo-controlled, multicenter study to investigate 
the effects of obeticholic acid (OCA) in subjects with primary biliary cholangitis (PBC, also 
called primary biliary cirrhosis), with high risk of liver-related clinical complications.  
Liver biopsy is no longer mandatory for diagnosis of PBC; however, biopsies can provide 
important information to assess the severity of the disease, as well as prognosis, progression, and 
response to treatment.  A paired biopsy substudy was, therefore, recommended by Regulatory 
Authorities, to further assess clinical outcomes in terms of histological progression to cirrhosis.  
This addendum2 to the 747-302 Study Protocol defines the paired biopsy substudy to assess the 
effect of OCA versus placebo on the histological severity of disease (fibrosis/cirrhosis) in 
subjects with PBC.  This substudy will also explore the relationship between histological 
changes in the liver versus clinical, laboratory, and noninvasive measures indicative of 
progression to cirrhosis in subjects with PBC treated with OCA.  
All information including, but not limited to, inclusion/exclusion criteria and study procedures 
provided in the current approved version of the study protocol should be followed, in addition to 
the guidance provided below. 
5. 
OBJECTIVES 
Primary Objective 
• To assess the effect of OCA compared to placebo on the histological severity of PBC 
by assessing the following:  
− Progression to cirrhosis, in subjects who are noncirrhotic at Baseline 
− Improvement in fibrosis/cirrhosis, in subjects who are cirrhotic at Baseline 
Secondary Objectives 
• To assess the effect of OCA on the histological changes in the liver 
• To assess the relationship between histological changes and measurements (clinical, 
laboratory, and noninvasive) indicative of progression to cirrhosis in subjects with 
PBC.  Noninvasive measurements include the following: 
− Transient Elastography (TE) 
− Noninvasive scores of liver fibrosis including enhanced liver fibrosis (ELF), and 
aspartate aminotransferase to platelet ratio index (APRI) 
                                                 
1 Study 747-302 is considered a Phase 4 study in regions where OCA has received regulatory approval for primary 
biliary cholangitis (PBC, also called primary biliary cirrhosis), ie, in the US and the EU; in all other regions, this 
study is considered Phase 3b.  In May 2016, the United States Food and Drug Administration (FDA) granted 
accelerated approval for OCA (Ocaliva) for the treatment of PBC.  In December 2016, Ocaliva received 
Conditional Approval from the European Medicines Agency’s Committee for Medicinal Products for Human Use.  
2 Note: Addendum 1 (dated 18 Jan 2017) to protocol 747-302 is a country-specific addendum.   
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6. 
DETAILS OF THE ADDIONAL PROCEDURES 
SUBJECT POPULATION AND STUDY CENTERS 
Number of Subjects:  This substudy will enroll approximately 45 subjects.  
Eligibility:   
• Subjects who are participating in the 747-302 study and meet all eligibility criteria in 
the current version of the main protocol.   
− For subjects who require a baseline biopsy, Screening Visit 1 data should be 
available, and a preliminary eligibility assessment should be performed, before 
the baseline biopsy sample is collected.   
− Subjects must remain enrolled in the main protocol to continue participation in 
biopsy substudy. 
• Must provide written informed consent and agree to comply with the requirements of 
the substudy protocol. 
• Is able to safely undergo a liver biopsy, in the opinion of the Investigator. 
• Subjects currently enrolled in the study who have not yet presented with signs and 
symptoms of progression to cirrhosis may also participate, provided a biopsy sample 
obtained ≤6 months prior to Day 0 is available. 
Study Centers: All sites participating in the 747-302 study with the capability to perform serial 
biopsies may participate in this optional substudy.  
STUDY PROCEDURES 
In addition to the procedures described in Section 7.1 of the main study protocol, the subjects 
enrolled in the biopsy substudy will also complete biopsy and additional noninvasive fibrosis 
assessments described in this addendum. 
Biopsy 
The goal of this substudy is to maximize the availability of data while minimizing the number of 
biopsies performed.  Thus, all subjects who consent to participate in this substudy will undergo a 
biopsy at Baseline (if none available from ≤6 months prior to Day 0) prior to initiating 
investigational product, and, based on the results of that biopsy, again upon clinical evidence of 
progression to cirrhosis or at the end of the treatment (EOT) or End of Study (EOS); see 
Table 1).  This strategy will allow for both histological confirmation of progression to cirrhosis, 
as well as possible histological improvement following treatment with OCA. 
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Table 1: 
Timing of Second Biopsy 
If Baseline biopsy result is: 
then second biopsy will be obtained at: 
Noncirrhotic 
• 
The time of presentation of clinical signs and symptoms of 
cirrhosis, or 
• 
The EOT (if the subject will continue to attend study visits) or 
EOS visit if no presentation of clinical signs and symptoms of 
cirrhosis during study, whichever comes first 
Cirrhotic 
• 
EOT (if the subject will continue to attend study visits) or EOS, 
whichever comes first 
EOT = end of treatment; EOS = end of study 
Biopsy-Related Assessments: 
• Baseline Biopsy may be performed at any time after the Screening Visit 1 eligibility 
criteria have been reviewed and prior to Day 0.  If a biopsy was obtained no more 
than 6 months before Day 0 and slides or sample quantity are sufficient and suitable 
for baseline reading, a biopsy at Screening need not be repeated.  Baseline biopsy 
must be collected prior to the first dose of the investigational product. 
• Post-treatment Biopsy:  If a subject develops evidence of probable progression to 
cirrhosis as assessed by the indicators listed below, the post-treatment biopsy will be 
performed as close as possible to when progression to cirrhosis is determined by the 
Investigator, and within approximately 3 months of progression.  Biopsy reports and 
available clinical, laboratory, and radiological assessments will be used as a basis for 
adjudication by the hepatic outcomes adjudication committee to assure that all events 
of progression to cirrhosis meet predefined criteria and are consistent across sites. 
• EOT or EOS Biopsy:  Biopsy will be performed as part of the EOT/EOS procedures 
on all subjects who have not already had a post-treatment biopsy based on evidence 
of the clinical, laboratory, or radiological indicators of progression to cirrhosis during 
the course of the study.  If, for scheduling purposes, a biopsy cannot be completed as 
part of the EOT/EOS Visit, the biopsy should be scheduled as close as possible to the 
actual EOT/EOS Visit date. 
Non-invasive Fibrosis Assessments: 
TE will be performed when a subject develops evidence of probable progression to cirrhosis.  In 
addition, laboratory samples needed to obtain noninvasive scores of liver fibrosis (ELF and 
APRI) will also be collected at the time a subject develops evidence of probable progression to 
cirrhosis. 
ASSESSMENT OF EFFICACY 
Liver Biopsy Instructions and Central Reading of Liver Histology 
Full instructions concerning the number and type of samples to be collected at each visit, the 
sample collection methods, sample processing, labeling, and shipping will be provided by the 
Sponsor in a study-specific histology manual.  Collection supplies will be provided by the central 
laboratory and will be appropriately assembled for the specific evaluations required at each visit. 
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Liver biopsies will generally be obtained from the right lobe of the liver as described in a 
study-specific histology manual.  If the initial biopsy was obtained from the left lobe, then 
subsequent biopsies should be obtained from the left lobe, and vice versa. 
All biopsy assessments, including screening and histology efficacy assessments, will be 
performed by study pathologist/central reader blinded to the treatment group assignment.  The 
biopsies will be graded by a central reader using a pre-defined scoring system.  Detailed 
information related to biopsy scoring will be provided to the central reader by the Sponsor in a 
study-specific histology manual. 
Paired biopsies (Screening/Baseline biopsy and post-treatment [or EOT/EOS] biopsy) will be 
read by a central reader blinded to the treatment group assignment.  
Biopsy Criteria for Progression to Cirrhosis 
The following criteria will be used for adjudication of progression to cirrhosis: 
• Persistent (ie, 2 consecutive measurements obtained at least 3 months apart) elevation 
in Fibroscan® TE >16.9 kPa, AND/OR 
• Presence of any of the following: 
− Gastroesophageal varices 
− Ascites 
− Radiological evidence of cirrhosis (nodular liver or enlargement of portal vein 
and splenomegaly) 
− Combined low platelet count (<140,000/mm3), with any of the following criteria: 
 
Persistent decrease in serum albumin, OR 
 
Elevation in prothrombin time/international normalized ratio (not due to 
antithrombotic agent use), OR 
 
Elevated total bilirubin >2x upper limit of normal 
Transient Elastography 
TE assessment will be performed at the investigational sites, where the device is available, using 
the Fibroscan instrument (Echosens, Paris, France), to assess liver fibrosis. 
Noninvasive Scores of Liver Fibrosis 
ELF score will be calculated using an algorithm that combines serum values of tissue inhibitor of 
metalloproteinases-1, procollagen type-3 N-terminal propeptide, and hyaluronic acid.  Likewise, 
APRI score will be obtained from serum aspartate aminotransferase and platelet values.  
ASSESSMENT OF SAFETY 
Safety assessments will be performed as in Section 12 of the main protocol.  In addition, the 
Investigator will document her/his opinion of the relationship of the adverse events (AEs) to liver 
biopsy using the criteria outlined in Table 2.  
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Table 2: 
Relationship of Adverse Events to Liver Biopsy 
Relationship 
Description 
Related 
A reaction that follows a reasonable temporal sequence from the liver biopsy; that follows a 
known or expected response pattern to the liver biopsy. 
Not Related 
Any event that does not meet the above criteria. 
STATISTICAL METHODS 
Primary Efficacy Analysis 
For each treatment group, the number and the proportion of subjects with and without biopsy-
assessed cirrhosis determined at EOT/EOS will be presented in a shift table from Baseline to the 
EOT/EOS, separated for two baseline biopsy-assessed cirrhosis status (ie, cirrhosis versus 
noncirrhosis).  For baseline noncirrhotic subjects without an EOT/EOS biopsy, the cirrhosis 
status will be presented in a shift table from Baseline to the time when a post-treatment biopsy is 
performed.  The proportion of subjects that have cirrhosis status change will be compared 
between OCA treatment group and placebo group.  
In addition, for the subset of subjects who were noncirrhotic at Baseline, Kaplan-Meier estimates 
of the time to cirrhosis (as assessed by biopsy) will be summarized and graphed by treatment 
group. 
Secondary Efficacy Analyses 
The TE, ELF and APRI scores will be summarized by treatment group using descriptive 
statistics at Baseline and at each on-study evaluation.  The change from Baseline and percentage 
change from Baseline will also be summarized.  Baseline is defined as the mean of all available 
evaluations before treatment.  Further details will be specified in the statistical analysis plan. 
Determination of Sample Size 
Based on the participation of approximately 10% of subjects in the optional biopsy component of 
the Phase 3 Study 747-3013, a similar percent of subjects are expected to consent to participate in 
this substudy.  With total enrollment anticipated to be 428 subjects, approximately 45 subjects 
are expected to enroll in this substudy.  
Assuming 45 subjects are noncirrhotic at Baseline, the biopsy data from 45 subjects will provide 
73% power to detect a difference in the event rate of progression to cirrhosis when OCA event 
rate is 0.23 (approximately 50% risk reduction); or 59% power to detect a difference in the event 
rates of progression to cirrhosis when OCA event rate is 0.28 (approximately 45% risk 
reduction) at a significance level of 0.1 for a one-sided test and placebo group’s event rate is 0.5.  
The above statistical justification is based on the assumptions that the biopsy substudy will have 
subjects with a close to 1:1 ratio between placebo and OCA arm. 
                                                 
3 A Phase 3, Double Blind, Placebo Controlled Trial and Long Term Safety Extension of Obeticholic Acid in 
Patients with Primary Biliary Cirrhosis. ClinicalTrials.gov number, NCT01473524. 
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ADJUDICATION COMMITTEE 
Adjudication of progression of cirrhosis will be performed by an independent hepatic outcomes 
adjudication committee (refer to Section 13.4 in “Adjudication Committee” subsection of the 
main protocol).  All available documentation of progression to cirrhosis, including biopsy 
reports, will be made available to the adjudicators. 
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Clinical Study Protocol 747-302 
OBETICHOLIC ACID (OCA) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cholangitis 
 
THE COBALT STUDY 
Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) 
 
Addendum 1:  02 Jan 2018 
Country-Specific Addendum for Turkey 
 
EudraCT Number:  2014-005012-42 
 
Sponsor 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA  92121 
USA 
 
TEL:  858-652-6800 
FAX:  858-558-5961 
 
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 747-302
Addendum I (Turkey): 02 Jan 2018
Paee2
SPONSOR'S APPROVAL OF THE PROTOCOL ADDEI\IDTJM
Reviewed and Approved by:
4 sroao?
PhD
 Clinical Development
Intercept Pharmaceuticals, Inc.
Confidential and Proprietary
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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 747-302, 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 747-302 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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COUNTRY-SPECIFIC ADDENDUM TO PROTOCOL 747-302:  TURKEY 
1. 
OVERVIEW AND RATIONALE 
The purpose of this Country-Specific Protocol Addendum (dated 02 Jan 2018) is to revise the study 
phase from Phase 4 to Phase 3b in Turkey for Protocol 747-302.  Obeticholic acid (OCA) has 
received regulatory approval in a number of regions (United States, European Union, and Canada) 
for the treatment of PBC in combination with UDCA in adults with an inadequate response to 
UDCA or as monotherapy in adults unable to tolerate UDCA.  Based on this regulatory approval, 
the phase of the 747-302 study changed to Phase 4 with Protocol Version 4 to reflect that this study 
is now considered a post-marketing study in these regions, where the majority of participating sites 
and countries in the 747-302 study are also located.  However, as OCA has not yet received 
regulatory approval in Turkey, this addendum was issued to document that Study 747-302 is 
considered a Phase 3b study in Turkey. 
The following referenced sections of the protocol reflect this change: 
Title Page and Synopsis, Title of Study:  A Phase 3b, Double Blind, Randomized, Placebo 
Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in 
Subjects with Primary Biliary Cholangitis 
Synopsis, Phase of Development:  3b 
Synopsis, Methodology:   
This Phase 3b, double-blind, randomized, placebo-controlled, multicenter study will evaluate the 
effect of OCA on clinical outcomes in subjects with PBC.   
Section 7.1, Overall Study Design 
This is a Phase 3b, double-blind, randomized, placebo-controlled, multicenter study.   
A copy of this addendum should be filed alongside the current approved version of the study protocol 
at all investigative sites in Turkey.  All information including, but not limited to, inclusion/exclusion 
criteria and study procedures provided in the current approved version of the study protocol should 
continue to be followed. 
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SAP_001.pdf: 
 
TITLE PAGE 
 
Statistical Analysis Plan 
OBETICHOLIC ACID (OCA) 
747-302 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cholangitis 
 
THE COBALT STUDY 
Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) 
 
 
EudraCT Number:  2014-005012-42 
ClinicalTrials.gov Identifier: NCT02308111 
 
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 747-302 
16.1.9 Documentation of Statistical Methods 
Page 1
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16.1.9 
DOCUMENTATION OF STATISTICAL METHODS 
747-302 Statistical Analysis Plan v5 30Mar2022
747-302 Clinical Pharmacology Analysis Plan v1 12Apr2022
747-302 Statistical Analysis Plan for Interim Analysis v1 20Aug2020
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OBETICHOLIC ACID (OCA) 
 
747-302 
THE COBALT STUDY 
Clinical Outcomes with OBeticholic Acid in Liver Treatment (COBALT) 
 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cholangitis 
 
 
Statistical Analysis Plan  
 
 
 
 
Author: 
 Ph.D.   
Associate Director, Biostatistics, Intercept Pharmaceutical 
 
 
Protocol Version and Date: 
Version 6:  05 November 2020 
Analysis Plan Version: 
5 
Analysis Plan Date: 
30 March 2022 
 
 
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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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
SCOPE ..........................................................................................................................8 
2. 
STUDY OBJECTIVES AND HYPOTHESES ............................................................8 
2.1. 
Study Objectives ...........................................................................................................8 
2.1.1. 
Primary Objective .........................................................................................................8 
2.1.2. 
Secondary Objectives ...................................................................................................9 
2.2. 
Hypotheses ..................................................................................................................10 
2.2.1. 
Primary Hypothesis ....................................................................................................10 
2.2.2. 
Secondary Hypothesis ................................................................................................10 
3. 
SUMMARY OF STUDY DESIGN............................................................................11 
3.1. 
Randomization and Blinding ......................................................................................12 
3.2. 
Sample Size Determination ........................................................................................12 
4. 
ANALYSIS POPULATIONS AND APPROACHES TO ANALYSIS ....................13 
4.1. 
Intent-to-Treat (ITT) Population .................................................................................13 
4.2. 
Per Protocol (PP) Population ......................................................................................13 
4.3. 
Safety Population ........................................................................................................14 
4.4. 
Pharmacokinetic (PK) Population ..............................................................................14 
5. 
SUBJECT DISPOSITION ..........................................................................................14 
5.1. 
Protocol Deviations ....................................................................................................14 
6. 
DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS ................14 
7. 
PRIOR THERAPY AND MEDICAL HISTORY ......................................................15 
8. 
EFFICACY ANALYSES ...........................................................................................16 
8.1. 
Primary Efficacy Endpoint .........................................................................................16 
8.1.1. 
Primary Analyses ........................................................................................................17 
8.1.2. 
Sensitivity Analyses ....................................................................................................18 
8.1.2.1. 
Win Ratio ....................................................................................................................20 
8.2. 
Key Secondary Efficacy Endpoints ............................................................................23 
8.2.1. 
Analyses of the Secondary Endpoints ........................................................................24 
8.2.2. 
Sensitivity Analyses ....................................................................................................24 
8.3. 
Additional Secondary Efficacy Endpoints ..................................................................24 
8.3.1. 
Time to Event Analyses ..............................................................................................24 
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8.3.2. 
Liver Biochemistry Analyses .....................................................................................25 
8.3.3. 
Prognostic Endpoints and Markers of Inflammation ..................................................26 
8.4. 
Exploratory Efficacy Analyses ...................................................................................26 
8.4.1. 
Acute-on-Chronic Liver Failure (ACLF) ...................................................................26 
8.4.2. 
Biochemical Responder Analyses ..............................................................................26 
8.4.3. 
Time-to-Event by Biochemical Response ..................................................................27 
8.4.4. 
Liver Histology ...........................................................................................................27 
8.5. 
Interim Analyses .........................................................................................................28 
8.6. 
Multiple Comparisons/Multiplicity ............................................................................28 
8.7. 
Subgroup Analyses of Efficacy ..................................................................................28 
9. 
SAFETY ANALYSES ...............................................................................................30 
9.1. 
Exposure to Study Treatment .....................................................................................30 
9.2. 
Adverse Events ...........................................................................................................31 
9.2.1. 
Treatment-Emergent Adverse Events .........................................................................31 
9.2.2. 
Serious Adverse Events (SAE) ...................................................................................31 
9.2.3. 
Adverse Events of Special Interest (AESI) ................................................................32 
9.2.4. 
TEAE Analyses ..........................................................................................................32 
9.3. 
Adjudicated Cardiovascular Events ............................................................................34 
9.4. 
Clinical Laboratory Evaluations .................................................................................34 
9.4.1. 
Hematology and Coagulation .....................................................................................34 
9.4.2. 
Chemistry ....................................................................................................................34 
9.5. 
Vital Signs ..................................................................................................................35 
9.6. 
Electrocardiograms .....................................................................................................35 
9.7. 
Concomitant Medications ...........................................................................................35 
9.8. 
Subgroup Analyses of Safety ......................................................................................35 
10. 
PHARMACOKINETIC ANALYSES ........................................................................36 
11. 
PHARMACOECONOMIC AND HEALTH OUTCOMES ANALYSES .................36 
12. 
PHARMACODYNAMIC ANALYSES .....................................................................36 
13. 
EXTERNAL CONTROL COMPARISON ................................................................36 
14. 
DEVIATIONS FROM PROTOCOL ..........................................................................36 
14.1. 
Primary Efficacy Endpoint and Analysis ...................................................................36 
14.2. 
Number of Interim Analyses ......................................................................................37 
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15. 
REFERENCES ...........................................................................................................38 
APPENDIX A. GENERAL ANALYSIS RULES AND DATA CONVENTIONS ...................39 
Baseline Definitions .......................................................................................................................39 
Visit Windows ...............................................................................................................................40 
Partial Dates ...................................................................................................................................40 
Data Conventions ...........................................................................................................................41 
Standard Calculations ....................................................................................................................42 
Inverse Probability of Censoring Weighting .................................................................................44 
Multiple Imputation (Missing Not At Random) Description ........................................................44 
 
 
LIST OF TABLES 
Table 1: 
MELD and MELD-Na Score Imputations for Missing Components at Any 
Given Timepoint .........................................................................................................17 
Table 2: 
Stopping Criteria Based on O’Brien-Fleming Boundaries .........................................37 
 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram Study 747-302 ............................................................................11 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical 
CI 
confidence interval 
CIF 
cumulative incidence function 
CK-18 
cytokeratin-18 
CLIF-C ADs 
Chronic Liver Failure Consortium Acute Decompensation score 
CP 
Child-Pugh 
CRF 
case report form 
CRP 
C-reactive protein 
CS 
clinically significant 
CSPH 
clinically significant portal hypertension 
CSR 
clinical study report 
DMC 
Data Monitoring Committee 
CMH 
Cochran–Mantel–Haenszel 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EHR 
electronic health records 
ELF 
enhanced liver fibrosis 
EMA 
European Medicines Agency 
FGF-19 
fibroblast growth factor-19 
GGT 
gamma-glutamyl transferase 
HCC 
hepatocellular carcinoma 
HR 
hazard ratio 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio  
IP 
investigational product 
IPCW 
Inverse Probability of Censoring Weighting 
IPTW 
Inverse Probability of Treatment Weights 
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Abbreviation or Specialist Term 
Explanation 
IWRS 
interactive web response system 
KM 
Kaplan-Meier 
LS 
least-squares 
MELD 
Model for End-Stage Liver Disease  
MMRM 
Mixed-effect Model Repeated Measures 
MRS 
Mayo risk score 
NCS 
not clinically significant 
OCA 
obeticholic acid 
ORAE 
on-risk adverse event 
PBC 
primary biliary cholangitis  
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PMN 
polymorph leucocytes 
PT 
preferred term 
QTcF 
QT interval corrected by the Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SEM 
standard error of the mean 
SOC 
system organ class 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
TNF-α 
tumor necrosis factor-alpha 
UDCA 
ursodeoxycholic acid 
UK 
United Kingdom  
ULN 
upper limit of normal 
US 
United States (of America) 
USPI 
United States Prescribing Information 
VLDL 
very low density lipoprotein 
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1.
SCOPE
This statistical analysis plan (SAP) describes the statistical analyses and data presentations 
planned for Protocol 747-302, Clinical Outcomes with OBeticholic Acid in Liver Treatment 
(COBALT), Version 6.  It provides a detailed description of the strategy, rationale, and statistical 
methods to be used to meet the study objectives, as well as additional details to the statistical 
analyses that were described in the study protocol.  Any deviations from the methods specified in 
this SAP will be documented in the clinical study report (CSR).  If after the database lock 
additional analyses are required to supplement the planned analyses described in this SAP or any 
addendums, they will be identified as post-hoc in the CSR.   
2.
STUDY OBJECTIVES AND HYPOTHESES
2.1. 
Study Objectives
To support the primary objective, the primary efficacy endpoint has been expanded beyond what 
was outlined in Protocol Version 6.  Further details are presented in Section 14.1. 
2.1.1. 
Primary Objective 
The primary objective of this study is to compare the effect of obeticholic acid (OCA) to 
placebo, in conjunction with established local standard of care, on clinical outcomes in subjects 
with primary biliary cholangitis (PBC) as measured by time to first occurrence of the following 
adjudicated events, derived as a composite event endpoint (including all Group 1 – Group 3 
events).   
Group 1: 
•
Death (all-cause)
•
Liver transplant
•
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 (confirmed by diagnostic paracentesis OR
presence of >250/mm3 polymorph leucocytes [PMNs] in the ascitic fluid)
−
Bacterial empyema (confirmed by diagnostic thoracentesis OR presence of
>250/mm3 PMNs in the pleural fluid)
•
Uncontrolled or refractory ascites (requiring large volume paracentesis)
•
Portal hypertension syndromes:
−
Hepatorenal syndrome (as defined by International Ascites Club [Angeli 2019])
−
Portopulmonary syndrome
−
Hepatopulmonary syndrome
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• Model of end-stage liver disease (MELD)-Na score ≥15 if MELD-Na <12 at baseline 
• MELD score ≥15 if MELD-Na ≥12 at baseline 
Group 2: 
• Progression to decompensated liver disease (for subjects without decompensation at 
baseline), prioritized as follows: 
− New onset of: 
 
Hepatic hydrothorax 
 Variceal bleeding 
 Ascites requiring treatment with sodium restriction, diet modification, or 
 
diuretics 
− Hepatic encephalopathy requiring lactulose and/or rifaximin 
− New onset of: 
 
Child-Pugh ≥7 
 
Total bilirubin >3 mg/dL 
Group 3: 
• Progression to clinical evidence of portal hypertension without decompensation (for 
subjects without decompensation or clinical evidence of portal hypertension at 
baseline) 
− Endoscopic evidence of portal hypertension without bleeding 
 
Gastroesophageal varices (requiring banding or progression to large 
 
varices if no or small varices were observed at baseline) 
 
Portal hypertensive gastropathy 
− Platelets <150 × 109/L with splenomegaly and/or with transient elastography 
>15 kPa 
2.1.2. 
Secondary Objectives 
• To assess the effect of OCA compared to placebo on time to first occurrence of death, 
liver transplant, MELD-Na score ≥15 if MELD-Na< 12 at baseline, MELD score ≥15 
if MELD-Na ≥12 at baseline, uncontrolled or refractory ascites, portal hypertension 
syndromes (hepatorenal syndrome, portopulmonary syndrome, hepatopulmonary 
syndrome), or hospitalization for new onset or recurrence of variceal bleed, hepatic 
encephalopathy, spontaneous bacterial peritonitis, or bacterial empyema. 
• To assess the effect of OCA compared to placebo on time to first occurrence of death, 
liver transplant, MELD ≥15, uncontrolled ascites, or hospitalization for new onset or 
recurrence of variceal bleed, hepatic encephalopathy, or spontaneous bacterial 
peritonitis. 
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• To assess the effect of OCA compared to placebo on time to first occurrence of each 
individual component of the primary endpoint as listed above. 
• To assess the effect of OCA compared to placebo on time to occurrence of liver-
related death.   
• To assess the effect of OCA compared to placebo on progression to cirrhosis.   
• To assess the effect of OCA compared to placebo on time to occurrence of 
hepatocellular carcinoma (HCC). 
• To assess the effect of OCA compared to placebo on disease progression via the 
following: 
− Liver biochemistry 
− Markers of inflammation and fibrosis 
• To characterize the PK of OCA and its conjugates in a subset of subjects. 
• To assess health outcomes and pharmacoeconomics including cost-effectiveness, 
resource utilization, and quality of life measures in subjects treated with OCA 
compared to placebo. 
• To assess the safety and tolerability in subjects treated with OCA compared to 
placebo. 
2.2. 
Hypotheses 
2.2.1. 
Primary Hypothesis 
The study is intended to assess whether there is a difference between OCA and placebo in the 
time from baseline to the first occurrence of the composite event endpoint (as defined in 
Section 2.1.1, Groups 1 – 3).  
Two-sided hypotheses are expressed in terms of: 
• The null hypotheses (H0) that the two hazard rates (hOCA, hPlacebo) are the same, that is, 
that there is no difference between the OCA and placebo populations in the 
probability of an event at any timepoint.  
• The alternative hypothesis (H1) that the two hazard rates are not the same (hOCA ≠ 
hPlacebo) 
2.2.2. 
Secondary Hypothesis 
The secondary hypotheses are intended to assess whether there is a difference between OCA and 
placebo in the time from baseline to the first occurrence of the composite event endpoint (as 
defined in Section 2.1.1) and other time-to-event endpoints.   
Two-sided hypotheses are expressed in terms of: 
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• The null hypotheses (H0) that the two hazard rates (hOCA, hPlacebo) are the same, that is, 
that there is no difference between the OCA and placebo populations in the 
probability of an event at any timepoint.   
• The alternative hypothesis (H1) that the two hazard rates are not the same 
(hOCA ≠ hPlacebo) 
3. 
SUMMARY OF STUDY DESIGN 
This Phase 4, double-blind, randomized, placebo-control, multicenter study will evaluate the 
effect of OCA on clinical outcomes in subjects with PBC who are at higher risk of liver-related 
clinical complications. 
Eligible subjects will have a diagnosis of PBC with bilirubin levels >ULN and ≤5x ULN and/ or 
ALP >3× ULN.  Subjects will be screened twice during a 1- to 8-week Screening period prior to 
entering the study to allow for the collection of repeat serum chemistry samples (at least 2 weeks 
apart) to confirm pretreatment alkaline phosphatase (ALP) and total bilirubin values. 
Investigational product (IP) will be taken orally, once daily for the majority of subjects; dose and 
frequency will be modified for subjects with cirrhosis (including subjects progressing to cirrhosis 
during the study) and classified as Child-Pugh B or C.  The randomization will be stratified by 
ursodeoxycholic acid (UDCA) treatment (yes/ no) and baseline bilirubin categories (> upper limit 
of normal [ULN]/ ≤ULN).  A minimum of 30% of subjects will have elevated bilirubin (>ULN) 
at Screening. 
The study is event driven and will continue until approximately 127 adjudicated primary 
endpoint events have been accrued in unique subjects, or until the Sponsor (eg, based on a 
recommendation from the Data Monitoring Committee (DMC)) terminates the study.  Subjects 
are expected to be followed for a minimum of approximately 6 years.  Figure 1 below displays 
the study design diagram.  Schedules of study procedures are outlined in Table 1 (Screening to 
Month 12) and Table 2 (Year 2 to End-of-Study Endpoints) of the study protocol, where more 
details are provided. 
Figure 1: 
Schematic Diagram Study 747-302 
 
EOS = end of study; M = month, OCA = obeticholic acid; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for subjects on all 
dosing regimens, based on tolerability and biochemical response (Up-titration should be considered when ALP and/ or total 
bilirubin are >ULN).  Subsequent dose titration(s) for subjects classified as Child Pugh B or Child-Pugh C and following a 
modified dosing schedule may occur no earlier than 6 weeks after the previous dose titration.
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Dosing frequency will be determined by the presence or absence of cirrhosis and, if cirrhosis is 
present, by Child-Pugh Score as described below: 
 
Planned Dosing Regimen 
Standard 
Modified 
Noncirrhotic/ 
Child-Pugh A 
Child-Pugh B or  
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weekly 
 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weekly 
 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject tolerability, biochemical response, 
and/or changes in cirrhosis status or Child-Pugh Score at any time during the study 
c Dosing per the twice weekly schedule must be at least 3 days apart. 
With the exception of liver transplant, if a subject experiences a suspected or confirmed clinical 
outcomes event, the subject should continue the regular visit schedule and continue taking IP as 
long as the subject has not met any of the criteria for discontinuation outlined in the protocol.  
Subjects who discontinue IP are expected to be followed through to study closure (or at the 
discretion of the Sponsor).   
3.1. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Allocation to one of 
two treatment groups (OCA or placebo) will occur on a 1:1 ratio across sites and will be 
stratified by UDCA treatment (yes/no) and mean baseline bilirubin categories (>ULN/≤ULN), as 
specified by the central laboratory.  The randomization will be based on a predefined 
randomization code (generated by the Sponsor or designee) using an interactive web response 
system (IWRS).  The IWRS will also serve as an investigational product inventory and 
management system and may be integrated with the study database.   
The unblinded data access during DMC and interim analysis is described in Safety Review 
Committee Charter. 
3.2. 
Sample Size Determination 
The following assumptions were used in the Protocol Version 6 sample size calculations:  
• Exponential survival curves, placebo survival estimate of 0.6 at 8 years with a hazard 
ratio of 0.60, and total study duration of 10 years (from first subject enrolled), 
allowing for 4 years of subject accrual and 6 years of follow up. 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA. 
• The 2 treatment groups will be compared using a 2-sided log rank test at the 5% level 
of significance. 
• Two interim analyses and one final analysis are planned, with interim analyses 
occurring after the accrual of 50% and 75% of clinical outcome events, respectively. 
• A dropout rate of 10% is assumed 
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Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
127 events (both groups combined) was to provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to liver-related outcomes, including 
all-cause mortality. 
In addition, based on the remaining assumptions stated above, it was estimated that 
approximately 428 subjects would be enrolled to attain 127 events.   
Sample size calculations were based on the following composite endpoint: time to first 
occurrence of death, liver transplant, MELD ≥15, uncontrolled ascites, or hospitalization for new 
onset or recurrence of variceal bleed, hepatic encephalopathy, or spontaneous bacterial 
peritonitis.   
Due to enrollment challenges and difficulties to keep patients in the study, the trial will be 
terminated early by sponsor.  To better evaluate the benefit-risk ratio, the composite endpoint 
will be revised to include additional components that occur earlier in the progression of PBC   
4. 
ANALYSIS POPULATIONS AND APPROACHES TO ANALYSIS 
4.1. 
Intent-to-Treat (ITT) Population 
The ITT Population includes all randomized subjects who receive any amount of investigational 
product (OCA or placebo).  The ITT Population will be the primary population used for efficacy 
analyses.  Treatment assignment will be based on the randomized treatment. 
4.2. 
Per Protocol (PP) Population 
The PP Population includes ITT subjects who do not have any major protocol deviations that 
potentially affect the primary efficacy conclusion.  Major protocol deviations that exclude 
subjects from the PP population are: 
• Subject randomized into the study despite not meeting inclusion criteria or meeting 
exclusion criteria. 
• Potential overdose, i.e.  investigational product compliance >120%, unless there’s 
clear documentation. 
• Subject met protocol criteria for down-titration, but dose was not adjusted. 
• Prohibited change in concomitant medication whilst actively on the study, including 
commercial OCA. 
• SAE not reported or not reported in required timeframe. 
• Failure to submit local subject level safety events per IRB/EC policy. 
• Withdraw criteria met, but subject not discontinued. 
The PP Population will be used for the sensitivity analyses of the primary and key secondary 
efficacy endpoints.  Treatment assignment will be based on the randomized treatment.  PP 
patients list will be determined prior to unblinding. 
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4.3. 
Safety Population 
The Safety Population includes all randomized subjects who receive any amount of 
investigational product (OCA or placebo).  The Safety Population will be the primary population 
used for safety analyses and treatment assignment will be based on the treatment actually 
received.  
4.4. 
Pharmacokinetic (PK) Population 
The PK Population includes all OCA subjects who have at least one confirmed fasted analyzable 
sample.  Subjects must have been fasting for approximately 8 hours prior to the visit and must 
not have any major protocol deviations that potentially affect exposure levels.  The PK 
Population will be used for OCA PK analyses.   
5. 
SUBJECT DISPOSITION 
Subject disposition will be tabulated by treatment group and overall and will include the number 
and proportion of subjects screened and enrolled, as well as subject discontinuation status and 
reasons for discontinuing treatment or study.  Discontinuation status will be additionally 
presented for subjects with and without a primary endpoint event.  Subject disposition will be 
summarized for all analysis populations defined in Section 4.  
Subjects are considered to have discontinued from the study if they discontinued study visits and 
did not consent to follow-up contact or medical record review, or if they withdrew consent for 
follow-up contact or medical record review.  Subjects are considered to have started commercial 
Ocaliva if they discontinued treatment or study visits due to initiating commercial Ocaliva, or if 
Ocaliva is recorded as a concomitant medication.  
5.1. 
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 subject’s safety to be compromised if immediate action is not taken.   
Protocol deviations identified during the conduct of the study will be summarized and listed.  
6. 
DEMOGRAPHICS AND BASELINE DISEASE 
CHARACTERISTICS 
Demographic variables (eg, age at informed consent, age categorized as < 65 years and ≥ 65 
years and by decades, sex, race, ethnicity, and geographic region), other baseline characteristics 
(eg, weight, height, body mass index, BMI categorized as < 30 kg/m2 and ≥ 30 kg/m2, use of 
UDCA at screening (Yes/No)), and key liver function test results at baseline (eg, ALP, total 
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bilirubin, albumin, platelets, international normalized ratio (INR), GGT, creatinine) will be 
summarized and presented by treatment and overall for each analysis population.  
Summaries of PBC disease characteristics will use data collected from the PBC Disease History 
electronic case report form (eCRF).  Variables from the PBC Disease History eCRF include the 
following: 
• Age at PBC diagnosis 
• Duration of PBC in years at time of informed consent 
• PBC stage of most recent liver biopsy 
• History of PBC related pruritus (Yes/No) 
• Severity of most recent pruritus event 
− Ongoing at screening 
• History of PBC-related fatigue (Yes/No) 
− Ongoing at screening 
• Overall severity of PBC-related fatigue  
• Use of UDCA (Never/Previous/Current) 
• Duration of previous/current UDCA use in years at time of informed consent 
For categorical variables, the number and percentage of subjects within each category, including 
a category for missing data, will be presented.  For continuous variables, summary statistics will 
include the number of subjects and the mean, standard deviation (SD), standard error of the mean 
(SEM), median, 25th and 75th quartiles, minimum, and maximum values.   
No inferential statistical comparisons will be performed.   
7. 
PRIOR THERAPY AND MEDICAL HISTORY 
Prior therapy and medical history includes any therapy or diseases that occurred or any 
medication taken prior to baseline date.   
Prior therapy will be mapped to Anatomic Therapeutic Chemical (ATC) class and preferred term 
(PT) using WHO Drug Dictionary version Global B3, March 2020 (or later version) 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. 
Medical history will be mapped to PTs and system organ classes (SOCs) using MedDRA 
dictionary version 23.1 (or later version) and summarized by SOC, PT, and treatment group in 
the Safety Population.  Summaries will be ordered by descending order of incidence of SOC and 
preferred term within each SOC.   
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8. 
EFFICACY ANALYSES 
The efficacy endpoints and the planned analyses of these endpoints are described below. 
8.1. 
Primary Efficacy Endpoint 
The following table identifies the elements of the intercurrent events and strategies to address for 
primary efficacy endpoint. 
Primary Estimand 
Population 
Adult subjects with PBC who are at higher risk of liver-related clinical complications. 
Endpoint (variable) 
Compare the effect of OCA to placebo, in conjunction with established local standard of 
care, on the composite clinical outcomes as measured by time from randomization to the 
first occurrence of the following post-randomization events:  
Group 1 (applies to all subjects): 
• Death (all-cause) 
• Liver transplant 
• 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 (confirmed by diagnostic paracentesis OR 
 presence of >250/mm3 PMNs in the ascitic fluid) 
− Bacterial empyema (confirmed by diagnostic thoracentesis OR presence of 
 >250/mm3 PMNs in the pleural fluid) 
• Uncontrolled or refractory ascites (requiring large volume paracentesis) 
• 
Portal hypertension syndromes (hepatorenal, portopulmonary, and 
hepatopulmonary)  
• MELD-Na score ≥15 (for subjects with baseline MELD-Na score <12) 
• MELD score ≥15 (for subjects with baseline MELD-Na score ≥12) 
 
Group 2 (applies to subjects without decompensation at baseline): 
• Progression to decompensated liver disease (for subjects without decompensation at 
baseline).  See Section 2.1.1 Group 2 and Section 8.1.1 for prioritization list and 
analysis. 
 
Group 3 (applies to subjects without decompensation or clinical evidence of portal 
hypertension at baseline): 
• Progression to clinical evidence of portal hypertension without decompensation (for 
subjects without decompensation or clinical evidence of portal hypertension at 
baseline).  See Section 2.1.1 Group 3 and Section  8.1.1 for prioritization list and 
analysis. 
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Primary Estimand 
Intercurrent events/ 
Strategies to address 
Use of commercial OCA as concomitant 
medication or IP/study visit discontinuation 
due to commercial OCA use 
Treatment policy will use for primary 
analysis: Treatment effect regardless of 
intercurrent event. 
IP discontinuation due to other reasons prior to 
termination of the study and continue to follow 
the regular visit schedule through to study 
closure 
Treatment policy will use for primary 
analysis: Treatment effect regardless of 
intercurrent event.   
Population-level 
summary 
Log rank test of clinical outcomes of OCA group vs.  placebo group. 
If at a given timepoint some components of the MELD or MELD-Na scores are available but 
others are missing, the missing components will be imputed as the most recent measure within a 
year prior to the timepoint (LOCF).  If no measure is available within a year prior to the 
timepoint, the missing component will be imputed as in Table 1.  
Table 1: 
MELD and MELD-Na Score Imputations for Missing Components at Any 
Given Timepoint 
Measure 
Imputed Value 
Total bilirubin (mg/dL) 
LLN 
International Normalized Ratio (INR) 
1 
Serum creatinine (mg/dL) 
LLN 
Serum sodium (mmol/L) 
ULN 
Serum glucose (mg/dL) 
LLN 
 
8.1.1. 
Primary Analyses 
The primary efficacy analyses will compare OCA to placebo with respect to the primary efficacy 
endpoint using the ITT Population.  Only adjudicated events will be included in the analysis.  
The number and percent of subjects censored and with events will be presented.  Descriptive 
statistics will be presented for the time-to-event endpoints.   
If a subject experiences more than one event in the composite primary endpoint (all Group 1 – 
Group 3 events), only the event that occurs first will be included in the analysis.  Subjects with 
no data after randomization will be censored on Day 1 (first day of IP dosing).  Subjects who do 
not experience an event will be censored at the time of their last contact.  Last contact is the date 
of discontinuation from regularly-scheduled study visits for subjects who did not consent to 
follow-up and the date of discontinuation from contact visits (medical record review / semi-
annual phone calls) for patients who consented to follow-up.  The total number of patient years 
observed, patient years and percentage of patient time accrued after discontinuation of IP, and 
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patient years and percentage of patient time accrued after initiation of commercial OCALIVA 
will be presented overall and by treatment group. 
The 2 treatment groups will be compared using the log rank test stratified by the randomization 
stratification factors, conducted at the 2-sided alpha level of significance described in 
Section 8.6.  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 
25th, 50th (median), and 75th percentiles and corresponding 2-sided 95% CIs, where the 
percentiles can be estimated.  KM tabulations will present time to event in days; KM graphs will 
present time to event in months.  The hazard ratio and 95% CI will be determined based on a 
Cox regression model stratified by randomization strata to estimate the magnitude of the effect.  
The proportionality of hazards will be assessed using Schoenfeld residuals.    
8.1.2. 
Sensitivity Analyses 
The following sensitivity analyses will be carried out on the primary endpoint, with different 
population, strategy to handle the intercurrent events, or summary. 
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No.   Population 
Strategies to address 
intercurrent events 
Population-level summary 
1 
Subset of primary 
population, who had 
no major protocol 
violations.   
Same as primary analysis 
Same as primary analysis 
2 
Same as primary 
analysis 
Same as primary analysis 
The 2 treatment groups will be 
compared using the win ratio 
(Pocock 2012) using the unmatched 
method within the bilirubin 
randomization strata.  The 95% 
confidence interval will be 
calculated using a bootstrapping 
method and a p-value will be 
calculated using the stratified 
Finkelstein-Schoenfeld test 
(Finkelstein 1999). 
3 
Same as primary 
analysis 
Data collected after the 
intercurrent events to be 
excluded (while on treatment 
policy) 
 For subjects who didn’t experience 
an event before the intercurrent 
event, multiple imputation will be 
carried out for time to event based 
on the available data after the 
intercurrent event.  Details is 
included in the appendix. 
4 
Same as primary 
analysis 
Exclude data after 90 days after 
a patient discontinues IP. 
Same as primary analysis. 
5 
Same as primary 
analysis 
Include only data prior to when a 
patient starts commercial 
OCALIVA. 
Same as primary analysis. 
6 
Same as primary 
analysis 
Include only data prior to when 
OCA was commercially 
available in the subject’s country 
. 
 
Same as primary analysis. 
7 
Same as primary 
analysis 
Hypothetical strategy, ie, as if 
the intercurrent events didn’t 
happen.   
 
Hazard ratio and 95% CI will be 
estimated using a weighted Cox 
regression model with Sandwich 
estimator.  The derivation of the 
weights based on Inverse Probability 
of Censoring Weighting (IPCW) is 
detailed in the appendix. 
 
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8.1.2.1. 
Win Ratio 
The win ratio analysis is intended to assess whether there is a difference between OCA and 
placebo in the hierarchical event endpoint (as defined in Section 2.1.1) while considering the 
clinical importance order and relative timing of its components.  
In the win ratio analysis, two-sided hypotheses are expressed in terms of: 
• The null hypotheses (H0) that the win ratio 𝑅𝑅𝑤𝑤= 1. 
• The alternative hypothesis (H1) that the win ratio 𝑅𝑅𝑤𝑤≠1. 
The 2 treatment groups will be compared using the win ratio (Pocock 2012) using the unmatched 
method within the bilirubin randomization strata.  The win ratio represents the odds of having a 
more favorable outcome versus a less favorable outcome when assigned to the OCA treatment 
group compared to the placebo treatment group.  If the estimated win ratio is greater than 1 then 
treatment with OCA is considered to be more favorable than treatment with placebo.   
8.1.2.1.1. Calculation of the Win Ratio 
The components of the composite endpoint are prioritized as follows:  
Group 1: 
1 
• Death (all-cause) 
2 
• Liver transplant 
3 
• 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 (confirmed by diagnostic paracentesis OR 
presence of >250/mm3 PMNs in the ascitic fluid) 
− Bacterial empyema (confirmed by diagnostic thoracentesis OR presence of 
>250/mm3 PMNs in the pleural fluid) 
4 
• Uncontrolled or refractory ascites (requiring large volume paracentesis) 
5 
• Portal hypertension syndromes: 
− Hepatorenal syndrome 
− Portopulmonary syndrome 
− Hepatopulmonary syndrome 
6.1 • MELD-Na score ≥15 when both subjects have a baseline MELD-Na score <12 
6.2 • MELD score ≥15 when one or more subjects have a baseline MELD-Na score 
≥12 
Within each baseline bilirubin strata, 𝑘𝑘∈(1, 2), each subject in the treatment group will be 
compared to each subject in the placebo group.  For each pair, the time to the most important 
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event (eg, all-cause death) determines the “winner.”  If this comparison is non-informative, then 
the time to the second-most important event (eg, liver transplant) is compared to determine a 
“winner,” and so on. 
For each composite endpoint c, each subject i has (Tic, Cic), a time of the event and time of 
censoring (only one observed).   
When comparing treated subject t to placebo subject p on time-to-event c,  
• The treated subject “wins” if  
− (Ttc, Ctc) > Tpc  
• The treated subject “loses” if 
− Ttc < (Tpc, Cpc) 
• The comparison is considered non-informative if 
− neither subject has event c,  
− min(Ctc, Cpc) < min(Ttc, Tpc), or 
− Ttc = Tpc. 
For pairs in which all priority-ranked endpoints are non-informative, the win/loss will be 
determined as follows: 
1. Progression to decompensated liver disease if neither subject has decompensation at 
baseline. (Group 2) 
2. If tiebreaker #1 is non-informative or not applicable: Progression to clinical evidence of 
portal hypertension without decompensation if neither patient has decompensation or 
clinical evidence of portal hypertension at baseline. (Group 3) 
Tiebreaker #1: progression to decompensated liver disease (for pairs in which both subjects do 
not have decompensation at baseline): 
The components of progression to decompensated liver disease are prioritized as follows 
(Group 2):  
1 
• New onset of:  
− Hepatic hydrothorax 
− Variceal bleeding 
− Ascites requiring treatment with sodium restriction, diet modification, or 
diuretics 
2 
• Hepatic encephalopathy requiring lactulose/or rifaximin 
3 
• New onset of Child-Pugh ≥7 
• New onset of total bilirubin >3 mg/dL 
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For each pair, the time to the subjects’ first event from the first priority category determines the 
“winner.”  If this comparison is non-informative, then the time to first occurrence of Child-Pugh 
≥7 and/or total bilirubin >3 mg/dL is compared to determine a “winner”.   
Tiebreaker #2: progression to clinical evidence of portal hypertension without decompensation 
(for pairs in which both subjects do not have decompensation or clinical evidence of portal 
hypertension at baseline): 
The components of progression to clinical evidence of portal hypertension are prioritized as 
follows (Group 3):  
1 
• Endoscopic evidence of portal hypertension without bleeding 
− Gastroesophageal varices (requiring banding or progression to large varices if 
no or small varices were observed at baseline) 
− Portal hypertensive gastropathy 
2 
• Platelets <150 x 109/L with splenomegaly and/or with transient elastography 
>15 kPa 
Once all pairs of OCA and placebo-treated subjects are classified as a win or loss for the 
treatment group (or as non-informative, if none of the tiebreakers determine a winner), the win 
ratio will be determined. 
The win ratio is the total number of wins for the OCA-treated group divided by the total number 
of losses for the OCA-treated group: 𝑅𝑅𝑤𝑤= 𝑁𝑁𝑤𝑤𝑁𝑁𝑙𝑙
ൗ
.  The 95% confidence interval will be 
calculated using a bootstrapping method and a p-value will be calculated using the stratified 
Finkelstein-Schoenfeld test (Finkelstein 1999). 
The number and percentage of pairs resulting in wins and losses will be presented by component 
of the composite endpoint determining the win or loss, by baseline bilirubin strata and overall.  
The number and percentage of pairs resulting in ties will be presented by baseline bilirubin strata 
and overall. 
8.1.2.1.2. Calculation of the (1-α)% confidence interval 
In the bootstrap method, the original data is sampled with replacement a large number of times, 
the win ratio is calculated for each sample, and an empirical distribution of the win ratio is 
determined from the total number of samples.  Because the distribution of the win ratio is 
skewed, the (1-α)% CI for the population win ratio will be calculated by application of a bias-
corrected method on the log-transformed win ratio, as recommended by Wang and Pocock 
(2016). The null hypothesis H0 will be rejected in favor of the alternative Ha at the α% significant 
level if the (1-α)% CI does not contain 1. 
The bootstrap method proceeds as follows: 
Step 1: Within each baseline bilirubin strata, draw a random sample SPlacebo of size NPlacebo with 
replacement from the original placebo treatment group in the ITT popuation and a random 
sample SOCA of NOCA with replacement from original OCA treatment group in the ITT 
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popuation, where NPlacebo and NOCA are the total number of placebo and OCA patients in the ITT 
population, respectively. 
Step 2: Perform the win ratio analysis on the sample (SPlacebo, SOCA) and calculate the log win 
ratio (log Rw). 
Step 3: Repeat steps 1 and 2 M times, where M is 5,000. 
Step 4: Obtain (1-α)% CI for log Rw using the bias correction and acceleration (BCa) method and 
exponentiate these percentiles: these are the estimated limits of the (1-α)% CI for the win ratio. 
8.1.2.1.3. Calculation of the Finkelstein-Schoenfeld Test Statistic 
The stratified Finkelstein-Schoenfeld test is a generalization of the Gehan-Wilcoxon test which 
compares each pair of subjects 𝑖𝑖 and 𝑗𝑗 within strata 𝑘𝑘 using a score: 
𝑢𝑢𝑖𝑖𝑖𝑖൝
1, if 𝑖𝑖 does "better than" 𝑗𝑗
−1, if 𝑖𝑖 does "worse than" 𝑗𝑗
0, if it is indeterminate,
 
where 𝑖𝑖, 𝑗𝑗= 1, … 𝑛𝑛𝑘𝑘, with 𝑖𝑖≠𝑗𝑗 and 𝑛𝑛𝑘𝑘 is the total number of subjects in the strata 𝑘𝑘.  All 
subjects are compared pairwise with wins, loses, and ties determined as described in 
Section 8.1.2.1.1. 
The “rank” for subject 𝑖𝑖 is 𝑈𝑈𝑖𝑖= ∑
𝑢𝑢𝑖𝑖𝑖𝑖
𝑗𝑗∈𝐴𝐴𝑘𝑘
, where 𝐴𝐴𝑘𝑘 is the set of indices of the 𝑛𝑛𝑘𝑘 subjects in 
strata 𝑘𝑘.  The test is based on 𝑇𝑇= ∑∑
𝑈𝑈𝑖𝑖𝐷𝐷𝑖𝑖
𝑖𝑖∈𝐴𝐴𝑘𝑘
𝑘𝑘
, where 𝐷𝐷𝑖𝑖= 1 for subjects in the treatment 
group and 𝐷𝐷𝑖𝑖= 0 for subjects in the placebo group, and variance 
 𝑉𝑉= ∑
𝑚𝑚𝑘𝑘(𝑛𝑛𝑘𝑘−𝑚𝑚𝑘𝑘)
𝑛𝑛𝑘𝑘(𝑛𝑛𝑘𝑘−1)
𝑘𝑘
൫∑
𝑈𝑈𝑖𝑖
2
𝑖𝑖∈𝐴𝐴𝑘𝑘
൯, where 𝑚𝑚𝑘𝑘 is the number of OCA-treated subjects in strata 𝑘𝑘. 
The null hypothesis of this test is that none of the survival nor tiebreaker measures is affected by 
treatment, and the alternative is that at least one measure is improved in the treatment arm 
compared to the placebo arm, and is tested by comparing 𝑇𝑇𝑉𝑉1 2
⁄
⁄
 to the normal distribution. 
8.2. 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are as follows: 
• To assess the effect of OCA compared to placebo on time to first occurrence of death, 
liver transplant, MELD-Na score ≥15 if MELD-Na< 12 at baseline, MELD score ≥15 
if MELD-Na ≥12 at baseline, uncontrolled or refractory ascites, portal hypertension 
syndromes (hepatorenal syndrome, portopulmonary syndrome, hepatopulmonary 
syndrome), or hospitalization for new onset or recurrence of variceal bleed, hepatic 
encephalopathy, spontaneous bacterial peritonitis, or bacterial empyema. 
• Time to first occurrence of death, liver transplant, MELD ≥15, uncontrolled ascites, 
or hospitalization for new onset or recurrence of variceal bleed, hepatic 
encephalopathy, or spontaneous bacterial peritonitis.  This will be used as the primary 
endpoint for European Medicines Agency (EMA) filing, and therefore all sensitivity 
analyses described in Section 8.1.2 will be performed for this endpoint, with the 
exception of the win ratio analysis.  The endpoint described in Section 8.1 will be 
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considered the first key secondary endpoint for the EMA filing, followed by the 
remaining key secondary efficacy endpoints described in this section. 
• Time to liver transplant or death (all-cause) 
8.2.1. 
Analyses of the Secondary Endpoints  
The key secondary efficacy endpoints will compare OCA to placebo using the ITT Population.  
Data collected after the intercurrent events will be included (the treatment policy).  Only 
adjudicated events will be included in the time-to-event analyses. 
The time-to-event secondary efficacy analyses will compare OCA to placebo with respect to the 
secondary efficacy endpoints using the ITT Population.  Only adjudicated events will be included 
in the time-to-event analyses.  Time-to-event secondary efficacy analyses will use the same 
methodology as specified for the primary efficacy endpoint (Section 8.1.1).   
8.2.2. 
Sensitivity Analyses 
The following sensitivity analyses will be carried out on the key secondary endpoints.   
1. For key secondary time-to-event endpoints, the same analyses will be performed for 
PP population.  Data collected after the intercurrent events will be included (treatment 
policy).  No KM plot will be generated. 
8.3. 
Additional Secondary Efficacy Endpoints 
8.3.1. 
Time to Event Analyses 
The following time-to-event secondary efficacy analyses will compare OCA versus placebo 
using the ITT population: 
• Time to each relevant component of the primary efficacy endpoint 
• Time to development of varix/varices 
• Progression to cirrhosis  
• Time to occurrence of HCC 
• Time to liver-related death 
• Time to liver-related death or liver transplant 
• Time to liver-related death, liver transplant, or MELD score ≥15 
All additional secondary time-to-event outcomes with the exception of death will be analyzed in 
the context of competing risks.     
For the following secondary endpoints, liver transplant and death will be considered competing 
risks: 
• Time to each relevant component of the primary efficacy endpoint, with the exception 
of death and liver-transplant 
• Time to development of varix/varices 
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• Progression to cirrhosis  
• Time to occurrence of HCC 
For the following secondary endpoints, death will be considered a competing risk: 
• Time to liver-transplant 
For the following secondary endpoints, non-liver-related death will be considered a competing 
risk: 
• Time to liver-related death 
• Time to liver-related death or liver transplant 
• Time to liver-related death, liver transplant, or MELD score ≥15 
Competing risk outcomes will be compared and summarized through a cumulative incidence 
function (CIF).  Gray’s (1988) non-parametric test will be used to compare the CIFs of the two 
treatment groups.  Hazard ratios and their 95% confidence intervals will be computed following 
the Fine and Gray model (1999).  Fine and Gray’s hazard model can be fit in SAS version 9.4 
and higher by specifying eventcode option in PROC PHREG. 
Progression to cirrhosis will be assessed in the subset of subjects considered noncirrhotic at 
Baseline using available medical history, clinical, and laboratory assessments as well as baseline 
transient elastography (TE), where available.  Specifically, subjects with no clinical, laboratory, 
or radiological evidence of cirrhosis at baseline and/or a TE liver stiffness of <16.9 kPa 
(Corpechot 2012) will be considered noncirrhotic.  Progression to cirrhosis will be assessed by 
the development of clinical, laboratory, or radiological evidence of cirrhosis and/or when liver 
stiffness increases to ≥16.9 kPa during the study in which case histological progression to 
cirrhosis should be confirmed by biopsy unless not medically indicated.   
The percentage of noncirrhotic subjects progressing to cirrhosis during the treatment period will 
also be summarized by treatment group and compared using a Cochran-Mantel-Haenszel (CMH) 
test stratified by the randomization stratification factor.   
8.3.2. 
Liver Biochemistry Analyses 
Analyses of changes in liver biochemistry (gamma-glutamyl transferase (GGT), ALT, AST, 
conjugated bilirubin, albumin, and INR) at each visit will be compared between treatment groups 
using a restricted maximum likelihood based mixed-effect model repeated measures (MMRM) 
with treatment, baseline, visit, visit by treatment interaction and randomization stratification 
factors to be included in the model.  Visits through Month 24 will be included.  An unstructured 
covariance model will be used.  If the computational algorithm fails to converge, the following 
structures will be tested in the order:  Toeplitz, AR(1) and compound symmetry (CS).  If the 
model still does not converge, the stratification factors will be dropped from the model one at a 
time (UDCA followed by bilirubin). 
Change from Baseline over time will be analyzed using analysis of covariance (ANCOVA) with 
change from Baseline as the dependent variable including treatment group and randomization 
stratification factor as fixed effects and the Baseline values as a covariate.  Descriptive statistics 
of the laboratory values will be summarized by treatment group.  The results, change from 
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Baseline, and percentage change from Baseline values, as well as estimates of least-square 
means, standard errors, and 95% CIs, will be presented by treatment group.  Estimates of the 
mean difference between treatment groups, the standard error of the difference, and 95% CI of 
the difference will be presented.   
8.3.3. 
Prognostic Endpoints and Markers of Inflammation 
Change and percentage change from Baseline for MELD score, MELD-Na score, Child-Pugh 
score, Mayo Risk Score (MRS), IgM, C-reactive protein (CRP), tumor necrosis factor-α (TNF-
α), FGF-19, cytokeratin-18 (CK-18), C4, and enhanced liver fibrosis (ELF) score will be 
summarized and analyzed using the Wilcoxon Rank Sum Test to compare groups at annual 
timepoints.  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 approximately symmetrical around the median, the Sign Test may be used. 
Values below or above the quantifiable limits will be handled as follows.  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) × 0.9. 
For laboratory test results that are above the quantifiable limit: 
Imputed laboratory results = (numeric portion of the result) × 1.1 
8.4. 
Exploratory Efficacy Analyses 
8.4.1. 
Acute-on-Chronic Liver Failure (ACLF) 
Shift tables (i.e., status at baseline versus status at follow-up visit) will be presented for the 
Chronic Liver Failure Consortium Acute Decompensation score (CLIF-C ADs) using the 
categories: CLIF-C ADs ≤ 45, 45 < CLIF-C ADs ≤ 60, and CLIF-C ADs > 60.  The number and 
percentage of subjects in each category will be presented by treatment group and visit. 
8.4.2. 
Biochemical Responder Analyses 
The percentage of subjects that meet the following criteria of a responder based on each of the 
definitions below will be summarized by treatment group and at each study visit: 
• Decrease in ALP of ≥15% and ≥40% from Baseline 
• ALP ≤ ULN 
• ALP ≤3x ULN and AST ≤2x ULN and total bilirubin ≤ULN (Corpechot 2008) 
• ALP ≤1.5x ULN and AST ≤1.5x ULN and total bilirubin ≤ULN (Corpechot 2011) 
• ALP ≤1.67x ULN and total bilirubin ≤ULN (Momah 2012) 
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• Normal bilirubin (values ≤ULN) and normal albumin (values ≥lower limit of normal) 
(Kuiper 2009) 
• ALP ≤1.76x ULN (Kumagi 2010) 
Responder analyses will compare treatment groups using a CMH test stratified by the 
randomization stratification factor.  Missing values will be considered as a non-responder.   
8.4.3. 
Time-to-Event by Biochemical Response 
Additional efficacy analyses of correlation of time-to-event outcomes and biochemical response 
will be run as supportive information for primary endpoint evaluation and in support of FDA 
PMR 3057-3 as described below. 
A biochemical responder is defined as a subject who attains an ALP <1.67 times the upper limit 
of normal (ULN) and total bilirubin ≤ULN and an ALP decrease of ≥15% from Baseline at their 
12-month visit.  Subjects missing values are considered non-responders.  The number and 
percent of subjects censored and with events and descriptive statistics for the time-to-event will 
be presented by biochemical response.  KM estimates of the distribution of the time-to-event 
using the primary composite endpoint will be tabulated and graphed by treatment group and 
biochemical responder status.  KM tabulations will present time to event in days; KM graphs will 
present time to event in months. 
Biochemical responders and non-responders will be compared using a log rank test stratified by 
treatment group.  The proportionality of hazards will be assessed using Schoenfeld residuals and 
the hazard ratio and 95% CI will be estimated based on a Cox regression model stratified by 
treatment group. 
The analysis will be repeated using the following alternative definitions of biochemical 
responder: 
• ALP ≤2.0 x ULN at their 12-month visit 
• Total bilirubin <1 x ULN at their 12-month visit 
For placebo subjects, OCA-treated subjects, and all ITT subjects, additional KM estimates of the 
distribution of the time-to-event will be graphed by biochemical response for the combined ALP 
and bilirubin categories: 
1. ALP ≤2.0 x ULN and Total bilirubin <1 x ULN at their 12-month visit 
2. ALP >2.0 x ULN and Total bilirubin <1 x ULN at their 12-month visit 
3. ALP ≤2.0 x ULN and Total bilirubin ≥1 x ULN at their 12-month visit 
4. ALP >2.0 x ULN and Total bilirubin ≥1 x ULN at their 12-month visit 
8.4.4. 
Liver Histology 
A paired biopsy sub-study was recommended by Regulatory Authorities, to further assess 
clinical outcomes in terms of histological progression to cirrhosis and is described in Protocol 
Addendum 2.  While biopsies were collected, no paired data exists; no analysis will be run. 
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8.5. 
Interim Analyses 
A single interim analysis was conducted when 63% of the total events were reached.  The 
interim analysis was conducted and reviewed by the Data Monitoring Committee (DMC) 
according to the Interim Analysis Statistical Analysis Plan.  No further interim analysis for 
superiority or futility is planned for this study.  This is a deviation from the protocol.  Further 
details are described in Section 14.1. 
8.6. 
Multiple Comparisons/Multiplicity  
An interim analysis was conducted after 80 events were observed.  A group sequential design 
using the O’Brien-Fleming type alpha-spending function (Lan 1983, Reboussin 2000) was used 
to control the overall two-sided 0.05 significance level that is at an information fraction of 0.63 
of the total of 127 events, corresponding to an alpha spend of 0.009.  The primary analysis will 
be conducted at 2-sided 0.041 significance level.  No interim analysis will be performed based 
on the updated endpoints and methodology.  The primary endpoint analysis for European 
Medicines Agency (EMA) filing will be conducted at 2-sided 0.041 significance level.   
For the final analysis, the hypothesis testing of key secondary analyses will compare placebo and 
OCA (the key secondary endpoints are stated in Section 8.2), provided that the primary efficacy 
endpoint comparison is statistically significant in favor of OCA.  If the primary comparison is 
not statistically significant then comparison of the key secondary endpoints will be considered as 
supportive or supplemental.  If the primary comparison is statistically significant, the key 
secondary endpoints will be tested hierarchically in the order described in Section 8.2 at a 
2-sided 0.041 significance level.  All other secondary endpoints will be tested at nominal 
0.041 alpha level. 
8.7. 
Subgroup Analyses of Efficacy 
The primary and all key secondary efficacy endpoints (Section 8.2), liver biochemistry 
(Section 8.3.2), and prognostic endpoints and markers of inflammation endpoints (Section 8.3.3) 
will be analyzed for subject subgroups based on the ITT population.  Sensitivity analyses will not 
be run for subgroup analyses.  Subgroups will be assessed at Baseline.  Baseline subgroups of 
interest are as follows:   
• Baseline disease stage:  
− On-label per United States Prescribing Information (USPI).  The on-label 
subgroup includes ITT subjects who had not experienced clinically evidence 
portal hypertension (CSPH) or decompensation at baseline.   
 A subject is defined to have CSPH at baseline if they had any of the 
following: a previous history of portal hypertension includes procedures 
for TIPS, sclerotherapy, ligation, HVPG measurement >10 mmHG, 
paracentesis, thoracentesis (due to hepatic hydrothorax); previous history 
or baseline observation of preferred terms for presence of collateral 
circulations secondary to CSPH, GI bleeding due to varices or portal 
hypertension, gastroesophageal varices without bleeding and portal 
hypertensive gastropathy, ascites, hepatopulmonary syndrome, 
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hepatorenal syndrome, portopulmonary hypertension, hepatic 
encephalopathy; platelets <150 × 109/L with splenomegaly and/or with 
transient elastography >15 kPa.   
 A subject is defined to have decompensation at baseline if they had any of 
the following: a Child-Pugh score of B or C; previous history or baseline 
observation of preferred terms for gastric variceal or esophageal variceal 
bleeding, ascites, hepatic hydrothorax, spontaneous bacterial peritonitis, 
hepatic encephalopathy, hepatorenal / hepatopulmonary / portopulmonary 
syndrome, prior TIPPS or other peritoneovenous shunt. 
− Compensated, non-cirrhosis or cirrhosis.  The pre-decompensation subgroup 
includes ITT subjects who had not experienced decompensation at baseline. 
− Decompensated.  The decompensated subgroup includes ITT subjects who had 
experienced decompensation at baseline. 
− Contraindicated per USPI.  The contraindicated subgroup includes ITT subjects 
who had experienced CSPH and/or decompensation at baseline.   
The primary efficacy endpoint and key secondary endpoints will also be assessed for the 
following baseline subgroups of interest if there are a sufficient number of subjects in each group 
(eg, >5 subjects per group):   
• Sex: male, female 
• Age categories (at time of informed consent): <65 years, ≥65 years  
• Age categories at PBC Diagnosis (at time of informed consent): <50 years, ≥50 years  
• Race: white, non-white  
• Ethnicity: Hispanic, non-Hispanic 
• Baseline bilirubin level: >ULN, ≤ULN  
• Baseline use of UDCA: Yes, No  
The primary efficacy endpoint will also be assessed across the spectrum of PBC disease stage as 
defined by Rotterdam criteria (Kuiper 2009)  
• Early (normal albumin and normal bilirubin) 
• Moderate (abnormal albumin or abnormal bilirubin) 
• Advanced (abnormal albumin and abnormal bilirubin) 
If a strong correlation between biochemistry and clinical outcomes using the ITT population is 
observed, the biochemical improvement in the subpopulations (baseline disease stage, Rotterdam 
disease severity, and monotherapy) will be further assessed. 
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9. 
SAFETY ANALYSES 
Safety analyses include exposure to study treatment, treatment-emergent adverse events 
(TEAEs), clinical laboratory parameters, electrocardiograms (ECGs), vital signs, and any 
abnormal findings observed during physical examinations after study enrollment and through 
discontinuation of study treatment or within 30 days after the discontinuation of study treatment.  
Data after a patient begins commercial OCALIVA will be excluded.  Safety analyses will be 
performed using the Safety Population including by treatment groups.  No inferential comparison 
of safety endpoints will be performed, unless otherwise specified.   
9.1. 
Exposure to Study Treatment 
The extent of exposure will be summarized using descriptive statistics.  Duration of exposure 
(days) to IP will be calculated as follows: 
Exposure to investigational product = Date of last IP dose – Date of first IP dose + 1 
– Total duration of temporary IP discontinuation. 
The duration of each incidence of temporary investigational product discontinuation will be 
calculated as follows: 
Duration of temporary discontinuation of investigational product = 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 will be calculated by adding the doses taken by a subject during the 
study and will be summarized using descriptive statistics. 
A summary of subjects who had an increase in dose and who had a decrease in dose at least once 
during the study will be provided in terms of frequency count (n) and percentages (%).   
Dose and frequency will be modified for subjects with cirrhosis (including subjects progressing 
to cirrhosis during the study) and classified as CP-B or CP-C.  Therefore, any adjustments, 
interruptions, discontinuation, and any rechallenge of IP will be summarized. 
Subject’s overall compliance (%) with IP will be calculated as follows: 
100 × (number of tablets consumed during study / number of tablets expected to be 
consumed during study) 
where 
• number of tablets expected to be consumed during study = number of dispensed 
tablets during the study 
and  
• number of tablets consumed during study = number of tablets dispensed – number of 
tablets returned. 
Subject compliance with IP will be summarized by treatment group using descriptive statistics.  
Percent compliance will be summarized separately for subjects who completed the study and 
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those who withdrew early so as to distinguish between those subjects who were compliant 
throughout the entirety of the study versus those who were compliant until they withdrew from 
the study.   
9.2. 
Adverse Events 
An adverse event (AE) is 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) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction.  For reporting purposes, pregnancy is not 
considered an AE. 
For subjects who enrolled into the study, AEs will be mapped to PTs and SOCs using MedDRA 
dictionary version 23.1 (or later version).  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.   
9.2.1. 
Treatment-Emergent Adverse Events  
A TEAE is any event not present prior to the initiation of the IP or any event already present that 
worsens in either intensity or frequency following exposure to the IP or within 30 days after the 
discontinuation of the study treatment.   
9.2.2. 
Serious Adverse Events (SAE) 
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-subject 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 subject 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 
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• Respite care or observation when there is no AE associated with the hospitalization 
9.2.3. 
Adverse Events of Special Interest (AESI) 
The following decompensation events are adverse events of special interest:   
• Hepatic decompensation/disorder events 
− Hepatic Disorders SMQ, excluding the following sub-SMQs: 
 Alcohol related 
 Congenital, familial, neonatal, and genetic disorders of the liver 
 Liver infections 
 Pregnancy-related hepatic disorders 
• Cholecystitis/Cholelithiasis 
− Defined by Gallbladder related disorders narrow SMQ and Gallstone related 
disorders narrow SMQ 
• Renal 
− Defined as events included in the following broad SMQs: acute renal failure, 
chronic kidney disease, proteinuria, renovascular disorders, or tubulointerstitial 
diseases 
• Cardiovascular 
− Defined by the embolic and thrombotic events broad SMQ, ischaemic heart 
disease broad SMQ, or central nervous system vascular disorders narrow SMQ. 
− These events may be reassessed stratified by statin (or other lipid lowering 
medication) usage 
• Dyslipidemia  
− Defined by the Dyslipidemia SMQ 
− These events may be reassessed stratified by statin (or other lipid lowering 
medication) usage 
• Pruritus 
− Defined as any preferred term within the Pruritus Not Elsewhere Classified 
(NEC) high level term or any preferred term including “prur” 
9.2.4. 
TEAE Analyses 
The number of events and counts and percentages of unique subjects experiencing a TEAE and 
TEAEs by PTs and SOC in the following categories will be presented for the Safety Population:   
• TEAEs 
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• TEAEs by highest severity (mild, moderate, severe):  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. 
• Serious AEs 
• Adverse events of special interest  
• AESIs by highest severity (mild, moderate, severe):  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. 
• TEAEs leading to study treatment 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. 
• TEAEs leading to study treatment interruption:  This is a subset of the AEs where 
action taken with study treatment is checked as “Drug interrupted”. 
• TEAEs leading to study treatment dose reduction:  This is a subset of the AEs where 
action taken with study treatment is checked as “Dose reduced”. 
• Deaths:  This is a subset of the AEs where “Fatal” is checked. 
• Subject incidence of TEAEs by MedDRA SOC, PT, and closest relationship to 
investigational product (Related/Not Related).  Related AEs are those with 
relationships reported by the Investigator 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. 
Summaries will be sorted in order of decreasing frequency in the treatment arm.  Summaries will 
also be presented by MedDRA SOC and PT, sorted in alphabetic order of SOC and then in order 
of decreasing frequency in the treatment arm. 
Exposure-adjusted incidence of TEAEs will also be provided by SOC and PT.  Each individual 
subject 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. 
Exposure-adjusted incidence rates will additionally be provided by SOC and PT for “on-risk” 
AEs.  An on-risk adverse event (ORAE) is any event not present prior to the initiation of the IP 
or any event already present that worsens in either intensity or frequency following exposure to 
the IP or within 30 days after the discontinuation of the regularly-scheduled study visits.  As 
some subjects may be on commercial OCALIVA after discontinuing study treatment and prior to 
discontinuing regularly scheduled study visits, ORAE events will be summarized prior to 
initiation of commercial OCALIVA. 
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9.3. 
Adjudicated Cardiovascular Events 
Major Adverse Cardiovascular Events (MACE) (defined as death, myocardial infarction, and 
stroke) are included in the Cardiovascular Adjudication Committee Charter for adjudication.  
The adjudication of these events will be handled separately from the adjudication of events for 
assessment of the primary clinical composite outcome endpoint in this study.   
Adjudicated MACE is a time-to-event endpoint and will be summarized for the Safety 
Population. 
OCA and placebo treatment groups will be compared using the log-rank test stratified by the 
randomization stratification factors.  In addition, the hazard ratio and 95% CI will be determined 
based on a Cox regression model stratified by randomization strata to estimate the magnitude of 
the effect. 
The number and percent of subjects censored and with events will be presented.  Descriptive 
statistics will be presented for the time-to-event. 
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 25th, 50th 
(median), and 75th percentiles and corresponding 95% CIs, where the percentiles can be 
estimated.  KM tabulations will present time to event in days; KM graphs will present time to 
event in months.  The hazard ratio and 95% CI will be estimated based on a Cox regression 
model stratified by randomization strata.   
Only adjudicated events will be included in analyses.  Subjects without any documentation of 
events will be censored at the date of last contact.  For subjects with more than one event, the 
earliest of the event dates will be used.   
9.4. 
Clinical Laboratory Evaluations 
Laboratory parameters will be summarized in both conventional units and the standard 
international (SI) system of units using the Safety Population by treatment group and descriptive 
statistics at Baseline and at each scheduled study visit.  Only central laboratory data will be used. 
9.4.1. 
Hematology and Coagulation 
Descriptive statistics will be used to summarize the results and change and percentage change 
from Baseline to each on-study evaluation visit for hemoglobin, hematocrit, white blood cell 
with differential (lymphocytes, monocytes, eosinophils, basophils, neutrophils), platelets, red 
blood cell count [including mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration], prothrombin time (PT) and INR, and partial 
thromboplastin time (PTT). 
9.4.2. 
Chemistry 
Descriptive statistics will be used to summarize the results and change and percentage change 
from Baseline to each on-study evaluation visit for albumin, blood urea nitrogen, creatinine, total 
bilirubin, unconjugated (indirect) bilirubin, conjugated (direct) bilirubin, GGT, AST, ALT, ALP, 
electrolytes (calcium, chloride, potassium, sodium), magnesium, phosphorous, bicarbonate, 
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glucose, total protein, total cholesterol, low-density lipoprotein, high-density lipoprotein, very 
low density lipoprotein (VLDL), triglycerides, free fatty acids. 
9.5. 
Vital Signs 
Descriptive statistics will be used to summarize the results and change and percentage change 
from Baseline to each on-study evaluation visit for systolic blood pressure, diastolic blood 
pressure, heart rate, and temperature.   
9.6. 
Electrocardiograms 
The central read ECG data will be analyzed based on methodology recommended in the 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. 
9.7. 
Concomitant Medications 
A concomitant medication is any medication that was started after the initiation of IP.   
Concomitant medications will be mapped to ATC class and PT using WHO Drug Dictionary 
version Global B3, March 2020 (or later version) and summarized by ATC class, PT, 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. 
9.8. 
Subgroup Analyses of Safety 
Demographics and baseline disease characteristics (Section 6), exposure to study treatment 
(Section 9.1) and the adverse events (Section 9.2) analyses listed below will be presented for the 
baseline disease stage subgroup described in Section 8.7. 
The number of events and counts and percentages of unique subjects experiencing a TEAE and 
TEAEs by PTs and SOC in the following categories will be presented:   
• TEAEs 
• Serious AEs 
• Adverse events of special interest  
• TEAEs leading to study treatment discontinuation 
• Deaths 
Exposure-adjusted incidence of TEAEs will also be provided by SOC and PT. 
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10. 
PHARMACOKINETIC ANALYSES 
Analyses of pharmacokinetic outcomes will be specified in a separate report. 
11. 
PHARMACOECONOMIC AND HEALTH OUTCOMES 
ANALYSES 
Analyses of pharmacoeconomic and health outcomes will be specified in a separate report. 
12. 
PHARMACODYNAMIC ANALYSES 
Analyses of pharmacodynamic outcomes will be specified in a separate report. 
13. 
EXTERNAL CONTROL COMPARISON 
The exploratory analyses comparing OCA to external control data will be performed as post-hoc 
analyses and will be described in a separate SAP. 
14. 
DEVIATIONS FROM PROTOCOL 
14.1. 
Primary Efficacy Endpoint and Analysis 
Due in part to high discontinuation rates and requests from sites to close, the decision was made 
to stop 747-302 early, at approximately 67% information (84 adjudicated Protocol Version 6 
endpoints observed).  To increase the number of endpoint events and power to detect a 
difference, the primary efficacy endpoint has been expanded to include:  
• Portal hypertension syndromes (hepatorenal, portopulmonary, or hepatopulmonary) 
• Progression to decompensated liver disease (for subjects without decompensation at 
baseline) 
• Progression to clinical evidence of portal hypertension without decompensation (for 
subjects without decompensation or clinical evidence of portal hypertension at 
baseline). 
The primary efficacy analysis remains the stratified log rank test.  With the inclusion of 
additional endpoints that occur earlier in the course of the disease, the log rank test is limited to 
each subject's first event, which is likely to be an outcome of lesser clinical importance.  A win 
ratio analysis was added as a sensitivity analysis, to allow for a hierarchical comparison of the 
composite endpoints.  The win ratio analysis allows for the comparison of more severe events 
such as death and liver transplant to be prioritized over the comparison of earlier-stage events 
such as progression to clinical evidence of portal hypertension.   
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14.2. 
Number of Interim Analyses 
Although the protocol did originally plan for two interim analyses, one at ~50% (64 events) and 
the other at ~75% (96 events) information fraction, the first interim analysis was postponed to 
occur after regulatory authority review of the interim SAP.  As a result, the first interim analysis 
occurred after the accrual of approximately 65% (83 events) of the required total clinical 
outcome events.  The Sponsor proposed and the regulatory authority agreed that the second 
interim analysis will be omitted.  O’Brien-Fleming Boundaries were used to determine the 
criteria for superiority in the interim analysis.  Table 2 provide the relevant estimates both for the 
original two-interim analyses and revised single-interim analysis scenarios. 
Table 2: 
Stopping Criteria Based on O’Brien-Fleming Boundaries 
Type 1 
Error 
Power 
Information 
Fraction 
Number of 
Clinical 
Events 
Incremental 
α Spend 
Cumulative  
α Spend 
Reject for 
Efficacy if 
Hazard Ratio 
Two Interim Analyses (Originally Planned) 
 
 
50% 
64 
0.003 
0.003 
≤0.473 
0.05 
0.80 
75% 
96 
0.018 
0.019 
≤0.611 
 
 
End of 
Study 
(100%) 
127 
0.044 
0.050 
≤0.695 
Single Interim Analysis 
 
 
65% 
83 
0.011 
0.011 
≤0.564 
0.05 
0.80 
End of 
Study 
(100%) 
127 
0.047 
0.050 
≤0.697 
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15. 
REFERENCES 
Angeli P, Garcia-Tsao G, Nadim MK, Parikh CR. News in pathophysiology, definition and 
classification of hepatorenal syndrome: a step beyond the International Club of Ascites (ICA) 
consensus document. Journal of hepatology. 2019 Oct 1;71(4):811-22. 
Corpechot C, Abenavoli L, Rabahi N, et al.  Biochemical response to ursodeoxycholic acid and 
long term prognosis in primary biliary cirrhosis.  Hepatology.  2008;48(3):871-877. 
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. 
Corpechot C, Chazouillères O, Poupon R.  Early primary biliary cirrhosis: Biochemical response 
to treatment and prediction of long-term outcome.  J Hepatol.  2011;55:1361–1367. 
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. 
Journal of the American statistical association. 1999 Jun 1;94(446):496-509. 
Finkelstein D.M.  and Schoenfeld D.A., Combining mortality and longitudinal measures in 
clinical trials.  Statistics in Medicine, 1999; 18(11): 1341-1354. 
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. 
The Annals of statistics. 1988 Sep 1:1141-54. 
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. 
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. 
Kumagi T, Guindi M, Fischer SE, et al.  Baseline ductopenia and treatment response predict 
long-term histological progression in primary biliary cirrhosis.  Am J Gastroenterol.  
2010;105(10):2186-94. 
Lan KKG and DeMets DL.  Discrete sequential boundaries for clinical trials.  Biometrika.  
1983;70:659-663. 
Momah N, Silveira MG, Jorgensen R, et al.  Optimizing biochemical markers as endpoints for 
clinical trials in primary biliary cirrhosis.  Liver Int.  2012;32(5):790-795. 
Pocock SJ, Ariti CA, Collier TJ,Wang D.  The Win Ratio: a new approach to the analysis of 
composite endpoints in clinical trials based on clinical priorities.  Eur Heart J.  2012;33(2):176-
82. 
Reboussin DM, DeMets, DL, Kim KM, et al.  Computations for Group Sequential Boundaries 
Using the Lan-DeMets Spending Function Method.  Controlled Clin Trials.  2000;21(3):190-207 
Robins JM.  Association, Causation, and Marginal Structural Models.  Synthese.  1999 Jan 
1:151-179. 
Wang D, Pocock S. A win ratio approach to comparing continuous non‐normal outcomes in 
clinical trials. Pharmaceutical statistics. 2016 May;15(3):238-45. 
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APPENDIX A. GENERAL ANALYSIS RULES AND DATA 
CONVENTIONS 
The general analysis rules and data conventions described herein that are pertinent to the interim 
analysis will be followed. 
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.  The preceding day is Day -1, the day before that is 
Day -2, etc.  The last day of investigational product is designated with an “L” (eg, Day 14L).  
Post-treatment study days are numbered relative to the last dose and are designated as Day 1P, 
Day 2P, etc. 
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, first and third quartiles (Q1 and Q3), minimum, and maximum 
values will be presented.  Other summaries (eg, quartiles, 5%, 95% intervals) may be used as 
appropriate.  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, in the table and listing shell.   
Time-to-event data will be summarized using Kaplan-Meier methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of 
censored observations. 
All statistical tests comparing groups will be conducted at the 2-sided, 0.05 level of significance, 
unless otherwise specified (eg, the primary efficacy analysis, Section 8.6).  Summary statistics 
for each treatment group will be presented, as well as 95% CIs comparing groups. 
Baseline Definitions 
The Baseline value for statistical analyses of quantitative parameters is defined as the mean of all 
available study evaluations after the subject signs the informed consent and prior to or on the 
first administration of investigational product, unless otherwise specified.  If there is only one 
evaluation prior to the first administration of investigational product then the available data from 
this evaluation will be used as the Baseline value. 
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The baseline value for analyses of lipid parameters is defined as the last fasted evaluation prior to 
the first administration of IP. 
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 investigational 
product and begins taking commercially marketed OCA.   
Visit Windows 
Visit windows, as provided below, will be established relative to an individual’s Day 0, the date 
of first administration of investigational product.  Analyses will use visit windows defined by 
relative day, overriding CRF designated visit numbers.    
OCA Therapy 3-Month Interval Visit Windows (Days) 
 
Analysis Window Study Day a 
Months 
Target Study Day a 
Low 
High 
Day 0 
1 
Closest visit to Day 1, 
 prior to first IP dose b 
Month 1 
30 
2 
46 
Month 3 
90 
47 
137 
Month 6 
183 
137 
227 
Month 9 
274 
228 
318 
Month 12 
365 
319 
410 
… 
… 
… 
… 
Month n b 
round(365.25/12*n) 
round(365.25/12*n) – 46 
round(365.25/12*(n+3)) – 47 
Note: Follow-up visits are not included in visits windows. 
a Study day will be calculated from first dose date.  
b For n in three month increments (15, 18, 21, …). 
 
Partial Dates 
If only a partial date is available and is required for calculation, the following standards will be 
applied: 
• Diagnostic Date (eg, PBC diagnostic date) 
− For missing day only – Day will be imputed as the first day of the month (ie, 1). 
− For missing day and month – Day and month will be imputed as the first day of 
the year (ie, 1 January). 
• Start Dates (eg, event date, AE onset date, or start date of medication) 
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− For missing start day only – Day will be imputed as the first day of the month 
(ie, 1) with the following exception:  if the partial date falls in the same month 
and year as the date being used in the calculation (eg, first dose date, informed 
consent date), then the partial date will be imputed to equal the date being used 
for the calculation. 
− For missing start day and month – Day and month will be imputed as the first day 
of the year (ie, 1 January) with the following exception:  if the partial date falls in 
the same year as the date being used in the calculation (eg, first dose date, 
informed consent date), then the partial date will be imputed to equal the date 
being used for the calculation. 
− Imputed start dates must be prior to the stop date. 
• Stop Dates (eg, AE resolution date or stop date of medication) 
− For missing stop day only – Day will be imputed as the last day of the month 
(ie, 28, 29, 30, or 31). 
− For missing stop day and month – Day and month will be imputed as the last day 
of the year (ie, 31 December). 
− Imputed stop dates must be on or after the start date. 
All data recorded on the case report form will be included in data listings that will accompany 
the clinical study report. 
Data Conventions 
The precision of original measurements will be maintained in summaries, when possible. 
Means, medians, SEMs, and SDs will be presented with an increased level of precision, where 
means and medians will be presented to one more decimal place than the raw data, and the SEMs 
and SDs will be presented to two more decimal places than the raw data.  In general, the decimal 
places should not exceed three decimal places, unless appropriate. 
For tables where rounding is required, rounding will be done to the nearest round-off unit.  For 
example, when rounding to the nearest integer, values ≥XX.5 will be rounded up to XX+1 
(eg, 97.5 will round up to 98), while values <XX.5 will be rounded down to XX (eg, 97.4 will 
round down to 97). 
Percentages based on frequency counts will be based on available data, and denominators will 
generally exclude missing values, unless otherwise stated.  For frequency counts of categorical 
variables, categories whose counts are zero will be displayed for the sake of completeness.  For 
example, if none of the subjects discontinue due to “lost to follow-up,” this reason will be 
included in the table with a count of 0.  Percentages based on frequency counts will be presented 
as a whole number (no decimal places), and values less than 1% will be presented as “<1%.”  
Values less than 100% but that round up from 99.5% to 100% will be presented as “>99%.” 
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: 
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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. 
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). 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
• First dose date is defined as the day of first dose of IP received after randomization 
• Last dose date is defined as day of the last dose of IP 
• Time to event – The time to an event will be calculated in days as the date of the first 
occurrence of the event minus the date of first investigational product administration 
plus 1 
• Days – A duration expressed in days between one date (date1) and another later date 
(date2) will be calculated using the following formulas:  
duration in days = date2 – date1 + 1, where date1 ≥first dose date 
duration in days = date2 – date1, where date1 <first dose date 
• Months – A duration expressed in months is calculated as the number of days divided 
by 365.25/12 (approximately 30.4) 
• Years – A duration expressed in years between one date (date1) and another date 
(date2) is calculated using the following formulas: 
duration in years = (date2 – date1 + 1)/365.25, where date1 ≥first dose date 
duration in years = (date2 – date1)/365.25, where date1<first dose date 
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• Age – Age is calculated as the number of years from the date of birth (DOB) to the 
specified date, eg, date of informed consent (DOIC).  If the month of DOIC <month 
of DOB or the month of DOIC = DOB and the day of DOIC <day of DOB, then the 
following formula is used: 
age (years) = year of DOIC – year of DOB – 1. 
Otherwise, the following formula is used: 
age (years) = year of DOIC – year of DOB. 
If only year is provided in DOB, then July 1 will be used for the month and day. 
• Change from Baseline – Change from Baseline will be calculated as: 
Change = post Baseline value – Baseline value 
• Percentage change from Baseline – Change from Baseline will be calculated as: 
Percentage change from Baseline = ([post Baseline value – Baseline value] / 
Baseline value) × 100 
• MELD score is derived using the following formula: 
MELD = 3.78 × ln[serum bilirubin (mg/dL)] + 11.2 × ln[INR] + 9.57 × ln[serum 
creatinine (mg/dL)] + 6.43 × aetiology(0: cholestatic or alcoholic, 1: otherwise).  
Laboratory values less than 1.0 are set to 1.0 when computing the MELD score.  
• MELD-Na score is derived using the following formula: 
MELD-Na = MELD + 1.32 × (137-[adjusted sodium (mmol/L)]) – [0.033 × 
MELD × (137-[adjusted sodium (mmol/L)])],  
where adjusted sodium is equal to 
• [serum sodium (mmol/L)] + 0.024 × ([serum glucose (mg/dL)] -100) 
when serum glucose >100 mg/dL 
• [serum sodium (mmol/L)]  
when serum glucose ≤100 mg/dL 
and adjusted sodium values less than 125 mmol/L are set to 125, and values 
greater than 137 mmol/L are set to 137. 
• Child Pugh classification (Noncirrhotic/A/B/C) is defined as follows:  Subjects 
deemed noncirrhotic at baseline by the PI are captured as “noncirrhotic” regardless of 
baseline Child-Pugh score and those without a cirrhosis assessment or who were 
deemed cirrhotic at baseline are summarized by their baseline (Screening or Day 0) 
Child-Pugh category.   
• Rotterdam Criteria (Mild/Moderate/Severe) is defined as follows: 
Mild - Total Bilirubin ≤ ULN and Albumin ≥ LLN 
Moderate - Total Bilirubin > ULN and Albumin ≥ LLN or 
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       Total Bilirubin ≤ ULN and Albumin < LLN 
Severe – Total Bilirubin > ULN and Albumin < LLN, where  
baseline values of total bilirubin and albumin are taken to be the average of all 
pre-dose measurements. 
• The CLIF-C ADs is derived using the following formula: 
CLIF-C ADs = 10 × 0.03 × [Age (years)] + 0.66 × ln[creatinine (mg/dL)] +  
1.71 × ln[INR] + 0.88 × ln[WBC (109 cells/L)] − 0.05 × [sodium (mmol/L)] + 8.  
Inverse Probability of Censoring Weighting 
The hazard ratio will be estimated using Inverse Probability of Censoring Weighting (IPCW) 
techniques (Robins 1999).  Baseline predictors of both censoring and clinical outcome will be 
identified in advance.  Augmented IPCW estimators described by Robins may be implemented to 
explore the possible impact of unmeasured confounding.  Baseline predictors of both censoring 
and clinical outcome for the IPCW analysis are: 
• Treatment Group: OCA/Placebo 
• Age (year) at Screening Visit 
• Sex:  Male/Female 
• UDCA use at Screening Visit:  Yes/No 
• Liver biochemistry at Baseline (alkaline phosphatase (ALP) (U/L), alanine 
transaminase (ALT) (U/L), aspartate transaminase (AST) (U/L), total bilirubin 
(µmol/L), albumin (g/L), and platelets) 
The post-baseline time-varying covariates are ALP, ALT, AST, total bilirubin, and AE of 
pruritus with severity of moderate and severe. 
To derive the IPCW weights, the patient’s follow-up time up until the time of censoring or event 
occurring will be partitioned into about 10 intervals.  The probability of remaining uncensored at 
the end of each time interval adjusted for baseline variables, and post-baseline time-varying 
covariates will be estimated using a pooled logistic regression model.  To avoid possible extreme 
values when taking the inverse of the estimated probabilities from the pooled logistic model with 
both baseline and time-varying post-baseline covariates, the inverse of these probabilities will be 
stabilized by multiplying the probability of remaining uncensored conditional only on baseline 
covariates.  Once the IPCW weights are derived, the hazard ratio of treatment effect and 
corresponding 95% CI will be estimated using a weighted Cox regression model with Sandwich 
estimator to obtain the robust estimate of the variance-covariance matrix of the parameter 
estimates.   
Multiple Imputation (Missing Not At Random) Description 
The event rate during off-treatment period (after the treatment discontinuation and before the 
study close-out) is calculated.  The survival time during off-treatment period is assumed to 
follow exponential distribution of calculated event rate.  The survival time during off-treatment 
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period is added to the survival time during on-treatment period for those subjects who require 
imputation (ie, early terminators).  If the total duration is longer than the period from 
randomization to study close-out, the survival time will be imputed to the study close-out as a 
censored observation.  Otherwise, the survival time will be imputed to the date of event.  
Multiple imputation is used to impute the survival time by 5000 iterations. 
Procedures: 
Step 
Description 
1 
From the ADSL dataset restricted to ITT population (ITTFL=’Y’), extract patient 
identifiers (USUBJID), randomization date (RANDDT), randomized treatment 
(TRT01PN), death date (DTHDT), treatment (TRT01PN) start (TRTSDT) and stop 
(TRTEDT) date for treatment, study termination date (WTHDRDT), date of last contact 
(LASTDT), follow-up after treatment discontinued (FUFL), and stratification factors. Sort 
dataset by USUBJID. 
2 
From the efficacy analysis dataset (ADTTE), select the primary endpoint event. Select 
patient identifiers (USUBJID), randomized treatment (TRT01PN), the censoring indicator 
(CNSR), follow-up length (ADY), and last contact date (ADT).  Sort dataset by 
USUBJID. 
3 
Identify patients that discontinued study drug (IPDISC=’YES’) from the ADDS 
dataset.  Retain USUBJID, analysis start date (ASTDT), and IPDISC variables. Sort 
dataset by USUBJID. 
4 
  
Merge ADSL, ADTTE, and ADDS data together to create a dataset for analysis named 
EFF1.  
•         Create a variable for start of close out period (e.g., 12 Feb 2022). 
•         Assess if last contact date (ADT) is non-missing and less than end of study date 
o    If ADT non-missing and less than study end and patient was censored in the primary 
analysis then create a variable called COMPLETER and assign a value of 0 (study 
termination). 
o    If ADT non-missing and greater than study end date, or the ADT is greater than the 
closeout date, or if non-censored in primary analysis then create a variable called 
COMPLETER and assign a value of 1 (primary endpoint event/completed study). 
•         Assess if patient discontinued study medication (IPDISC=’YES’), or was 
randomized and not treated, and evaluate this based on the censoring status in primary 
analysis and the COMPLETER status described above. 
•         If IPDISC=’YES’ and patient was censored in primary analysis (CNSR=1) and did 
not complete the study (COMPLETER=0)   then create a variable indicating the follow-up 
data will be imputed for the patient (IMPUTE=1). 
-          Create a variable called EVENT and set to missing to hold the censoring indicator 
used in analysis following multiple imputation. 
-          Create a variable called T2EVENT and set to missing to hold the follow-up time 
used in analysis following multiple imputation. 
-          Create a variable called T0 to hold the follow-up time from primary analysis 
(T0=ADY) 
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Step 
Description 
-          Create a variable called T1 to hold the follow-up time from primary analysis (if 
DTHDT>. then T1=DTHDT – ADT + 1, otherwise T1= 12 Aug 2022 – ADT + 1).  
•         If patient had a primary endpoint event in the primary analysis (CNSR=0), or 
completed the trial (CNSR=1 and COMPLETER=1), or patient did not discontinue drug 
prior to start of close out period (IPDISC ^= ‘YES’) and COMPLETER=1) then create a 
variable indicating the follow-up data will be not imputed for the patient (IMPUTE=0). 
-          Create a variable called EVENT and set equal to 1 (EVENT=1) if patient 
experienced a primary endpoint event in primary analysis (CNSR=0), and 0 otherwise 
(EVENT=0). 
-          Create a variable called T2EVENT and set to equal to the follow-up time from 
primary analysis (T2EVENT=AVAL). 
Sort dataset by treatment (TRT01PN) and randomization strata  
5 
For patients with IPDISC=’Y’, and remained in follow-up after discontinuation 
(ADT>TRTEDT  and (DTHDT=. or DTHDT> ADT)), or for patients randomized and not 
treated that remained in follow-up IPDISC=’Y’ and (ADT>. and TRTSDT=.  and 
(DTHDT=. or DTHDT> ADT)),  sum the number of primary endpoint events (EVENT) 
by treatment group and randomization strata.  Output dataset named EFF_COUNT. 
6 
For those same patients from Step 5 sum the person-years of follow-up from 
discontinuation (TRTEDT) or from RANDDT (when TRTSDT=.) to the earliest of a 
primary endpoint event, last visit, death, or start of close out period (ADT).  Output 
dataset named EFF_EXP. 
7 
Create a dataset called EFF_RATE merging EFF with EFF_COUNT and EFF_EXP by 
treatment group and primary analysis strata.  Derive hazard rates for primary endpoint 
event for each patient in a new variable named RATE.  Set RATE=365.25*(primary 
endpoint event sum/follow-up time sum). 
8 
Create a new dataset called IMPUTE from EFF_RATE restricted to patients that required 
follow-up imputation (IMPUTE=1).  Derive 5,000 follow-up times for each patient for 
imputation in a variable named T2 as T2 is the randomly sampled from the exponential 
distribution given the event rate.  When generating the exponential random variate specify 
a SEED equal to 1234 prior to derivation of T2.  Assign the sequence of the T2 generated 
to a variable named ITERATION. 
9 
Create a dataset called IMPUTE2 from the IMPUTE dataset.  For each of the 5,000 
observations created in Step 8, derive variables EVENT=1 and T2EVENT=T0+T2 if T2 
is less than the time from study termination (LASTDT) to the earlier of the start of close 
out period   or (post-termination) death (T2< DTHDT - LASTDT if DTHDT>, or 
T2<Aug 12, 2022 – LASTDT).  Otherwise, set T2=0 and T2EVENT equal to the time 
from randomization to the earlier of the start of close out period, or post-termination) 
death (whichever occurs first).  Here T2EVENT= DTHDT - RANDDT+1 if DTHDT> 
LASTDT, otherwise T2EVENT=Aug 12, 2022 – RANDDT+1 
10 
Create 5,000 (virtual) datasets called IMPUTE3 by concatenating IMPUTE2 (for each 
iteration) with EFF with restriction to subjects that did not terminate the study 
(separately).  For each of the 5,000 datasets perform a primary analysis (fit a stratified 
Cox model or KM method). Save parameter estimates for each iteration, and save the 
iteration variable.   
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Step 
Description 
11 
Concatenate output from Step 10 and calculate p-value.  Combine using Rubin’s rule via 
PROC MIANALYZE.  
12 
Table results from Step 11 and stop. 
 
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CLINICAL PHARMACOLOGY ANALYSIS PLAN 
End of Study Noncompartmental Analyses for Study 747-302 
 
Version 1:  12 April 2022  
 
Study Protocol Number:  
747-302 
 
Study Title:  
A Phase 4, Double-Blind, Randomized, 
Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on 
Clinical Outcomes in Subjects with Primary 
Biliary Cholangitis 
 
THE COBALT STUDY 
Clinical Outcomes with OBeticholic Acid in 
Liver Treatment (COBALT) 
 
 
 
 
 
 
This document is a confidential communication of Intercept Pharmaceuticals, Inc. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published or disclosed 
without written authorization from Intercept Pharmaceuticals, Inc.  
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
STUDY TITLE .............................................................................................................6 
2. 
SCOPE OF ANALYSIS PLAN....................................................................................6 
3. 
STUDY OBJECTIVES ................................................................................................6 
3.1. 
Primary Objectives .......................................................................................................6 
3.2. 
Secondary Objectives ...................................................................................................7 
4. 
STUDY DESIGN .........................................................................................................7 
5. 
SUBJECTS ...................................................................................................................8 
6. 
PK BACKGROUND ....................................................................................................8 
7. 
PK SAMPLING ............................................................................................................8 
8. 
DATA HANDLING .....................................................................................................9 
8.1. 
Missing Values .............................................................................................................9 
8.2. 
Results Below Limit of Quantification (BLQ) .............................................................9 
8.3. 
Results Above Limit of Quantification (ALQ) .............................................................9 
8.4. 
Handling Anomalous Values ........................................................................................9 
8.5. 
Calculation of Total OCA ...........................................................................................10 
8.6. 
Number Precision .......................................................................................................10 
8.7. 
Actual versus Nominal Times ....................................................................................10 
9. 
SOFTWARE USED ...................................................................................................10 
10. 
SUBJECT POPULATION TO BE ANALYZED ......................................................10 
11. 
PROCESS FOR ANALYSES ....................................................................................11 
11.1. 
Data Presentation Conventions ...................................................................................14 
11.2. 
Execution of NCA ......................................................................................................15 
12. 
FILE STORAGE ........................................................................................................15 
12.1. 
Key Subgroups for Evaluation ....................................................................................15 
 
 
 
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LIST OF TABLES 
Table 1: 
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score ....................................8 
Table 2: 
PK Parameters to be Calculated for Study 747-302 ...................................................14 
Table 3: 
PK Parameter Summary Statistics ..............................................................................14 
Table 4: 
Adverse Event Terms Associated Used to Define Presence or Absence of 
Clinically Significant Portal Hypertension (CSPH) ...................................................16 
 
LIST OF FIGURES 
Figure 1: 
Study Diagram: .............................................................................................................7 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALQ 
above limit of quantification 
AUC0-6h 
area under the concentration versus time curve from time 0 to 6 hours 
AUC0-24h 
area under the concentration versus time curve from time 0 to 24 hours 
BLQ 
below the limit of quantification 
C4 
7α-hydroxy-4-cholesten-3-one 
CI 
confidence interval 
CPAP 
Clinical Pharmacology Analysis Plan 
CP 
Child-Pugh 
CP-A 
Child-Pugh Class A cirrhosis  
CP-B 
Child-Pugh Class B cirrhosis  
CP-C 
Child-Pugh Class C cirrhosis  
CSPH 
clinically significant portal hypertension 
Ctrough 
the concentration immediately prior to administration of the next dose 
CV 
coefficient of variation 
glyco-OCA 
glycine conjugate of OCA 
HVPG 
hepatic venous pressure gradient 
LC/MS/MS 
liquid chromatography and tandem mass spectrometry method 
LS 
least-squares 
MELD 
model for end-stage liver disease 
NCA 
noncompartmental analysis 
OCA 
obeticholic acid 
PBC 
primary biliary cholangitis 
PD 
pharmacodynamic 
PK 
pharmacokinetic  
QC 
quality control 
SD 
standard deviation 
SMQ 
Standardized MedDRA Query 
tauro-OCA 
taurine conjugate of OCA 
TIPS 
transjugular intrahepatic portosystemic shunt 
Tmax 
time to achieve peak (maximum) plasma concentration 
UDCA 
ursodeoxycholic acid 
ULOQ 
upper limit of quantification 
ULN 
upper limit of normal 
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1. 
STUDY TITLE  
A Multicenter, Open Label, A Phase 4, Double-Blind, Randomized, Placebo-Controlled, 
Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cholangitis 
The COBALT Study:  Clinical Outcomes with Obeticholic Acid in Liver Treatment (COBALT) 
Study Protocol Number:  747-302 
2. 
SCOPE OF ANALYSIS PLAN 
This Clinical Pharmacology Analysis Plan (CPAP) defines the end of study noncompartmental 
analysis (NCA) of pharmacokinetics (PK) of Study 747-302.  
Background and Scope 
Obeticholic acid (OCA) was approved under the tradename Ocaliva® on 27 May 2016 for the 
treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid 
(UDCA) in adults with inadequate response to UDCA, or as monotherapy in adults unable to 
tolerate UDCA.  The indication was approved under the Accelerated Approval regulations based 
on a reduction in alkaline phosphatase (ALP).  Study 747-302 (COBALT) is a postmarketing 
requirement study conducted to evaluate the effect of OCA on clinical outcomes in subjects with 
PBC.  
Predose/trough plasma samples were collected on Day 1, and at Month 3, 6, 9, and 12; during the 
follow-up period predose plasma samples were taken annually at 12-month intervals until the 
end of the study.  At Month 9 subjects were given the opportunity to opt into a PK sub study and 
have plasma samples collected prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours 
postdose.   
This CPAP describes the evaluation of the data, execution of NCA, and the reporting of 
pharmacokinetic results.  For various reasons, the actual analysis may deviate from the guidance 
in this document.  Deviations from this CPAP will be documented in the clinical study report. 
Biomarker (C4, ALP, bile acids, etc.) values will be analyzed as specified in the statistical 
analysis plan.  Further analysis of any PK/ pharmacodynamic (PD) relationships may be 
explored as the data suggest. 
3. 
STUDY OBJECTIVES 
This section presents the study objectives from the protocol to provide context for the scope of 
this CPAP, as described in Section 2. 
3.1. 
Primary Objectives 
To assess the effect of OCA compared to placebo, in conjunction with established local standard 
of care, on clinical outcomes in subjects with PBC as measured by time to first occurrence of any 
of adjudicated events as specified in the Study 747-302 final SAP.  
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3.2. 
Secondary Objectives 
In addition, the SAP specified secondary objectives which includes: 
• To characterize the pharmacokinetics of OCA and its conjugates in a subset of 
subjects. 
4. 
STUDY DESIGN 
This study started pre-approval as a Phase 3 and continued post-approval as a Phase 4, 
double-blind, randomized, placebo-controlled, multicenter study to evaluate the effect of OCA 
on clinical outcomes in subjects with PBC.  Subjects were screened twice during a 1 to 8-week 
Screening period prior to entering the study to allow for the collection of repeat serum chemistry 
samples (at least 2 weeks apart) to confirm pretreatment ALP and total bilirubin values. 
Investigational product was taken orally, once daily for the majority of subjects; dose and 
frequency were modified for subjects with cirrhosis (including subjects progressing to cirrhosis 
during the study) and classified as Child-Pugh B or C.  The randomization was stratified by 
ursodeoxycholic acid (UDCA) treatment (yes/ no) and baseline bilirubin categories (> upper limit 
of normal [ULN]/ ≤ ULN). 
Figure 1: 
Study Diagram: 
 
EOS = end of study; ULN = upper limit of normal 
Initial dose titration of investigational product should occur at the Month 3 visit, or any study visit thereafter for 
subjects on all dosing regimens, based on tolerability and biochemical response.  Subsequent dose titration(s) for 
subjects classified as Child-Pugh B or Child-Pugh C and following a modified dosing schedule may occur no earlier 
than 6 weeks after the previous dose titration. 
Dosing frequency was determined by the presence or absence of cirrhosis and, if cirrhosis was 
present, by CP Score as described below: 
• Noncirrhotic subjects or subjects classified as CP-A at screening will receive 5 mg 
OCA or matching placebo once daily for 3 months.  Subjects should titrate to a 
maximum dose of 10 mg OCA once daily (or matching placebo) at the Month 3 visit 
or at any study visit following the Month 3 visit based on tolerability and biochemical 
response of the product.    
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• For those subjects that up-titrate to 10 mg, dosing may be decreased to 5 mg at any 
time during the study as considered clinically appropriate (e.g., based on tolerability).  
Subjects may be titrated back to a maximum dose of 10 mg once daily based on 
tolerability and clinical judgment of the Investigator.    
• Subjects who are cirrhotic and classified as CP-B or CP-C will initiate a modified 
treatment regimen with 5 mg OCA or matching placebo once weekly for at least 
3 months.  Subjects classified as CP-B should eventually titrate to a maximum dose 
of 5 mg OCA or matching placebo once daily, based on tolerability and biochemical 
response.  Subjects classified as CP-C should titrate to a maximum dose and 
frequency of 10 mg OCA or matching placebo twice weekly, based on tolerability 
and biochemical response. 
Table 1: 
Planned Dosing Regimen by Cirrhosis and Child-Pugh Score 
 
Planned Dosing Regimen 
Standard 
Modified 
Noncirrhotic/ 
Child-Pugh A 
Child-Pugh B 
Child-Pugh C 
Starting Dose a  
(Day 0) 
5 mg daily 
5 mg once weekly 
5 mg once weekly 
Titration 1b  
(≥Month 3) 
10 mg daily 
5 mg twice weekly 
5 mg twice weekly 
Titration 2b  
(≥6 weeks after Titration 1) 
NA 
10 mg twice weekly 
10 mg twice weekly 
Titration 3b 
(≥6 weeks after Titration 2) 
NA 
5 mg daily 
NA 
a Starting dose based on subject’s cirrhosis status and Child-Pugh Score at Screening. 
b Planned titration regimen is shown; however, the titration of dose and/or frequency is dependent on subject 
tolerability, biochemical response, and/or changes in cirrhosis status or Child-Pugh Score at any time during the 
study 
5. 
SUBJECTS 
The study aimed to enroll approximately 428 subjects.  At study end, approximately 334 subjects 
were enrolled, and approximately 40 consented to the serial PK substudy.   
6. 
PK BACKGROUND  
Subjects enrolled in the study had trough measurement s  of OCA and the glyco- and tauro-
conjugates determined at 3-month intervals for the first year of the study, and annually thereafter 
until the end of study.  A substudy at 9 months was initiated to determine a plasma 
concentration/time curve from predose to 6 hours, and to allow imputation of a 24-hour curve. 
7. 
PK SAMPLING 
Predose/trough plasma samples were collected on Day 1, and at Month 3, 6, 9, and 12; during the 
follow-up period predose plasma samples will be taken annually into the follow-up period and at 
the end of the study.  
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At Month 9/Week 36 a voluntary PK substudy was conducted at select sites.  Subjects had 
plasma samples collected prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours 
postdose.  Plasma concentrations of unconjugated OCA, glyco-OCA, and tauro-OCA will be 
measured using a validated liquid chromatography and tandem mass spectrometry method 
(LC/MS/MS).  Drug concentrations will be reported from the laboratory in units of ng/mL.  
In addition, a trough PK sample for the assessment of systemic concentrations of OCA and its 
major metabolites should be obtained in any patient who develops an adverse event (AE) that is 
indicative of or consistent with hepatic injury or decompensation. 
Subjects in Study 747-302 were randomized to treatment with either OCA or matching placebo 
in a 1:1 ratio. 
8. 
DATA HANDLING 
8.1. 
Missing Values 
The 6-hour PK profile has been optimized for characterization of the early part of the PK profile.  
A 24-hour profile can be generated by using the predose sample value as the 24-hour timepoint 
and thus estimating the AUC0-24h.  Missing values prior to the first dose will be set to zero; any 
other missing value will be set to missing and no imputation will be conducted.   
8.2. 
Results Below Limit of Quantification (BLQ) 
BLQ values will be imputed to zero for all timepoints prior to the first quantifiable value.  BLQ 
values occurring between 2 quantifiable values will be set to missing.  Those BQL values that 
occur after the last quantifiable value will be set to ½ the lower limit of quantification (LLOQ).  
Other BLQ approaches may be used with rationale and documentation.   
8.3. 
Results Above Limit of Quantification (ALQ) 
Typically, PK and PD samples with concentrations greater than the upper limit of quantification 
(ULOQ) are diluted into the range of the bioanalytical assay.  However, if insufficient sample 
volume prevents repeat testing of the ALQ sample, the sample will be imputed to the AQL of the 
assay.  
8.4. 
Handling Anomalous Values 
Drug concentration values that appear anomalous may be queried to the bioanalytical laboratory 
to see if there is a procedural explanation for the incongruous value(s).  No repeat testing will be 
performed on samples for which there is no documented sample collection or bioanalytical error.  
Handling of anomalous values will be at the discretion of the Clinical Pharmacology Scientist.  
Final treatment of the anomalous values must be documented in the clinical study report. 
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8.5. 
Calculation of Total OCA 
Total OCA will be calculated as the molar sum of unconjugated OCA, glyco-OCA, and 
tauro-OCA, converted back to ng/mL-equivalents of the parent unconjugated OCA.  
1. Convert units for each component of total OCA from ng/mL to μM using the molecular 
weight and formula: 
Unconjugated OCA (μM) = unconjugated OCA (ng/mL) / 420.6 g/mol 
Glyco-OCA (μM) = glyco-OCA (ng/mL) / 477.7 g/mol 
Tauro-OCA (μM) = tauro-OCA (ng/mL) / 527.8 g/mol 
2. Sum molar-based components of total OCA: 
Total OCA (μM) = unconjugated OCA (μM) + glyco-OCA (μM) + tauro-OCA(μM) 
3. Convert total OCA from μM to ng/mL-equivalents: 
Total OCA (ng/mL) = total OCA (μM) * 420.6 g/mol 
Note that if there is not a valid value (BLQ imputations 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.  
8.6. 
Number Precision 
Drug concentration values from the bioanalytical laboratory will not be rounded prior to use in 
NCA.  Total OCA AUC0-6h and AUC0-24h values will be reported in the outputs from WinNonlin 
(Section 11) to the default precision dictated by the WinNonlin software. 
8.7. 
Actual versus Nominal Times 
Actual collection times will be used for NCA.  In cases where nominal times are used, a rationale 
will be documented.   
9. 
SOFTWARE USED 
NCA-ready datasets may be produced using SAS Version 9.4 or higher.  NCA will be performed 
using Phoenix WinNonlin Version 8 or higher.  
10. 
SUBJECT POPULATION TO BE ANALYZED 
The process described herein will be executed for the PK populations as described in the 
protocol.   
• The PK population will include all OCA subjects who have at least one confirmed 
fasted analyzable sample.  Subjects must have been fasting for approximately 8 hours 
prior to the visit and must not have any major protocol deviations that potentially 
affect exposure levels.  The PK population will be used for OCA PK analyses.  
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11. 
PROCESS FOR ANALYSES 
The end of study NCA for Study 747-302 will follow the steps described below.  
• An analysis-ready dataset is created by merging the dosing and PK sampling data 
with the drug concentration data for unconjugated OCA, glyco-OCA, tauro-OCA, and 
total OCA 
o Units for concentrations will be ng/mL and units for time will be hours 
o Actual time since last dose will be calculated as the time variable.  While PK 
parameters will be calculated for PK profiles with deviations from nominal times, 
gross deviations may render PK parameters incompatible for inclusion in 
summary statistics.  In such a case, the parameters in question would be included 
in listings (and flagged) but excluded from summary tables and figures. 
o BLQ values will be imputed as per Section 8.2.  
o Total OCA will be calculated as per Section 8.5.  In general, Categorical variables 
will be summarized by counts and by percentage of subjects in corresponding 
categories. 
Evaluation of the data should include: 
• The drug concentrations and PK parameters will be available for: 
o Unconjugated OCA 
o Glyco-OCA 
o Tauro-OCA 
o Total OCA (molar sum of OCA, glyco-OCA, tauro-OCA) 
• Examples of potential reasons for exclusion of data from PK summary analyses 
include, but are not limited to: 
o Subject not fasted for 8 hours prior to PK visit 
o Subjects not adhering to standardized meal timing (or missed meal) during PK 
profile collection 
o Non-standard dosing (e.g., 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 (and flagged 
with footnote) but will be excluded from summary tables and figures. 
• Drug concentration data in ng/mL units will be summarized by analyte (unconjugated 
OCA, glyco-OCA, tauro-OCA, and total OCA), baseline CP category (or 
noncirrhotic), dosing regimen, study visit, and timepoint using the following 
descriptive statistics:  n, number and % BLQ, arithmetic mean, SD, CV%, minimum, 
median, maximum, interquartile range, geometric mean, and geometric CV%. 
• Trough PK samples for the assessment of plasma concentrations of OCA and its 
conjugates, obtained in any subject who develops an AE that is indicative of or 
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consistent with hepatic injury or decompensation, will be summarized separately 
from scheduled PK collections and stratified by baseline CP category (or 
noncirrhotic) and dosing regimen. 
• Actual collection date and time, time since reference dose, time deviation between 
actual and nominal collection times, flags for exclusion from summaries, and 
stratification variables should be included. 
• PK concentration summary tables presenting descriptive statistics over time by 
analyte and including stratification by any relevant factors.   
PK parameters will be calculated and examined using the execution of NCA (Section 11.2).  The 
data will be summarized as follows: 
• PK parameters will be calculated in subjects at Month 9 for whom a PK profile can be 
produced.  Parameters to be calculated are found in Table 2. 
• Individual PK parameters for unconjugated OCA, glyco-OCA, tauro-OCA, and total 
OCA will be listed by subject and include information for baseline CP category, 
dosing regimen, study visit, and timepoint. 
• PK parameters will be summarized by analyte (unconjugated OCA, glyco-OCA, 
tauro-OCA, or total OCA, PK parameter, baseline CP Category (noncirrhotic, CP-A, 
CP-B, or CP-C), baseline MELD category (>/≤8 and >/≤11), dosing regimen (dose 
strength/frequency), and study visit.  For the “All Visits” category, if an individual 
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 3.  
Reporting precision is generally to 3 significant figures except for the following:  
time to achieve peak (maximum) plasma concentration (Tmax) is reported to same 
precision as nominal time, SD is reported to same precision as mean and median, and 
CV and geometric CV are reported to the same precision as mean and geometric 
mean, respectively. 
• The following figures will be produced for mean concentration data for all analytes: 
o Mean (+SD) 6-hour and 24-hour PK profiles for unconjugated OCA, glyco-OCA, 
tauro-OCA, and total OCA will be provided as follows: 
o Nominal hours on continuous x-axis 
o Mean (+SD) plasma concentration (ng/mL) on linear y-axis 
o Unconjugated OCA, glyco-OCA, tauro-OCA, and total OCA are presented on 
same figure (5 lines) 
o Outputs should present one visit per page which will involve a matrixed panel of 
figures to stratify for CP category (or noncirrhotic) and dosing/regimen at each 
visit. 
• Boxplots of the relevant AUCs (AUC0-6h and AUC0-24h) will be provided for each PK 
study visit, stratified by baseline CP category (or noncirrhotic) and the dosing 
regimen used at the time of the PK visit.  Separate figures will be produced for 
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unconjugated OCA, glyco-OCA, tauro-OCA, and total OCA.  Boxplots will also 
include the individual AUC values from each subject.   
• Boxplots of Ctrough will also be generated.  Separate figures will be generated for 
unconjugated OCA, glyco-OCA, tauro-OCA, and total OCA at each PK study visit 
(Day 0, Month 3, Month 6, Month 9, Month 12, and annual visits thereafter).  
Stratification within each figure will be by CP category (noncirrhotic and CP-A 
subjects only) and the dosing regimen used at the time of the PK visit.  Boxplots will 
also include the individual Ctrough values from each subject.   
• Statistical comparisons (e.g., Proc Mixed) of the ln-transformed PK parameters from 
Study 747-302 will compare exposures from the following groups:  noncirrhotic 5 mg 
OCA daily, CP-A 5 mg OCA daily, noncirrhotic 10 mg OCA daily, and CP-A 10 mg 
OCA daily.  Separate analyses will be performed for each PK parameter/Visit to 
include total OCA AUC0-6h from Month 9 and total OCA Ctrough from Month 3, 
Month 6, Month 12, or subsequent annual visits (provided sufficient data are 
available).  The geometric least-squares (LS) means, geometric LS mean ratios 
(test/reference), and associated 90CIs will be presented and will be exponentiated to 
the original scale.  The reference group presented will alternately be the 5 mg OCA 
daily noncirrhotic group or the 10 mg OCA daily noncirrhotic group.  Additional 
analyses may be generated if deemed appropriate. 
• PK parameter summaries may be re-analyzed as a function of the key subgroups 
following the preliminary PK analysis. 
• Depending on the information available for biomarkers, PK/PD analyses may be 
performed if deemed appropriate.  The description of these analyses will be provided 
on an ad hoc basis. 
In addition, trough PK samples for assessment of drug concentrations of OCA and its conjugates, 
obtained in any patient who develops an AE that is indicative of or consistent with hepatic injury 
or decompensation, will be identified as such in the listings.  The actual and nominal sampling 
times of PK sample collection will also be listed for each subject and will include the deviation 
in time from nominal, if applicable.  All measured concentrations will be presented in original 
units as reported by the bioanalytical lab (i.e., ng/mL).  Columns in the listing for unconjugated 
OCA, glyco-OCA, tauro-OCA, and total OCA will be displayed on the same page.  Any 
individual concentrations excluded from summaries or analyses will be flagged and footnoted. 
If the values for one or more of the components of total OCA are missing, then total OCA will 
not be calculated and will be set to missing.  If the value for one or more of the components of 
total OCA are BLQ then appropriate BLQ imputation will be performed prior to the calculation 
of total OCA.  Total OCA will be calculated in units of “unconjugated OCA ng/mL equivalents” 
but for the sake of brevity, total OCA results will be reported in units of “ng/mL.” 
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Table 2: 
PK Parameters to be Calculated for Study 747-302  
PK 
Parameter 
Units 
Definition 
AUC0-6h 
ng*h/mL 
Area under the concentration versus time curve from zero time to 6 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 
AUC0-6h 
AUC0-24h 
ng*h/mL 
Area under the concentration versus time curve from zero time to 24 hours. 
The predose sample for each profile is to be used as the 24-hour timepoint 
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 
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) 
Molar metabolite to parent ratio for AUC0-6h 
MRCmax 
unitless 
(ratio) 
Molar metabolite to parent ratio for Cmax 
 
Table 3: 
PK Parameter Summary Statistics 
Variable 
Summarized with: 
AUC0-6h, AUC0-24h, Ctrough, Cmax, MRAUC, and 
MRCmax 
n, arithmetic mean, SD, CV%, minimum, Q1 (25% 
percentile), 
median, Q3 (75% percentile), maximum, geometric 
mean and 
geometric CV% 
Tmax 
n, minimum, Q1 (25% percentile), median, Q3 (75% 
percentile) 
and maximum 
 
11.1. 
Data Presentation Conventions 
The precision of original measurements will be maintained in summaries, when possible.  
Means, medians, and SDs will be presented with an increased level of precision, where means 
and medians will be presented to 1 more decimal place than the raw data, and the SDs will be 
presented to 2 more decimal places than the raw data.  In general, the number of decimal places 
should not exceed 3 decimal places, unless deemed appropriate.  For tables where rounding is 
required, rounding will be done to the nearest round-off unit.  For example, when rounding to the 
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nearest integer, values ≥XX.5 will be rounded up to XX + 1 (e.g., 97.5 will round up to 98), 
while values <XX.5 will be rounded down to XX (e.g., 97.4 will round down to 97). 
Percentages based on frequency counts will be based on available data, and denominators will 
generally exclude missing values.  Percentages based on frequency counts will be presented to 
1 decimal place, and values less than 0.1% will be presented as “<0.1%.”  Values less than 100% 
but that round up to 100% will be presented as “>99.9%.”  Date variables will be formatted as 
YYYY-MM-DD for presentation.  Time will be formatted in military time as HH:MM for 
presentation. 
11.2. 
Execution of NCA 
Using the analysis-ready dataset, NCA will be performed according to the following: 
• Review data on fed status prior to dosing and prior to 24-hour sampling 
• Review data on dose (mg) and timing of meal during PK profile 
• Exploratory data analysis will be performed by creating XY plots of concentration 
versus actual time, grouped by analyte (unconjugated OCA, glyco-OCA, tauro-OCA, 
and total OCA) to inspect the PK profiles 
• NCA will be performed for each analyte with the following settings: 
o Linear trapezoidal/linear interpolation methodology 
o ‘Disable Curve Stripping’ setting to avoid calculation of an elimination slope 
o Use of actual time since last dose as time variable (hours) 
• Calculate the AUC0-6.  Estimate AUC0-24h by using the predose value and setting that 
value to 24 hours. 
• Carry the study, subject, and visit variables into the analysis for output purposes 
12. 
FILE STORAGE 
The work associated with this plan will be stored in the standardized folder structure on the 
SASShare drive at the following project folder location: 
\Compounds\INT747\POPPK\ 747-302 
The saved work will be organized in such a manner that it is easy to find, for any given subject, 
the Primary, QC, and final NCA results along with the associated signed QC form. 
12.1. 
Key Subgroups for Evaluation 
To fulfill the scope of the analysis, the following subgroups have been identified for the 
evaluation based on known association of risk with clinical outcomes PBC or end-stage liver 
disease.  Further PK assessment by these groups may be required, based on outcomes. 
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Subgroups Defined by Baseline Disease Severity: 
• Cirrhotic vs Noncirrhotic  
o Cirrhosis as defined by baseline status on the cirrhosis case report form and 
screening/baseline CP Evaluation  
• Noncirrhotic vs Child Pugh A vs Child Pugh B  
o Subjects who received daily dosing vs those who received the modified dosing 
regimen 
• Noncirrhotic vs Child Pugh A5 vs Child Pugh A6 vs Child Pugh B7 vs Child Pugh 
B8 vs Child Pugh B9 
• Baseline/Medical History of clinically significant portal hypertension (CSPH) vs 
Patients with No Baseline/Medical History of CSPH defined by any of the following: 
o Previous history of portal hypertension includes procedures for transjugular 
intrahepatic portosystemic shunt (TIPS), sclerotherapy, ligation, hepatic venous 
pressure gradient (HVPG) measurement >10 mmHG, paracentesis, thoracentesis 
(due to hepatic hydrotorax) 
o Baseline biochemical evidence of portal hypertension 
o Previous history or baseline observation of the terms defined in Table 4. 
Table 4: 
Adverse Event Terms Associated Used to Define Presence or Absence of 
Clinically Significant Portal Hypertension (CSPH) 
Presence of CSPH based on SMQ terms  
Severity 
Presence of collateral circles secondary to CSPH  
(SMQ Terms:  Varices - Anorectal, Duodenal, Esophageal, Gastric, Intestinal, 
Splenic, Gallbladder, Peripancreatic – Portal Hypertensive Gastropathy and 
Enteropathy) 
 
 
Any 
GI Bleeding (SMQ Terms Gastric Variceal Hemorrhage, Oesophageal Variceal 
Hemorrhage, Anorectal variceal hemorrhage) 
Any 
Ascites (SMQ terms Ascites, Hepatic Hydrotorax, Oedema due to hepatic disease, 
Peritonitis Bacterial, bacterascites) 
Any 
Multiorgan complication:  Hepatopulmonary syndrome, hepatorenal syndrome.  
Any 
Portopulmonary Hypertension 
Any  
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• Baseline MELD >/≤ the following thresholds: 
o 8 
o 11  
• Baseline Rotterdam Classification (mild vs moderate vs severe)  
• Baseline GLOBE Score >/≤ the following thresholds: 
o Age Specific Thresholds  
 -0.52 for <45 years; 0.01 for ≥45 to <52 years; 0.60 for ≥52 to <58 years; 
1.01 for ≥58 to <66 years; 1.69 for ≥66 years 
o 0.9 
• Baseline Mayo Risk Score >/≤ the following thresholds: 
o 7.43 
o 8.50 
o 9.10 
• Baseline Platelets >/≤ the following thresholds: 
o 150,000 109/L 
o 100,000 109/L 
o 50,000 109/L 
• Baseline Albumin >/≤ the following thresholds: 
o 4 g/dL 
o 3.5 g/dL 
o 3 g/dL 
• Baseline Bilirubin >/≤ the following thresholds: 
o ULN 
o 1.5xULN 
o 2xULN 
Subgroups Defined by the Occurrence of Key On-Treatment Events:  
• Evidence of CSPH  
o Yes vs No defined by any of the following criteria: 
 Including history of, baseline, or on treatment occurrence of terms described 
in Table 4  
 Including history of, baseline, or on treatment occurrence of procedure of 
TIPS, sclerotherapy, ligation, HVPG measurement >10 mmHG, paracentesis, 
thoracentesis (due to hepatic hydrotorax) 
 Baseline or on treatment biochemical evidence at baseline of portal 
hypertension 
• On treatment occurrence of a composite negative outcome event (as defined by 
Table 4)  
o Yes vs No 
In the situation where small cell count of certain subgroup occurs (cell count <5) in any of the 
subgroup analysis, it may not be deemed necessary for the subgroup analysis to be performed. 
Page 65 of 89


 
 
Statistical Analysis Plan for Interim Analysis  
for Protocol 747-302 
A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects 
with Primary Biliary Cirrhosis  
 
OBETICHOLIC ACID (OCA) 
 
Protocol Version and Date: 
Version 6:  05 November 2019 
Phase: 
Phase 4 
Methodology: 
Double-Blind, Randomized, Placebo-Controlled Study 
Sponsor: 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
Tel: 
858-652-6800 
Fax: 
858-558-5961 
 
Independent Statistician: 
 Cytel 
Study Statistician: 
 PhD  
Sr. Manager, Biostatistics, Intercept Pharmaceuticals, Inc. 
Analysis Plan Date: 
20 August 2020 
Analysis Plan Version: 
Amendment 1.0  
 
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 66 of 89
PPD
PPD


Stoti~tical /\nalysis l'lan for lnkrim /\11alysis 
Protocol 747-30') 
APPROVAL 
20 August 2020 
Page 2 
Upon review ot'this document, including table and listing shells, the undersigned approves the 
Statistical Analysis Plan. The analysis methods and data presentation are acceptable. 
PhD 
Director, Biostatistics 
lnten.:ept Pharmaceuticals, Inc. 
 PhD 
 Biostatistics and Data Management 
Intercept Pharmaceuticals, Inc. 
Confidential and Proprietary 
~ t 2 / J ;?oJ-o 
Date 
Date 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................5 
1. 
INTRODUCTION ........................................................................................................6 
1.1. 
Study Objectives ...........................................................................................................6 
1.1.1. 
Primary Objective .........................................................................................................6 
1.2. 
Study Design .................................................................................................................7 
1.2.1. 
Synopsis of Study Design .............................................................................................7 
1.2.2. 
Primary Efficacy Endpoint ...........................................................................................7 
2. 
SAMPLE SIZE JUSTIFICATION ...............................................................................8 
2.1. 
Sample Size ..................................................................................................................8 
3. 
ANALYSIS POPULATIONS ......................................................................................8 
4. 
EFFICACY ANALYSES .............................................................................................9 
4.1. 
Primary Efficacy Analysis and Multiplicity Adjustment .............................................9 
4.2. 
Time–to-Event Endpoints .............................................................................................9 
4.2.1. 
Primary Efficacy Analysis ............................................................................................9 
4.2.2. 
Sensitivity Analyses ....................................................................................................10 
4.3. 
Additional Efficacy Analyses .....................................................................................11 
4.3.1. 
Subgroup Analysis by Child-Pugh Classification ......................................................11 
4.3.2. 
Relationship between Time-to-Event Outcomes and Biochemical Response ............12 
4.3.3. 
Progression to Cirrhosis ..............................................................................................12 
5. 
ANALYSES TO EVALUATE THE FEASIBILITY OF CONTINUING 
THE STUDY ..............................................................................................................12 
5.1. 
Study Discontinuation ................................................................................................12 
5.2. 
Sample Size Recalculation .........................................................................................13 
6. 
DEVIATIONS FROM PROTOCOL ..........................................................................14 
6.1. 
Number of Interim Analyses ......................................................................................14 
6.2. 
Additional Sensitivity and Efficacy Analyses ............................................................14 
6.3. 
Study Discontinuation ................................................................................................15 
6.4. 
Sample Size Recalculation .........................................................................................15 
7. 
APPENDIX:  GENERAL ANALYSIS RULES AND DATA 
CONVENTIONS ........................................................................................................15 
7.1. 
Baseline Definitions ....................................................................................................16 
7.2. 
Partial Dates ................................................................................................................16 
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7.3. 
Data Conventions ........................................................................................................17 
7.4. 
Standard Calculations .................................................................................................18 
7.5. 
Sample Size Recalculation .........................................................................................19 
8. 
REFERENCES ...........................................................................................................20 
9. 
REVISION HISTORY ...............................................................................................21 
9.1. 
Rationale of the Revision ............................................................................................21 
9.2. 
Changes from Previous Version .................................................................................21 
 
LIST OF TABLES 
Table 1: 
Stopping Criteria Based on O’Brien-Fleming Boundaries ...........................................9 
Table 2: 
Stopping Criteria Based on O’Brien-Fleming Boundaries .........................................14 
 
  
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
ALP 
alkaline phosphatase 
CI 
confidence interval 
CPS 
Child-Pugh Score 
dL 
deciliter 
DMC 
Data Monitoring Committee 
DOB 
date of birth 
DOIC 
date of informed consent 
INR 
international normalized ratio 
ITT 
Intent-to-Treat  
KM 
Kaplan-Meier 
MELD 
Model for End Stage Liver Disease 
mg 
milligram  
OCA 
obeticholic acid 
PBC 
primary biliary cirrhosis 
SAP 
statistical analysis plan 
SD 
standard deviation 
SEM 
standard error of the mean 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
 
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1. 
INTRODUCTION 
Study 747-302 is a double-blind, randomized, placebo-controlled, time-to-event study with 
two planned interim analyses and one final, end of study (EOS) analysis.  According to the 
study protocol (version 6), two interim analyses were planned after accrual of approximately 
50% (64 adjudicated events) and 75% (96 adjudicated events) of clinical outcome events, 
respectively; however, one interim analysis will be performed after the accrual of approximately 
65% (83 adjudicated events) of clinical outcome events.    
In addition to the interim efficacy analyses pre-specified in the protocol, the Sponsor also plans 
to include the following analyses at the time of the interim analysis:  perform a sample size 
re-evaluation; evaluate the feasibility of the study due to treatment discontinuation, overall and 
specifically related to use of commercial OCA or baseline disease characteristics (ie, Child-Pugh 
score and Rotterdam Criteria).  The rationale to perform these additional analyses are described 
in Section 6.  Axio, an independent DMC vendor, will perform the interim analysis and the 
unblinded results of the interim analysis will be reviewed by the DMC.  The DMC will make 
recommendations according to the criteria outlined in this interim statistical analysis plan (SAP).  
The DMC will also assess continued feasibility of the study.  The Sponsor will remain blinded to 
the data generated at the time of the interim analysis.   
This statistical analysis plan (SAP) outlines the specific methodology and the analyses for the 
interim analysis, which is focused on efficacy and the study feasibility assessment.  The 
statistical analysis plan for the end-of-study analysis will be developed as a separate document.  
In addition to the analyses presented within this document, the Sponsor will evaluate the viability 
of including progression to cirrhosis in the primary efficacy endpoint in a blinded fashion.  The 
method of evaluating progression to cirrhosis will be described in a separate document. 
1.1. 
Study Objectives 
1.1.1. 
Primary Objective 
The primary objective of this study is to compare the effect of obeticholic acid (OCA) to 
placebo, in conjunction with established local standard of care, on clinical outcomes in subjects 
with primary biliary cholangitis (PBC) as measured by time to first occurrence of any of the 
following adjudicated events, derived as a composite event endpoint:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
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1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
This is a Phase 4, double-blind, randomized, placebo-controlled, multicenter study.  Eligible 
subjects have a diagnosis of PBC with bilirubin levels of >ULN and ≤5x ULN and/or 
ALP >3x ULN.  Subjects enrolled are at higher risk of liver-related clinical complications. 
Approximately 428 subjects meeting all enrollment criteria will be recruited into the study over 
an approximate 4-year period, randomly allocated to treatment with either OCA or matching 
placebo in a 1:1 ratio.  Randomization will be stratified by UDCA treatment (yes/no) and 
baseline bilirubin categories (>ULN/≤ULN).  A minimum of 30% of subjects will have elevated 
bilirubin (>ULN) at Screening.  In addition to the placebo control arm, multiple external control 
groups (concurrent and retrospective) will be used to compare OCA-treated patients to standard-
of-care-treated patients.   
Subjects will be dosed according to their cirrhosis status and Child-Pugh Score (CPS), receiving 
a maximum 10 mg OCA or matching placebo once daily, based on tolerability and biochemical 
response.  
Subjects are expected to be followed for a minimum of approximately 6 years.  The study will 
continue until approximately 127 adjudicated primary endpoint events have been accrued in 
unique subjects, or until the Sponsor (eg, based on a recommendation from the Data Monitoring 
Committee; DMC) terminates the study.  One interim analysis is planned, after the accrual of 
~65% (83 adjudicated events) of clinical outcome events. 
This study will be conducted in a double-blind, placebo-controlled manner.  The randomization 
will be stratified by UDCA treatment (yes/no) and Baseline total bilirubin categories 
(>ULN/≤ULN) where the normal range is specified by the central laboratory.   
Schedules of study procedures are outlined in Table 1 (Screening to Month 12) and Table 2 
(Year 2 to End-of-Study Endpoints) of the study protocol. 
The protocol provides further study details.   
1.2.2. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the time to first occurrence of one of the following 
post-randomization:  
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
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• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
If a subject experiences more than one of the outcomes above, the primary efficacy analysis will 
include only the outcome that occurs first. 
2. 
SAMPLE SIZE JUSTIFICATION 
2.1. 
Sample Size  
The following assumptions were used in sample size calculations for the study:  
• Exponential survival curves, placebo survival estimate of 0.6 at 8 years with a hazard 
ratio of 0.60 comparing between placebo and OCA treatments, and total study 
duration of 10 years, allowing for 4 years of accrual and 6 years of follow up of the 
last subject enrolled. 
• Subjects will be randomized in a 1:1 ratio to placebo or OCA.  
• The 2 treatment groups will be compared using a 2-sided log rank test at the 5% level 
of significance. 
• Two interim analyses and one final analysis are planned, with interim analyses 
occurring after the accrual of 50% and 75% of clinical outcome events, respectively. 
Based on the randomization ratio, significance level, and assumed hazard ratio, a total of 
127 events (both groups combined) will provide 80% power to demonstrate a statistically 
significant difference between OCA and placebo on time to liver-related outcomes, including 
all-cause mortality. 
Based on the remaining assumptions stated above, approximately 428 subjects will need to be 
enrolled to attain 127 events. 
3. 
ANALYSIS POPULATIONS  
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
• Randomized Population will include all randomized subjects.  
• The Intent-to-Treat (ITT) Population will include all randomized subjects who 
receive any amount of investigational product (OCA or placebo).  Treatment 
assignment will be based on the randomized treatment.  For example, subjects who 
discontinue placebo treatment and start open-label or commercially marketed OCA 
will be analyzed as placebo subjects.   
The primary endpoint analysis will be conducted in the ITT population. 
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4. 
EFFICACY ANALYSES 
4.1. 
Primary Efficacy Analysis and Multiplicity Adjustment 
The primary efficacy endpoint will undergo one interim analysis prior to final database lock and 
results will be reviewed by the independent DMC. A group sequential design using the O’Brien-
Fleming type alpha-spending function (Lan & DeMets 1983) (Reboussin 2000) will be used to 
control the overall two-sided 0.05 significance level allocated to hepatic clinical outcomes 
(Table 1).  The interim analysis will occur after accrual of approximately 65% (83 adjudicated 
events) of clinical outcome events (actual number of events based on observed data at interim 
analysis will be used for analysis) and the final analysis will occur after the accrual of 
127 adjudicated clinical outcome events.  To determine the timing for conducting these analyses, 
the number of pre-adjudicated endpoint events will be monitored and used for the projection.  
Stopping criteria for efficacy at the planned timepoints based on group sequential boundaries are 
provided in Table 1 for the Type I error rate comprising the sum of prespecified alpha for clinical 
outcomes and carried forward alpha from the interim analysis.  The exact alpha level and 
corresponding hazard ratio criterion at the time of the interim analysis will be calculated based 
on the actual observed number of clinical events.  
The criteria for the DMC to recommend that the study stop for efficacy will be met at the interim 
analysis when the estimated hazard ratio is less than δ*, where δ* is the hazard ratio efficacy 
criterion calculated based on observed data at the interim analysis. 
Table 1: 
Stopping Criteria Based on O’Brien-Fleming Boundaries  
Overall  
Type 1 
Error 
Overall 
Power 
Information 
Fraction 
Number of 
Clinical 
Events 
Incremental 
α Spent 
Cumulative  
α Spent 
Reject for 
Efficacy if 
Hazard Ratio  
0.05 
0.80 
65% 
83 
0.011 
0.011 
≤0.564 (≤δ*) 
End of Study 
(100%) 
127 
0.047 
0.050 
≤0.697 
Note:  Estimates for information fraction and number of clinical events at interim analysis are provided in Table 1 
for illustration, and the hazard ratio efficacy criteria δ* will be calculated based on observed data. 
4.2. 
Time–to-Event Endpoints 
For the time to event analyses, subjects who do not experience an event will be censored at the 
time of their last contact.  Missing data will be assumed to be missing at random.  Details of 
sensitivity analyses are described in Section 4.2.2. 
4.2.1. 
Primary Efficacy Analysis 
The primary efficacy analysis will compare OCA and Placebo treatment groups with respect 
to the primary efficacy endpoint using the ITT population.  The analysis will only include 
adjudicated events.  The number and percent of subjects censored and with events will be 
presented.  Descriptive statistics will be presented for the time-to-event.  The 2 treatment groups 
will be compared using a log rank test stratified by the randomization stratification factor, 
conducted at the 2-sided alpha level of significance described in Section 2.1.  Kaplan-Meier 
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(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 25th, 50th (median), and 
75th percentiles and corresponding 2-sided 95% CIs, where the percentiles can be estimated.  KM 
tabulations will present time to event in days; KM graphs will present time to event in months.  
The proportionality of hazards will be assessed using Schoenfeld residuals.  The hazard ratio and 
95% CI will be estimated based on a Cox regression model stratified by randomization strata.  
All subjects will be analyzed according to their randomized treatment assignment, regardless of 
actual treatment received.  
Subjects without any documentation of events will be censored at the date of last contact.  For 
subjects with an event, the earliest of the following event dates will be used: 
• Death (all-cause) 
• Liver transplant 
• Model of end stage liver disease (MELD) score ≥15 
• 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 (confirmed by diagnostic paracentesis) 
• Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a 
frequency of at least twice in a month) 
If a subject experiences more than one of these events, only the event that occurs first will be 
included in the primary analysis.  
4.2.2. 
Sensitivity Analyses 
The following sensitivity analyses will be carried out on the primary endpoint.  They are 
intended to assist the DMC in assessing potential bias in the study:  
1. The hazard ratio will be estimated using Inverse Probability of Censoring Weighting 
(IPCW) techniques (Robins 1999).  The DMC will use this analysis to assess the impact 
of censoring on the hazard ratio.  Baseline predictors of both censoring and clinical 
outcome will be identified in advance. Augmented IPCW estimators described by Robins 
may be implemented to explore the possible impact of unmeasured confounding.  
Baseline predictors of both censoring and clinical outcome for the IPCW analysis are: 
• Treatment Group:  OCA/Placebo 
• Age (year) at Screening Visit 
• Sex:  Male/Female 
• UDCA use at Screening Visit:  Yes/No 
• Baseline Total Bilirubin (µmol/L)  
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• Baseline Alanine Transaminase (U/L)  
• Baseline Aspartate Transaminase (U/L)  
• Baseline Alkaline Phosphatase (U/L)  
• Baseline Albumin (g/L)  
• Baseline Platelets count  
The post-baseline time-varying covariates are:  ALP, ALT, AST, Total Bilirubin, and AE 
of pruritus with severity of moderate and severe. 
To derive the IPCW weights, the patient’s follow-up time up until the time of censoring 
or event occurring will be partitioned into about 10 intervals.  The probability of 
remaining uncensored at the end of each time interval adjusted for baseline variables, and 
post-baseline time-varying covariates will be estimated using a pooled logistic regression 
model.  To avoid possible extreme values when taking the inverse of the estimated 
probabilities from the pooled logistic model with both baseline and time-varying post-
baseline covariates, the inverse of these probabilities will be stabilized by multiplying the 
probability of remaining uncensored conditional only on baseline covariates. Once the 
IPCW weights are derived, the HR of treatment effect and corresponding 95% CI will be 
estimated using a weighted Cox regression model with Sandwich estimator to obtain the 
robust estimate of the variance-covariance matrix of the parameter estimates.    
2. The primary efficacy analysis will be repeated using only data accrued before subjects 
discontinued regularly scheduled study visits.  The DMC will use this analysis to assess 
whether the time subjects spent off-treatment/off study-visits is affecting the hazard ratio. 
3. The primary efficacy analysis will be repeated using only data accrued before subjects 
started commercial use of OCA.  The DMC will use this analysis to assess whether the 
initiation of commercial use of OCA impedes the evaluation of the primary endpoint.  
The date a subject started commercial use of OCA will be taken to be the minimum of: 
a. The date of treatment discontinuation due to commercial OCA use 
b. The date of study visit discontinuation due to commercial OCA use 
c. The start date of OCA recorded as a concomitant medication 
Kaplan-Meier (KM) estimates of the distribution of the time-to-event will not be graphed for any 
sensitivity analyses. 
4.3. 
Additional Efficacy Analyses 
4.3.1. 
Subgroup Analysis by Child-Pugh Classification  
The primary efficacy analysis will be repeated within each of the baseline Child-Pugh 
Classification subgroups.  Baseline Child Pugh classification is described in Section 7.4. 
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4.3.2. 
Relationship between Time-to-Event Outcomes and Biochemical Response  
Additional efficacy analyses of correlation of time-to-event outcomes and biochemical response 
will be run as supportive information for primary endpoint evaluation and in support of FDA 
PMR 3057-3 as described below. 
A biochemical responder is defined as a subject who attains an ALP <1.67 times the upper limit 
of normal (ULN) and total bilirubin ≤ULN and an ALP decrease of ≥15% from Baseline at their 
12-month visit.  Subjects missing values are considered non-responders.  The number and 
percent of subjects censored and with events and descriptive statistics for the time-to-event will 
be presented by biochemical response.  KM estimates of the distribution of the time-to-event 
using the primary composite endpoint will be tabulated and graphed by treatment group and 
biochemical responder status, and by biochemical responder status only. KM tabulations will 
present time to event in days; KM graphs will present time to event in months. 
Biochemical responders and non-responders will be compared using a log rank test stratified by 
treatment group, conducted at the 2-sided 0.05-level of significance.  The proportionality of 
hazards will be assessed using Schoenfeld residuals and the hazard ratio and 95% CI will be 
estimated based on a Cox regression model stratified by treatment group. 
The analysis will be repeated using the following alternative definitions of biochemical 
responder: 
• ALP ≤ 2.0 x ULN at their 12-month visit 
• Total bilirubin < 1 x ULN at their 12-month visit 
For placebo patients, OCA-treated patients, and all ITT patients, additional KM estimates of the 
distribution of the time-to-event will be graphed by biochemical response for the combined ALP 
and bilirubin categories: 
1. ALP ≤ 2.0 x ULN and Total bilirubin < 1 x ULN at their 12-month visit 
2. ALP > 2.0 x ULN and Total bilirubin < 1 x ULN at their 12-month visit 
3. ALP ≤ 2.0 x ULN and Total bilirubin ≥ 1 x ULN at their 12-month visit 
4. ALP > 2.0 x ULN and Total bilirubin ≥ 1 x ULN at their 12-month visit 
4.3.3. 
Progression to Cirrhosis  
The Sponsor will evaluate the viability of including progression to cirrhosis in the primary 
efficacy endpoint in a blinded fashion.  The method of evaluating progression to cirrhosis will be 
described in a separate document. 
5. 
ANALYSES TO EVALUATE THE FEASIBILITY OF 
CONTINUING THE STUDY 
5.1. 
Study Discontinuation 
Subject discontinuation, which will be tabulated by treatment group and overall, will include the 
number randomized, the number in ITT population for analysis, the number who withdrew from 
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investigational product and reason(s) for withdrawal, the number who started commercial use of 
OCA, the number who withdrew from study visits prior to completing the study and reason(s) for 
withdrawal, the number of subjects who were contacted for follow-up, the number who withdrew 
from the study, the number of subjects who withdrew from the study prior to a potential endpoint 
event, and the number of subjects who withdrew from the study prior to a positively adjudicated 
endpoint event.  Subjects are considered to have withdrawn from the study if they discontinued 
study visits and did not consent to follow-up contact or medical record review or if they 
withdrew consent for follow-up contact or medical record review.  Subjects are considered to 
have started commercial OCA if they discontinued treatment or study visits due to initiating 
commercial OCALIVA, or if OBETICHOLIC ACID is recorded as a concomitant medication.  
Percentages of the number treated in total within each category will be provided. 
Subject discontinuation summaries by treatment group and overall will be repeated by baseline 
Child Pugh classification, baseline Rotterdam score, and by geography (region and country).  
Baseline Child Pugh classification and baseline Rotterdam scoring are described in Section 7.4. 
Subject discontinuation information will be used by the DMC, among with other factors, to 
assess feasibility of continued conduct of the study as designed. 
5.2. 
Sample Size Recalculation 
A sample size recalculation is included in order to re-assess the assumptions for the sample size 
and power evaluation.  The original study sample size calculation assumed a 10-year study 
(4 years enrollment, 6 years follow-up) and 80% power to demonstrate a statistically significant 
difference between OCA and placebo on time to liver-related outcomes.  The sample size 
recalculation described here allows for a 12-year study (10 years enrollment, 2 years follow-up) 
and 70% power to detect a difference between OCA and placebo on time to liver-related 
outcomes.   
If the criteria for the DMC to recommend that the study stop for efficacy, ie, the estimated 
hazard ratio is less than δ*, where δ* is the hazard ratio efficacy criterion at the interim analysis, 
are not met at the interim analyses, the conditional power for rejecting the null hypothesis in 
favor of the alternative (ie, the probability of success at end of trial given the interim results) will 
be computed.  If the conditional power is >70% at the interim analysis, the DMC will 
recommend that the study continue as is (ie, the study will not stop for efficacy nor will the 
sample size be increased). If the conditional power is less than 70% and the estimated hazard 
ratio is within the “promising zone” of δ* and 0.85, the number of clinical endpoint events will 
be re-estimated using the methods described in Cui, Hung and Wang 1999 to achieve a 
conditional power of at least 70% for the end-of-study primary endpoint analysis.  If the 
re-computed required number of events is less than 127, the original required number of events, 
127, will be used.  The total number of subjects to be enrolled in the study will be recalculated 
based on the new number of required endpoint events, observed placebo hazard rate at data 
cut-off of the interim analysis, assuming a total study duration of 12 years allowing for 10 years 
accrual and 2 years of follow up.  The placebo hazard estimate will be calculated by fitting an 
exponential survival curve to time-to-endpoint data from placebo subjects, limited to time prior 
to switching to commercial use of OCA.  If the re-computed sample size is less than 428, the 
original sample size of 428 subjects will be used. If the conditional power is less than 70% and 
the hazard ratio is greater than 0.85, the DMC may request additional analyses to evaluate the 
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feasibility of continued conduct of the study as designed.  Additional details on the sample size 
recalculation may be found in Section 7.5. 
6. 
DEVIATIONS FROM PROTOCOL 
6.1. 
Number of Interim Analyses 
Although the protocol did originally plan for two interim analyses, one at ~50% (64 events) and 
the other at ~75% (96 events) information fraction, the first interim analysis was postponed to 
occur after regulatory authority review of the interim SAP.  As a result, it is anticipated that the 
first interim analysis will occur after the accrual of approximately 65% (83 events) of the 
required total clinical outcome events.  The Sponsor proposed and the regulatory authority 
agreed that the second interim analysis be omitted.  Regardless of the number of interim 
analyses, O’Brien-Fleming Boundaries will be used to determine the criteria for superiority.  
Table 2 provide the relevant estimates both for the original two-interim analyses and revised 
single-interim analysis scenarios. 
Table 2: 
Stopping Criteria Based on O’Brien-Fleming Boundaries 
Type 1 
Error 
Power 
Information 
Fraction 
Number of 
Clinical 
Events 
Incremental 
α Spend 
Cumulative  
α Spend 
Reject for Efficacy 
if Hazard Ratio 
Two Interim Analyses 
 
 
50% 
64 
0.003 
0.003 
≤0.473 
0.05 
0.80 
75% 
96 
0.018 
0.019 
≤0.611 
 
 
End of Study 
(100%) 
127 
0.044 
0.050 
≤0.695 
Single Interim Analysis 
 
 
65% 
83 
0.011 
0.011 
≤0.564 
0.05 
0.80 
End of Study 
(100%) 
127 
0.047 
0.050 
≤0.697 
6.2. 
Additional Sensitivity and Efficacy Analyses 
As OCA is commercially available to many subjects enrolled in the study, informative censoring 
and its potential to induce bias in the primary efficacy analysis is a concern.  To inform the DMC 
in its recommendation on the continued conduct of the study, the following additional sensitivity 
analyses will be conducted:  
1. The hazard ratio will be estimated using Inverse Probability of Censoring Weighting 
(IPCW) techniques (Robins 1999).  The DMC will use this analysis to assess the impact 
of censoring on the hazard ratio.  
2. The primary efficacy analysis will be repeated using only data accrued prior to subjects 
discontinuing regularly scheduled study visits.  The objective of this analysis is to assess 
whether the time subjects spend off-treatment/off study-visits is diluting the hazard ratio. 
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3. The primary efficacy analysis will be repeated using only data accrued prior to subjects 
starting commercial use of OCA.  The objective of this analysis is to assess whether use 
of commercial use of OCA impacts the hazard ratio. 
Additional efficacy analyses of correlation of time-to-event outcomes and biochemical response 
will be run as supportive information for primary endpoint evaluation and in support of FDA 
PMR 3057-3. 
In addition, the Sponsor will evaluate the viability of including progression to cirrhosis in the 
primary efficacy endpoint in a blinded fashion (to be described in a separate document). 
6.3. 
Study Discontinuation 
To further inform the DMC on the potential existence of informative censoring, subject 
discontinuation information, which is already available for DMC review, will be further detailed 
by baseline disease severity.  The DMC will consider observed differences in censoring rates by 
treatment group and baseline disease severity or lack thereof when making a recommendation 
regarding the feasibility to conduct of the study.  
6.4. 
Sample Size Recalculation 
Due to higher-than-expected study and treatment discontinuation rates and slower-than-expected 
enrollment rates, a sample size recalculation has been added in order to re-assess the assumptions 
for the sample size and power evaluation.  The observed hazard ratio at data cut-off of the 
interim analysis will guide the assessment of the required number of events.  Evaluation of the 
sample size needed to reach the required number of events will be based on the observed placebo 
hazard rate at data cut-off of the interim analysis, assuming a total study duration of 12 years 
allowing for 10 years accrual and 2 years of follow-up. 
7. 
APPENDIX:  GENERAL ANALYSIS RULES AND DATA 
CONVENTIONS 
The general analysis rules and data conventions described herein that are pertinent to the interim 
analysis will be followed. 
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.  The preceding day is Day -1, the day before that is 
Day -2, etc.  The last day of investigational product is designated with an “L” (eg, Day 14L).  
Post-treatment study days are numbered relative to the last dose and are designated as Day 1P, 
Day 2P, etc. 
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.   
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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, first and third quartiles (Q1 and Q3), minimum, and maximum 
values will be presented.  Other summaries (eg, quartiles, 5%, 95% intervals) may be used as 
appropriate.  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, in the table and listing shell.   
Time-to-event data will be summarized using Kaplan-Meier methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% CIs, as well as percentage of 
censored observations. 
All statistical tests comparing groups will be conducted at the 2-sided, 0.05 level of significance, 
unless otherwise specified (eg, the primary efficacy analysis, Section 4.2.1).  Summary statistics 
for each treatment group will be presented, as well as 95% CIs comparing groups. 
7.1. 
Baseline Definitions 
The Baseline value for statistical analyses of quantitative parameters is defined as the mean of all 
available study evaluations after the subject signs the informed consent and prior to the first 
administration of investigational product, unless otherwise specified.  If there is only one 
evaluation prior to the first administration of investigational product then the available data from 
this evaluation will be used as the Baseline value.  
Baseline values defined above will not change regardless if a subject stops taking investigational 
product and begins taking commercially marketed OCA.  
7.2. 
Partial Dates 
If only a partial date is available and is required for calculation, the following standards will be 
applied: 
• Diagnostic Date (eg, PBC diagnostic date) 
− For missing day only – Day will be imputed as the first day of the month (ie, 1). 
− For missing day and month – Day and month will be imputed as the first day of 
the year (ie, 1 January). 
• Start Dates (eg, event date, AE onset date, or start date of medication) 
− For missing start day only – Day will be imputed as the first day of the month 
(ie, 1) with the following exception:  if the partial date falls in the same month 
and year as the date being used in the calculation (eg, first dose date, informed 
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consent date), then the partial date will be imputed to equal the date being used 
for the calculation. 
− For missing start day and month – Day and month will be imputed as the first day 
of the year (ie, 1 January) with the following exception:  if the partial date falls in 
the same year as the date being used in the calculation (eg, first dose date, 
informed consent date), then the partial date will be imputed to equal the date 
being used for the calculation. 
− Imputed start dates must be prior to the stop date. 
• Stop Dates (eg, AE resolution date or stop date of medication) 
− For missing stop day only – Day will be imputed as the last day of the month 
(ie, 28, 29, 30, or 31). 
− For missing stop day and month – Day and month will be imputed as the last day 
of the year (ie, 31 December). 
− Imputed stop dates must be on or after the start date. 
All data recorded on the case report form will be included in data listings that will accompany 
the clinical study report. 
7.3. 
Data Conventions 
The precision of original measurements will be maintained in summaries, when possible. 
Means, medians, SEMs, and SDs will be presented with an increased level of precision, where 
means and medians will be presented to one more decimal place than the raw data, and the SEMs 
and SDs will be presented to two more decimal places than the raw data.  In general, the decimal 
places should not exceed three decimal places, unless appropriate. 
For tables where rounding is required, rounding will be done to the nearest round-off unit.  For 
example, when rounding to the nearest integer, values ≥XX.5 will be rounded up to XX+1 
(eg, 97.5 will round up to 98), while values <XX.5 will be rounded down to XX (eg, 97.4 will 
round down to 97). 
Percentages based on frequency counts will be based on available data, and denominators will 
generally exclude missing values, unless otherwise stated.  For frequency counts of categorical 
variables, categories whose counts are zero will be displayed for the sake of completeness.  For 
example, if none of the subjects discontinue due to “lost to follow-up,” this reason will be 
included in the table with a count of 0.  Percentages based on frequency counts will be presented 
as a whole number (no decimal places), and values less than 1% will be presented as “<1%.”  
Values less than 100% but that round up from 99.5% to 100% will be presented as “>99%.” 
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. 
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For laboratory test results that are above the quantifiable limit: 
Imputed laboratory results = (numeric portion of the result) x 1.1. 
7.4. 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
• Time to event – The time to an event will be calculated in days as the date of the first 
occurrence of the event minus the date of first investigational product administration 
plus 1 
• Days – A duration expressed in days between one date (date1) and another later date 
(date2) will be calculated using the following formulas:  
duration in days = date2 – date1 + 1, where date1 ≥first dose date 
duration in days = date2 – date1, where date1 <first dose date 
• Months – A duration expressed in months is calculated as the number of days divided 
by 365.25/12 (approximately 30.4) 
• Years – A duration expressed in years between one date (date1) and another date 
(date2) is calculated using the following formulas: 
duration in years = (date2 – date1 + 1)/365.25, where date1 ≥first dose date 
duration in years = (date2 – date1)/365.25, where date1<first dose date 
• Age – Age is calculated as the number of years from the date of birth (DOB) to the 
specified date, eg, date of informed consent (DOIC).  If the month of DOIC <month 
of DOB or the month of DOIC = DOB and the day of DOIC <day of DOB, then the 
following formula is used: 
age (years) = year of DOIC – year of DOB – 1. 
Otherwise, the following formula is used: 
age (years) = year of DOIC – year of DOB. 
• Change from Baseline – Change from Baseline will be calculated as: 
Change = post Baseline value – Baseline value 
• Percentage change from Baseline – Change from Baseline will be calculated as: 
Percentage change from Baseline = ([post Baseline value – Baseline value] / 
Baseline value) × 100 
• MELD score is derived using the following formula: 
MELD = 3.78 × ln[serum bilirubin (mg/dL)] + 11.2 × ln[INR] + 9.57 × ln[serum 
creatinine (mg/dL)] + 6.43 × aetiology(0: cholestatic or alcoholic, 1: otherwise).  
• Child Pugh classification (Noncirrhotic/A/B/C) is defined as follows:  Subjects 
deemed noncirrhotic at baseline by the PI are captured as “noncirrhotic” regardless of 
baseline Child-Pugh score and those without a cirrhosis assessment or who were 
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deemed cirrhotic at baseline are summarized by their baseline (Screening or Day 0) 
Child-Pugh category.  
• Rotterdam Criteria (Mild/Moderate/Severe) is defined as follows: 
Mild - Total Bilirubin ≤ ULN and Albumin ≥ LLN 
Moderate - Total Bilirubin > ULN and Albumin ≥ LLN or 
       Total Bilirubin ≤ ULN and Albumin < LLN 
Severe – Total Bilirubin > ULN and Albumin < LLN, where  
baseline values of total bilirubin and albumin are taken to be the average of all 
pre-dose measurements. 
7.5. 
Sample Size Recalculation 
With a single interim analysis at 65% information fraction, the interim analysis and final 
study analysis are anticipated to occur at 83 and 127 events, respectively.  The pre-specified 
weights that will be used for the sample size re-assessment will be: 
𝑤𝑤1 = 𝐷𝐷1
127 ; 𝑤𝑤2 = 127 −𝐷𝐷1
127
 
D1 is the number of actual observed events at the interim analysis. 
Let  
• 𝛿𝛿= ln (𝐻𝐻𝑅𝑅) 
• 𝑏𝑏1 and 𝑏𝑏2 denote the α-level stopping boundaries at the planned interim and final 
analysis, respectively 
• 𝑟𝑟 denote the proportion of subjects in the OCA treatment group 
• Z*j;cum denote the Z-score based on the stratified logrank statistic at look j 
• 𝐷𝐷1
∗ and 𝐷𝐷2
∗ denote the altered cumulative events at the interim and final analyses 
resulting from an adaptation of the original design 
• 𝛿𝛿̂𝑖𝑖 and 𝑠𝑠𝑠𝑠
ෞ(𝛿𝛿̂𝑖𝑖) denote the estimates of treatment effect and standard error of treatment 
effect from fitting the Cox proportional hazard model to the cumulative data at look 𝑗𝑗 
The CHW statistic for the interim (𝑗𝑗= 1) and final (𝑗𝑗= 2) analyses are: 
𝑍𝑍1,𝐶𝐶𝐶𝐶𝐶𝐶
∗
= √𝑤𝑤1𝑍𝑍∗(1)
√𝑤𝑤1
 and 𝑍𝑍2,𝐶𝐶𝐻𝐻𝐻𝐻
∗
= √𝑤𝑤1𝑍𝑍∗(1)+√𝑤𝑤2𝑍𝑍∗(2)
√𝑤𝑤1+𝑤𝑤2
, respectively, 
where  𝑍𝑍∗(𝑖𝑖) is the incremental statistic at look 𝑗𝑗: 
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𝑍𝑍∗(𝑖𝑖) =
ට𝐼𝐼𝑖𝑖
∗𝑍𝑍𝑖𝑖,𝑐𝑐𝑐𝑐𝑚𝑚
∗
−ට𝐼𝐼𝑖𝑖−1
∗
𝑍𝑍𝑖𝑖−1,𝑐𝑐𝑐𝑐𝑚𝑚
∗
ට𝐼𝐼𝑖𝑖
∗−𝐼𝐼𝑖𝑖−1
∗
 
and 𝐼𝐼𝑖𝑖
∗≈
1
൫𝑠𝑠𝑠𝑠
ෞ(𝛿𝛿෡𝑗𝑗)൯
2  
If the CHW statistic at the interim analysis is 𝑍𝑍1,𝐶𝐶𝐶𝐶𝐶𝐶
∗
= 𝑧𝑧1 and 𝐷𝐷2
∗ cumulative events are required 
at the final analysis, the conditional power at the interim analysis is: 
𝐶𝐶𝐶𝐶𝛿𝛿(𝑧𝑧1) = 1 −Φ ቐ𝑏𝑏2ඨ1 + 
𝐷𝐷1
𝐷𝐷2 −𝐷𝐷1
−𝑧𝑧1ඨ
𝐷𝐷1
𝐷𝐷2 −𝐷𝐷1
−𝛿𝛿ඥ𝑟𝑟(1 −𝑟𝑟)ඥ𝐷𝐷2
∗−𝐷𝐷1ቑ 
Where the log hazard ratio 𝛿𝛿 will be estimated using 𝛿𝛿̂1, the estimate of treatment effect from 
fitting the Cox proportional hazard model to the cumulative data at the interim analysis. 
8. 
REFERENCES 
Cui L, Hung HM, Wang SJ. Modification of Sample Size in Group Sequential Clinical Trials. 
Biometrics. 1999. Sep;55(3):853-857 
Lan KKG and DeMets DL. Discrete Sequential Boundaries for Clinical Trials. Biometrika. 
1983;70:659-663. 
Reboussin DM, DeMets, DL, Kim KM, et al.  Computations for Group Sequential Boundaries 
Using the Lan-DeMets Spending Function Method.  Controlled Clin Trials. 2000;21(3):190-207. 
Robins JM. Association, Causation, and Marginal Structural Models. Synthese. 1999 Jan 
1:151-179. 
 
 
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9. 
REVISION HISTORY 
9.1. 
Rationale of the Revision 
IND 063307 Advice-Information Request was received from the agency after the submission of 
the SAP v1.0, dated 14 July 2020.  The SAP was amended in response to the agency’s comments. 
9.2. 
Changes from Previous Version 
The following changes have been implemented in this SAP amendment: 
 
Section 
Original Text  
(Version 1.0, 14 Jul 2020) 
Revised Text  
(Amendment 1.0, 20 Aug 2020) in Red 
1.1.1 
1.2.2 
4.2.1 
- Uncontrolled ascites (diuretic 
resistant ascites requiring therapeutic 
paracentesis at a frequency of at least 
twice in a month) 
• Format changes for this bullet point 
as this is one component of the 
composite event endpoint and should 
not be under the hospitalization. 
4.1 
Group sequential boundaries for efficacy 
at the planned timepoints are provided in 
Table 1 for the Type I error rate 
comprising the sum of prespecified 
alpha for clinical outcomes and carried 
forward alpha from the interim analysis. 
Exact boundaries and alpha levels will 
be calculated at the time of analysis 
based on the actual observed 
information fraction and observed 
discontinuation rates.  
The criteria for the DMC to recommend 
that the study stop for efficacy will be 
met at the interim analysis when the 
estimated hazard ratio is less than δ*, 
where δ* is the hazard ratio efficacy 
boundary calculated based on observed 
data at the interim analysis. 
 
Stopping criteria for efficacy at the 
planned timepoints based on group 
sequential boundaries are provided in 
Table 1 for the Type I error rate 
comprising the sum of prespecified 
alpha for clinical outcomes and carried 
forward alpha from the interim analysis. 
The exact alpha level and corresponding 
hazard ratio criterion at the time of 
interim analysis will be calculated based 
on the actual observed number of 
clinical events.  
The criteria for the DMC to recommend 
that the study stop for efficacy will be 
met at the interim analysis when the 
estimated hazard ratio is less than δ*, 
where δ* is the hazard ratio efficacy 
criterion calculated based on observed 
data at the interim analysis. 
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Section 
Original Text  
(Version 1.0, 14 Jul 2020) 
Revised Text  
(Amendment 1.0, 20 Aug 2020) in Red 
4.1 
 
Table 1: O’Brien-Fleming Boundaries 
 
Note: Estimates for information fraction and 
number of clinical events at interim analysis are 
provided in Table 1 for illustration, and the 
hazard ratio efficacy boundary δ* will be 
calculated based on observed data. 
Table 1: Stopping Criteria Based on 
O’Brien-Fleming Boundaries  
 
Note: Estimates for information fraction and 
number of clinical events at interim analysis are 
provided in Table 1 for illustration, and the 
hazard ratio efficacy criteria δ* will be calculated 
based on observed data. 
4.2.2 
1. The hazard ratio will be estimated 
using Inverse Probability of 
Censoring Weighting (IPCW) 
techniques (Robins 1999).  The 
DMC will use this analysis to assess 
the impact of censoring on the 
hazard ratio.  Baseline predictors of 
both censoring and clinical outcome 
will be identified in advance. 
Augmented IPCW estimators 
described by Robins may be 
implemented to explore the possible 
impact of unmeasured confounding. 
1. The hazard ratio will be estimated 
using Inverse Probability of 
Censoring Weighting (IPCW) 
techniques (Robins 1999).  The 
DMC will use this analysis to assess 
the impact of censoring on the 
hazard ratio.  Baseline predictors of 
both censoring and clinical outcome 
will be identified in advance. 
Augmented IPCW estimators 
described by Robins may be 
implemented to explore the possible 
impact of unmeasured confounding. 
Baseline predictors of both censoring 
and clinical outcome for the IPCW 
analysis are: 
• Treatment Group: 
OCA/Placebo 
• Age (year) at Screening Visit 
• Sex: Male/Female 
• UDCA use at Screening Visit: 
Yes/No 
• Baseline Total Bilirubin 
(µmol/L)  
• Baseline Alanine 
Transaminase (U/L)  
• Baseline Aspartate 
Transaminase (U/L)  
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Section 
Original Text  
(Version 1.0, 14 Jul 2020) 
Revised Text  
(Amendment 1.0, 20 Aug 2020) in Red 
• Baseline Alkaline Phosphatase 
(U/L)  
• Baseline Albumin (g/L)  
• Baseline Platelets count  
The post-baseline time-varying 
covariates are: ALP, ALT, AST, 
Total Bilirubin, and AE of pruritus 
with severity of moderate and severe. 
To derive the IPCW weights, the 
patient’s follow-up time up until the 
time of censoring or event occurring 
will be partitioned into about 
10 intervals. The probability of 
remaining uncensored at the end of 
each time interval adjusted for 
baseline variables, and post-baseline 
time-varying covariates will be 
estimated using a pooled logistic 
regression model. To avoid possible 
extreme values when taking the 
inverse of the estimated probabilities 
from the pooled logistic model with 
both baseline and time-varying post-
baseline covariates, the inverse of 
these probabilities will be stabilized 
by multiplying the probability of 
remaining uncensored conditional 
only on baseline covariates. Once the 
IPCW weights are derived, the HR of 
treatment effect and corresponding 
95% CI will be estimated using a 
weighted Cox regression model with 
Sandwich estimator to obtain the 
robust estimate of the variance-
covariance matrix of the parameter 
estimates. 
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Section 
Original Text  
(Version 1.0, 14 Jul 2020) 
Revised Text  
(Amendment 1.0, 20 Aug 2020) in Red 
5.2 
If the criteria for the DMC to 
recommend that the study stop for 
efficacy, ie, the estimated hazard ratio is 
less than δ*, where δ* is the hazard ratio 
efficacy boundary at the interim 
analysis, are not met at the interim 
analyses, the conditional power for 
rejecting the null hypothesis in favor of 
the alternative (ie, the probability of 
success at end of trial given the interim 
results) will be computed.   
If the criteria for the DMC to 
recommend that the study stop for 
efficacy, ie, the estimated hazard ratio is 
less than δ*, where δ* is the hazard ratio 
efficacy criterion at the interim analysis, 
are not met at the interim analyses, the 
conditional power for rejecting the null 
hypothesis in favor of the alternative (ie, 
the probability of success at end of trial 
given the interim results) will be 
computed.   
6.1 
Table 2: O’Brien-Fleming Boundaries 
Table 2: Stopping Criteria Based on 
O’Brien-Fleming Boundaries  
7.5 
With a single interim analysis at 65% 
information fraction, the interim analysis 
and final study analysis are anticipated 
to occur at 𝐷𝐷1 = 83 and 𝐷𝐷2 = 127 
events, respectively. 
With a single interim analysis at 65% 
information fraction, the interim analysis 
and final study analysis are anticipated 
to occur at 83 and 127 events, 
respectively.  
 
D1 is the number of actual observed 
events at the interim analysis. 
9 
N/A 
Revision History section added 
 
 
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