Clinical trial NCT02177136
Conditions: Primary Sclerosing Cholangitis (PSC)
Keywords: PSC
Sponsor: Intercept Pharmaceuticals
Start date: 2015-02-09; Completion date: 2018-03-22
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a phase 2, double-blind (DB), placebo-controlled trial in participants with primary sclerosing cholangitis to evaluate the effect of obeticholic acid on liver biochemistry, in particular, serum alkaline phosphatase; and, safety. The long-term safety extension (LTSE) phase was conducted to evaluate the safety, tolerability, and efficacy of long-term, open-label use of OCA in participants with PSC who had completed the DB phase of the study.

Detailed description:
This was a phase 2, randomized, double-blind, placebo-controlled, dose-finding evaluation of the efficacy and safety of OCA in participants with PSC. Approximately 75 participants who provided written informed consent and met all of the inclusion and none of the exclusion criteria were randomized to 1 of 3 treatment groups as follows: 1.5 milligrams (mg) titrating to 3 mg OCA, 5 mg titrating to 10 mg OCA, or placebo, in a 1:1:1 ratio. Participants self-administered investigational product (IP) orally, once daily for 2 consecutive 12-week periods.

For the first 12 weeks, the participant's dose was 1.5 mg OCA, 5 mg OCA, or placebo. After 12 weeks, the participant's dose was titrated as follows, providing there were no limiting safety or tolerability concerns in the opinion of the Investigator, while maintaining the trial blind: the 1.5 mg OCA treatment group titrated to 3 mg, the 5 mg OCA treatment group titrated to 10 mg OCA, and the placebo group remained on placebo. Double-blind treatment continued for a further 12 weeks at that dose.

Any participant whose dose was not titrated, due to safety or tolerability concerns, remained on their starting treatment (1.5 mg OCA, 5 mg OCA, or placebo) for the remainder of the DB phase to Week 24.

Randomization was stratified by the presence or absence of concomitant ursodeoxycholic acid (UDCA) use and total bilirubin level (≤1.5x upper limit of normal \[ULN\] or \>1.5x ULN but \<2.5x ULN).

Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the open-label LTSE phase (planned as a further 24 months).

Arms: arm 1: Participants randomized to 1.5 mg OCA took 1.5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 3 mg OCA daily for an additional 12 weeks. arm 2: Participants randomized to 5 mg OCA took 5 mg OCA daily for 12 weeks during the DB phase. If tolerated, the dose was increased to 10 mg OCA daily for an additional 12 weeks. arm 3: Participants randomized to placebo took placebo for 24 weeks during the DB phase. arm 4: Following completion of the DB phase, participants were asked to reconfirm their consent for participation in the LTSE phase (planned as a further 24 months) beginning at 5 or 10 mg OCA, based on the last treatment received during the DB phase. Doses up to 10 mg daily were evaluated. All participants received open-label OCA during the LTSE phase of the study.
Interventions: intervention 1: Obeticholic Acid (OCA) intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
TITLE PAGE 
 
Clinical Trial Protocol 747-207 
OBETICHOLIC ACID 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, 
Clinical Trial Evaluating the Efficacy and Safety of Obeticholic Acid in 
Subjects with Primary Sclerosing Cholangitis  
 
Version 5:  18 March 2016 
 
EudraCT Number:  2014-002205-38 
 
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. 
 


Protocol741-2O7
Version 5: l8 Mar 2016
Page 2
SPONSOR'S APPROVAL OF THE PROTOCOL
Reviewed and Approved by:
Leigh MacConell, PhD
Vice President, Clinical Development
Intercept Pharmaceuticals, lnc.
6n*u,
Confi dential and Proprietary


Protocol 747-207 
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Confidential and Proprietary 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the current version of the Investigator’s Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-207.  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 trial and not previously published 
is confidential information.  This includes the IB, Clinical Trial Protocol, Case Report Forms 
(CRF) and any other nonclinical 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 747-207 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 trial has the right to discontinue the trial at any time. 
 
 
 
 
 
 
Investigator’s Name (Printed) 
 
 
 
 
 
 
Investigator’s Signature 
 
Date 


Protocol 747-207 
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Page 4 
Confidential and Proprietary 
 
 
PROCEDURES IN CASE OF EMERGENCY 
 
Sponsor Contact Information 
Medical Monitor - 24 hour Emergency Reporting 
Contact: 
Barbara Scholz, MD, MPH 
Telephone: 
+ 1 844 250 6398 (Pacific Time Zone) 
Email: 
barbara.scholz@interceptpharma.com 
SAE Fax: 
+1 800 497 8521 
SAE Email: 
sae@interceptpharma.com 
 
Clinical Operations and Project Management 
Contact: 
Tessa Beecher-Jones BSc (Hons) 
VP, Head of Clinical Operations, EU  
Telephone: 
Mobile: 
Email: 
+44 1491 640 710 (GMT) 
+44 7969 621 504 (GMT) 
tbeecherjones@interceptpharma.com 


Protocol 747-207 
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1. 
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) 
Title of Trial:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, 
Clinical Trial Evaluating the Efficacy and Safety of Obeticholic Acid in Subjects with Primary 
Sclerosing Cholangitis 
Trial Number:  747-207 
Number of Subjects:  Approximately 75 
Planned Number of Trial Sites:  Approximately 35 (Europe and United States [US]) 
Trial Period (Months): Approximately 50 months (first subject consented to last subject 
completing last study visit)   
Phase of Trial:  Phase 2 
Objectives:  
Primary 
To evaluate the effects of OCA on the following in subjects with primary sclerosing cholangitis 
(PSC): 
• Serum alkaline phosphatase (ALP)  
• Safety 
Secondary 
To evaluate the effects of OCA on the following in subjects with PSC:  
• Hepatic biochemistry and indices of function  
• Markers of: 
− Hepatic fibrosis and GI inflammation and disease  
− Farnesoid X receptor (FXR) activity 
− Inflammatory bowel disease (IBD) 
• Pharmacokinetics (PK) of OCA and other bile acids  
• Exposure response of total OCA (OCA and its conjugates) to biomarkers (eg, ALP 
and bile acids) 
• Long-term efficacy and safety of OCA 
• Disease-specific symptoms. 
 


Protocol 747-207 
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Methodology:  
Double-blind Phase (DB) 
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding evaluation of the 
efficacy and safety of OCA in subjects with PSC.  Approximately 75 subjects who provide 
written informed consent and meet all of the inclusion and none of the exclusion criteria will be 
randomized to 1 of 3 treatment groups as follows:  1.5 mg titrating to 3 mg OCA, 5 mg titrating 
to 10 mg OCA, or placebo, in a 1:1:1 ratio.  Subjects will administer investigational product 
orally, once daily for 2 consecutive 12-week periods.   
For the first 12 weeks, the subject’s dose will be 1.5 mg OCA, 5 mg OCA, or placebo.  After 
12 weeks, the subject’s dose will be titrated as follows, providing there are no limiting safety or 
tolerability concerns in the opinion of the Investigator, while maintaining the trial blind:  the 
1.5 mg OCA treatment group will titrate to 3 mg, the 5 mg OCA treatment group will titrate to 
10 mg OCA, and the placebo group will remain on placebo.  DB treatment will continue for a 
further 12 weeks at that dose.   
Any subjects whose dose is not titrated, due to safety or tolerability concerns, will remain on 
their starting treatment (1.5 mg OCA, 5 mg OCA, or placebo) for the remainder of the DB phase 
to Week 24. 
Randomization will be stratified by the presence or absence of concomitant ursodeoxycholic acid 
(UDCA) use and total bilirubin level (≤1.5x upper limit of normal [ULN] or >1.5x ULN but 
<2.5x ULN). 
Long-Term Safety Extension Phase (LTSE) 
Following completion of participation in the DB phase, subjects will be asked to reconfirm their 
consent for participation in the open-label long-term safety extension (LTSE) phase (a further 
24 months).   
Upon a subject’s completion of the DB phase, the trial blind will be broken in order to assign the 
starting OCA dose for the LTSE phase.  It is intended that subjects will commence treatment at 
5 mg OCA, except those subjects who completed treatment in the DB phase with 10 mg OCA 
who will continue at 10 mg OCA unless safety and tolerability warrant a dose reduction to 5 mg.   
• Placebo at end of DB  5 mg OCA in LTSE 
• 3 mg OCA at end of DB  5 mg OCA in LTSE 
• 10 mg OCA at end of DB  10 mg OCA in LTSE 
Those subjects who did not up-titrate their dose at Week 12 in the DB phase can remain on their 
DB dose, or commence at 5 mg at the decision of the Investigator based on safety and tolerability 
of the DB dose at Week 24.  If an investigator does not wish for a subject to be titrated in line 
with the above schedules, this may be discussed with the Medical Monitor. 
During the LTSE phase, subjects may titrate to higher doses of OCA, at a frequency not greater 
than 3 monthly (ie, at each of the scheduled LTSE visits), up to a maximum dose of 10 mg daily.  
The guideline for an increase in the dose of OCA is based on tolerability and the goal of 
achieving an ALP level <1.5x ULN.  Doses of OCA should be titrated as follows, unless 
clinically indicated:  1.5 mg to 3 mg, 3 mg to 5 mg, and 5 mg to 10 mg.  Intermediate doses 


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c. Subjects with ulcerative colitis (UC) must either be in remission or have mild disease. 
Remission is defined as a partial Mayo score of ≤2 with no individual sub-score 
exceeding 1.  Mild disease is defined as a partial Mayo score ≤3 with no individual 
sub-score exceeding 1 point.  
7. For subjects being administered UDCA as part of their standard of care, the dose must 
have been stable for ≥3 months prior to, and including, Day 0 and must not have 
exceeded 20 mg/kg/day during this time.  
Note 2:  Subjects not taking UDCA at Day 0 must not have taken UDCA for ≥3 months 
prior to, and including, Day 0 and must not take UDCA during the DB period.  Subjects 
will be stratified according to UDCA use, and no more than 50% of subjects 
administering UDCA at Day 0 will be enrolled. 
8. Subjects being administered biologic treatments (eg, anti-TNF or anti-integrin 
monoclonal antibodies), immunosuppressants, systemic corticosteroids, or statins, must 
have been on a stable dose for ≥3 months prior to, and including, Day 0 and should plan 
to remain on a stable dose throughout the trial. 
9. Contraception:  female subjects of childbearing potential must use ≥1 effective method 
(≤1% failure rate) of contraception during the trial and until 4 weeks following the last 
dose of investigational product (including LTSE doses).  Effective methods of 
contraception are considered to be those listed below: 
• Barrier method, ie, (a) condom (male or female) with spermicide or (b) diaphragm 
with spermicide; or 
• Intrauterine device; or 
• Vasectomy (partner), or 
• Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection); or 
• Abstinence, if in line with the preferred and usual lifestyle of the subject [where 
abstinence is defined as refraining from heterosexual intercourse during the trial 
duration (from first administration of investigational product until 4 weeks after the 
last dose of investigational product)] 
Exclusion Criteria 
Subjects will be excluded from trial participation if they meet any of the following: 
1. Evidence of a secondary cause of sclerosing cholangitis at Screening 
2. Immunoglobulin G4 (IgG4) >4x ULN at Screening or evidence of IgG4 sclerosing 
cholangitis 
3. Small duct cholangitis in the absence of large duct disease 
4. Presence of clinical complications of chronic liver disease or clinically significant hepatic 
decompensation, including:  
• Current Child-Pugh classification B or C 


Protocol 747-207 
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• History of, or current diagnosis or suspicion of, cholangiocarcinoma or other 
hepatobiliary malignancy, or biliary tract dysplasia 
• History of liver transplantation, or current model of end stage liver disease (MELD) 
score ≥12 
• History of, or current, cirrhosis with complications, including history or presence of 
spontaneous bacterial peritonitis, hepatocellular carcinoma or hepatic encephalopathy 
(as assessed by the Investigator) 
• Current known portal hypertension with complications, including known gastric or 
large esophageal varices, poorly controlled or diuretic resistant ascites, history of 
variceal bleeds, or related therapeutic or prophylactic interventions (eg, beta blockers, 
insertion of variceal bands, or transjugular intrahepatic portosystemic shunt [TIPS]) 
• History of, or current, hepatorenal syndrome (type I or II) or Screening serum 
creatinine >2 mg/dL (178 μmol/L) 
• Platelet count <50 x109/L 
5. Current clinical evidence of dominant strictures that are considered clinically relevant in 
the opinion of the Investigator or current biliary stent at Screening 
6. Current cholecystitis or evidence of current biliary obstruction due to gallstones. 
Asymptomatic gallstones that are not considered a safety risk in the opinion of the 
Investigator might be acceptable subject to discussion and agreement with the Medical 
Monitor  
7. Colonic dysplasia within ≤5 years prior to Day 0 
8. History of small bowel resection  
9. History of other chronic liver diseases, including, but not limited to, primary biliary 
cirrhosis (PBC), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), 
autoimmune hepatitis, hepatitis B virus (unless seroconverted and no positive Hepatitis B 
Virus DNA), hepatitis C virus, and overlap syndrome 
10. Known Gilbert’s syndrome or history of elevations in unconjugated (indirect) bilirubin 
>ULN or unconjugated (indirect) bilirubin >ULN at Screening. 
11. Known history of human immunodeficiency virus (HIV) infection 
12. Currently experiencing, or experienced within ≤3 months of Screening, pruritus requiring 
systemic or enteral treatment. 
13. Known or suspected acute cholangitis in the 3 months prior to, and including, Day 0 
including cholangitis treated with antibiotics.  
14. Administration of antibiotics is prohibited ≤1 month of Day 0 (unless subject is on a 
stable prophylaxis dose for at least 3 months prior to Day 0). 
15. Administration of the following medications is prohibited ≤6 months of Day 0 and 
throughout the trial:  fenofibrate or other fibrates and potentially hepatotoxic medications 
(including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin). 


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16. IBD flare during Screening (up to and including Day 0), where “flare” is defined as 
follows: 
• UC flare:  partial Mayo Score ≥5, and  
• CD flare:  CDAI ≥250 
17. Evidence of deleterious effects of alcohol abuse (as assessed by the Investigator) or 
excessive alcohol consumption (>4 units/day for males, >2 units/day for females) 
18. Known or suspected use of illicit drugs or drugs of abuse (allowed if medically 
prescribed or indicated) within 3 months of Day 0 
19. If female:  known pregnancy, or has a positive urine pregnancy test (confirmed by a 
positive serum pregnancy test), or lactating 
20. Other concomitant disease, malignancy, or condition likely to significantly decrease life 
expectancy to less than the duration of the trial (eg, moderate to severe congestive heart 
failure) 
21. Participation in another investigational drug, biologic, or medical device trial within 
30 days prior to Screening 
22. History of noncompliance with medical regimens, or subjects who are considered to be 
potentially unreliable 
23. Blood or plasma donation within 30 days prior to Day 0 
24. Mental instability or incompetence such that the validity of informed consent or 
compliance with the trial is uncertain. 
Investigational Product, Dosage and Mode of Administration:  OCA, 1.5 mg tablet and 
matching placebo and OCA 5 mg tablet and matching placebo. 
Doses will be 1.5 mg, 3mg, 5mg, 10 mg OCA or matching placebos, as follows: 
DB phase:  2 tablets administered once daily during weeks 0 through 12 and 4 tablets 
administered once daily during weeks 12 through 24 
LTSE Phase:  All subjects will receive open-label OCA at a starting dose that is dependent upon 
their dose at completion of DB phase, as well as safety and tolerability.  Doses may be 1.5 mg, 
3 mg, 5 mg, or 10 mg, ie, 1 or 2 tablets, once daily.  Intermediate doses (eg, 6.5 mg) may be 
considered as deemed appropriate by the Investigator.  Dose should not exceed 10 mg. 
Duration of Treatment:  30 months (6 month DB period followed by a 24 month, open-label 
LTSE) 
Duration of Subject Participation: up to 32 months (up to 30 day Screening period, 6 month 
DB period, followed by a 24 month open-label LTSE period, and a 1 month follow-up period) 


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Criteria for Evaluation:  
Primary Objectives 
Assessments 
Serum ALP 
ALP   
Safety 
Adverse events (AEs) 
Clinical findings and laboratory values 
Secondary Objectives 
 
Hepatic biochemistry and indices of 
function 
ALP  
Albumin, alanine transaminase (ALT), aspartate aminotransferase 
(AST), bilirubin, gamma-glutamyl transferase (GGT), 
international normalized ratio (INR)  
Markers of hepatic and GI 
inflammation, disease, and fibrosis 
Autotaxin and its metabolites, calprotectin, C-reactive protein 
(CRP), Cytokeratin-18 (CK-18), Enhanced liver fibrosis (ELF) 
markers, Immunoglobulin A (IgA), IgG, Immunoglobulin M 
(IgM), Interleukin-6 (IL-6), 
Interleukin-12 (IL-12), Interleukin-23 (IL-23),  
Transient elastography (TE; at participating sites), Transforming 
growth factor-beta (TGF-β), Tumor necrosis factor-alpha (TNF-α) 
Markers of farnesoid X receptor 
(FXR) activity 
Fibroblast growth factor-19 (FGF-19) 
PK of OCA and other bile acids  
Plasma OCA bile acids and conjugates including 7α-hydroxy-4-
cholesten-3-one (C4) 
Exposure response of total OCA to 
biomarkers 
Relationship of total OCA (OCA and its conjugates) to 
biomarkers such as change in ALP and change in bile acids. 
Long-term efficacy and safety 
As above 
Disease-specific symptoms 
Pruritus Visual Analogue Scale (VAS) 
Pruritus 5-D questionnaire 
Partial Mayo scoring system for assessment of ulcerative colitis 
activity (partial Mayo score) 
Crohn’s disease activity index (CDAI) 
Statistical Methods:  
Efficacy Analyses 
The primary efficacy endpoint is the Week 24 change from Baseline in ALP.  The primary 
efficacy analysis will compare the Week 24 change from Baseline in ALP between the OCA 
10 mg treatment group and placebo using an analysis of covariance (ANCOVA) model with 
fixed effects for treatment group and randomization strata, and Baseline as a covariate.   
Secondary efficacy analyses of hepatic biochemistry and function parameters will use the same 
ANCOVA models as the primary endpoints.  A hierarchical approach will be used for 
multiplicity adjustments.  If the primary efficacy analysis is statistically significant (p <0.05), the 


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following order will be used in the testing procedure to compare the change from Baseline in 
ALP between OCA and placebo: 
• Week 12:  OCA 5 mg treatment group (randomized to 5 mg for the initial 12 weeks 
followed by 10 mg for the latter 12 weeks) vs. placebo 
• Week 24:  OCA 3 mg treatment group (randomized to 1.5 mg for the initial 12 weeks 
followed by 3 mg for the latter 12 weeks) vs. placebo  
• Week 12:  OCA 1.5 mg treatment group (randomized to 1.5 mg for the initial 
12 weeks followed by 3 mg for the latter 12 weeks) vs. placebo 
If at any step the comparison is not statistically significant, then all subsequent comparisons will 
be exploratory rather than confirmatory.   
In addition, secondary efficacy analyses of ALP response rates, defined as ALP to <1.5x ULN, 
will compare OCA treatment groups vs. placebo at Week 12 and Week 24 using a 
Cochran-Mantel-Haenszel test stratified by the randomization stratification factor.  Missing 
values will be considered a non-response.  
Safety Analyses 
The incidence of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) 
will be tabulated by system organ class and preferred term for each treatment group, and 
similarly by severity and relationship to treatment. 
Laboratory parameters and vital signs will be summarized by treatment group using descriptive 
statistics at Baseline and at each scheduled post-Baseline visit.  The change from Baseline will 
also be summarized.  Electrocardiograms (ECGs) will be summarized by treatment group using 
frequency at each visit.  The shift from baseline will also be summarized.  Baseline is defined as 
the mean of all available evaluations prior to treatment (except for lipoprotein assessments where 
Baseline will be Day 0).   
Pharmacokinetic and Pharmacodynamic Analyses 
The pharmacokinetics (PK) of OCA and other bile acids will be evaluated, including AUCt, 
Cmax, and tmax.  An exposure response analysis of total plasma OCA (OCA and its conjugates) to 
biomarkers, such as change in ALP and change in bile acids, will be performed to help identify 
optimal doses for this patient population.   
Full details of the statistical methodology, analyses, and outputs will be detailed in the statistical 
analysis plan (SAP). 
Interim Analysis 
An unblinded interim analysis for planning purposes will be conducted after approximately 
50% of subjects have completed the initial 12-weeks of blinded treatment.  The trial will not be 
terminated early for futility.  The interim analysis will compare at Week 12, the same variable as 
will be analyzed for the primary endpoint:  the change from Baseline in ALP, between OCA 
treatment groups (1.5 mg and 5 mg) and placebo using an analysis of covariance (ANCOVA) 
model with fixed effects for treatment group and randomization strata and Baseline as a 
covariate.  No adjustments to the alpha level will be made. 


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Sample Size Justification 
A sample size of 25 subjects per treatment group, a total of 75 subjects, will provide at least 
90% power to detect a treatment difference for change in ALP assuming the mean absolute 
change in ALP for OCA and placebo treatment groups are approximately -20% and -5%, 
respectively, with a pooled standard deviation of 16, based on a 2-sided independent 2-group 
t-test at an alpha level of 0.05. 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................20 
4. 
INTRODUCTION ......................................................................................................24 
4.1. 
Overview of Primary Sclerosing Cholangitis and Obeticholic Acid ..........................24 
4.2. 
Mechanism of Action of Obeticholic Acid .................................................................24 
4.3. 
Nonclinical Experience with Obeticholic Acid ..........................................................25 
4.3.1. 
Nonclinical Anti-fibrotic and Anti-inflammatory Properties .....................................25 
4.3.2. 
Nonclinical Effects on Cholestasis .............................................................................26 
4.4. 
Clinical Experience with Obeticholic Acid ................................................................26 
4.5. 
Summary of Known Potential Risks with Investigational Product ............................27 
4.6. 
Rationale for Trial Design and Dose for Investigational Product ..............................28 
4.6.1. 
Rationale for Trial Design ..........................................................................................28 
4.6.2. 
Rationale for Doses .....................................................................................................29 
5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................30 
5.1. 
Primary Objective .......................................................................................................30 
5.2. 
Secondary Objectives .................................................................................................30 
6. 
INVESTIGATIONAL PLAN .....................................................................................31 
6.1. 
Overall Trial Design ...................................................................................................31 
6.1.1. 
Trial Design Diagram .................................................................................................32 
6.1.2. 
Trial Duration .............................................................................................................39 
6.2. 
Number of Subjects ....................................................................................................39 
6.3. 
Treatment Assignment ................................................................................................39 
6.4. 
Dose Adjustment Criteria and Dose Titration ............................................................39 
6.4.1. 
Double-Blind Phase ....................................................................................................39 
6.4.2. 
LTSE Phase ................................................................................................................40 
6.4.3. 
Safety Criteria for Adjustment or Stopping Doses .....................................................40 
6.5. 
Criteria for Trial Termination .....................................................................................41 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................41 
7.1. 
Subject Population ......................................................................................................41 
7.2. 
Subject Inclusion Criteria ...........................................................................................41 
7.3. 
Subject Exclusion Criteria ..........................................................................................43 
7.4. 
Subject Withdrawal Criteria .......................................................................................44 
7.4.1. 
Reasons for Mandatory Investigational Product or Trial Discontinuation .................44 
7.4.2. 
Other Reasons for Study Discontinuation ..................................................................45 
7.4.3. 
Subject Discontinuation Notification .........................................................................47 
8. 
TREATMENT OF SUBJECTS ..................................................................................48 
8.1. 
Investigational Product Treatment Regimen ..............................................................48 
8.2. 
Concomitant Medications ...........................................................................................49 
8.2.1. 
Ursodeoxycholic Acid ................................................................................................49 
8.2.2. 
Bile Acid Sequestrants ................................................................................................49 
8.2.3. 
Prohibited Medications ...............................................................................................50 
8.3. 
Treatment Compliance ................................................................................................50 
8.4. 
Randomization and Blinding ......................................................................................51 
8.4.1. 
Stratification ...............................................................................................................51 
8.4.2. 
Unblinding Procedures – Emergency Unblinding ......................................................51 
8.5. 
Assignment of Site and Subject Numbers ..................................................................52 
8.5.1. 
Site Numbers ..............................................................................................................52 
8.5.2. 
Subject Numbers .........................................................................................................52 
8.6. 
Visit Procedures ..........................................................................................................52 
8.6.1. 
Visit Windows ............................................................................................................52 
8.6.2. 
Informed Consent Procedures .....................................................................................52 
8.6.3. 
Screening Procedures (Within 30 Days of Day 0) ......................................................53 
8.6.4. 
Day 0 Procedures ........................................................................................................54 
8.6.5. 
Week 2 Procedures .....................................................................................................55 
8.6.6. 
Week 6 Procedures .....................................................................................................56 
8.6.7. 
Week 12 (Titration Visit) Procedures .........................................................................57 
8.6.8. 
Week 14 Procedures ...................................................................................................58 
8.6.9. 
Week 18 Procedures ...................................................................................................59 
8.6.10. 
Week 24/LTSE Day 1 Procedures ..............................................................................60 


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8.6.11. 
Early Discontinuation and/or Early Termination Procedures:  Double-Blind 
Phase ...........................................................................................................................62 
8.6.12. 
Follow-Up Visit:  Double-Blind Phase .......................................................................63 
8.6.13. 
Long-Term Safety Extension Visits ...........................................................................64 
8.6.14. 
LTSE Day 1 (DB Week 24) Procedures .....................................................................64 
8.6.15. 
LTSE Week 2 Procedures ...........................................................................................64 
8.6.16. 
LTSE Month 3, 9, 15, and 21 Procedures ...................................................................64 
8.6.17. 
LTSE Month 6 Procedures .........................................................................................65 
8.6.18. 
LTSE Month 12 Procedures .......................................................................................66 
8.6.19. 
LTSE Month 18 Procedures .......................................................................................67 
8.6.20. 
LTSE Month 24 Procedures .......................................................................................68 
8.6.21. 
Early Discontinuation and/or Early Termination Procedures:  LTSE Phase ..............69 
8.6.22. 
Follow-Up Visit:  LTSE .............................................................................................70 
8.6.23. 
Unscheduled Safety Visit ...........................................................................................71 
9. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............71 
9.1. 
Investigational Product ...............................................................................................71 
9.2. 
Investigational Product Packaging and Labeling .......................................................71 
9.3. 
Investigational Product Storage ..................................................................................72 
9.4. 
Investigational Product Administration ......................................................................72 
9.4.1. 
Investigational Product Dispensation .........................................................................72 
9.4.2. 
Missed Doses ..............................................................................................................72 
9.4.3. 
Overdose .....................................................................................................................72 
9.5. 
Investigational Product Accountability and Disposal .................................................73 
10. 
ASSESSMENTS OF EFFICACY ..............................................................................73 
10.1. 
Sample Collection .......................................................................................................73 
10.2. 
Primary Efficacy Assessments ...................................................................................73 
10.3. 
Secondary Assessments ..............................................................................................74 
10.4. 
Additional Exploratory Assessments ..........................................................................75 
10.5. 
Pharmacokinetics and Bile Acid Assessments ...........................................................76 
11. 
ASSESSMENT OF SAFETY .....................................................................................76 
11.1. 
Adverse Events and Serious Adverse Events .............................................................76 
11.1.1. 
Definitions ..................................................................................................................76 
11.1.1.1. 
Adverse Event .............................................................................................................76 


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11.1.1.2. 
Serious Adverse Event ................................................................................................77 
11.1.1.3. 
Treatment Emergent Adverse Event ...........................................................................77 
11.1.2. 
Relationship to Investigational Product ......................................................................77 
11.1.3. 
Recording Adverse Event Severity .............................................................................78 
11.1.3.1. 
Severity of Pruritus (as an AE) ...................................................................................78 
11.1.4. 
Reporting of Adverse Events and Serious Adverse Events ........................................80 
11.1.4.1. 
Reporting of Adverse Events ......................................................................................80 
11.1.4.2. 
Reporting of Serious Adverse Events .........................................................................80 
11.1.5. 
Anticipated Serious Adverse Events Associated with PSC ........................................81 
11.1.6. 
Additional Investigator Responsibilities for SAEs .....................................................82 
11.1.7. 
Notification of Post-Trial SAEs ..................................................................................82 
11.1.8. 
Follow-Up of AEs and SAEs ......................................................................................82 
11.1.9. 
Pregnancy and Follow-Up ..........................................................................................83 
11.2. 
Other Safety Parameters .............................................................................................83 
11.2.1. 
Medical History/Demographics ..................................................................................83 
11.2.2. 
Physical Examination .................................................................................................83 
11.2.3. 
Vital Signs ..................................................................................................................84 
11.2.4. 
Electrocardiogram .......................................................................................................84 
11.2.5. 
Laboratory Assessments .............................................................................................84 
12. 
STATISTICS ..............................................................................................................85 
12.1. 
Analysis Populations ..................................................................................................85 
12.2. 
Determination of Sample Size ....................................................................................86 
12.3. 
Efficacy Analysis ........................................................................................................86 
12.3.1. 
Primary Efficacy Analysis ..........................................................................................86 
12.3.2. 
Secondary Efficacy Analysis ......................................................................................86 
12.4. 
Pharmacokinetics ........................................................................................................87 
12.5. 
Safety Analysis ...........................................................................................................87 
12.5.1. 
Adverse Events ...........................................................................................................87 
12.5.2. 
Clinical Laboratory Evaluations .................................................................................88 
12.5.3. 
Additional Safety Analysis .........................................................................................88 
12.6. 
Interim Analyses and Data Monitoring ......................................................................88 
12.6.1. 
Interim Analysis ..........................................................................................................88 
12.6.2. 
Data and Safety Monitoring Committee .....................................................................88 


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................89 
13.1. 
Trial Monitoring .........................................................................................................89 
13.2. 
Investigator Audits and Inspections ............................................................................90 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................90 
15. 
ETHICS ......................................................................................................................90 
15.1. 
Ethics Review .............................................................................................................90 
15.2. 
Ethical Conduct of the Trial .......................................................................................91 
15.3. 
Written Informed Consent ..........................................................................................91 
15.4. 
Subject Confidentiality and Data Protection ..............................................................91 
16. 
INVESTIGATOR OBLIGATIONS ...........................................................................92 
16.1. 
AE Reporting ..............................................................................................................92 
16.2. 
Protocol Deviations ....................................................................................................92 
16.3. 
Regulatory Documentation .........................................................................................92 
16.4. 
Ethics Review .............................................................................................................92 
16.5. 
Archiving and Record Retention ................................................................................92 
17. 
PUBLICATION POLICY ..........................................................................................93 
18. 
LIST OF REFERENCES ............................................................................................94 
APPENDIX A. 
LIST OF PLANNED LABORATORY ANALYTES ..................................97 
APPENDIX B. 
PARTIAL MAYO SCORING SYSTEM FOR ASSESSMENT OF 
ULCERATIVE COLITIS ACTIVITY .......................................................100 
APPENDIX C. 
PRURITUS VISUAL ANALOGUE SCALE .............................................101 
APPENDIX D. 
5-D ITCH SCALE ......................................................................................102 
APPENDIX E. 
SUBJECT RESEARCH QUESTIONNAIRE.............................................103 
APPENDIX F. 
CROHN’S DISEASE ACTIVITY INDEX ................................................104 
APPENDIX G. 
PROTOCOL VERSION 2 – SUMMARY OF CHANGES .......................105 
APPENDIX H. 
PROTOCOL VERSION 3 – SUMMARY OF CHANGES .......................140 
APPENDIX I. 
PROTOCOL VERSION 4 – SUMMARY OF CHANGES .......................178 
APPENDIX J. 
PROTOCOL VERSION 5 – SUMMARY OF CHANGES .......................181 
 


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LIST OF TABLES 
Table 1: 
Schedule of Trial Procedures:  Double-Blind Phase ..................................................33 
Table 2: 
Schedule of Trial Procedures:  LTSE Phase ...............................................................36 
Table 3: 
Planned Duration of Trial Phases ...............................................................................39 
Table 4: 
Initial LTSE Doses of OCA ........................................................................................40 
Table 5: 
Initial LTSE Doses of OCA for Non-Titrating Subjects ............................................40 
Table 6: 
Daily Tablet Regimen by Treatment Group ...............................................................49 
Table 7: 
Relationship of AEs to Investigational Product ..........................................................78 
Table 8: 
Severity of AEs ...........................................................................................................78 
Table 9: 
Severity of Pruritus .....................................................................................................79 
 
LIST OF FIGURES 
Figure 1: 
Trial Design Schematic ...............................................................................................32 
  


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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 
AASLD 
American Association for the Study of Liver Diseases 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUCt  
area under the concentration time curve 
β- hCG 
beta human chorionic gonadotrophin 
BAS 
Bile acid sequestrants 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C4 
7α-hydroxy-4-cholesten-3-one 
CCA 
cholangiocarcinoma 
CCl4 
carbon tetrachloride 
CD 
Crohn’s disease 
CDAI 
Crohn’s disease activity index 
CDCA 
chenodeoxycholic acid 
CFR 
Code of Federal Regulations 
CK-18 
cytokeratin 18 
Cmax 
maximum concentration observed 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRP 
C-reactive protein 
Css 
steady state concentration 
CYP7A1 
cholesterol 7-α hydroxylase;  
DB 
double-blind 
D/d 
day/days 
dL 
deciliter 
DSMC 
Data Safety Monitoring Committee 


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Abbreviation or Specialist Term 
Explanation 
EASL 
European Association for the Study of Liver 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ELF 
enhanced liver fibrosis 
EOT 
end of treatment 
ERCP 
endoscopic retrograde cholangiopancreatography 
FDA 
Food and Drug Administration 
FGF 
fibroblast growth factor 
FU 
follow-up 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
Glyco-OCA 
glyco-obeticholic acid 
GMP 
good manufacturing practice 
HA 
hyaluronic acid 
HDL 
high density lipoprotein 
HEENT 
head, eyes, ears, nose and throat 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HSC 
hepatic stellate cells 
IB 
investigator’s brochure 
IBD 
inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ID 
identification 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG4 
Immunoglobulin G4 
IgM 
Immunoglobulin M 
IL 
interleukin 


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Abbreviation or Specialist Term 
Explanation 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
L 
liter 
LCA 
lithocholic acid 
LDL 
low density lipoprotein 
LTSE 
long-term safety extension 
MedDRA 
medical dictionary of regulatory activities 
MELD 
model of end stage liver disease 
μmol/L 
micromoles per liter 
mg 
milligram 
mRNA 
messenger ribonucleic acid 
NAFLD 
nonalcoholic fatty liver disease 
NASH 
nonalcoholic steatohepatitis 
NMR 
nuclear magnetic resonance 
OCA 
obeticholic acid 
P3NP 
procollagen-3 N-terminal peptide 
PBC 
primary biliary cirrhosis 
PD 
pharmacodynamic 
PIS 
patient information sheet 
PK 
pharmacokinetic 
PSC 
primary sclerosing cholangitis 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
serious adverse reaction 
SUSAR 
suspected unexpected serious adverse reaction 
TAA 
thioacetamide 


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Abbreviation or Specialist Term 
Explanation 
Tauro-OCA 
tauro-obeticholic acid 
TE 
transient elastography 
TEAE 
treatment emergent adverse event 
TG 
triglycerides 
TGF-β1 
transforming growth factor – beta 1 
TIMP-1 
tissue inhibitor of metalloproteinase 1 
TIPS 
transjugular intrahepatic portosystemic shunt 
tmax 
time to Cmax 
TNF-α 
tumor necrosis factor - alpha 
UC 
ulcerative colitis 
UDCA 
ursodeoxycholic acid 
U/L 
units per liter 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
VLDL 
very low density lipoprotein 
W/wk 
week 
WBC 
white blood cell 


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4. 
INTRODUCTION 
4.1. 
Overview of Primary Sclerosing Cholangitis and Obeticholic Acid 
Primary sclerosing cholangitis (PSC) is a rare, life-threatening, chronic cholestatic liver disease 
characterized by progressive destruction of bile ducts with eventual onset of cirrhosis and its 
complications.  Despite evaluation of multiple treatments, liver transplant is currently the only 
treatment shown to improve clinical outcome.  
PSC is usually diagnosed by preliminary assessment of liver biochemistry, with or without 
reported symptoms, and confirmed by cholangiography, typically magnetic resonance 
cholangiopancreatography or endoscopic retrograde cholangiopancreatography (ERCP).  
Alkaline phosphatase (ALP) is elevated in most PSC patients, consistent with cholestasis; 
alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) are typically elevated as 
well, but not in all cases.  Bilirubin is often normal in early stage PSC but increases with 
progression of the disease.  The mean age at diagnosis is 40 years, and men are affected twice as 
often as women.   
PSC is a serious and life-threatening condition.  Median survival for PSC patients has been 
previously estimated as 8 to 12 years from diagnosis in symptomatic patients, depending upon 
stage of the disease at the time of diagnosis (Levy 2006, Worthington 2006, Lee 1995).  
Complications involving the biliary tree are common and include cholangitis as well as ductal 
strictures and gallstones, both of which may require frequent endoscopic or surgical 
interventions.  PSC is often complicated by the development of malignancies, with 
cholangiocarcinoma (CCA) being the most common.  CCA drastically worsens mortality 
(Fevery 2007, Lazaridis 2006).  In a large Swedish trial, the 5-year survival rate for patients 
diagnosed with either CCA or gallbladder cancer was approximately 5% compared to 
>85% survival in PSC patients without hepatobiliary cancer (Bergquist 2002).   
Obeticholic acid (OCA) is a modified bile acid and is a potent agonist of the farnesoid X receptor 
(FXR).  OCA has marked anti-fibrotic and anti-inflammatory properties in animal models of 
liver disease.  In addition, the safety and tolerability of OCA has been evaluated in clinical trials 
in the ‘sister’ cholestatic liver disease, primary biliary cirrhosis (PBC).  Phase 2 and Phase 3 
trials in PBC subjects have shown that treatment with OCA resulted in highly statistically 
significant improvements in liver biochemistry associated with cholestasis and was generally 
well tolerated.  These findings render OCA potentially useful for the treatment of PSC.  OCA has 
received orphan drug designation for the treatment of PSC in Europe and the USA. 
4.2. 
Mechanism of Action of Obeticholic Acid 
For a detailed description of OCA’s mechanism of action please refer to the current OCA 
Investigator’s Brochure (IB).  FXR is an essential and pleiotropic regulator of a variety of 
activities involved in bile acid homeostasis (Lefebvre 2009).  Its activation affects genes that 
control bile salt synthesis and transport (Makishima 1999, Wang 1999); activation of FXR 
reduces the expression of messenger ribonucleic acid (mRNA) for cholesterol 7-α hydroxylase 
(CYP7A1; the rate-limiting enzyme of bile salt synthesis) and the sinusoidal bile salt uptake 
pump, while inducing the bile salt export pump.  Activation of FXR in the ileum leads to 
increased release of fibroblast growth factor 19 (FGF-19) into the portal vein, transporting it to 


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the liver where it also acts as a brake on endogenous bile acid production by repressing CYP7A1 
(Cipriani 2011, Pols 2011).  In addition to being the key regulatory gatekeeper for bile acid 
synthesis, FXR has also been implicated as having a role in modulating immune response, 
decreasing portal hypertension, and potentially being anti-atherogenic (Lefebvre 2009).  
Chenodeoxycholic acid (CDCA) is the principal natural ligand of FXR in humans.  When 
cellular levels are already high, the negative feedback pathway inhibits the further synthesis of 
bile.  CDCA, and its epimer ursodeoxycholic acid (UDCA), have a long history of use in of the 
dissolution of cholesterol gallstones (although currently laparoscopic surgery is more typically 
used).  In cholestasis, the primary mode of action of UDCA is thought to be choleretic, ie, 
facilitating bile flow to relieve cholestasis rather than suppressing its synthesis and buffering the 
bile (Beuers 2006).  UDCA has no FXR agonist properties.  
OCA is structurally related to CDCA and differs by the addition of a single ethyl group.  The 
chemical name of OCA is 3α,7α-dihydroxy-6α-ethyl-5βcholan-24-oic acid.  It is also referred to 
as 6α-ethylchenodeoxycholic acid, or 6-ECDCA, and as an agonist it is approximately 100-fold 
more potent than CDCA in vitro (Pellicciari 2002).  OCA is also highly selective for FXR and 
does not bind other nuclear receptors, and with the exception of weakly activating the dedicated 
bile acid receptor TGR5, it does not activate any G-protein coupled receptors (CEREP 2008).  
OCA is in clinical development in a series of chronic liver and metabolic disease indications in 
which the functions regulated by FXR activation are critical etiological components.   
4.3. 
Nonclinical Experience with Obeticholic Acid 
Administration of OCA to rats (for 6 months) and dogs (for 9 months) in repeat dose toxicity 
trials resulted primarily in adverse effects on the liver and gastrointestinal (GI) tract at only the 
highest dose levels.  OCA was not genotoxic in a battery of 3 genotoxicity studies.  Reproductive 
and developmental toxicity studies in rats and rabbits demonstrated no adverse effects on fertility 
and embryo/fetal development at doses where OCA caused maternal toxicity. 
A summary of the toxicology studies is provided in the IB.  The nonclinical pharmacology 
experience with OCA is summarized below.  For more information on the nonclinical data for 
OCA, please refer to the current IB. 
4.3.1. 
Nonclinical Anti-fibrotic and Anti-inflammatory Properties 
In vitro exposure of both murine and human hepatic stellate cells (HSC) to OCA represses 
fibrogenic α1(I) collagen and transforming growth factor-beta 1 (TGF-β1) expression by 60% to 
70%, indicating that OCA is a potent regulator of HSC mediated fibrogenesis.   
OCA significantly inhibits fibrogenesis and reverses liver cirrhosis, as determined by Sirius red 
immunostaining and morphometry in a thioacetamide (TAA)-induced liver injury model 
(Albanis 2005).  In addition, OCA inhibits NF κB–regulated pro-inflammatory genes in 
hepatocytes and in vascular cells, inhibiting induction of pro-inflammatory cytokines, such as 
tumor necrosis factor (TNF-α), and inflammatory mediators, such as cyclooxygenase-2 (COX-2) 
and inducible nitric oxide synthase (Li 2007, Wang 2008).  OCA also inhibits production of 
TNF-α by human peripheral blood mononuclear cells and human monocytes, and inhibits 
differentiation of human monocytes into dendritic cells (Gadaleta 2011).  Furthermore, OCA 


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inhibits production of TNF-α, interleukin (IL)-17, and interferon-γ in lymphocyte-enriched 
human lamina propria cells (Gadaleta 2011).  
4.3.2. 
Nonclinical Effects on Cholestasis 
The results of trials performed in rodent models of cholestasis involving the administration of 
chemical agents that severely injure bile ducts (such as carbon tetrachloride [CCl4] or lithocholic 
acid [LCA]) provide evidence that OCA is effective in preventing or reducing cholestasis in vivo.  
In the LCA model, co-infusion of OCA fully reversed the impairment of bile flow and protected 
against liver cell injury (Pellicciari 2002). 
Results of other trials have demonstrated that OCA significantly reduces fibrotic collagen 
synthesis in vitro and in various rodent models of chronic liver injury that involve fibrosis and 
eventual cirrhosis, consistent with the progression of PSC (Albanis 2005, Mookerjee 2015).   
4.4. 
Clinical Experience with Obeticholic Acid 
To date, OCA has been evaluated in the clinic in a total of 25 completed and 8 ongoing trials, 
including patients with PBC and other chronic liver diseases (eg, portal hypertension and 
nonalcoholic steatohepatitis [NASH]) and healthy volunteers.  Additional trials are also planned 
to further characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of OCA 
as well as the safety and efficacy of OCA in subjects with PBC and other chronic liver diseases. 
As of 31 Jan 2015, approximately 1650 subjects have received at least one dose of OCA in 
completed or ongoing trials.  Overall, the PK profile of OCA is consistent with that expected of a 
bile acid.  Phase 1 PK trials demonstrated that OCA was rapidly absorbed and extensively 
conjugated with glycine and taurine to form glyco-OCA and tauro-OCA, respectively.  OCA and 
its conjugates were 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 peaked shortly after meals, 
consistent with gall bladder emptying into the duodenum as expected of a bile acid.   
Phase 2 Trial 747-201 evaluated 2 doses of OCA (10 mg and 50 mg) given as monotherapy 
versus placebo in subjects with PBC.  Significant relative and absolute reductions in 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 + 0.4% with placebo.  
Absolute ALP reductions were -233.5 U/L and -161.3 U/L with OCA doses of 10 mg and 50 mg, 
respectively compared to +11 U/L with placebo.  Further, significant improvements in GGT and 
in conjugated bilirubin were observed with both doses compared with placebo (p <0.05).  OCA 
doses of 10 mg and 50 mg resulted in decreased alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) but the change did not achieve statistical significance.  
Phase 2 trial 747-202 evaluated 3 doses of OCA (10 mg, 25 mg, and 50 mg) versus placebo in 
subjects with PBC on a stable therapeutic dose of UDCA.  Overall, the data from 747-202 were 
consistent with the monotherapy trial.  Statistically significant relative and absolute reductions in 
ALP were achieved with all 3 doses of OCA versus placebo (p <0.0001).  Mean ALP reductions 
ranged from 21% to 25% compared to 3% with placebo.  Absolute ALP reductions ranged from 
approximately 65 U/L to 75 U/L versus 5 U/L for placebo.  Significant improvements were also 


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seen in GGT and ALT levels with all 3 doses, in AST at 10 mg and 25 mg, and in conjugated 
bilirubin (% change) at 25 mg and 50 mg. 
The long term safety extension (LTSE) phases of both trials (completed LTSE phase from 
Trial 747-202 providing exposures out to one year and ongoing LTSE phase of Trial 747-201 
providing exposures up to approximately 4.5 years to date) support the long-term safety of OCA 
and demonstrate a durable therapeutic response. 
Phase 3 Trial 747-301 evaluated 2 OCA treatment arms (10 mg and 5 mg titrating to 10 mg 
based on efficacy and tolerability) versus placebo in subjects with PBC on a stable therapeutic 
dose of UDCA or who could not tolerate UDCA.  The primary efficacy endpoint was the 
proportion of subjects who achieved an ALP <1.67x upper limit of normal (ULN) with a 
minimum 15% reduction in ALP and a normal bilirubin after 12 months of treatment.  Both 
OCA treatment groups showed statistically significant differences (p <0.0001) versus placebo for 
the composite endpoint at all post-baseline timepoints with 47%, and 46% achieved the endpoint 
at 12 months in the 10 mg and titration groups compared to 10% with placebo.  Consistent with 
the Phase 2 trials, statistically significant relative and absolute reductions in ALP were achieved 
in both treatment groups (p <0.0001).  Mean ALP reductions were 39% and 33% compared to 
5% with placebo.  
Overall, OCA has been demonstrated to be safe and generally well tolerated in PBC patients.  
The primary adverse event (AE) shown to be related to OCA is pruritus.  This reflects a drug and 
dose related exacerbation of the most common symptom of PBC and is thought to be due to the 
choleretic effect of OCA that increases bile flow and hepatic clearance, but may also increase 
exposure to a pruritogen present in the bile that can induce pruritus in susceptible patients.  Of 
note, UDCA therapy initiation also can induce pruritus in patients, which can be ameliorated by 
dose titration.  Pruritus has also been observed in clinical trials with OCA in other indications, 
but with a much lower frequency than that observed in subjects with PBC.  Other potential risks 
identified include liver toxicity at high doses.  Detailed clinical information can be found in the 
OCA IB.  
4.5. 
Summary of Known Potential Risks with Investigational Product 
Investigators are referred to the current IB for a thorough presentation of the safety data 
associated with OCA.  An overview is as follows: 
Pruritus is a common symptom of chronic cholestatic diseases such as PBC and PSC.  In subjects 
with PBC, treatment with OCA has been shown to cause a dose-dependent exacerbation of this 
common symptom and similar results can be expected in subjects with PSC.  Pruritus has also 
been observed in clinical trials with OCA in other indications and in healthy volunteers, but at a 
lower frequency and at higher doses than that observed in subjects with chronic cholestasis.  
Investigator guidance for pruritus management strategies are outlined in Section 11.1.3.1 of the 
protocol. 
Other potential risks include liver toxicity, especially at higher doses of OCA, which is 
consistent with nonclinical findings and the chemical characteristics of OCA as a bile acid and 
detergent.  An increase in liver function tests and hepatobiliary AEs, including jaundice, ascites 
and acute cholecystitis were observed in subjects with PBC and NASH who were treated at 
doses that are several fold higher (primarily 20 mg to 50 mg daily) than those studied in this 


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protocol (1.5 mg, 3 mg, 5 mg, and 10 mg) doses.  This is an important potential risk in subjects 
with PSC, where there is the possibility of dominant strictures of intra- and extra-hepatic bile 
ducts that could restrict bile flow.  In order to monitor bile duct patency, the trial protocol 
requires that sites perform an ultrasound at Screening, at the end of the DB phase, and annually 
in the LTSE.  Consistent with this potential risk, the present trial excludes subjects who have 
had, or who are suspected of having, a recent dominant stricture (Section 7.3).  In addition, the 
trial calls for mandatory discontinuation of investigational product in those subjects whose liver 
chemistry (AST, ALT and or bilirubin) display clinically significant increases following the 
initiation of therapy (Section 7.4.1).  The doses used in the present trial (1.5 mg to 10 mg) are 
amongst the lowest doses of OCA tested to date in a clinical setting. 
Lipoprotein changes have also been observed with OCA dosing in subjects with PBC (including 
a decrease in high-density lipoprotein [HDL]).  The clinical significance of these lipid findings 
remains unclear and is being studied further.  Notably, despite an observed decrease in HDL 
levels, they generally remained within normal limits.  The relevance of these findings to subjects 
with PSC is unclear and will be investigated further in this trial.  
In addition, the Data Safety Monitoring Committee (DSMC) will review safety data from the 
present trial as well as other ongoing OCA trials at approximately quarterly intervals but at least 
every 6 months.  Adjustments to or stopping of the protocol-defined doses may be considered 
based on DSMC evaluation of OCA safety and tolerability as noted in Section 6.4.3.   
4.6. 
Rationale for Trial Design and Dose for Investigational Product 
4.6.1. 
Rationale for Trial Design 
Rationale for Treatment Indication 
PSC is a rare, chronic cholestatic liver disease characterized by progressive inflammation, 
fibrosis, and destruction of the intrahepatic and extra-hepatic bile ducts with no identifiable cause 
(Eaton 2013, Hirschfield 2013).  PSC disease progression can vary, but typically begins in portal 
tracts; fibrosis and commensurate inflammatory responses induce a progressive spread of the 
fibrotic condition.  No treatment to date, aside from liver transplant, has been associated with an 
improvement in clinical outcome.  As such, the unmet medical need for PSC is very high. 
Drugs that can improve bile acid flow (reducing toxic bile acid concentrations in hepatocytes) 
and have anti-inflammatory and anti-apoptotic effects should have beneficial effects in PSC.  
UDCA, which is an epimer of the primary human bile acid CDCA, is often used for the 
treatment of PSC due to improvements in liver biochemistry following initiation of therapy. 
Despite general biochemical improvement, UDCA has not been shown to improve transplant 
free survival and, at high doses, has been associated with increased risk for serious complications 
(Lindor 2009).  Consequently, The European Association for the Study of the Liver (EASL) does 
not provide a recommendation for the use of UDCA for the treatment of PSC, and The American 
Association for the Study of Liver Diseases (AASLD) recommends against its use (EASL 2009, 
Chapman 2010).  However, as there are no approved drugs for the treatment of PSC, some 
physicians treat patients with UDCA, typically at a dose of 13 to 15 mg/kg/day. 
FXR has been shown to be an essential regulator of bile acid homeostasis with its activation 
being associated with decreased bile acid synthesis (Lefebvre 2009).  FXR is the nuclear receptor 


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involved in the regulation of hepatic bile acid production and flow and the modulation of hepatic 
inflammation, fibrosis, and regeneration.  As such, FXR is a strong potential target for the 
treatment of cholestatic diseases such as PSC.  Consistently, nonclinical models evaluating the 
properties of OCA have shown it to have anti-fibrotic and anti-inflammatory properties as well 
as being effective at reducing cholestasis (Section 4.3).  Clinical data from trials in PBC showing 
marked reductions in liver biochemistry associated with cholestasis further support the rationale 
for evaluating OCA as a treatment for PSC (Section 4.4). 
Rationale for Primary Efficacy Endpoint 
The cholestatic conditions of PSC and PBC are both characterized by persistent increases in 
ALP.  While UDCA did not show a treatment effect on clinical outcomes (Lindor 1997, 
Olsson 2005), follow up analyses showed that robust improvements in ALP, the achievement of 
normalized ALP levels or levels <1.5x ULN were associated with improved prognosis 
(Lindstrom 2013, Al Mamari 2013, Talwalkar 2013).  Evaluation of OCA in PBC subjects has 
shown OCA to be associated with a clinically and statistically significant reduction in ALP.  As 
such, this first trial of OCA in subjects with PSC will evaluate therapeutic response in terms of 
change from Baseline in ALP.  Categorical improvements (ie, normalization or <1.5x ULN) will 
also be evaluated as secondary endpoints. 
4.6.2. 
Rationale for Doses 
This trial is intended to evaluate the safety, tolerability, and efficacy of a range of doses of OCA 
in subjects with PSC with an overall goal of identifying doses that are therapeutic and generally 
well tolerated.  Patients will be randomized to 1 of 3 dose groups:  1.5 mg titrating to 3 mg OCA, 
5 mg titrating to 10 mg OCA, or placebo.  
While this is the first trial to evaluate OCA in subjects with PSC, the safety and tolerability of 
multiple doses of OCA have been established in healthy subjects and subjects with PBC (another 
cholestatic liver disease), at doses up to 50 mg once daily, and in subjects with alcoholic 
cirrhosis and portal hypertension at doses up to 25 mg.  In healthy subjects, 12 days dosing of up 
to 100 mg per day was safe and well tolerated.   
As demonstrated in the Phase 2 PBC trials, OCA can significantly reduce 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 trial 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.  Starting patients on 5mg OCA and titrating to 10mg based on 
the clinical response appears to be an appropriate dosing strategy in patients with PBC.  
Building on these data from patients with PBC, we plan to use the same titration dosing strategy 
for patients with PSC.  This considered approach provides a means for the treating physician to 
carefully manage tolerability issues while still providing an opportunity for efficacy.  The 
titration arm of 5 mg to 10 mg OCA is well-within the range shown to be safe and effective in 
PBC patients and in healthy volunteers.  However, given the detergent properties of OCA and 
the potential for dominant intra- and extra-hepatic strictures that could lead to bile acid retention 
in subjects with PSC (Section 4.5), evaluation of additional titration arm with 1.5 mg titrating to 
3 mg OCA (ie, ≤10 mg daily) is warranted.   


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The dose-ranging aspect of the trial design targets doses known to be therapeutic for PBC (5 mg 
and 10 mg), another cholestatic liver disease, but also incorporates lower doses to 1) Allow 
identification of the minimally safe and effective dose, and 2) Further characterize the 
exposure-response relationship in this patient population.  The nested dose-rising approach 
allows for a more robust characterization of the value of titration to address potential tolerability 
concerns and the exposure-response relationship by addressing intra-subject variability.  The 
nested dose-rising approach also limits the needed number to treat which is important given the 
rarity of the disease and limited pool of patients from which to recruit, and minimizes the 
number of patients unnecessarily exposed to study medication. 
Rationale for Placebo 
There are no approved therapies for the treatment of PSC that could be used as an active control. 
As such, the use of a placebo control is warranted to maintain the study blind and scientific 
validity of the trial.  UDCA is used by some physicians due to associated improvements in liver 
biochemistry.  However, EASL does not provide a recommendation regarding UDCA use in 
PSC, and AASLD recommends against its use (EASL 2009, Chapman 2010).  Based on this 
guidance, UDCA would not be an appropriate active control.  However, the Sponsor does 
recognize that UDCA is used in this orphan disease, and patients who are currently taking 
UDCA may be eligible to participate in the trial (Section 7.2).  Subjects will be stratified by the 
presence or absence of UDCA use, then randomized, in equal proportions, to each of the 
treatment groups (Section 8.4.1).  
Rationale for Duration of Dosing 
In the Phase 2 PBC trials with OCA, the double-blind (DB) evaluation of the reduction in ALP 
associated with OCA treatment was evaluated over 85 days.  Significant reductions in ALP were 
observed as early as 2 to 4 weeks with maximal reductions (at a single dose level) apparent by 
8 weeks.  Due to similarities in the cholestatic etiology of PSC and PBC, it is anticipated that a 
similar evaluation period will be sufficient to evaluate OCA in PSC.  As such, the present trial 
will evaluate each dose over 12 week periods. 
5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. 
Primary Objective 
To evaluate the effects of OCA on the following in subjects with PSC: 
• Serum ALP 
• Safety 
5.2. 
Secondary Objectives 
The secondary objectives are to evaluate the effects of OCA on the following in subjects with 
PSC: 


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• Hepatic biochemistry and indices of function  
• Markers of: 
− Hepatic fibrosis and GI inflammation and disease  
− FXR activity 
− Inflammatory bowel disease (IBD) 
• PK of OCA and other bile acids 
• Exposure response of total OCA (OCA and its conjugates) to biomarkers eg, ALP and 
bile acids 
• Long-term efficacy and safety of OCA  
• Disease-specific symptoms 
6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Trial Design 
Double-blind phase (DB) 
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding evaluation of the 
efficacy and safety of OCA in subjects with PSC.  The trial design is shown in Figure 1 and the 
schedule of trial procedures for the DB phase is presented in Table 1.  Approximately 75 subjects 
who provide written informed consent and meet all of the inclusion and none of the exclusion 
criteria will be randomized to 1 of 3 treatment groups as follows:  1.5 mg titrating to 3.0 mg 
OCA, 5 mg titrating to 10 mg OCA, or placebo in a 1:1:1 ratio.  Subjects will administer 
investigational product orally, once daily for 2 consecutive 12-week periods.   
For the first 12 weeks after randomization, the subject’s dose will be 1.5 mg OCA, 5 mg OCA, 
or placebo.  After 12 weeks, the subject’s dose will be titrated as detailed in Section 6.4.1 and 
DB treatment will continue for a further 12 weeks at that dose.   
Randomization will be stratified by the presence or absence of concomitant UDCA use and total 
bilirubin level (≤1.5x ULN or >1.5x ULN but <2.5x ULN). 
Long-Term Safety Extension Phase (LTSE) 
Following completion of participation in the DB phase, subjects will be asked to reconfirm their 
consent for participation in the LTSE phase (a further 24 months).  The schedule of trial 
procedures for the LTSE is shown in Table 2. 
Upon a subject’s completion of the DB phase, the trial blind will be broken in order to assign the 
starting OCA dose for the LTSE phase.  It is intended that subjects will commence treatment at 
5 mg OCA, except those subjects who completed treatment in the DB phase with 10 mg OCA 
who will continue at 10 mg OCA unless safety and tolerability warrant a dose reduction to 5 mg.  
The titration schedule and options for the LTSE phase are detailed in Section 6.4.2.  If an 
Investigator does not wish for a subject to be titrated in line with Table 4, this may be discussed 
with the Medical Monitor. 


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Table 1: 
Schedule of Trial Procedures:  Double-Blind Phase 
Visit Type
a 
Screening 
(Day -30 to 
Day -1) 
Day 0b 
Visit  
W2 
Visit  
W6 
Visit 
W12c 
Visit  
W14 
Visit  
W18 
Visit W24d/ 
LTSE D1/ 
EOTe 
FU  
(4 wks)f 
Visit Windowg 
≤30d 
 
±3d 
±1wk 
±1wk 
±1wk 
±1wk 
±1wk 
±1wk 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
Physical Exam 
Xh 
 
 
 
 
 
 
X 
 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
X 
 
Transient Elastographyj 
 
X 
 
 
 
 
 
X 
 
Hepatic Ultrasoundk 
X 
 
 
 
 
 
 
X 
 
Partial Mayo Scorel,m  
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDAIm,n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pruritus VAS and 5-Do 
 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Research 
Questionnaireo 
 
 
 
 
 
 
 
X 
 
Adverse Events 
 
Xp 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 


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Table 1: 
Schedule of Trial Procedures:  Double-Blind Phase (Continued) 
Visit Type
a 
Screening 
(Day -30 to 
Day -1) 
Day 0b 
Visit  
W2 
Visit  
W6 
Visit 
W12c 
Visit  
W14 
Visit  
W18 
Visit W24d/ 
LTSE D1/ 
EOTe 
FU  
(4 wks)f 
Visit Windowg 
≤30d 
 
±3d 
±1wk 
±1wk 
±1wk 
±1wk 
±1wk 
±1wk 
Dispense Investigational 
Product 
 
Xq 
 
 
X 
 
 
Xr 
 
Investigational Product 
Accountability/ 
Compliances 
 
 
X 
X 
X 
X 
X 
X 
 
Laboratory Evaluationst 
Serum Chemistry, 
Hematology, & Coagulation 
Parameters 
Xu 
X 
X 
X 
X 
X 
X 
X 
X 
FGF-19 
 
X 
 
 
X 
 
 
X 
 
CRP 
 
X 
 
 
X 
 
 
X 
 
ELF Markers & Other 
Analytesv 
 
X 
 
 
X 
 
 
X 
 
Plasma Bile Acids  
 
X 
 
 
X 
 
 
X 
 
C4 
 
X 
 
 
X 
 
 
X 
 
PKw 
 
 
 
 
X 
 
 
X 
 
Apolipoprotein & NMR 
Lipoprotein Panel 
 
X 
 
 
X 
 
 
X 
 
Dipstick Urinalysis 
X 
X 
 
 
X 
 
 
X 
 
Urine Pregnancy Testx 
X 
X 
 
 
X 
 
 
X 
X 
Fecal Sampley 
 
X 
 
 
X 
 
 
X 
 
Genetics Studyz 
 
X 
 
 
 
 
 
X 
 
 


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a Subjects must be fasted prior to all clinic visits (except Screening) and investigational product should not be administered prior to clinic visits (see Section 8.1). 
b Day 0 must occur by Day 31 for a subject to be eligible to continue in the trial. 
c Week 12 is the Dose Titration visit. 
d The Week 24 visit is the final visit during the DB treatment period.  For subjects who continue into the LTSE, the Week 24 visit is also Day 1 of the LTSE, and 
unblinding occurs after the Week 24/LTSE Day 1 procedures have been completed (except dispensing of open-label investigational product). 
e End of treatment (EOT) visit is completed for any randomized subject who discontinues the study prior to reaching Week 24 of the DB phase; this should occur 
as close as possible to the final dose of investigational product.  If a subject discontinues on the day of a scheduled trial visit, the procedures from the scheduled 
visit will be recorded as EOT in the CRF. 
f Follow-Up visit: If a subject discontinues the study prior to the end of Week 24 or does not proceed into the LTSE, he/she returns to the site for a Follow-Up 
visit, which should occur 4 weeks (±1 week) after her/his last dose of investigational product. 
g Timing of all visits is relative to Day 0.  
h Height is measured at the Screening visit only. 
i Vital signs:  oral temperature, sitting heart rate (HR), respiratory rate, and sitting blood pressure ([BP] systolic and diastolic).  When taking HR, respiratory 
rate, and BP readings, subjects should be seated quietly for a minimum of 3 minutes before the readings are taken. 
j TE: at trial sites where the Fibroscan® TE device is available.  TE has a 5-day visit window.  For the Day 0 assessment, TE should occur either on Day 0 or 
within 5 days prior to Day 0.  For the Week 24 assessment, the TE should occur within ±5 days of the onsite visit if it is not possible to schedule the TE on the 
same day as that visit, but the visit(s) should remain within the overall visit window. 
k Hepatic ultrasound has a ±5-day visit window (ie, if it is not possible to schedule the ultrasound on the same day as the onsite visit, it may occur within 5 days 
on either side of the visit, but the visit(s) should remain within the overall visit window). 
l Partial Mayo score completed only for subjects with UC. 
m Subjects with UC will be asked to complete a diary the day prior to their next trial visit, recording details since their last scheduled visit.  Subjects with CD 
should complete the diary in the 7 days prior to their next clinic visit.  Diary card data from the Screening period are collected at the Day 0 visit. 
n CDAI completed only for subjects with CD. 
o Questionnaire completed by the subject. 
p Adverse events will be collected from the time that signed informed consent is obtained. 
q All subjects are instructed to administer the first dose of investigational product on Day 1 and at approximately the same time of day for the duration of the trial 
(see Section 8.1). 
r Investigational product is dispensed only for subjects who continue into the LTSE.  (Dispensing of open-label investigational product occurs after completion 
of the Week 24/LTSE Day 1 procedures and the subsequent unblinding of the subject’s treatment allocation.) 
s Investigational product accountability/compliance will include review of tablets and bottles dispensed and returned at each clinic visit 
t All laboratory samples (except urine and serum pregnancy test, if applicable) are analyzed by the Central Laboratory.  
u IgG4 is included in the assessment panel at Screening only. 
v Other analytes includes an additional blood sample for exploratory analysis. 
w PK samples will be collected from those subjects who have consented for PK sampling procedures.  Please refer to Section 10.5 for a schedule of sampling. 
x For female subjects of child bearing potential, a urine β-hCG test is used.  If the urine test is positive, it is to be repeated as a serum pregnancy test.  See 
Section 7.1 for procedures to be followed for a subject whose pregnancy is early terminated and wishes to continue in the trial.  
y Fecal sample:  for measurement of calprotectin and gut fecal microbiome; provision of a fecal sample by subjects is not mandatory.  The subject should be 
instructed to collect a fecal sample within 2 days of the scheduled visit, as described in the laboratory manual. 
z Genetics study:  blood samples will be collected from those subjects who have consented for RNA sampling procedures. 


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Table 2: 
Schedule of Trial Procedures:  LTSE Phase 
Visit Type
a,b 
LTSE D1/DB 
Visit W24
c 
Contact 
W2 
Visit 
M3 
Visit 
M6 
Visit 
M9 
Visit 
M12 
Visit 
M15 
Visit 
M18 
Visit 
M21 
Visit M24/ 
EOT
d 
FU
e 
(4 wks) 
Visit Window
f 
±1wk 
±3 d 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
±1wk 
Safety Contactg 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
Review 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
X 
 
Vital Signsh 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
X 
 
Transient Elastographyi 
X 
 
 
 
 
X 
 
 
 
X 
 
Hepatic Ultrasoundj 
X 
 
 
 
 
X 
 
 
 
X 
 
Partial Mayo Scorek,l 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDAIl,m 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pruritus VAS and 5-Dn 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Research 
Questionnairen 
X 
 
 
 
 
 
 
 
 
X 
 
Adverse Events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Investigational 
Product 
Xo 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Investigational Product 
Accountability/ 
Compliancep 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Table 2: 
Schedule of Trial Procedures:  LTSE Phase (Continued) 
Visit Type
a,b 
LTSE D1/DB 
Visit W24
c 
Contact 
W2 
Visit 
M3 
Visit 
M6 
Visit 
M9 
Visit 
M12 
Visit 
M15 
Visit 
M18 
Visit 
M21 
Visit M24/ 
EOT
d 
FU
e 
(4 wks) 
Visit Window
f 
±1wk 
±3 d 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
±2wk 
±1wk 
Laboratory Evaluationsq 
Serum Chemistry, 
Hematology, & 
Coagulation Parameters 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FGF-19 
X 
 
 
 
 
X 
 
 
 
X 
 
CRP 
X 
 
 
X 
 
X 
 
X 
 
X 
 
ELF Markers & Other 
Analytesr 
X 
 
 
 
 
X 
 
 
 
X 
 
Plasma Bile Acids & C4 
X 
 
 
X 
 
X 
 
 
 
X 
 
PKs 
X 
 
 
 
 
 
 
 
 
 
 
Apolipoprotein & NMR 
Lipoprotein Panel 
X 
 
 
 
 
 
 
 
 
 
 
Dipstick Urinalysis 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Urine Pregnancy Testt 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fecal Sampleu 
X 
 
 
 
 
X 
 
 
 
X 
 
Genetics Studyv 
X 
 
 
 
 
X 
 
 
 
X 
 
a Subjects must be fasted prior to all clinic visits and investigational product should not be administered prior to clinic visits (see Section 8.1). 
b If the Investigator is planning on up-titrating a subject at an LTSE visit, the subject needs to return for an additional Pre-Titration visit, approximately 1 week 
prior to the scheduled LTSE visit to enable blood to be taken for laboratory sample analysis.  The subject then attends for the scheduled 3 month visit.  Subjects 
experiencing significant AEs (eg, severe pruritus) or other symptoms that are not tolerated, may not be eligible for titration.  After any increase in OCA dose, 
the Investigator or designee should contact the subject approximately 2 weeks following the titration visit to assess for AEs and to verify that the subject is 
dosing as directed. 
c The LTSE D1 is also the final visit (Week 24) of the DB treatment period.  For subjects continuing into the LTSE, unblinding occurs after the Week 24/LTSE 
Day 1 procedures have been completed (except dispensing of open-label investigational product). 
d End of treatment (EOT) visit is completed for any randomized subject who discontinues the LTSE prior to reaching Month 24; this should occur as close as 
possible to the final dose of investigational product.  If a subject discontinues on the day of a scheduled trial visit, the procedures from the scheduled visit will 
be recorded as EOT in the CRF. 


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e Follow-Up visit:  If a subject discontinues the LTSE prior to the end of Month 24, he/she returns to the site for a Follow-Up visit, which should occur 4 weeks 
(±1 week) after his/her last dose of investigational product.  
f Timing of all visits is relative to LTSE Day 1. 
g The Safety Contact can be either via telephone or email, and does not require an onsite visit. 
h Vital signs: oral temperature, sitting HR, respiratory rate, and sitting BP (systolic and diastolic).  When taking HR, respiratory rate, and BP readings, subjects 
should be seated quietly for a minimum of 3 minutes before the readings are taken.   
i TE:  at trial sites where the Fibroscan® TE device is available. The TE should occur within ±5 days of the onsite visit if it is not possible to schedule the TE on 
the same day as that visit, but the visit(s) should remain within the overall visit window. 
j Hepatic ultrasound has a ±5-day visit window (ie, if it is not possible to schedule the ultrasound on the same day as the onsite visit, it may occur within 5 days 
on either side of the visit, but the visit(s) should remain within the overall visit window). 
k Partial Mayo score completed only for subjects with UC. 
l Subjects with UC will be asked to complete a diary the day prior to their next trial visit, recording details since their last scheduled visit.  Subjects with CD 
should complete the diary in the 7 days prior to their next clinic visit. 
m CDAI completed only for subjects with CD. 
n Questionnaire completed by the subject.  
o Investigational product is dispensed only for subjects who continue into the LTSE.  (Dispensing of open-label investigational product occurs after completion 
of the Week 24/LTSE Day 1 procedures and the subsequent unblinding of the subject’s treatment allocation.)  
p Investigational product accountability / compliance will include review of tablets and bottles dispensed and returned at each clinic visit. 
q All laboratory samples (except urine and serum pregnancy test, if applicable) are analyzed by the Central Laboratory. 
r Other analytes includes an additional blood sample for exploratory analysis. 
s PK samples will be collected from those subjects who have consented for PK sampling procedures.  Please refer to Section 10.5 for a schedule of sampling.  
t For female subjects of child bearing potential, a urine based β-hCG test is used.  If the urine pregnancy test is positive, the test is to be repeated as a serum 
pregnancy test.  See Section 7.4.1 for procedures to be followed for a subject whose pregnancy is early terminated and wishes to continue in the trial.  
u Fecal sample:  for measurement of calprotectin and gut fecal microbiome; provision of a fecal sample by subjects is not mandatory.  The subject should be 
instructed to collect a fecal sample within 2 days of the scheduled visit, as described in the laboratory manual. 
v Genetics study:  blood samples will be collected from those subjects who have consented for RNA sampling procedures. 
 


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6.1.2. 
Trial Duration 
Table 3: 
Planned Duration of Trial Phases 
DB Phase 
Time expected for all subjects to be enrolled 
Approximately 18 months 
Duration of individual subject participation 
Up to 7 months (including screening)  
LTSE 
Duration of individual subject participation 
Up to 24 months 
DB Phase & LTSE 
Total duration of the trial (first subject consented to 
last subject completing last study visit) 
Approximately 50 months 
The LTSE may be extended on an annual basis beyond 24 months and this will be determined by 
the Sponsor.  Prior to any extension of the LTSE, the protocol will be amended and submitted for 
regulatory and Institutional Review Board/Independent Ethics Committee (IRB/IEC) review and 
approval. 
6.2. 
Number of Subjects 
Approximately 75 subjects who meet eligibility criteria will be included in the trial. 
6.3. 
Treatment Assignment 
Eligible subjects will be randomized to 1 of 3 treatment groups and will initiate treatment with 
1.5 mg OCA, 5 mg OCA, or matching placebo.  Randomization will be in accordance to a 
1:1:1 ratio (ie, 25 subjects/group).   
Subjects will be stratified by the presence or absence of concomitant UDCA use and total 
bilirubin level at Screening, according to defined stratification criteria (Section 8.4.1) and then 
randomized in equal proportions to each of the treatment groups.  
6.4. 
Dose Adjustment Criteria and Dose Titration 
6.4.1. 
Double-Blind Phase 
Following randomization, subjects will administer the assigned, blinded treatment once daily for 
12 weeks.   
After 12 weeks, the subject’s dose will be titrated as follows, providing there are no limiting 
safety or tolerability concerns in the opinion of the Investigator, while maintaining the trial blind:  
the 1.5 mg OCA treatment group will titrate to 3 mg, the 5 mg OCA treatment group will titrate 
to 10 mg OCA, and the placebo group will remain on placebo.  DB treatment will continue for a 
further 12 weeks at that dose.   
Any subjects whose dose is not titrated, due to safety or tolerability concerns, will remain on 
their starting treatment (1.5 mg OCA, 5 mg OCA, or placebo) for the remainder of the DB phase 
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6.4.2. 
LTSE Phase 
Upon a subject’s completion of the Week 24 visit, at the end of the DB phase, the trial blind will 
be broken in order to assign the starting OCA dose for the LTSE phase.  It is intended that 
subjects will commence treatment at 5 mg OCA, except those subjects who completed treatment 
in the DB phase with 10 mg OCA who will continue at 10 mg OCA (Table 4) unless safety and 
tolerability warrant a dose reduction to 5 mg.    
Table 4: 
Initial LTSE Doses of OCA 
Investigational Product at End of DB Phase 
(once daily) 
Investigational Product at Start of LTSE  
(once daily) 
Placebo 
5 mg OCA 
3 mg OCA 
5 mg OCA 
10 mg OCA 
10 mg OCA 
Those subjects who did not up-titrate their dose at Week 12 in the DB phase can remain on their 
DB dose as indicated in Table 5, or commence at 5 mg at the decision of the Investigator based 
on safety and tolerability of the DB dose at Week 24. 
Table 5: 
Initial LTSE Doses of OCA for Non-Titrating Subjects 
Investigational Product at End of DB Phase 
(once daily) 
Investigational Product at Start of LTSE  
(once daily) 
1.5 mg OCA 
1.5 mg OCA 
5 mg OCA 
5 mg OCA 
If an Investigator does not wish for a subject to be titrated in line with the above schedules, this 
may be discussed with the Medical Monitor.   
During the LTSE phase subjects may titrate to higher doses of OCA, at a frequency not greater 
than 3 monthly (ie, at each of the scheduled visits), up to a maximum dose of 10 mg daily.  The 
guideline for an increase in the dose of open-label OCA is based on the goal of achieving 
ALP <1.5x ULN and tolerability.  Doses of OCA should be titrated as follows, unless clinically 
indicated:  1.5 mg to 3 mg, 3 mg to 5 mg, and 5 mg to 10 mg.  Intermediate doses (eg, 6.5 mg) 
may be considered as deemed appropriate by the Investigator.  Dose should not exceed 10 mg. 
The Investigator may decrease the dose of OCA, or dosing frequency, in line with safety and 
tolerability as required for that subject.  Following a change in OCA dose or dose frequency, an 
Investigator may be permitted to return the subject to a prior dose or dosing frequency and this 
should be discussed with the Intercept Medical Monitor in advance. 
6.4.3. 
Safety Criteria for Adjustment or Stopping Doses 
The Data Safety Monitoring Committee (DSMC) will review safety data from this trial as well as 
other ongoing OCA trials at approximately quarterly intervals but at least every 6 months.  
Adjustments to or stopping of the protocol-defined doses may be considered based on DSMC 


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evaluation of OCA safety and tolerability.  At a minimum, the occurrence of 2 life threatening 
serious adverse events (SAEs) or an SAE resulting in death will trigger an unscheduled and 
unblinded review of the data by the DSMC to determine if the trial should continue.  Section 6.5 
details the criteria for trial termination.  Reasons for discontinuation of individual subjects are 
noted in Section 7.4.1 and Section 7.4.2. 
6.5. 
Criteria for Trial Termination 
The Sponsor reserves the right to terminate the trial at any time.  Additionally, it is agreed that, 
for reasonable cause, the Investigator may terminate the trial at his/her site at any time. 
It is normal procedure to review the emerging safety data.  As a result of such a review or a 
recommendation by the DSMC, it may be necessary to stop the trial before all subjects have 
completed the trial.  In addition, the Sponsor may terminate the trial at an investigational site at 
any time (eg, due to the quality of data), as determined by the number of subjects enrolled or the 
quality of the data from the site. 
The Investigator and/or Sponsor (or designee) must notify the IRB/IEC of discontinuation of a 
site or the trial and the reason for doing so.  Local requirements for notification of trial 
termination will be adhered to. 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Population 
Approximately 75 subjects with PSC will be randomly assigned to treatment groups using an 
interactive web response system (IWRS).  Up to 50% of the trial population may be taking 
concomitant UDCA.  Once this cap is reached, only those subjects who have not been treated 
with UDCA for at least 3 months prior to and including Day 0 may be enrolled.  In addition, a 
maximum of 25% of enrolled subjects will have a total bilirubin between >1.5x ULN and <2.5x ULN 
at Screening.  Prospective subjects will be identified primarily from the hospital and/or 
physician’s database of PSC subjects, or may be referred from other physicians.  Subjects may 
self-refer themselves to an Investigator if they become aware of the trial through local, national 
or international PSC patient societies, forums and networks or websites (eg, 
www.clinicaltrials.gov). 
7.2. 
Subject Inclusion Criteria 
Subjects must meet all of the following to be eligible to participate: 
1. Male or female aged 18 to 75 years 
2. Must provide written informed consent and agree to comply with the trial protocol 
3. Must have a diagnosis of PSC (based on cholangiography at any point in time) 
4. ALP at Screening ≥2x ULN.  


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5. Total bilirubin at Screening <2.5x ULN.  
Note 1:  Subjects will be stratified according to total bilirubin level and no more than 
25% of subjects recruited will have a total bilirubin >1.5x ULN and <2.5x ULN at 
Screening.  
6. For subjects with concomitant IBD:  
a. Colonoscopy (if subject has a colon) or other appropriate endoscopic procedure 
within 12 months of Day 0 confirming no dysplasia or colorectal cancer 
b. Subjects with Crohn’s Disease (CD) must be in remission as defined by a Crohn’s 
Disease Activity Index (CDAI) <150.  
c. Subjects with ulcerative colitis (UC) must either be in remission or have mild disease. 
Remission is defined as a partial Mayo score of ≤2 with no individual sub-score 
exceeding 1.  Mild disease is defined as a partial Mayo score ≤3 with no individual 
sub-score exceeding 1 point.  
7. For subjects being administered UDCA as part of their standard of care the dose must 
have been stable for ≥3 months prior to, and including, Day 0 and must not have 
exceeded 20 mg/kg/day during this time.  
Note 2:  Subjects not taking UDCA at Day 0 must not have taken UDCA for ≥3 months 
prior to, and including, Day 0 and must not take UDCA during the DB period.  Subjects 
will be stratified according to UDCA use, and no more than 50% of subjects 
administering UDCA at Day 0 will be enrolled.  
8. Subjects being administered biologic treatments (eg, anti-TNF or anti-integrin 
monoclonal antibodies), immunosuppressants, systemic corticosteroids, or statins, must 
have been on a stable dose for ≥3 months prior to, and including, Day 0 and should plan 
to remain on a stable dose throughout the trial. 
9. Contraception:  female subjects of childbearing potential must use ≥1 effective method 
(≤1% failure rate) of contraception during the trial and until 4 weeks following the last 
dose of investigational product (including LTSE doses).  Effective methods of 
contraception are considered to be those listed below: 
• Barrier method, ie, (a) condom (male or female) with spermicide or (b) diaphragm 
with spermicide; or 
• Intrauterine device; or 
• Vasectomy (partner), or 
• Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection) 
• Abstinence, if in line with the preferred and usual lifestyle of the subject [where 
abstinence is defined as refraining from heterosexual intercourse during the trial 
duration (from first administration of investigational product until 4 weeks after the 
last dose of investigational product)] 


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7.3. 
Subject Exclusion Criteria 
Subjects will be excluded from trial participation if they meet any of the following: 
1. Evidence of a secondary cause of sclerosing cholangitis at Screening 
2. Immunoglobulin G4 (IgG4) >4x ULN at Screening or evidence of IgG4 sclerosing 
cholangitis 
3. Small duct cholangitis in the absence of large duct disease 
4. Presence of clinical complications of chronic liver disease or clinically significant hepatic 
decompensation, including:  
• Current Child-Pugh classification B or C 
• History of, or current diagnosis or suspicion of, CCA or other hepatobiliary 
malignancy, or biliary tract dysplasia. 
• History of liver transplantation, or current model of end stage liver disease (MELD) 
score ≥12 
• History of, or current, cirrhosis with complications, including history or presence of 
spontaneous bacterial peritonitis, hepatocellular carcinoma, or hepatic 
encephalopathy (as assessed by the Investigator) 
• Current known portal hypertension with complications, including known gastric or 
large esophageal varices, poorly controlled or diuretic resistant ascites, history of 
variceal bleeds, or related therapeutic or prophylactic interventions (eg, beta blockers, 
insertion of variceal bands or transjugular intrahepatic portosystemic shunt [TIPS]) 
• History of, or current, hepatorenal syndrome (type I or II) or Screening serum 
creatinine >2 mg/dL (178 μmol/L) 
• Platelet count <50 x109/L 
5. Current clinical evidence of dominant strictures that are considered clinically relevant in 
the opinion of the Investigator or current biliary stent at Screening 
6. Current cholecystitis or evidence of current biliary obstruction due to gallstones. 
Asymptomatic gallstones that are not considered a safety risk in the opinion of the 
Investigator might be acceptable subject to discussion and agreement with the Medical 
Monitor 
7. Colonic dysplasia within ≤5 years prior to Day 0  
8. History of any small bowel resection. 
9. History of other chronic liver diseases, including, but not limited to, PBC, alcoholic liver 
disease, non-alcoholic fatty liver disease (NAFLD), autoimmune hepatitis, hepatitis B 
virus (unless seroconverted and no positive Hepatitis B Virus DNA), hepatitis C virus, 
and overlap syndrome 
10. Known Gilbert’s syndrome or history of elevations in unconjugated (indirect) bilirubin 
>ULN or unconjugated (indirect) bilirubin >ULN at Screening 


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11. Known history of human immunodeficiency virus (HIV) infection 
12. Currently experiencing, or experienced within ≤3 months of Screening, pruritus requiring 
systemic or enteral treatment. 
13. Known or suspected acute cholangitis in the 3 months prior to, and including, Day 0 
including cholangitis treated with antibiotics 
14. Administration of antibiotics is prohibited ≤1 month of Day 0 (unless subject is on a 
stable prophylaxis dose for at least 3 months prior to Day 0). 
15. Administration of the following medications is prohibited ≤6 months of Day 0 and 
throughout the trial:  fenofibrate or other fibrates and potentially hepatotoxic medications 
(including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin) 
16. IBD flare during Screening (up to and including Day 0), where “flare” is defined as 
follows: 
• UC flare:  partial Mayo Score ≥5, and  
• CD flare:  CDAI ≥250 
17. Evidence of deleterious effects of alcohol abuse (as assessed by the Investigator) or 
excessive alcohol consumption (>4 units/day for males, >2 units/day for females) 
18. Known or suspected use of illicit drugs or drugs of abuse (allowed if medically 
prescribed or indicated) within 3 months of Day 0 
19. If female:  known pregnancy, or has a positive urine pregnancy test (confirmed by a 
positive serum pregnancy test), or lactating 
20. Other concomitant disease, malignancy, or condition likely to significantly decrease life 
expectancy to less than the duration of the trial (eg, moderate to severe congestive heart 
failure) 
21. Participation in another investigational drug, biologic, or medical device trial within 
30 days prior to Screening 
22. History of noncompliance with medical regimens, or subjects who are considered to be 
potentially unreliable 
23. Blood or plasma donation within 30 days prior to Day 0 
24. Mental instability or incompetence such that the validity of informed consent or 
compliance with the trial is uncertain. 
7.4. 
Subject Withdrawal Criteria 
7.4.1. 
Reasons for Mandatory Investigational Product or Trial Discontinuation 
Pregnancy of a Female Subject 
If a female subject becomes pregnant, she must stop investigational product administration 
immediately and be withdrawn from the trial.  The subject must be followed by the Investigator 
through the pregnancy outcome.  The mother and infant will be followed as considered 
appropriate by the Investigator and the Intercept Medical Monitor.   


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The Investigator must contact the Intercept Medical Monitor and discuss, in advance, any subject 
whose pregnancy is early terminated and would like to continue to participate in the trial.  A 
minimum requirement for allowing the subject to restart dosing is documentation of a negative 
serum beta human chorionic gonadotrophin (β-hCG) test.  However, this is not in and of itself a 
guarantee for being allowed to continue in the study.  For reporting purposes, pregnancy is not 
considered a SAE but is reported on the Pregnancy Notification Form (see Section 11.1.9). 
Clinical Laboratory Values 
Development of the following clinical laboratory values, without explanation, during the course 
of the DB and LTSE phases of the trial mandates investigational product discontinuation: 
• AST and/or ALT >3x ULN AND 2x the Baseline value OR 
• Two consecutive measurements of total bilirubin >ULN AND >2x the Baseline value 
in the absence of evidence of new biliary obstruction.  
The term “Baseline” within this protocol, unless otherwise specified, is intended to mean, 
“pretrial” or “pretreatment” (of investigational product).  It refers to values obtained 
during the Screening, retests, or Day 0 visits, prior to the subject’s first dose of 
investigational product. 
If a subject is required to discontinue investigational product due to an increase in AST, ALT, or 
bilirubin, the subject must be followed at appropriate intervals until these parameters have 
returned to within the normal range or pretrial values, and/or are stable or there is are stable, or 
there is no ongoing clinical concern.  
IBD Flares 
Subjects who experience 3 or more IBD flare-ups in one year during the study will be 
discontinued, where “flare” is defined as follows: 
• For UC flare:  as a partial Mayo Score ≥5, and  
• For CD flare:  as a CDAI ≥250 
Section 7.4.2 below describes treatment guidelines for managing IBD flares during the study. 
7.4.2. 
Other Reasons for Study Discontinuation 
A subject should be discontinued from the study if:  
• The subject decides that it is in his/her best interest.  It is fully understood that all 
subjects volunteer for the trial and that they may withdraw their consent to continue 
in the trial at any time. 
• The Investigator considers that it is advisable or in the best interest of the subject.  
• There is a major violation of the clinical trial protocol for the subject that would 
jeopardize the subject’s safety and/or data quality. 
• There is significant noncompliance of the subject that would jeopardize the subject’s 
safety and/or data quality. 


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• The development of any exclusion criteria (see Section 7.3) that would jeopardize the 
subject’s safety and/or data quality. 
• The subject is consistently unable to provide blood or urine samples. 
• There is an occurrence of clinical or laboratory AEs considered by the Investigator to 
be clinically important, such that they would jeopardize the subject’s safety. 
A reasonable effort must be made to determine the reason(s) why a subject fails to return for 
his/her final visit or is discontinued from the trial.  This information and date must be recorded 
on the appropriate case report form (CRF). 
Bacterial Cholangitis 
It is anticipated that 10% to15% of subjects may experience bacterial cholangitis at some point 
during participation in the trial (Lee 2002).  Bacterial cholangitis is generally associated with 
elevation of serum bilirubin, ALP, and transaminases in conjunction with clinical signs and 
symptoms and positive diagnostic imaging tests.  Local guidelines should be followed for the 
management of patients with acute bacterial cholangitis.  In the absence of such local guidelines, 
the following guidelines should be followed if acute cholangitis is suspected:  
• Diagnosis of acute cholangitis should be established based on a combination of 
typical clinical features, laboratory data, and imaging findings.  Subsequent to an 
intervention to relieve biliary obstruction acute cholangitis may occur with typical 
signs and symptoms including intermittent fever with chills, right upper quadrant 
pain, and jaundice (also known as the Charcot triad).  Further confirmation of the 
diagnosis should then be made via laboratory data (eg, elevated C-reactive protein 
levels and/or leukocytosis) and abdominal imaging tests (magnetic resonance 
cholangiopancreatography).   
• Treatment of acute cholangitis should be directed towards treatment of the biliary 
infection and relieving obstruction.  Therefore, treatment is comprised of systemic 
antibiotic therapy and biliary drainage procedures, with appropriate supportive care. 
• Antibiotic agents should be administered empirically as early as possible.  Blood and 
bile cultures should also be performed at the earliest opportunity and prior to 
initiating antibiotic treatment, if possible. 
• The selection of an antibiotic agent should be based on likely infecting bacteria, the 
severity of the disease, and the presence of comorbidities.  Empiric antibiotic agents 
may be replaced by directed therapies once the blood and bile culture results become 
available.  The use of amoxicillin/clavulanate and other antibiotic treatments with 
potential for hepatotoxicity should be avoided. 
Investigational product may be interrupted at the discretion of the Investigator.  Discontinuation 
from the trial is not mandatory in cases of bacterial cholangitis unless signs and symptoms do not 
resolve within a clinically reasonable timeframe (typically within 1 month or as agreed upon 
with the Medical Monitor) or the cholangitis becomes life-threatening in the opinion of the 
Investigator or Medical Monitor.  In any event, investigational product should not be restarted 
until signs and symptoms have resolved and the subject’s liver biochemistry has returned to 
pre-cholangitis levels.   


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A subject with ≥3 bacterial cholangitis events in one year during the study should be 
discontinued from the trial. 
IBD Flare 
If a subject experiences an IBD flare during the trial (post-Day 0), he/she may remain on 
investigational product but this should be discussed with the Medical Monitor and IBD flares 
should be treated as follows (but adjusted based upon local guidelines and standards of care, 
disease severity and personal patient preferences, as appropriate):  aminosalicylates alone (high 
dose if appropriate) or with a topical aminosalicylate and/or topical, oral, or intravenous 
corticosteroids or immunosuppressant therapy, including anti-TNF therapy.  Surgery may be 
required in severe cases that are refractory to medicinal treatment.  
Subjects who experience 3 or more IBD flare-ups in 1 year during the study will be discontinued. 
Bile Duct Stricture 
Investigational product may be interrupted at the discretion of the Investigator if a subject 
develops a stricture requiring intervention (eg, drainage, ERCP, stent) in order to re-establish bile 
flow.  If the investigational product has been interrupted and the subject does not show 
improvement within 1 month of treatment, further evaluation by the Investigator and discussion 
and agreement with the Medical Monitor is required before a subject is considered eligible to 
resume investigational product administration or to continue in the trial. 
Pruritus 
Pruritus is a common symptom in PBC but less common in PSC (Chapman 2011).  Investigator 
guidance for pruritus management strategies are outlined in Section 11.1.3.1 of this protocol.  
Subjects who experience one or more episodes of severe pruritus that are not tolerable based on 
Investigator assessment, despite optimal supportive treatment as outlined in Section 11.1.3.1, 
should be discontinued from the trial. 
7.4.3. 
Subject Discontinuation Notification 
The Investigator must notify the Intercept CRA by telephone as soon as possible if any subject 
prematurely discontinues or withdraws their consent from the trial.  The date when the subject is 
withdrawn and the primary reason(s) for discontinuation must be recorded in the CRF; additional 
information may be requested by the Sponsor to complete a discontinuation narrative.  A subject 
will be considered “lost to follow-up” (fail to return for a visit) only after reasonable, 
documented attempts to reach the subject prove unsuccessful.  In all cases, a reasonable effort 
must be made to determine the reason(s) that a subject fails to return for required trial visits or 
discontinues from the trial.  This information must be documented in the CRF. 
If a subject is withdrawn from either the DB phase or the LTSE phase of the trial early 
(regardless of the cause), all of the End of Treatment (EOT) evaluations are to be performed at 
the time of withdrawal, and as close as possible to the administration of the last dose of 
investigational product, to the extent possible. 


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Investigational Product Treatment Regimen 
Subjects enrolled in the trial will be treated with OCA and/or placebo.  On Day 0, subjects will 
be randomized to one of the following treatments:  placebo, 1.5 mg OCA, or 5 mg OCA.  
Because there are 2 different sizes of tablet used in this trial (1.5 mg OCA tablet and matching 
placebo are smaller than the 5 mg OCA and matching placebo), in the DB phase all subjects 
randomized to receive OCA will be administered with both OCA and placebo tablets, whereas 
subjects randomized to placebo will receive only placebo tablets (ie, a double-dummy approach).  
In order to maintain the blind, the daily treatment regimen for each effective dose is shown in 
Table 6.  At the Week 12 titration visit, placebo subjects will remain on placebo tablets only, the 
1.5 mg OCA dosing group will be increased to a daily dose of 3 mg OCA, and the 5 mg dosing 
group will be increased to a daily dose of 10 mg OCA.   The trial blinding will be maintained 
during this process.  Any subject whose dose is not titrated, due to safety or tolerability concerns, 
will remain on their starting treatment (1.5 mg OCA, 5 mg OCA, or placebo) for the final 
12 weeks of the DB phase. 
Investigational product will be dispensed in bottles of 100 tablets, and subjects will be instructed 
to take the number of tablets indicated by their treatment group.  During the first 12 weeks of the 
DB phase, subjects will be instructed to administer 2 tablets daily with water:  one 1.5 mg 
(small) tablet and one 5 mg (big) tablet.  During weeks 12 through 24 of the DB phase, subjects 
will be instructed to administer four tablets daily:  two 1.5 mg (small) tablets and two 5 mg (big) 
tablets. 
During the LTSE subjects will administer open-label OCA as described in Section 6.4.2 and 
Table 6, below. 
All subjects will administer the first dose of investigational product on Day 1, and investigational 
product is to be administered at approximately the same time of day throughout the duration of 
the trial.  On trial visit days, subjects who usually administer investigational product in the 
morning should wait until after they have completed their trial visit and blood draws before 
taking their investigational product. 
Subjects are instructed that their last dose of investigational product will be administered on the 
day prior to their LTSE Month 24 visit. 


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Table 6: 
Daily Tablet Regimen by Treatment Group 
Effective Dose 
1.5 mg OCA 
Tablet 
1.5 mg Placebo 
Tablet 
5 mg OCA 
Tablet 
5 mg Placebo 
Tablet 
DB Phase After Day 0 
Placebo 
- 
1 
- 
1 
1.5 mg OCA 
1 
- 
- 
1 
5 mg OCA 
- 
1 
1 
- 
DB Phase After Week 12 
Placebo 
- 
2 
- 
2 
3 mg OCA 
2 
- 
- 
2 
10 mg OCA 
- 
2 
2 
- 
LTSE 
1.5 mg OCA 
1 
- 
- 
- 
3 mg OCA 
2 
- 
- 
- 
5 mg OCA 
- 
- 
1 
- 
10 mg OCA 
- 
- 
2 
- 
8.2. 
Concomitant Medications 
Relevant information about all concomitant drugs (including prescribed, over-the-counter, or 
herbal preparations) taken prior to (ie, within 30 days of Screening) and during the trial must be 
recorded in the source documents and CRF, as well as any dose or dose regimen changes that 
occur during the trial. 
8.2.1. 
Ursodeoxycholic Acid 
Subjects taking UDCA at Day 0 should maintain this dose and the timing of administration of 
UDCA for the duration of the DB phase of the trial (24 weeks).  Subjects who are not taking 
UDCA on entry into the trial should not initiate UDCA therapy at any time during their 
participation in the DB phase of the trial. 
During the LTSE phase, UDCA may be used as considered clinically appropriate, provided the 
dose of UDCA does not exceed 20 mg/kg/day. 
8.2.2. 
Bile Acid Sequestrants 
While systemic or enteral therapy for pruritus is an exclusion criterion at trial entry, the treatment 
of pruritus during the trial is permitted if required.   
Bile acid sequestrants (BAS), aluminium hydroxide, or smectite-containing antacids should be 
administered at least 4 hours apart from investigational product (ie, they should be used 4 hours 
prior to or 4 hours after investigational product administration). 


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In addition, BAS, aluminium hydroxide, or smectite-containing antacids should be administered 
at least 4 hours apart from UDCA (ie, they should be used 4 hours prior to or 4 hours after 
UDCA administration). 
8.2.3. 
Prohibited Medications 
Administration of the following medications is prohibited as specified below unless discussed 
and agreed with the Medical Monitor:  
• Systemic or enteral therapy for pruritus in the 3 months prior to Screening.  A subject 
may remain in the study if they require systemic or enteral therapy for pruritus after 
the initiation of investigational product administration. 
• Administration of antibiotics within 1 month of Day 0 (unless subject is on a stable 
prophylaxis dose for at least 3 months prior to Day 0), except if administered for 
acute cholangitis whereby its use is prohibited within 3 months of Day 0.  
• NOTE:  Antibiotics are permitted as required during participation in the trial except 
amoxicillin/clavulanate (Augmentin) which has restrictions as detailed below. 
• Prohibited from 6 months prior to Day 0 and throughout the LTSE phase of the trial 
unless as noted to discuss with Medical Monitor:  
− Fenofibrate or other fibrates  
− Potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, 
isoniazide, or nitrofurantoin)  
− Amoxicillin/clavulanate (Augmentin) should not be used unless there are no other 
treatment options (this should be discussed with the Medical Monitor in advance 
of their use in this situation, where possible).  Augmentin is also discouraged in 
the treatment of cholangitis but is not outright excluded (Section 7.4.2). 
Subjects being administered the following medications at Day 0 may enter the trial provided they 
have been on a stable dose for ≥3 months prior to, and including, Day 0 and remain on a stable 
dose throughout the trial:  
• Anti-TNF and anti-integrin antibodies 
• Immunosuppressants (eg, azathioprine, colchicine, cyclosporine, methotrexate, 
mycophenolate mofetil, pentoxifylline) 
• Corticosteroids 
• Statins 
8.3. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product 
on an ongoing basis and at each contact and onsite visit; this should be confirmed by conducting 
drug accountability (ie, count of returned tablets) during subjects’ on site visits. 
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 drug 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 she/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.  Continued trial eligibility should be 
assessed. 
8.4. 
Randomization and Blinding 
At Day 0, after review of Inclusion and Exclusion criteria, subjects will be allocated to 1 of 
3 treatment groups in a 1:1:1 ratio based on a predefined randomization code (generated by the 
Sponsor or designee) using the IWRS, which will serve as the registration system for subjects at 
Screening, Day 0, and entry into the LTSE phase.  The IWRS will serve as an investigational 
product inventory and management system and may be integrated with the trial 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 randomize and allocate the subject to treatment.  
A randomization number will be assigned and investigational product dispensing information 
(eg. bottle number[s]) will be provided while maintaining the trial blind.  The subjects, 
Investigator, and trial site staff will be blinded to the subject’s treatment allocation during the 
subject’s participation in the DB phase of the trial.  The IWRS system will facilitate the 
unblinding of an individual subject at the time the subject completes the DB phase and enters the 
LTSE phase of the trial (ie, subjects’ treatment allocations are unblinded one-by-one.   
8.4.1. 
Stratification 
In order to ensure that factors which could potentially affect treatment response are randomized 
in equal proportions to the different treatment groups, subjects will be stratified by the following: 
• The presence or absence of concomitant UDCA use, where no more than 50% of 
subjects recruited will be administering UDCA as part of standard of care at Day 0 
• Total bilirubin level, where no more than 25% of subjects recruited will have a total 
bilirubin >1.5x ULN and <2.5x ULN at Screening 
8.4.2. 
Unblinding Procedures – Emergency Unblinding 
For the DB phase of the trial, treatment assignment will be made available to the Investigator for 
emergency use only through the IWRS.  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 
accidental unblinding or unblinding due to 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 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. 


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The DSMC (refer to Section 12.6.2) will have access to the IWRS and will be able to unblind 
individual subjects.  Refer to Section 12.6.2 for further details regarding DSMC access to 
blinded and unblinded data.  The DSMC will document, 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), details about any unblinded subject data reviews.  Cases of premature unblinding 
(as noted above) will be reviewed by the DSMC. 
Access to treatment assignments will also be made available through the IWRS to the 
appropriate, named individual(s) responsible for reporting SAEs and suspected unexpected 
serious adverse reactions (SUSARs) to the regulatory authorities. 
8.5. 
Assignment of Site and Subject Numbers 
8.5.1. 
Site Numbers 
Each trial site selected to participate in this trial will be assigned a Site Number by the Sponsor.  
The Site Number will be used to identify the site and or Investigator within trial documents.  
This number will also be recorded in the CRF. 
8.5.2. 
Subject Numbers 
Subjects will be identified by a 6 digit number.  The first 3 digits will represent the site number 
and the last 3 digits, the screening number.  The first screening number used at any site will be 
001 and as each new subject is screened, the subject will be assigned the next sequentially 
available number (eg, 001, 002, 003, etc).  
8.6. 
Visit Procedures 
8.6.1. 
Visit Windows 
All trial visits during the DB period are relative to Day 0 (eg, if the Week 6 visit occurs 4 days 
late, the Week 12 visit should still be 12 weeks from Day 0).  The Screening visit should occur 
≤30 days (ie, Day -30 to Day -1) prior to the Day 0 visit.  All visits during the DB treatment 
period should occur within ±1 week of the indicated time.  The exception to this is the Week 2 
visit, which should occur within ±3 days of the indicated time.  
During the LTSE period, visits are relative to LTSE Day 1 (which is also the DB Week 24 visit) 
and all visits during this period should occur within ±2 weeks of the indicated time, except for 
the Week 2 Safety Contact which should occur within ±3 days and the Follow-Up visit, which 
should occur within ±1 week.  
8.6.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, and risks of the trial to the subject 
and will provide him/her with a copy of the patient information sheet (PIS), containing the 
written information, and the informed consent form (ICF).  The subject will be given sufficient 
time to consider the trial before deciding whether or not to participate, in line with local 
requirements where applicable.  The subject will be informed that participation is voluntary and 
that her/his future medical treatment will not be compromised by participation in the trial and 
that she/he can withdraw from the trial at any time.  The subject must be willing and able to 


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provide written informed consent before entering the trial.  The Investigator or a medically 
qualified designee is responsible for administering and documenting the written informed 
consent of the subject in the subject’s medical notes/source worksheet.  The subject will be 
provided with copies of their PIS and signed and dated ICF. 
At selected trial sites, subjects will have the option to consent to participate in an additional PK 
and bile acid assessment.   
As part of the consenting process, the Investigator or designee will describe the intention for and 
implications of providing blood samples for the analysis of RNA to each subject.  Subjects who 
agree to provide these samples will be required to sign a separate ICF and will be provided with 
a copy of this, in addition to the overall study ICF.  The samples will be stored for up to 1 year 
after the end of the study. 
8.6.3. 
Screening Procedures (Within 30 Days of Day 0) 
The Screening visit assessments must be performed within ≤30 days (ie, Day -30 to Day -1) prior 
to Day 0 to determine whether the subject meets all the inclusion criteria and none of the 
exclusion criteria.   
Subjects who do not meet all eligibility criteria during Screening may undergo repeat Screening 
assessments (one repeat only) at any time after 30 days from their initial date of consenting for 
the trial.  Re-screened subjects will be allocated a new screening number.   
The term “Baseline” within this protocol, unless otherwise specified, is intended to mean, 
“pretrial” or “pretreatment” (of investigational product).  It refers to values obtained during the 
Screening, retests, or Day 0 visits, prior to the subject’s first dose of investigational product.  The 
statistical or calculated definition(s) of “Baseline” to be used in the analyses of the data may be 
different and will be further defined in the statistical analysis plan (SAP) for this trial. 
Screening visit procedures are as follows: 
• The subject is to review the PIS and sign the ICF.  Written informed consent must be 
obtained from the subject before performing any trial related procedures, including 
Screening procedures.  (Note:  Collection of AEs commences from the point the 
subject signs the consent form.) 
• Assign subject number. 
• Collect medical history. 
• Record prior (within 30 days of Screening) and current concomitant medications. 
• Verify inclusion and exclusion criteria for eligibility. 
• Perform a physical examination, including height and weight.  See Section 11.2.2 for 
physical examination requirements. 
• Record vital signs. 
• Perform a standard 12-lead electrocardiogram (ECG). 
• Perform hepatic ultrasound to assess bile duct patency. 


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• For subjects with UC:  provide the diary and request subject completes this the day 
prior to the Day 0 visit, to reflect their symptoms since the Screening visit.   
• For subjects with CD:  provide the diary and request subject completes this for each 
of the 7 consecutive days prior to the Day 0 visit.   
• Obtain blood samples for serum chemistry, hematology, and coagulation.  
Note:  
If a subject has an ALP value <2x ULN, a further sample may be taken during the 
Screening period (at least 14 days after the initial sample was taken), and provided 
the mean ALP is ≥2x ULN, the subject will have met inclusion criterion 4 (ALP at 
Screening ≥2x ULN) 
If a subject has a total bilirubin value >1.5x ULN, a further sample may be taken 
during the Screening period (at least 14 days after the initial sample was taken), and 
provided the mean total bilirubin is <2.5x ULN, the subject will have met inclusion 
criterion 5 (total bilirubin at Screening <2.5x ULN – in line with the bilirubin 
stratification factor:  no more than 25% of subjects recruited will have a bilirubin 
>1.5x ULN and <2.5x ULN). 
• Obtain urine sample for dipstick analysis 
• Perform a urine-based beta human chorionic gonadotrophin (β-hCG) pregnancy test 
in females of childbearing potential.  If the urine pregnancy test is positive, it should 
be repeated as a serum pregnancy test. 
• The subject should be: 
− Provided with a fecal sampling kit and instructed to collect the sample within 
2 days of their Day 0 visit, as described in the laboratory manual.   
− Instructed to fast overnight (at least 8 hours) prior to the next visit.  Fasting is 
required prior to all on site trial visits, but water is permitted. 
8.6.4. 
Day 0 Procedures 
• Verify inclusion and exclusion criteria for eligibility. 
• Record current concomitant medications. 
• Record vital signs. 
• Perform transient elastography (TE) at sites where the Fibroscan® TE device is 
available.  
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy) using the 
data from the diary card provided at the Screening visit. See Appendix B for details. 
• For subjects with CD:  complete CDAI assessments using the data from the diary card 
provided at the Screening visit.  See Appendix F for details. 
• Administer pruritus visual analogue scale (VAS) subject questionnaire and 5-D Itch 
Questionnaire.  See Appendix C for details. 


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• Assess and record AEs.  
• Obtain blood samples for the following: 
− Serum chemistry, hematology, and coagulation  
− FGF-19   
− C-reactive protein (CRP) 
− Enhanced liver fibrosis (ELF) markers and other analytes 
− Plasma bile acids and 7α-hydroxy-4-cholesten-3-one (C4) 
− Apolipoprotein and nuclear magnetic resonance (NMR) lipoprotein panel 
− Genetics study (if subject has consented to provide a sample for RNA analysis) 
• Obtain urine sample for dipstick urinalysis. 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test.  
• Obtain fecal sample for calprotectin and microbiome assessments (from subjects 
willing to provide a fecal sample). 
• After verifying eligibility, randomize the subject via the IWRS system.  
• Dispense the indicated investigational product. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects).  
• Reiterate dosing instructions and advise the subject: 
− All subjects are to administer the first dose of investigational product on Day 1 
and administration of investigational product should occur at approximately the 
same time of day throughout the duration of the trial.  Further details are included 
in Section 8.1. 
− NOT to take investigational product on the morning of the next trial visit, and  
− To bring the investigational product bottle(s) and 
− To fast overnight (at least 8 hours) prior to the next trial visit.  Fasting is required 
prior to all trial visits, but water is permitted, and the subject should dose at the 
visit after all assessments have been performed. 
8.6.5. 
Week 2 Procedures 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  


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• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch Questionnaire. 
• Obtain blood samples for serum chemistry, hematology, and coagulation.  
• 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 trial 
visits, but water is permitted, and the subject should dose at the visit after all 
assessments have been performed. 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles and document returns. 
• Record the visit in IWRS. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects).  
• Reiterate dosing instructions and advise the subject: 
− NOT to take investigational product on the morning of the next trial visit, and  
− To bring the investigational product bottle(s) and 
− To fast overnight (at least 8 hours) prior to the next trial visit.  Fasting is required 
prior to all trial visits, but water is permitted, and the subject should dose at the 
visit after all assessments have been performed. 
8.6.6. 
Week 6 Procedures 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Obtain blood samples for serum chemistry, hematology, and coagulation. 
• 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 trial 


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visits, but water is permitted, and the subject should dose at the visit after all 
assessments have been performed. 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles and document returns. 
• Record the visit in IWRS. 
• Subjects with UC or CD: provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
• 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) and 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all trial visits, but water is permitted, and the subject should dose at the visit 
after all assessments have been performed. 
• The subject should be provided with a fecal sampling kit and instructed to collect the 
sample within 2 days of her/his Week 12 visit, as described in the laboratory manual.   
8.6.7. 
Week 12 (Titration Visit) Procedures 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Obtain blood samples for the following: 
− Serum chemistry, hematology, and coagulation  
− FGF-19  
− CRP 
− ELF markers and other analytes 
− Plasma bile acids and C4 
− Apolipoprotein and NMR lipoprotein panel 
• For sites and subjects participating in PK sampling:  obtain samples for PK analysis 
(see Section 10.5 for sampling schedule).  Subjects undergoing PK sampling should 
take the currently assigned dose (ie, lower dose); the titrated dose should be taken by 
the subject the following day. 


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• Obtain urine sample for dipstick urinalysis. 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• Obtain fecal sample for calprotectin and microbiome assessments (from subjects 
willing to provide a fecal sample). 
• 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 trial 
visits, but water is permitted, and the subject should dose at the visit after all 
assessments have been performed. 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles and document returns. 
• Record the visit in IWRS and indicate if the subject will follow the titration schedule 
and dispense bottles of investigational product as indicated by IWRS.  
Note:  The subject’s dose will be titrated as follows, providing there are no limiting 
safety, or tolerability concerns in the opinion of the Investigator, while maintaining 
the trial blind: the 1.5 mg OCA treatment group will titrate to 3 mg, the 5 mg OCA 
treatment group will titrate to 10 mg OCA, and the placebo group will remain on 
placebo.  DB treatment will continue for a further 12 weeks at that dose.   
Any subjects whose dose is not titrated, due to safety or tolerability concerns, will 
remain on their starting treatment (1.5 mg OCA, 5 mg OCA, or placebo) for the 
remainder of the DB phase to Week 24. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
• 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) and 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all trial visits, but water is permitted, and the subject should dose at the visit 
after all assessments have been performed. 
8.6.8. 
Week 14 Procedures 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 


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• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Obtain blood samples for serum chemistry, hematology, and coagulation. 
• 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 trial 
visits, but water is permitted, and the subject should dose at the visit after all 
assessments have been performed. 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles and document returns. 
• Record the visit in IWRS. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
• 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) and 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all trial visits, but water is permitted. 
8.6.9. 
Week 18 Procedures 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Obtain blood samples for serum chemistry, hematology, and coagulation.  
• 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 trial 


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visits, but water is permitted, and the subject should dose at the visit after all 
assessments have been performed. 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles and document returns. 
• Record the visit in IWRS. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects).  
• 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) and 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all trial visits, but water is permitted. 
• The subject should be provided with a fecal sampling kit and instructed to collect the 
sample within 2 days of their Week 24 visit, as described in the laboratory manual.   
8.6.10. 
Week 24/LTSE Day 1 Procedures 
• Assess and record AEs. 
• Record current concomitant medications. 
• Perform a physical examination, including weight. 
• Record vital signs. 
• Perform a standard 12-lead ECG. 
• Perform TE at sites where the Fibroscan® TE device is available. 
• Perform hepatic ultrasound to assess bile duct patency. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Subject to complete the Subject Research Questionnaire. 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation  
− FGF-19  
− CRP 
− ELF markers and other analytes 
− Plasma bile acids and C4 


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− Apolipoprotein and NMR lipoprotein panel 
− Genetics study (if subject has consented to provide a sample for RNA analysis) 
• For sites participating in PK sampling:  obtain samples for PK analysis (see 
Section 10.5 for sampling schedule). 
• Obtain urine sample for dipstick urinalysis. 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• Obtain fecal sample for calprotectin and microbiome assessments (in subjects willing 
to provide a fecal sample). 
• 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 trial 
visits, but water is permitted. 
• Record the visit in the IWRS and indicate if the subject plans to participate in the 
LTSE. 
For Subjects Participating in the LTSE: 
• Re-confirm their consent to participate in the LTSE phase of the trial.  
• Unblind the subject’s treatment allocation in IWRS (as detailed in a separate trial 
document) and document the dose of OCA on which the subject will commence the 
LTSE. 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles and document returns. 
• Dispense indicated bottle(s) of investigational product. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
• 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); and 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all trial visits, but water is permitted, and the subject should dose at each visit 
after all assessments have been performed. 


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For Subjects NOT Participating in the LTSE: 
• Remind the subject of the date of their Follow-Up visit. 
• Perform a final investigational product accountability check verifying the amount of 
investigational product dispensed and returned. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
8.6.11. 
Early Discontinuation and/or Early Termination Procedures:  Double-Blind 
Phase 
Subjects who terminate participation in the trial prior to the Week 24 visit should have an EOT 
visit as soon as possible following the decision to discontinue therapy.  EOT visit procedures are 
as follows: 
• Assess and record AEs. 
• Record current concomitant medications. 
• Perform a physical examination, including weight. 
• Record vital signs. 
• Perform a standard 12-lead ECG. 
• Perform TE at sites where the Fibroscan® TE device is available. 
• Perform hepatic ultrasound to assess bile duct patency. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Subject to complete the Subject Research Questionnaire. 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation 
− FGF-19  
− CRP 
− ELF markers and other analytes 
− Plasma bile acids and C4 
− Apolipoprotein and NMR lipoprotein panel 
− Genetics study (if subject has consented to provide a sample for RNA analysis) 
− For sites participating in PK sampling:  obtain samples for PK analysis (see 
Section 10.5 for sampling schedule) 


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• Obtain urine sample for dipstick urinalysis. 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• Obtain fecal sample for calprotectin and microbiome assessments (in subjects willing 
to provide a fecal sample). 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles 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. 
• Perform a final investigational product accountability check verifying the amount of 
investigational product dispensed and returned. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
• Remind the subject of the date of their Follow-Up visit. 
• Record the visit in IWRS. 
8.6.12. 
Follow-Up Visit:  Double-Blind Phase 
Subjects who terminate participation in the trial prior to the Week 24 visit or complete the 
Week 24 visit but do not proceed to LTSE, should have a Follow-Up visit 4 weeks after their last 
dose of investigational product: 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy). 
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Obtain blood samples for serum chemistry, hematology, and coagulation. 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• Record the visit in IWRS. 


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8.6.13. 
Long-Term Safety Extension Visits 
LTSE visits will take place once every 3 months ±2 weeks.  
If the Investigator is planning on up-titrating a subject during the LTSE, the subject needs to 
attend an additional study visit (Pre-Titration visit) as well as have a study contact. 
Pre-Titration Visit 
The Pre-Titration visit occurs approximately 1 week prior to the scheduled LTSE visit to assess 
serum chemistry (ie, ALP and bilirubin) and complete all other laboratory assessments.   
Titration Visit 
Following the Pre-Titration visit, the subject attends for the scheduled 3 monthly visit to 
determine her/his eligibility for titration.  All procedures (except laboratory sample collection) 
for the scheduled trial visit occur as noted in the Schedule of Trial Procedures (Table 2).  
Subjects experiencing significant AEs (eg, severe pruritus) or other symptoms that are not 
tolerated, may not be eligible for titration.  Under these circumstances, the Investigator should 
contact the Intercept Medical Monitor if he/she still plans to up-titrate the subject. 
Contact 
The Investigator or designee should contact the subject approximately 2 weeks after the Titration 
visit to assess for AEs.  This contact will be recorded in the CRF.  The Investigator may schedule 
an at-clinic Unscheduled/Safety visit at any time if clinically warranted. 
If the Investigator is not planning on up-titrating a subject during an LTSE visit, the subject 
attends the scheduled 3 month visit without an additional visit or contact.   
8.6.14. 
LTSE Day 1 (DB Week 24) Procedures 
See Section 8.6.10 for the LTSE Day 1 (DB Week 24 visit) procedures. 
8.6.15. 
LTSE Week 2 Procedures 
The subject will be contacted by the study site staff 2 weeks after the start of the LTSE phase to 
assess safety. 
8.6.16. 
LTSE Month 3, 9, 15, and 21 Procedures 
The following procedures will occur at the Month 3, 9, 15, and 21 LTSE visits: 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy). 
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Obtain blood samples for serum chemistry, hematology, and coagulation.  


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• Perform a urine based beta β-hCG pregnancy test in females of childbearing potential.  
If the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• 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 trial 
visits, but water is permitted. 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles and document returns. 
• Record the visit in IWRS and dispense indicated bottles of investigational product. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
• 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) and 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all trial visits, but water is permitted. 
• For the Month 9 and Month 21 visits only: 
− The subject should be provided with a fecal sampling kit and instructed to collect 
the sample within 2 days of their next visit, as described in the laboratory manual.  
• For the Month 21 visits only: 
− The subject should be advised that their last dose of investigational product is 
administered on the day prior to their Month 24 visit. 
8.6.17. 
LTSE Month 6 Procedures 
The following procedures will occur at the Month 6 LTSE visit: 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation 


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− CRP  
− Plasma bile acids and C4 
• Obtain urine sample for dipstick urinalysis. 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• 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 trial 
visits, but water is permitted. 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles and document returns. 
• Record the visit in IWRS and dispense indicated bottles of investigational product. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects).  
• 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) and 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all trial visits, but water is permitted. 
8.6.18. 
LTSE Month 12 Procedures 
The following procedures will occur at the Month 12 LTSE visit: 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 
• Perform TE at sites where the Fibroscan® TE device is available. 
• Perform hepatic ultrasound to assess bile duct patency. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation 


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− FGF-19 
− CRP  
− ELF markers and other analytes 
− Plasma bile acids and C4 
− Genetics study (if subject has consented to provide a sample for RNA analysis) 
• Obtain urine sample for dipstick urinalysis. 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• Obtain fecal sample for calprotectin and microbiome assessments (in subjects willing 
to provide a fecal sample). 
• 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 trial 
visits, but water is permitted. 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles and document returns. 
• Record the visit in IWRS and dispense indicated bottles of investigational product. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
• 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) and 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all trial visits, but water is permitted. 
8.6.19. 
LTSE Month 18 Procedures 
The following procedures will occur at the Month 18 LTSE visit: 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy). 
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 


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• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation 
− CRP  
• Obtain urine sample for dipstick urinalysis. 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• 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 trial 
visits, but water is permitted. 
• Assess investigational product compliance and perform accountability; retrieve used 
bottles and document returns. 
• Record the visit in IWRS and dispense indicated bottles of investigational product. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
• 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) and 
− To fast overnight (at least 8 hours) prior to the next visit.  Fasting is required prior 
to all trial visits, but water is permitted. 
8.6.20. 
LTSE Month 24 Procedures 
The following procedures will occur at the Month 24 LTSE visit: 
• Assess and record AEs. 
• Record current concomitant medications. 
• Perform a physical examination, including weight. 
• Record vital signs. 
• Perform a standard 12-lead ECG. 
• Perform TE at sites where the Fibroscan® TE device is available. 
• Perform hepatic ultrasound to assess bile duct patency. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 


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• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Subject to complete the Subject Research Questionnaire 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation 
− FGF-19 
− CRP  
− ELF markers and other analytes 
− Plasma bile acids and C4 
− Genetics study (if subject has consented to provide a sample for RNA analysis) 
• Obtain urine sample for dipstick urinalysis. 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• Obtain fecal sample for calprotectin and microbiome assessments (in subjects willing 
to provide a fecal sample). 
• 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.  
• Perform a final investigational product accountability check verifying the amount of 
investigational product dispensed and returned. 
• Subjects with UC or CD:  provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
• Remind the subject of the date of their Follow-Up visit. 
• Record the visit in IWRS. 
8.6.21. 
Early Discontinuation and/or Early Termination Procedures:  LTSE Phase 
Subjects who terminate participation in the trial during the LTSE should have an EOT visit as 
soon as possible following the decision to discontinue therapy.  EOT visit procedures are as 
follows:   
• Assess and record AEs. 
• Record current concomitant medications. 
• Perform a physical examination, including weight. 
• Record vital signs. 
• Perform a standard 12-lead ECG. 


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• Perform TE at sites where the Fibroscan® TE device is available. 
• Perform hepatic ultrasound to assess bile duct patency. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy).  
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 
• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Subject to complete the Subject Research Questionnaire 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation 
− FGF-19 
− CRP  
− ELF markers and other analytes 
− Plasma bile acids and C4 
− Genetics study (if subject has consented to provide a sample for RNA analysis) 
• Obtain urine sample for dipstick urinalysis. 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• Where possible, obtain fecal sample for calprotectin and microbiome assessments 
(in subjects willing to provide a fecal sample). 
• Perform a final investigational product accountability check verifying the amount of 
investigational product dispensed and returned. 
• Subjects with UC or CD: provide the appropriate diary card and request this is 
completed for the 7 consecutive days prior to their next scheduled visit (for subjects 
with CD) and the day prior to their next scheduled visit (for UC subjects). 
• Remind the subject of the date of their Follow-Up visit. 
• Record the visit in IWRS. 
8.6.22. 
Follow-Up Visit:  LTSE 
All subjects who entered LTSE attend for a Follow-Up visit 4 weeks after their last dose of 
investigational product: 
• Assess and record AEs. 
• Record current concomitant medications. 
• Record vital signs. 
• For subjects with UC:  obtain partial Mayo score (excluding endoscopy). 
• For subjects with CD:  complete CDAI assessments and assign CDAI score. 


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• Administer pruritus VAS subject questionnaire and 5-D Itch questionnaire. 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation 
• Perform a urine based β-hCG pregnancy test in females of childbearing potential.  If 
the urine pregnancy test is positive it should be repeated as a serum pregnancy test. 
• Record the visit in IWRS. 
8.6.23. 
Unscheduled Safety Visit 
The Investigator may schedule an Unscheduled/Safety visit at any time if clinically warranted or 
requested by the Medical Monitor.  Unscheduled and/or repeat assessments, including additional 
laboratory tests or investigations, may be conducted.  As appropriate, the Medical Monitor 
should be contacted.  
9. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
9.1. 
Investigational Product  
For the purpose of this protocol, the term “investigational product” describes both OCA and 
placebo tablets. 
The investigational product used for this trial will be 1.5 mg and 5 mg OCA and matching 
placebo tablets.  The 1.5 mg OCA tablet and matching placebo are white, round tablets with no 
markings.  The 5 mg OCA tablet and matching placebo are white, round tablets debossed with 
“INT” on one side and “3547” on the other side.  OCA tablets contain the following inactive 
ingredients:  microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.   
All investigational product will be provided as a tablet for oral administration and provided in 
high density polyethylene bottles with an induction seal and child resistant closures.  The 1.5 mg 
OCA tablet and matching placebo are smaller tablets (approximately 6 mm diameter) and will be 
provided in 40 cc bottles.  The 5 mg OCA and matching placebo (approximately 8 mm diameter) 
and will be provided in 85 cc bottles.  
All investigational product will be manufactured according to Good Manufacturing Practice 
(GMP). 
9.2. 
Investigational Product Packaging and Labeling 
The packaging and labeling of investigational product supplies will be performed according to 
GMP standards by a designated qualified vendor.  A designated vendor will also be responsible 
for the distribution of the investigational product to the Investigator and, where applicable, for 
providing the Qualified Person release of the investigational product. 
Investigational product will be packaged and labeled as single bottles containing 100 OCA or 
placebo tablets and should be dispensed to the subject as received.  For the DB phase of the 
clinical study, investigational product bottles will be blinded.  Each bottle will be labeled with a 


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unique non-sequential bottle number.  More than one bottle of investigational product may be 
dispensed to the subject at a visit to provide sufficient tablets for daily dosing until the next trial 
visit. 
9.3. 
Investigational Product Storage 
The investigational product should be stored in the containers in which it is received from the 
Sponsor’s supplier, at 15°C to 25°C. 
9.4. 
Investigational Product Administration 
Subjects will be instructed to begin dosing on the day after the Day 0 visit (ie, on Day 1).  
Investigational product administration should occur at approximately the same time of day 
throughout the duration of the trial.  Subjects must be instructed to swallow the indicated number 
of tablets whole with water; they must not chew, divide, or crush the tablets. 
9.4.1. 
Investigational Product Dispensation 
On Day 0, after confirmation of subject eligibility, the Investigator or designee will dispense 
investigational product to the subject.  Subjects will receive 2 bottles of investigational product 
on Day 0.  Before leaving the clinic, trial site staff will ensure that the subject fully understands 
the dosing instructions. 
At the 12 Week visit during the DB phase of the clinical study, subjects will receive 4 bottles of 
investigational product. 
During the LTSE phase of the trial, subjects will receive 1 or 2 bottles of investigational product 
per visit depending on the dose of OCA they are receiving. 
If necessary in exceptional circumstances, and only after approval by Intercept, investigational 
product may be delivered to subjects by courier, with proper precautions and documentation of 
shipping. 
9.4.2. 
Missed Doses 
Subjects who miss a dose of investigational product should be instructed to take it later the same 
day, as soon as they remember.  Missed doses should not be taken on a subsequent day (ie, the 
subject should not take more than the prescribed daily dose, as directed).   
9.4.3. 
Overdose 
The maximum dose of OCA that has been given to humans is 500 mg as a single dose and 
250 mg as a multiple dose.  Reversible increases in aminotransferases were seen in most of the 
healthy volunteers who took 250 mg OCA.  If overdose occurs in a subject enrolled in the trial, 
general medical supportive measures should be provided, including observation and follow-up 
(eg, serum chemistry) as appropriate.  Due to the extensive enterohepatic recirculation of OCA 
it is likely that it will take several days before blood (and organ) concentrations of the drug will 
decrease.  Treatment with cholestyramine (eg, Questran™), colesevelam (eg, Welcol™) and 
other BAS is recommended given that they should bind and eliminate the drug in feces.  The 
Sponsor should be notified immediately in the event of a significant overdose. 


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9.5. 
Investigational Product Accountability and Disposal 
A designated vendor will send investigational product to the trial 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 trial 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, missed doses, tablets/bottles 
returned at each visit, and final return or disposition (as directed by the Sponsor).  
The trial 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 trial is completed, or if it is prematurely 
terminated.  The CRA will retrieve documentation detailing and confirming the return to depot 
or destruction of the investigational product by the trial site. 
10. 
ASSESSMENTS OF EFFICACY  
10.1. 
Sample Collection 
Blood samples for the assessment of efficacy will be collected at visits indicated in the Schedule 
of Trial Procedures (Table 1 and Table 2, Section 6.1).  The complete list of planned assessments 
can be found in Appendix A.   
Fasting (8 hours) blood samples are required for efficacy analyses.  For consistency, subjects will 
be instructed to attend each of their at-site visits 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 onsite visits. 
Fecal samples will be collected in a subset of subjects for the assessment of GI inflammation, at 
visits indicated in the Schedule of Trial Procedures.  
Instructions concerning the number and type of samples, including the PK assessments, to be 
collected at each visit, the required sample volumes, sample collection methods, sample 
processing, labeling, and shipping will be provided in a trial-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.   
10.2. 
Primary Efficacy Assessments  
The primary efficacy assessment is serum ALP.  


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10.3. 
Secondary Assessments 
Hepatic Biochemistry and Indices of Function 
Hepatic biochemistry and indices of function will be assessed by measuring the following:  
ALP, ALT, AST, GGT, bilirubin, albumin, and international normalized ratio (INR) 
Hepatic and GI Inflammation, Hepatic Disease and Fibrosis 
Hepatic and GI inflammation, hepatic disease, and fibrosis will be assessed by measuring the 
following:   
Autotaxin and its metabolites, calprotectin, C-reactive protein (CRP), Cytokeratin-18 (CK-18), 
ELF markers, transient elastography (TE), Immunoglobulin A (IgA), IgG, Immunoglobulin M 
(IgM), Interleukin-6 (IL-6), Interleukin-12 (IL-12), Interleukin-23 (IL-23), transforming growth 
factor-beta (TGF-β), tumor necrosis factor-alpha (TNF-α). 
The Enhanced Liver Fibrosis (ELF™) test is a blood test that measures hyaluronic acid (HA), 
procollagen-3 N-terminal peptide (P3NP), and a tissue inhibitor of metalloproteinase 1 
(TIMP-1), as a measure of hepatic fibrosis. 
Transient Elastography (TE) is an assessment of hepatic fibrosis using a Fibroscan® TE device 
(Echosens, Paris, France) that measures hepatic stiffness.  It is a validated and non-invasive 
measure and will be performed at trial sites that have the equipment.  Trial sites must have staff 
trained in the use and data interpretation of the device. 
GI inflammation will be assessed by measuring fecal calprotectin in subjects who provide fecal 
samples. 
FXR Activity 
FXR activity will be assessed by measuring fibroblast growth factor-19 (FGF-19) concentrations. 
Disease-Specific Symptoms 
Disease-specific symptoms of IBD and pruritus will be assessed using the partial Mayo score 
(only for subjects with UC), CDAI (only for subjects with CD) and as a Pruritus VAS and 5-D 
itch questionnaire, respectively. 
IBD Symptoms 
• Partial Mayo Score  
The partial Mayo score will be performed by the Investigator at specified visits to assess 
symptoms associated with IBD (Rutgeerts 2005).  The full Mayo scoring system includes 
questions related to stool frequency and rectal bleeding, endoscopic findings, and the physician’s 
global assessment.  The partial score does not include an endoscopy and will be used in this trial. 
Details of the partial Mayo Ulcerative Colitis Score are shown in Appendix B. 
• CDAI 
The CDAI will be performed by the Investigator at specified visits to assess symptoms 
associated with CD (Best 1976) and will be based on the subject’s recount of their symptoms in 
addition to hematocrit and body weight measurements.  Details of the CDAI are shown in 
Appendix F. 


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To assist sites with recording and calculating the partial Mayo score and the CDAI, subjects with 
UC will be asked to complete a diary the day prior to the next scheduled visit, recording details 
since their last visit; and subjects with CD should complete the diary in the 7 days prior to their 
next clinic visit.  The PI will transcribe relevant information into the subject’s medical records 
for SDV and retain the diary cards.  Pertinent aspects of these data will be recorded in the CRF.  
Data from the Screening period diary card will be recorded at Day 0. 
Pruritus 
In addition to the assessment of pruritus as an AE with mild, moderate and severe categories, 
pruritus will be specifically assessed by patient questionnaires: 
• Pruritus VAS 
Subjects will be asked to complete the Pruritus VAS to assess any experiences of pruritus during 
the trial; they will be asked to initial and date to document confirmation of their responses, and 
the questionnaires should be filed in the subject’s trial records.  Details of the Pruritus VAS are 
shown in Appendix C. 
• 5-D Itch 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).   
10.4. 
Additional Exploratory Assessments 
Gut Microbiome Genetic Profile 
The gut microbiome will be assessed from fecal samples provided by subjects who agreed to 
provide fecal samples.  
Genetics Study 
RNA expression resulting from treatment with OCA will be assessed at indicated timepoints 
during the trial.  Subjects will be permitted to decline to provide a blood sample for the genetics 
study, without affecting their involvement in the trial.  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. 
Exploratory Analytes 
Blood samples for future analysis related to the effects of OCA or FXR activation will be 
collected at specified timepoints during the study and may be assayed on an exploratory research 
basis.  The samples will be stored for up to 2 years after the end of the study. 
Subject Research Questionnaire 
A Subject Research Questionnaire will be administered upon completing participation in the DB 
phase – either at the DB Week 24 visit or, if the subject terminates early during the DB phase, or 
at the EOT visit.  This simple questionnaire requests feedback about the subject’s perception of 
the trial and asks subjects if they felt that their participation in the trial was worthwhile and 
whether they would recommend a similar trial to a family member.  The Subject Research 
Questionnaire is included in Appendix E. 


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10.5. 
Pharmacokinetics and Bile Acid Assessments 
At selected investigational sites, subjects will have the option to consent to participate in an 
additional PK and bile acid assessment.  This is optional and subjects may decline to participate 
without affecting their involvement in the rest of the trial.   
OCA and its conjugates will be assessed at indicated visits and times (see Table 1 and Table 2).  
In addition, total bile acids, UDCA, OCA, CDCA, LCA, cholic acid, deoxycholic acid 
(conjugated and unconjugated forms) and C4 will also be analyzed. 
Following collection of the fasted laboratory samples (8 hour overnight fast) at Week 12 and 
Week 24 (as noted in Table 1), subjects who are participating in the PK/bile acid assessment will 
each receive a single dose of their allocated investigational product with approximately 240 mL 
of water.  At Week 12, subjects will receive their dose assigned prior to titration (ie, the lower 
dose of investigational product).  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.  
The trial-specific laboratory manual will include details of the volume of blood required to be 
drawn during each sampling timepoint as well as other logistical details and sample handling 
requirements.  
Subjects should not drink additional water for 1 hour after taking the dose of investigational 
product.  After approximately 1 hour postdose, subjects will be fed a meal replacement drink.  
As a secondary efficacy analysis, an exposure response analysis of total plasma OCA (OCA and 
its conjugates) to biomarkers, such as change in ALP and change in bile acids, will be performed 
to help identify optimal doses for this patient population. 
11. 
ASSESSMENT OF SAFETY 
Safety will be monitored and assessed by AEs/SAEs, medical history, physical examination, 
vital signs measurements, ECG results, and clinical laboratory assessments. 
11.1. 
Adverse Events and Serious Adverse Events 
11.1.1. 
Definitions  
11.1.1.1. Adverse Event  
Adverse events (AE) are defined as any untoward medical occurrence associated with the use of 
the investigational product in humans, whether or not considered related to investigational 
product.  An AE (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally associated 
with any use of the investigational product, without any judgment about causality and 
irrespective of route of administration, formulation, or dose, including an overdose.   
AEs include, but are not limited to:  (1) a worsening or change in nature, severity, or frequency 
of condition(s) present at the start of the trial; (2) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction. 


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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.  
11.1.1.2. Serious Adverse Event  
An AE is considered ‘serious’ if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
• Death; 
• Is immediately life threatening; 
• Requires in-patient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability or incapacity; 
• Results in a congenital abnormality or birth defect; 
• Is an important medical event that may jeopardize the 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. 
11.1.1.3. Treatment Emergent Adverse Event  
A treatment emergent adverse event (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. 
11.1.2. 
Relationship to Investigational Product 
The Investigator will document her/his opinion of the relationship of the AE to treatment with 
the investigational product using the criteria outlined in Table 7.  An AE for which there is a 
‘reasonable possibility’ that the investigational product caused the AE is otherwise referred to as 
suspected adverse reaction (SAR).  ‘Reasonable possibility’ means there is evidence to suggest a 
causal relationship between the investigational product and the AE.   
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible”, “probable” or “definite” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 


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Table 7: 
Relationship of AEs 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 drug; 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. 
11.1.3. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity).  A severity category of mild, moderate, or severe, 
as defined in Table 8 must be entered on the AE 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 8: 
Severity of AEs 
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. 
11.1.3.1. Severity of Pruritus (as an AE) 
Pruritus was the most common AE seen in the Phase 2 and Phase 3 PBC trials and thus may 
occur in this trial.  Subjects experiencing, or who have experienced within ≤3 months of 


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Screening, pruritus requiring systemic or enteral treatment are excluded from participating in this 
trial.  
To ensure consistency in reporting, the following guidelines for assessing severity of pruritus 
should be used both for AE reporting and during pretreatment assessment.  As pruritus is a 
subjective symptom, clinical judgment should be used to determine its severity and management.  
Subjects who experience a treatment emergent AE of severe pruritus should not be titrated to a 
higher dose. 
Table 9: 
Severity of Pruritus 
Pruritus Grade Clinical Description of Severity for Pruritus 
Titration Eligibility 
Guideline 
1 = Mild 
Generally localized; causing no limitation of usual activities 
or minimal sleep disturbance; the subject may experience 
slight discomfort.  Medicinal intervention is not indicated. 
Yes 
2 = Moderate 
Intense or widespread; causing some limitation of usual 
activities or sleep disturbance; the subject may experience 
annoying discomfort.  Medicinal intervention may be 
indicated. 
Yes; use clinical 
judgment 
3 = Severe 
Intense or widespread and interfering with activities of daily 
living (ADL), ie, causing inability to carry out usual activities, 
or severe sleep disturbance; the subject may experience 
intolerable discomfort. Medicinal intervention is typically 
indicated. 
No 
In the phase 2 PBC trials, Investigators tried a number of different approaches to help relieve 
pruritus symptoms.  Severe pruritus typically appears to occur shortly (ie, within the first 
2 weeks after starting therapy).  In the 747-202 trial, about 80% of the patients who were started 
on BAS or other drugs or interventions during the trial completed the trial as planned.  In the 
Phase 3 trial, similar approaches were employed in addition to evaluation of lower doses:  27% 
of subjects in the 10 mg group added a BAS compared to 20% of subjects in the titration arm and 
11% of placebo subjects.  Consistent with the use of lower doses and pruritus mitigation 
strategies withdrawals due to pruritus were minimized (1 subject in the titration arm and 7 in the 
10 mg OCA arm withdrew due to pruritus compared to none in the placebo arm). 
Since pruritus is such a subjective symptom (and the most common symptom in PBC patients), 
clinical judgment needs to be applied to the management of each subject.  However, the 
following recommendations are made for the management of subjects experiencing significant 
pruritus in this PSC trial: 
• Prescribe BAS, eg, cholestyramine, colestipol, colestimide, or colesevelam.  The 
greatest experience to date has been with cholestyramine.  Theoretically, colesevelam 
may be more palatable (tablet) and more effective.  Patients taking BAS should be 
instructed to stagger their dosing of investigational product and UDCA ensuring at 
least 4 hours between doses of the BAS and investigational product (and UDCA).   


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• Dose frequency modification:  Less frequent dosing of investigational product (eg, on 
alternate days) may be tried, after which subjects may return to their original daily 
dose, if and as tolerated.   
• Drug holiday:  A drug holiday is defined as an Investigator ‘prescribed’ complete 
interruption of dosing for 1 or more consecutive days (ie, non-daily dosing does not 
constitute a drug holiday).  For subjects with severe pruritus, instruct the subject to 
stop taking investigational product until the pruritus subsides to an acceptable level at 
which time it should be restarted (likely, on a modified, alternate day dosing 
schedule).  Details of drug holidays and/or nondaily dosing regimens should be 
recorded in the CRF.  Such cases should be discussed with the Medical Monitor. 
• Other therapies may be tried as deemed clinically appropriate. 
11.1.4. 
Reporting of Adverse Events and Serious Adverse Events 
11.1.4.1. 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 trial participation of the trial. 
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. 
11.1.4.2. 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.  SAEs are reported by entering the SAE data into the 
study specific EDC system.  Entering the SAE data into the EDC system will automatically 
notify the Sponsor of the event.  In the event that the EDC system is inaccessible, an SAE may 
reported by: 
• E-mail to the SAE email address:  sae@interceptpharma.com 
• Fax using a paper SAE report form:  +1 800 497 8521 
• Telephone:  + 1 844 250 6398 
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  


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• Name and title of the reporting individual   
• Causal relationship to the investigational product 
The Investigator will assess whether the event is causally related to the investigational product.  
The Sponsor, will also assess whether the event is causally related to the investigational product 
in addition to assessing the overall safety profile of the investigational product.  The Sponsor will 
notify the appropriate regulatory agencies as well as all participating Investigators of 
investigational new drug (IND) Safety Reports/Expedited Safety Reports that occur during the 
trial within the time frames required by each regulatory agency.  An SAE assessed with possible, 
probable, or definite causal relationship to the investigational product and unexpected according 
to the IB Reference Safety Information (RSI), is known as a suspected unexpected serious 
adverse reaction (SUSAR).  The Investigator must report SUSARs using the SAE reporting 
method described above. 
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 Safety Reports/Expedited Safety Reports received 
from the Sponsor to her/his local IRB/IEC, in compliance with the local country requirements.  
For the European Union, the Sponsor will notify the regulatory agencies and report SUSARs via 
the Eudra Vigilance database within 7 calendar days of a SUSAR involving death or a life-
threatening SUSAR, and all other SUSARs within 15 calendar days.  Documentation of the 
submissions to IRBs/IECs and health authorities (as applicable) must be retained in the 
appropriate trial file(s).  As instructed by the Sponsor, Safety Reports/Expedited Safety Reports 
should be retained in the appropriate Investigator site trial files, or with the IB.  
11.1.5. 
Anticipated Serious Adverse Events Associated with PSC 
There are a number of events which are commonly associated with PSC and for the Sponsor’s 
regulatory reporting purposes, these events are considered to be ‘Expected’ in this patient 
population and are listed in the IB.   
The Investigator remains responsible for reporting to the Sponsor all SAEs including the events 
identified here: 
• GI and hepatic malignancies including CCA, pancreatic cancer, colorectal cancer 
• Ascites 
• Cholecystitis 
• Cholangitis (including bacterial cholangitis) 
• Pancreatitis 
• IBD and IBD flare (including UC and CD) 
• Bile duct strictures (dominant or otherwise) 
• Steatorrhea 


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• Vitamin deficiency 
• Osteoporosis/osteopenia 
• Fractures 
• Variceal bleeding 
• Cirrhosis 
• Worsening PSC 
• Any of the above that result in Death 
11.1.6. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the CRF represent the official record of all AEs and SAEs reported in 
the trial.  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 Sponsor, the Investigator should provide 
input into the SAE narrative and provide timely information to ensure prompt follow-up and 
closure of the SAE report. 
The Investigator and supporting personnel responsible for 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.   
11.1.7. 
Notification of Post-Trial 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 trial, the Sponsor 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 trial, must be reported to the Sponsor within 24 hours by following 
the instructions provided in Section 11.1.4.2. 
11.1.8. 
Follow-Up of AEs and SAEs 
All AEs must be followed during the course of the trial 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. 


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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. 
11.1.9. 
Pregnancy and Follow-Up  
Pregnancies are not considered SAEs in and of themselves; however if a female trial participant 
becomes pregnant while she is enrolled in the clinical trial investigational product must be 
stopped immediately.  The Sponsor must be notified within 24 hours of the Investigator’s 
awareness 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.  
The subject must be followed by the Investigator through pregnancy outcome.  The Investigator 
should notify the Sponsor of the outcome of the pregnancy by completing the Pregnancy 
Outcome Form and faxing or emailing to the Sponsor.  The mother (and infant) will be followed 
as considered appropriate by the Investigator and the Medical Monitor. 
The Investigator must contact the Intercept Medical Monitor and discuss, in advance, any subject 
whose pregnancy is early terminated and would like to continue to participate in the trial.  A 
minimum requirement for allowing the subject to restart dosing is documentation of a negative 
serum β-hCG test.  However, this is not in and of itself a guarantee for being allowed to continue 
in the study. 
11.2. 
Other Safety Parameters 
11.2.1. 
Medical History/Demographics 
A complete medical history will be obtained from the subject at screening.  Demographic 
characteristics (age, gender, race, ethnicity, etc) will be recorded, as will any historical or on 
study data on colonoscopies (mucosal and histological) within the last 3 years and prior and on 
study liver biopsies, hepatic imaging, etc.  Reports should be available in source data. 
11.2.2. 
Physical Examination 
To assess the Subject for clinical findings, the Investigator or designee will perform a physical 
examination at the time points specified in the Schedule of Trial Procedures (Table 1 and 
Table 2).  If clinically significant abnormalities are observed before administration of the first 
dose of investigational product on Day 1, they should be reported as adverse events.  If clinically 
significant abnormalities are observed after the first administration of investigational product on 
Day 1, the Investigator should assess and decide if they are new adverse events and report them 
accordingly.  The physical examination should include the following at a minimum:   
• General appearance 
• Height (Screening visit only) 
• Weight 
• Skin 


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• Head, eyes, ears, nose and throat (HEENT) 
• Neck 
• Lymph nodes 
• Chest/Respiratory system 
• Cardiovascular system 
• Abdominal region 
• Extremities 
• Musculoskeletal system 
• Mental status 
• Neurological system. 
11.2.3. 
Vital Signs 
Vital signs will be assessed at indicated visits: oral temperature, sitting heart rate, respiratory rate 
and sitting blood pressure (BP).  When taking heart rate, respiratory rate and BP readings, 
subjects should be seated quietly for a minimum of 3 minutes before the readings are taken.   
11.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected.  The Investigator or designee will review the 12-lead 
ECG and findings will be recorded in the CRF as normal, abnormal but not clinically significant, 
or abnormal and clinically significant.  Any clinically significant abnormalities on ECGs 
recorded after Screening will also be documented as AEs and entered on the AE page of the 
CRF.  
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 ID number, date and time. 
11.2.5. 
Laboratory Assessments 
All laboratory tests will be analyzed by a Central Laboratory (except urine or serum pregnancy 
tests).  Blood and urine samples will be collected and analyzed or tested, according to the SOP of 
the testing facility and all samples will be collected while the subject is fasting.  Full instructions 
concerning the number, volume, and type of samples to be collected at each visit will be detailed 
in the trial-specific laboratory manual.  The manual will also include details of sample collection 
methods, labelling, and shipping information. 
Fasting (8 hours) blood samples are required for lipid, glucose (serum chemistry), and bile acid 
analyses.  For consistency, subjects will be instructed to attend each of their onsite 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 whether the subject has fasted for 
at least 8 hours and record fasting status in the source and CRF.  If the subject reports having 


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eaten (water is permitted) within 8 hours, this should be documented accordingly in the source 
and CRF and remind the subject that fasting is required prior to all trial visits. 
• Hematology and Coagulation  (hemoglobin, hematocrit, white blood cell [WBC] 
count with differential, platelets, red blood cell [RBC] count, INR, prothrombin time,  
partial thromboplastin time) 
• Serum chemistry including albumin, blood urea nitrogen (BUN), creatinine, direct 
(conjugated) bilirubin, indirect (unconjugated) bilirubin, total bilirubin, AST), ALT, 
ALP, GGT, electrolytes [calcium, chloride, potassium, sodium, magnesium], glucose, 
total protein, and blood lipids (total cholesterol, low density lipoprotein [LDL], HDL 
and very low density lipoprotein (VLDL) fractions and triglycerides [TG]) 
• Apolipoprotein and NMR lipoprotein panel: ApoA1, ApoB, ApoE, HDL, LDL, 
triglycerides, VLDL.  HDL, LDL, and VLDL cholesterol concentrations, particle 
numbers and sizes will be assessed.  
• IgG4 (Screening visit only) 
• Urine dipstick (pH, specific gravity, protein, glucose, ketones, bilirubin, blood) 
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 
test-article related AE, is identified; or until further follow-up is deemed medically unnecessary. 
Urine based β-hCG pregnancy tests will be performed in female subjects of childbearing 
potential per protocol specified visits.  Additionally, in accordance with local country or site 
requirements, additional urine pregnancy tests may be performed.  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 11.1.9 until 
pregnancy outcome.  
12. 
STATISTICS 
12.1. 
Analysis Populations 
The following analysis populations will be used: 
Intent-to-Treat (ITT) Population 
All randomized subjects who receive any amount of investigational product will be included in 
the ITT population.  Treatment assignment will be based on the randomized treatment.  The ITT 
population will be used for the analysis of all efficacy data.  
Week 12 Completer Population 
Completer population will include all ITT subjects who complete the DB Week 12 ALP 
assessment.  Treatment assignment will be based on the randomized treatment.     
Week 24 Completer Population 
Completer population will include all ITT subjects who complete the DB Week 24 ALP 
assessment.  Treatment assignment will be based on the randomized treatment.     


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Safety Population 
The Safety population will include all subjects who receive any amount of investigational 
product.  Treatment assignment will be based on the treatment actually received.  The Safety 
population will be used for the analysis of all safety data.  
12.2. 
Determination of Sample Size 
A sample size of 25 subjects per treatment group, a total of 75 subjects, will provide at least 90% 
power to detect a treatment difference for change in ALP assuming 20% dropout and the mean 
absolute changes in ALP for OCA and placebo treatment groups are approximately -20% 
and -5%, respectively, with a pooled standard deviation of 16, based on a 2-sided independent 
2-group t-test at an alpha level of 0.05.  
12.3. 
Efficacy Analysis 
One of the primary objectives of this proof of concept trial is to evaluate the efficacy of OCA in 
subjects with PSC.  The primary population for efficacy analyses is the ITT population.  
Sensitivity analyses will be conducted using the Completer population. 
12.3.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is the Week 24 change from Baseline in ALP.  The primary 
efficacy analysis will compare the Week 24 change from Baseline in ALP between OCA 10 mg 
treatment group and placebo using an analysis of covariance (ANCOVA) model with fixed 
effects for treatment group and randomization strata, and Baseline as a covariate.   
12.3.2. 
Secondary Efficacy Analysis 
Secondary efficacy analyses of hepatic biochemistry and function parameters (eg, ALT, AST, 
and GGT) will be summarized by treatment group using descriptive statistics at Baseline and at 
each scheduled post-Baseline visit.  The change from Baseline will also be summarized.  
Baseline is defined as the mean of all available evaluations prior to treatment.  Hepatic 
biochemistry and function parameters will be analyzed using the same ANCOVA model as 
specified for the primary efficacy analysis. 
A hierarchical approach will be used for multiplicity adjustments.  If the primary efficacy 
analysis is statistically significant (p <0.05), the following order will be used in the testing 
procedure to compare the change from Baseline in ALP between OCA and placebo: 
• Week 12:  OCA 5 mg treatment group (randomized to 5 mg for the initial 12 weeks 
followed by 10 mg for the latter 12 weeks) vs. placebo 
• Week 24:  OCA 3 mg treatment group (randomized to 1.5 mg for the initial 12 weeks 
followed by 3 mg for the latter 12 weeks) vs. placebo  
• Week 12:  OCA 1.5 mg treatment group (randomized to 1.5 mg for the initial 
12 weeks followed by 3 mg for the latter 12 weeks) vs. placebo 
If at any step a comparison above is not statistically significant, then all subsequent comparisons 
will be exploratory rather than confirmatory.   


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In addition, secondary efficacy analyses of ALP response rates, defined as ALP to <1.5x ULN, 
will compare OCA treatment groups and placebo at Week 12 and Week 24 using a 
Cochran-Mantel-Haenszel test stratified by the randomization stratification factor.  
Hepatic stiffness measurements (based on TE) will be summarized by treatment group using 
descriptive statistics at Baseline and at each scheduled post-Baseline visit.  The ELF score and its 
components (HA, P3NP, T1MP-1) and the other markers of fibrosis and/or inflammation will be 
summarized based on available data by treatment group using descriptive statistics at Baseline 
and at each scheduled post-Baseline visit.  The change from Baseline will be analyzed using the 
same ANCOVA model as specified for the primary efficacy analysis. 
Subgroup analyses will be evaluated as deemed appropriate, including but not limited to, those 
subjects who start antibiotics after first dose of investigational product. 
Full details regarding the planned analyses, methods, and outputs for the trial will be included in 
the SAP. 
12.4. 
Pharmacokinetics 
PK parameters will be determined for OCA, glyco-OCA, tauro-OCA, and total OCA (OCA plus 
conjugates).  PK parameters, including the following, will be calculated using non-
compartmental methods where appropriate: 
• Cmax:  maximum concentration (observed) 
• tmax:  time to Cmax  
• AUCt:  area under the concentration-time curve from time 0 to the last sampling time 
with measurable analyte concentration, calculated by the linear trapezoidal method 
An exposure-response assessment will be made comparing endpoints such as ALP and bile acids 
(eg, change in ALP relative to baseline) to the average exposure of total OCA (eg, AUC or Css 
[steady-state concentration]) to help define an appropriate dose of OCA in this patient 
population.   
Full details regarding the planned analyses, methods, and outputs for the trial will be detailed in 
the SAP. 
12.5. 
Safety Analysis 
12.5.1. 
Adverse Events 
A treatment emergent AE (TEAE) is any AE that newly appeared, increased in frequency, or 
worsened in severity following initiation of investigational product.  AEs occurring between the 
signing of informed consent but prior to first dose of investigational product are considered 
pretreatment AEs.  Treatment-emergent AEs will be summarized by treatment, system organ 
class, and preferred term defined using the Medical Dictionary of Regulatory Activities 
(MedDRA).  The number of events, the number of subjects, and the percent of subjects who 
experienced at least one TEAE will be presented for each system organ class and for each 
preferred term by treatment group.  TEAEs that lead to early withdrawals, serious TEAEs, and 
TEAEs by severity and relationship will be summarized in the same manner.  Additional details 
will be provided in the SAP. 


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12.5.2. 
Clinical Laboratory Evaluations 
Planned laboratory assessments are listed in Appendix A.  All hematology, clinical chemistry, 
urinalysis, and fecal sampling results will be listed by treatment, subject, and visit, including 
scheduled and unscheduled/repeat measurements.  Laboratory assessments that are outside of 
normal ranges will be flagged.  Baseline values, the values at each visit, and changes from 
Baseline values will be summarized for each of the quantitative laboratory assessments by 
treatment group.  Baseline is defined as the mean of all available evaluations prior to treatment 
(except for lipoprotein assessments where Baseline will be the fasted Day 0 assessment).   
12.5.3. 
Additional Safety Analysis 
Additional safety assessments include vital signs and ECGs.  Vital signs will be summarized by 
treatment group using descriptive statistics at Baseline and at each scheduled post-Baseline visit.  
The change from Baseline will also be summarized.  ECGs will be summarized by treatment 
group using frequency at each visit.  The shift from baseline will also be summarized.  Baseline 
is defined as the mean of all available evaluations prior to treatment.   
12.6. 
Interim Analyses and Data Monitoring 
12.6.1. 
Interim Analysis 
An unblinded interim analysis will be conducted after approximately 50% of subjects have 
completed the initial 12-weeks of blinded treatment.  The trial will not be terminated early for 
futility.  The interim analysis will compare at Week 12, the same variable as will be analyzed for 
the primary endpoint, the change from Baseline in ALP, between OCA treatment groups (1.5 mg 
and 5 mg) and placebo using an analysis of covariance (ANCOVA) model with fixed effects for 
treatment group and randomization strata and Baseline as a covariate.  No adjustments to the 
alpha level will be made. 
In addition, once all subjects have completed the DB phase of the study, the DB database will be 
locked, unblinded, and full analyses will be performed.  The specific details of both the interim 
and end of double-blind analyses will be documented in the SAP. 
12.6.2. 
Data and Safety Monitoring Committee 
An independent DSMC will review safety data from this trial, as well as other ongoing OCA 
trials at approximately quarterly intervals, but at least every 6 months.  The DSMC includes 
internationally recognized hepatologists, pharmaceutical physicians and statistician(s).  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 will 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 trial and will not otherwise 
consult for the Sponsor.   
SAE information will be provided to the DSMC on an ongoing basis as SAEs occur.  Adhoc 
(closed) DSMC meetings for review of unblinded data from subjects who experience SAEs, as 


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requested by the DSMC, will be arranged.  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 trial.   
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 
trial.  The DSMC will prepare written minutes of both its open and closed sessions for each trial.  
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 patient 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, MedDRA coded AEs, and AEs leading to early withdrawal of study 
drug.  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.  At a minimum, the occurrence of 2 life threatening SAEs or an SAE resulting in 
death will trigger an unscheduled and unblinded review of the data by the DSMC. 
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 trial.  The Investigators will inform the subjects of such actions and the protocol, 
PIS and consent will be revised, as appropriate. 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Trial Monitoring 
Trial 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 trial, 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 


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must be completed promptly after each visit to allow the progress and results of the trial to be 
closely followed by the Medical Monitor. 
13.2. 
Investigator Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC, and/or 
a regulatory agency to conduct one or more site audits during or after the trial and agrees to 
allow access to all trial related documentation and information and be available for discussion 
about the trial.   
14. 
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 trial at the trial 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 trial data.  Investigators’ meetings and/or onsite trial 
initiations will be performed to prepare Investigators and other trial site personnel for appropriate 
collection of trial data. 
To ensure compliance with Good Clinical Practices (GCP) and all applicable regulatory 
requirements, the Sponsor may conduct a quality assurance audit.  Please see Section 13.2 for 
more details regarding the audit process. 
15. 
ETHICS 
15.1. 
Ethics Review 
The final trial protocol, including the final version of the PIS and ICF 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 Intercept before he or 
she can enroll any subject into the trial.  The Investigator is responsible for providing the IB and 
any other available safety information and information about payments and compensation 
available to trial 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 substantial amendments will be 
obtained prior to implementation, unless the amendment is necessary to reduce immediate risk to 
trial participants.  In addition, the IRB/ IEC must approve all advertising used to recruit subjects 
for the trial.  The protocol must be reapproved by the IRB/ IEC upon receipt of amendments and 
annually, as local regulations require. 
The Investigator is also responsible for providing the IRB with reports of any SARs any other 
trial conducted with the investigational product.  The Sponsor will provide this information to 
the Investigator. 


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Progress reports and notifications of SARs will be provided to the IRB/IEC according to local 
regulations and guidelines.  Investigators or the Sponsor or its designee will provide reports to 
the IRB/IEC as requested, as a minimum annually, and after the trial is complete. 
15.2. 
Ethical Conduct of the Trial 
The trial will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013) and are 
consistent with ICH/GCP, applicable regulatory requirements. 
15.3. 
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 trial.  Subjects 
must also be notified that they are free to discontinue from the trial 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 trial procedures. 
The Investigator(s) must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the subject. 
15.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the trial 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 trial 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 subjects’ 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 trial 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 PIS will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IRB/IEC may require direct access to parts of the hospital 
or trial site records relevant to the trial, including subject’s medical history. 


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16. 
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 trial.  If the Investigator 
is not present in the trial site during the assessment, he or she will leave instructions for the trial 
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. 
16.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject or discovered by any 
other means during the trial.  In agreeing to the provisions of this protocol, the Investigator 
accepts all legal responsibilities for immediate reporting of SAEs to the Sponsor. 
16.2. 
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 trial 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. 
16.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided and maintained: 
• Approved PIS and ICF (all versions) 
• IRB/IEC approvals (of protocol/amendments, subject questionnaires, etc)  
• Form FDA 1572  
• Current medical license (US) 
• Curriculum vitae 
• Laboratory certification and reference ranges 
• Financial disclosure forms 
16.4. 
Ethics Review  
Please see Section 15.1 for the Investigator’s responsibilities regarding ethics review. 
16.5. 
Archiving and Record Retention 
The Investigator should retain all correspondence relating to this trial in the Investigator Site File 
(ISF).  Any trial documents stored elsewhere should have their location referenced in the ISF. 
All Sponsor-specific essential documents relating to the trial, including the ISF itself, source 
documents and subject medical files (retained per country specific regulations), completed trial 
subject log, and confidential subject identification list will be retained by the Investigator for 


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until 2 years after the approval of a marketing application 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 trial site is 
transferred.  The Sponsor will inform Investigators should it become aware of any changes in 
storage requirements. 
17. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical trials that it sponsors consistent 
with the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, 
October 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 trial 
(http://www.icmje.org/ethical_1author.html, accessed May 22, 2013).  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 trial data have been raised in 
the medical press.  Accordingly, the Sponsor has developed publication guidelines for clinical 
trials that are appropriate for this trial.  Key issues include the following: 
• Clinical Trial Registries (eg, clinicaltrials.gov):  A description of the trial and relevant 
design elements (eg, basic design, objectives and endpoints, sample size, trial 
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 trial databases and the analyses conducted. 
• Data Management:  The Sponsor will establish data management and the 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 
trial.  The audit should be conducted in a timely manner to allow the resolution of 
discrepancies before a clean file is established.  The Investigators will bear all the 


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costs for the conduct of audits that they initiate, except those related to the resolution 
of data queries which the Sponsor will bear.  Such audits must be conducted in such a 
manner as to minimize the time to create the clean file. 
• Authorship:  Intercept, in collaboration with the Investigators, will establish the 
appropriate authorship and responsibility for drafting trial 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 trial and 
is designed to be published with complete data from all the trial sites.  Single center 
publications are therefore not considered appropriate.  Any such publications should 
clearly state that the data are ‘extracted’ from a multicenter trial and that the trial was 
not intended, or statistically powered, for data presentation by a single trial site.   
• Intercept Review of External Manuscripts:  Consistent with this, Investigators must 
submit any drafts of any publications or presentations that may arise from this trial 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 nonclinical studies or chemical formulae) 
may still need to remain confidential. 
• Medical Journal Review:  Upon request, all pertinent trial 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. 
18. 
LIST OF REFERENCES 
Al Mamari S, Djordjevic J, Halliday JS, et al. Improvement of serum alkaline phosphatase to 
<1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in 
primary sclerosing cholangitis. J Hepatol. 2013 Feb;58(2):329-34. 
Albanis E, Alvarez CE, Pruzanski M, et al. INT-747, a novel FXR activator, reverses hepatic 
fibrosis and cirrhosis in thiocetamideinduced liver injury in rats. Hepatology. 
2005;42(Supplement 1):Abstract 1040. 
Bergquist A, Ekbom A, Olsson R, et al. Hepatic and extrahepatic malignancies in primary 
sclerosing cholangitis. J Hepatol. 2002 Mar;36(3):321-7. 


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Best WR, Becktel JM, Singleton JW, et al.  Development of a Crohn's disease activity index. 
National Cooperative Crohn's Disease Study. Gastroenterology. 1976 Mar; 70 (3): 439-444. 
Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. 
Nat Clin Pract Gastroenterol Hepatol. 2006 Jun;3(6):318-28. 
CEREP. In Vitro pharmacology:High-throughput profile - Study of INT-747. 2008 June 7, 
2008;Study #14862. 
Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing 
cholangitis. Hepatology. 2010 Feb;51(2):660-78. 
Chapman R. Primary sclerosing cholangitis. Autoimmune Liver Disease. 2011; 39(10):558-591. 
Cipriani S, Mencarelli A, Chini MG, et al. The bile acid receptor GPBAR-1 (TGR5) modulates 
integrity of intestinal barrier and immune response to experimental colitis. PLoS One. 
2011;6(10):e25637. 
EASL. EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. Journal of 
Hepatology. 2009;51:237-67. 
Eaton JE, Talwalkar JA, Lazaridis KN, et al. Pathogenesis of primary sclerosing cholangitis and 
advances in diagnosis and management. Gastroenterology. 2013 Sep;145(3):521-36. 
Elman S, Hynan L, Gabriel V, et al. The 5-D itch scale: a new measure of pruritus. British 
Journal of Dermatology. 2010 Dec; 162: 587-593 
Fevery J, Verslype C, Lai G, et al. Incidence, diagnosis, and therapy of cholangiocarcinoma in 
patients with primary sclerosing cholangitis. Dig Dis Sci. 2007 Nov;52(11):3123-35. 
Gadaleta RM, van Erpecum KJ, Oldenburg B, et al. Farnesoid X receptor activation inhibits 
inflammation and preserves the intestinal barrier in inflammatory bowel disease. 
Gut. 2011 Apr;60(4):463-72. 
Hirschfield GM, Karlsen TH, Lindor KD, et al. Primary sclerosing cholangitis. Lancet. 
2013 Nov 9;382(9904):1587-99. 
Lazaridis KN, Gores GJ. Primary sclerosing cholangitis and cholangiocarcinoma. Semin Liver 
Dis. 2006 Feb;26(1):42-51. 
Lee YM, Kim DJ. Primary Sclerosing Cholangitis. New England Journal of Medicine. 
1995;332:924-33. 
Lee YM, Kaplan M, and the Practice Guideline Committee of the ACG.  Management of 
Primary Sclerosing Cholangitis. AJG 2002 Mar; 97(3):528-534. 
Lefebvre P, Cariou B, Lien F, et al. Role of bile acids and bile acid receptors in metabolic 
regulation. Physiol Rev. 2009 Jan;89(1):147-91. 
Levy C, Lindor KD. Primary sclerosing cholangitis: epidemiology, natural history, and 
prognosis. Semin Liver Dis. 2006 Feb;26(1):22-30. 
Li YT, Swales KE, Thomas GJ, et al. Farnesoid x receptor ligands inhibit vascular smooth 
muscle cell inflammation and migration. Arterioscler Thromb Vasc Biol. 
2007 Dec;27(12):2606-11. 


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Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing 
Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med. 1997 Mar 6;336(10):691-5. 
Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment 
of primary sclerosing cholangitis. Hepatology. 2009 Sep;50(3):808-14. 
Lindstrom L, Hultcrantz R, Boberg KM, et al. Association between reduced levels of alkaline 
phosphatase and survival times of patients with primary sclerosing cholangitis. Clin 
Gastroenterol Hepatol. 2013 Jul;11(7):841-6. 
Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. 
Science. 1999 May 21;284(5418):1362-5. 
Mookerjee RP, Mehta G, Balasubramaniyan V, et al, Hepatic dimethylarginine-
dimethylaminohydrolase1 is reduced in cirrhosis and is a target for therapy in portal 
hypertension. J Hepatol. 2015 Feb; 62(2):325-331. 
Olsson R, Boberg KM, de Muckadell OS, et al. High-dose ursodeoxycholic acid in primary 
sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology. 
2005 Nov;129(5):1464-72. 
Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), 
a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 
2002 Aug 15;45(17):3569-72. 
Pols TW, Noriega LG, Nomura M,:  The bile acid membrane receptor TGR5 as an emerging 
target in metabolism and inflammation. J Hepatol. 2011;54:1263-1272. 
Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy 
for ulcerative colitis. N Engl J Med. 2005 Dec 8;353(23):2462-76. 
Talwalkar JA, Chapman RW. The resurgence of serum alkaline phosphatase as a surrogate 
biomarker for prognosis in primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 
2013 Jul;11(7):847-9. 
Wang H, Chen J, Hollister K, et al. Endogenous bile acids are ligands for the nuclear receptor 
FXR/BAR. Mol Cell. 1999 May;3(5):543-53. 
Wang YD, Chen WD, Wang M, et al. Farnesoid X receptor antagonizes nuclear factor kappaB in 
hepatic inflammatory response. Hepatology. 2008 Nov;48(5):1632-43. 
Worthington J, Chapman R. Primary sclerosing cholangitis. Orphanet J Rare Dis. 2006;1:41. 


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APPENDIX A. LIST OF PLANNED LABORATORY ANALYTES  
Serum Chemistry  
alanine transaminase (ALT; SGPT)  
albumin  
alkaline phosphatase (ALP)  
aspartate aminotransferase (AST; SGOT) 
bicarbonate  
bilirubin: total, unconjugated (indirect) & conjugated (direct) 
blood urea nitrogen (BUN) 
calcium 
chloride  
creatinine 
free fatty acids  
gamma-glutamyl transpeptidase (GGT)  
glucose 
HDL 
LDL 
magnesium 
phosphorus 
potassium 
sodium 
thyroid hormones (T3, T4, TSH)  
total cholesterol  
total protein  
triglycerides  
vitamin D 
VLDL  
Apolipoprotein and NMR Lipoprotein Analysis 
ApoA1 
ApoB 
ApoE 
HDL 


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LDL 
triglycerides 
VLDL 
HDL, LDL, and VLDL cholesterol concentrations, particle numbers and sizes will be 
assessed. 
Hematology  
hematocrit  
hemoglobin  
platelets  
RBC count (incl. MCV, HBE [MCH], MCHC)  
WBC with differential  
neutrophils* 
lymphocytes* 
monocytes* 
eosinophils* 
basophils* 
Coagulation Parameters 
prothrombin time (PT and INR) 
partial thromboblastin time (PTT) 
Biomarkers of Inflammation  
autotaxin & its metabolites 
CRP 
IgA 
IgG 
IgG4 
IgM 
IL-6 
IL-12 
IL-23 
TGF-β 
TNF-α 


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Biomarkers of Fibrosis 
Enhanced Liver Fibrosis (ELF) markers: Hyaluronic acid, P3NP, TIMP-1 
CK-18 
FXR Activity 
FGF-19 
Bile Acids (conjugated & unconjugated forms) 
C4 
CDCA 
Cholic acid 
Deoxycholic acid 
Lithocholic acid 
OCA 
Total bile acids 
UDCA 
Genetics Test 
 
RNA 
Urine Dipstick 
bilirubin 
blood 
glucose 
ketones 
pH 
protein 
specific gravity 
Urine Pregnancy 
Urine β-hCG pregnancy test in females of childbearing potential.  If the urinary test is 
positive it should be repeated as a serum pregnancy test. 
Fecal Samples 
calprotectin 
gut microbiome (fecal bacterial genome) 
* Further evaluation if appropriate 
Note:  The above list is not all inclusive and some tests may not be performed if not required. 
 


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APPENDIX B. PARTIAL MAYO SCORING SYSTEM FOR 
ASSESSMENT OF ULCERATIVE COLITIS ACTIVITY 
Partial Mayo Scoring System for Assessment of Ulcerative Colitis Activity 
(The Partial Mayo Score ranges from 0-9, with higher scores indicating more severe disease) 
Stool Frequency (Each patient serves as his or her own control to establish the degree of abnormality of 
the stool frequency) 
0 = Normal no. of stools for this patient 
1 = 1 to 2 stools more than normal 
2 = 3 to 4 stools more than normal 
3 = 5 or more stools more than normal 
Subscore, 0 to 3 
Rectal Bleeding (The daily bleeding score represents the most severe bleeding of the day) 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
Subscore, 0 to 3 
Physician’s Global Assessment (This assessment acknowledges the two other criteria, the patient’s daily 
recollection of abdominal discomfort and general sense of wellbeing, and other observations, such as 
physical findings and the patient’s performance status) 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
Subscore, 0 to 3 


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APPENDIX C. PRURITUS VISUAL ANALOGUE SCALE  
Visual Analog Scale 
Severity: Draw a line anywhere on the scale that best represents the severity of your itching   
 
 
 
 
 
 
 
                   No itching 
 
 
                                        Worst possible itching               
 
 
 
             
 
(See example below) 
                                            
 
 
 
 
 
  
 
 
0                 2                 4                 6                8               10 
 
 
 
 
                                                        Example: 
 
 
 
 
 
 
           
 
Note:  Size of actual VAS is 10cm. 
 


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APPENDIX D. 5-D ITCH SCALE 
 
 
 


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APPENDIX E.  SUBJECT RESEARCH QUESTIONNAIRE  
Subject Research Questionnaire  
 
We are very grateful to you for participating in this clinical study and hope that you found it worthwhile.  
 
We ask that you spend a few minutes to complete the following questionnaire. We are interested in your views about 
this study and any comments that you may have.  
 
Your identity will remain entirely confidential. Thank you!  
 
Did you feel that participating in this clinical study was 
worthwhile?  
(1 – Disagree strongly - 5 – Agree strongly)  
1   
2   
3   
4   
5  
Comment:  
Would you recommend participation in a clinical study 
to a relative or a close friend, with the same condition? 
(1 – Disagree strongly - 5 – Agree strongly)  
1   
2   
3   
4   
5  
Comment: 
What were some of the features of the study that you 
liked (tick all that apply)?  
 Better medical care / attention  
 Helping others with my disease  
 Better understanding of my disease  
 Friendly environment with other patients  
 Study offered good change from usual routine  
 Other, please specify:  
 
Comment: 
What were some of the features of the study that you 
disliked (tick all that apply)?  
 Study was overly invasive  
 Expectations of study were not met  
 Study was overly disruptive to usual routine  
 Medical care was less than I expected  
 Interaction with medical staff was less than I expected 
 Other, please specify:  
 
Comment: 
Thank you very much for your participation. 


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APPENDIX F. CROHN’S DISEASE ACTIVITY INDEX 
 
(CDAI: adapted from Best 1976)  
 
Clinical or laboratory variable 
Weighting 
factor 
Number of liquid or soft stools each day for seven days 
x 2 
Abdominal pain (graded from 0-3 on severity) each day for seven days 
x 5 
General wellbeing, subjectively assessed from 0 (well) to 4 (terrible) each day 
for seven days 
x 7 
Presence of complications* 
x 20 
Taking Lomotil or opiates for diarrhea 
x 30 
Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite) 
x 10 
Hematocrit of <0.47 in men and <0.42 in women 
x 6 
Percentage deviation from standard weight 
x 1 
 
*One point each is added for each set of complications: 
 
• the presence of joint pains (arthralgia) or frank arthritis 
• inflammation of the iris or uveitis 
• presence of erythema nodosum, pyoderma gangrenosum, or aphthous ulcers 
• anal fissures, fistulae or abscesses 
• other fistulae 
• fever during the previous week 
 
 
 
 


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APPENDIX G. PROTOCOL VERSION 2 – SUMMARY OF CHANGES  
 
1. Background 
Protocol 747-207 has been prepared as a Phase 2 trial to evaluate the potential clinical 
benefit of OCA in PSC. 
 
The original protocol dated 06 June 2014 was submitted to the US FDA on 29 July 2014.  
Comments were received by Intercept Pharmaceuticals on 21 August 2012.  The original 
protocol was not submitted to IRBs/IECs. 
 
2. Rationale 
The changes detailed below address comments raised by the FDA and include other 
editorial changes or clarifications by the Sponsor.   
 
3. Summary of Changes 
The following revisions were made to the protocol in Protocol Version 2.   
 
(Note:  Differences have been indicated in bold font.)  
 
 


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Revised Text 
Synopsis, 
Inclusion 
Criterion #5 
Note 2: Subjects with documented Gilbert’s syndrome 
may be allowed to participate in the study after 
discussion with the medical monitor. 
Note 2 has been deleted from this section and moved to 
Synopsis, Exclusion Criterion #10 (see below). 
Synopsis, 
Inclusion 
Criterion #6 
For subjects with concomitant IBD:  colonoscopy within 
12 months of Day 0 confirming no dysplasia or colorectal 
cancer 
For subjects with concomitant IBD:   
a. Colonoscopy within 12 months of Day 0 confirming 
no dysplasia or colorectal cancer 
b. Subjects with Crohn’s Disease (CD) must be in 
remission as defined by a Crohn’s Disease Activity 
Index (CDAI) <150. 
c. Subjects with ulcerative colitis (UC) must either be 
in remission or have mild disease.  Remission is 
defined as a partial Mayo score of ≤2 with no 
individual sub-score exceeding 1.  Mild disease is 
defined as a partial Mayo score ≤3 with no 
individual sub-score exceeding 1 point. 
Synopsis, 
Inclusion 
Criterion #7 
Note 3: 
Note 2: 
Synopsis, 
Inclusion 
Criterion #9 
Contraception:  female subjects of childbearing potential 
must use ≥1 effective (≤1% failure rate) method of 
contraception during the trial and until 4 weeks following 
the last dose of IP (including LTSE doses).  
Contraception:  female subjects of childbearing potential 
must use ≥1 effective method of contraception during the 
trial and until 4 weeks following the last dose of IP 
(including LTSE doses).  
Synopsis, 
Exclusion 
Criterion #3 
Exclusion criterion has been added/inserted; all other 
criteria numbering has subsequently shifted. 
Small duct cholangitis in the absence of large duct 
disease 
Synopsis, 
Exclusion 
Criterion #4 
Presence of clinical complications of chronic liver disease 
or clinically significant hepatic decompensation, 
including:  
Presence of clinical complications of chronic liver disease 
or clinically significant hepatic decompensation, 
including:  


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(Change to 7th bullet, only.) 
• Current splenomegaly as evidenced by ultrasound 
or platelets <50 x109/L 
(Change to 7th bullet, only.) 
• Platelet count <50 x 109/L 
Synopsis, 
Exclusion 
Criterion #8 
History of any bowel resection unless permitted with 
prior discussion and written approval from Sponsor 
medical monitor 
History of small bowel resection  
Synopsis, 
Exclusion 
Criterion #9 
History of other chronic liver diseases, … non-alcoholic 
fatty liver disease (NAFLD), hepatitis B virus (unless 
seroconverted and no positive Hepatitis B Virus DNA) and 
hepatitis C virus 
History of other chronic liver diseases … non-alcoholic 
fatty liver disease (NAFLD), autoimmune hepatitis , 
hepatitis B virus (unless seroconverted and no positive 
Hepatitis B Virus DNA) and hepatitis C virus 
Synopsis, 
Exclusion 
Criterion #10 
Moved from Synopsis, Inclusion Criterion # 5, which 
previously read:   
Note 2:  Subjects with documented Gilbert’s syndrome 
may be allowed to participate in the study after 
discussion with the medical monitor. 
Known Gilbert’s syndrome or elevations in 
unconjugated (indirect) bilirubin >ULN 
Synopsis, 
Exclusion 
Criterion #14 
Exclusion criterion inserted. 
Administration of antibiotics is prohibited ≤1 month 
of Day 0. 
Synopsis, 
Exclusion 
Criterion #15 
Administration of the following medications is prohibited 
≤6 months of Day 0 and throughout the DB phase of the 
trial: ... or nitrofurantoin). 
Administration of the following medications is prohibited 
≤6 months of Day 0 and throughout the trial: … or 
nitrofurantoin). 
Synopsis, 
Exclusion 
Criterion #16 
IBD flare during Screening (up to and including Day 0). 
IBD flare during Screening (up to and including Day 0), 
where “flare” is defined as follows: 
• UC flare:  partial Mayo Score ≥5, and  
• CD flare:  CDAI ≥250 


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Synopsis, 
Criteria for 
Evaluation: 
Disease 
Specific 
Symptoms 
Two additional items added 
Pruritus 5-D questionnaire 
 
Crohn’s disease activity index (CDAI) 
Synopsis, 
Statistical 
Methods: 
Efficacy 
Analyses 
The co-primary efficacy endpoints are the absolute 
changes from Baseline in ALP at Week 12 and 
Week 24.  The primary efficacy analysis at Week 12 will 
compare the absolute change from Baseline in ALP 
between OCA treatment groups (1.5 mg and 5 mg) and 
placebo using an analysis of covariance (ANCOVA) 
model with fixed effects for treatment group and 
randomization strata and Baseline as a covariate.  The 
primary efficacy analysis at Week 24 will compare the 
absolute change from Baseline in ALP between OCA 
treatment groups (3 mg and 10 mg) and placebo using the 
same ANCOVA model as the Week 12 analysis.   
 
The co-primary endpoints will be tested using a 
hierarchical approach to control the overall 
significance level for multiple visit and dose 
comparisons.  
  
Secondary efficacy analyses of hepatic biochemistry 
and function parameters will use the same ANCOVA 
models as the primary endpoints. 
  
In addition, secondary efficacy analysis of ALP response 
rates, defined as ALP to <1.5x ULN, will compare OCA 
The primary efficacy endpoint is the Week 24 change 
from Baseline in ALP.  The primary efficacy analysis 
will compare the Week 24 change from Baseline in 
ALP between the OCA 10 mg treatment group and 
placebo using an analysis of covariance (ANCOVA) 
model with fixed effects for treatment group and 
randomization strata and Baseline as a covariate. 
Secondary efficacy analyses of hepatic biochemistry 
and function parameters will use the same ANCOVA 
models as the primary endpoints.  A hierarchical 
approach will be used for multiplicity adjustments.  If 
the primary efficacy analysis is statistically significant 
(p <0.05), the following order will be used in the testing 
procedure to compare the change from Baseline in 
ALP between OCA and placebo: 
• 
Week 12:  OCA 5 mg treatment group 
(randomized to 5 mg for the initial 12 weeks 
followed by 10 mg for the latter 12 weeks) vs. 
placebo 
• 
Week 24:  OCA 3 mg treatment group 
(randomized to 1.5 mg for the initial 12 weeks 
followed by 3 mg for the latter 12 weeks) vs. 
placebo  


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treatment groups and placebo at Week 12 and Week 24 
using a Cochran Mantel-Haenszel test stratified by the 
randomization stratification factor.  Missing values are 
considered a non-response. 
• 
Week 12:  OCA 1.5 mg treatment group 
(randomized to 1.5 mg for the initial 12 weeks 
followed by 3 mg for the latter 12 weeks) vs. 
placebo 
If at any step the comparison is not statistically 
significant, then all subsequent comparisons will be 
exploratory rather than confirmatory.   
In addition, secondary efficacy analyses of ALP response 
rates, defined as ALP to <1.5x ULN, will compare OCA 
treatment groups vs. placebo at Week 12 and Week 24 
using a Cochran Mantel-Haenszel test stratified by the 
randomization stratification factor.  Missing values will 
be considered a non-response.  
An unblinded interim analysis for planning purposes 
will be conducted after approximately 50% of patients 
have completed the initial 12-weeks of blinded 
treatment.  The trial will not be terminated early for 
futility.  The interim analysis will compare at Week 12, 
the same variable as will be analyzed for the primary 
endpoint, the change from Baseline in ALP, between 
OCA treatment groups (1.5 mg and 5 mg) and placebo 
using an analysis of covariance (ANCOVA) model with 
fixed effects for treatment group and randomization 
strata and Baseline as a covariate.  No adjustments to 
the alpha level will be made. 


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Synopsis, 
Statistical 
Methods: 
Safety 
Analyses, 2nd 
paragraph 
… The absolute change from Baseline will also be 
summarized.   
... The change from Baseline will also be summarized. 
Synopsis, 
Statistical 
Methods: PK 
and PD 
Analyses 
The pharmacokinetics (PK) of OCA and other bile acids 
will be evaluated, including AUCt, Cmax, tmax, etc.   
The pharmacokinetics (PK) of OCA and other bile acids 
will be evaluated, including AUCt, Cmax, and tmax, 
Synopsis, 
Statistical 
Methods: 
Sample Size 
Justification 
A sample size of 25 subjects per treatment group, a total of 
75 subjects, will provide at least 95% power to detect a 
treatment difference for change in ALP assuming the mean 
percentage change in ALP for OCA and… 
A sample size of 25 subjects per treatment group, a total 
of 75 subjects, will provide at least 90% power to detect a 
treatment difference for change in ALP assuming the 
mean absolute change in ALP for OCA and…. 
List of 
Abbreviations 
New text inserted 
 
 
 
Text correction:  IgG4:  immunoglobulin G4 
CD:  Crohn’s disease 
CDAI:  Crohn’s disease activity index 
UC:  ulcerative colitis 
 
IgG4:  Immunoglobulin G4 
5.5, 2nd 
paragraph 
An increase in liver function tests … that are several fold 
higher (20 to 50 mg daily) than those studied in this 
protocol (1.5 mg, 3 mg, 5 mg, and 10 mg) doses.   
An increase in liver function tests …. that are several fold 
higher (primarily 20 to 50 mg daily) than those studied 
in this protocol (1.5 mg, 3 mg, 5 mg, and 10 mg) doses.   
7.1, LTSE, 
2nd 
paragraph 
Upon a subject’s completion of the Week 24 visit, at the 
end of the DB phase, the trial blind will be broken in 
order to assign the starting OCA dose for the LTSE phase.   
Upon a subject’s completion of the DB phase, the trial 
blind will be broken in order to assign the starting OCA 
dose for the LTSE phase.   


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Table 1, 
footnote b 
Week 2 and 14 visits are contacts to assess AEs and 
treatment compliance; these are not clinic visits. 
Week 12 is the Dose Titration Visit. 
Table 1, 
footnote j 
TE: at trial sites where the Fibroscan® TE device is 
available. 
Partial Mayo score completed only for subjects with 
UC. 
Table 1, 
footnote l 
Questionnaire completed with input from the subject. 
CDAI completed only for subjects with CD. 
Table 1, 
footnote q 
IP accountability/compliance will include review of tablets 
and bottles dispensed and returned at each clinic visit.  For 
subject contacts (ie, non-clinic visits), compliance with 
dosing and evaluation of missed doses should be 
discussed with the subject. 
IP accountability/compliance will include review of 
tablets and bottles dispensed and returned at each clinic 
visit.   
Table 1, 
footnote t 
For female subjects of child bearing potential, a urine β-
hCG test is used.  If the urine test is positive, it is to be 
repeated as a serum pregnancy test.  See Section 8.1 for 
procedures to be followed for a subject whose pregnancy 
is early terminated and wishes to continue in the trial.   
Other analytes includes an additional blood sample for 
exploratory analysis. 
Table 1, 
footnote u 
Fecal sample:  for measurement of calprotectin and gut 
fecal microbiome; provision of a fecal sample by subjects 
is not mandatory.  The subject should be instructed to 
collect a fecal sample within 2 days of the scheduled visit, 
as described in the laboratory manual. 
PK samples will be collected from those subjects who 
have consented for PK sampling procedures. 
Table 1, 
footnote k 
New footnote 
Subjects with UC and CD will be asked to complete a 
diary recording details of their symptoms in the 7 days 
prior to their next scheduled visit. 
Table 2 
New procedures added 
Partial Mayo Score (M3, M9, M15, M21 & Follow-Up 
Visit) 
CDAI (all visits) 


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Table 2 
Pruritus VAS 
Pruritus VAS and 5-D 
Table 2, 
Laboratory 
Evaluations 
Serum Bile Acids & C4 
Plasma Bile Acids & C4 
Table 2, 
footnote i 
Questionnaire completed with input from the subject. 
Partial Mayo score completed only for subjects with 
UC. 
Table 2, 
footnote k 
IP accountability / compliance will include review of 
tablets and bottles dispensed and returned at each clinic 
visit. 
CDAI completed only for subjects with CD. 
Table 2, 
footnote o 
Fecal sample:  for measurement of calprotectin and gut 
fecal microbiome; provision of a fecal sample by subjects 
is not mandatory.  The subject should be instructed to 
collect a fecal sample within 2 days of the scheduled visit, 
as described in the laboratory manual. 
Other analytes includes an additional blood sample 
for exploratory analysis. 
Table 2, 
footnote j 
New footnote 
Subjects with UC and CD will be asked to complete a 
diary recording details of their symptoms in the 
7 days prior to their next scheduled visit. 
7.4.2, 3rd 
paragraph 
During the LTSE phase subjects may titrate to higher 
doses of OCA, at a frequency not greater than monthly, up 
to a maximum dose of 10 mg daily. 
During the LTSE phase subjects may titrate to higher 
doses of OCA, at a frequency not greater than 3 monthly 
(ie, at each of the scheduled visits), up to a maximum 
dose of 10 mg daily. 


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7.4.3 
Adjustments to or stopping of the protocol-defined doses 
may be considered based on DSMC evaluation of OCA 
safety and tolerability. 
Adjustments to or stopping of the protocol-defined doses 
may be considered based on DSMC evaluation of OCA 
safety and tolerability.  At a minimum, the occurrence 
of two life threatening serious adverse events (SAEs) 
or an SAE resulting in death will trigger an 
unscheduled and unblinded review of the data by the 
DSMC to determine if the trial should continue. 
8.2, Inclusion 
Criterion #3 
Cholangiography, or other appropriate imaging modality, 
within 12 months of Day 0 consistent with a diagnosis of 
primary sclerosing cholangitis 
Must have a diagnosis of PSC (based on 
cholangiography at any point in time) and must have 
had a cholangiography within the past 12 months. 
8.2, Inclusion 
Criterion #5  
Note 2: Subjects with documented Gilbert’s syndrome 
may be allowed to participate in the study after discussion 
with the medical monitor. 
Note 2 has been deleted from this section and moved to 
Synopsis, Exclusion Criterion #10 (see below). 
8.2, Inclusion 
Criterion #6 
For subjects with concomitant IBD:  colonoscopy within 
12 months of Day 0 confirming no dysplasia or colorectal 
cancer 
 
For subjects with concomitant IBD:   
a. Colonoscopy within 12 months of Day 0 
confirming no dysplasia or colorectal cancer 
b. Subjects with Crohn’s Disease (CD) must be 
in remission as defined by a Crohn’s Disease 
Activity Index (CDAI) <150. 
c. Subjects with ulcerative colitis (UC) must 
either be in remission or have mild disease.  
Remission is defined as a partial Mayo score 
of ≤2 with no individual sub-score exceeding 
1.  Mild disease is defined as a partial Mayo 
score ≤3 with no individual sub-score 
exceeding 1 point. 
8.2, Inclusion 
Criterion #7 
Note 3: 
Note 2: 


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8.2, Inclusion 
Criterion #9 
Contraception:  female subjects of childbearing potential 
must use ≥1 effective (≤1% failure rate) method of 
contraception during the trial and until 4 weeks following 
the last dose of IP (including LTSE doses).  
Contraception:  female subjects of childbearing potential 
must use ≥1 effective method of contraception during the 
trial and until 4 weeks following the last dose of IP 
(including LTSE doses).  
8.2, 
Exclusion 
Criterion #3 
Exclusion criterion has been added/inserted; all other 
criteria numbering has subsequently shifted. 
Small duct cholangitis in the absence of large duct 
disease 
8.2, 
Exclusion 
Criterion #4 
Presence of clinical complications of chronic liver disease 
or clinically significant hepatic decompensation, 
including:  
(Change to 7th bullet, only.) 
• Current splenomegaly as evidenced by ultrasound 
or platelets <50 x109/L 
Presence of clinical complications of chronic liver disease 
or clinically significant hepatic decompensation, 
including:  
(Change to 7th bullet, only.) 
• Platelet count <50 x 109/L 
8.2, 
Exclusion 
Criterion #8 
History of any bowel resection unless permitted with 
prior discussion and written approval from Sponsor 
medical monitor 
History of small bowel resection  
8.2, 
Exclusion 
Criterion #9 
History of other chronic liver diseases, … non-alcoholic 
fatty liver disease (NAFLD), hepatitis B virus (unless 
seroconverted and no positive Hepatitis B Virus DNA) and 
hepatitis C virus 
History of other chronic liver diseases, … non-alcoholic 
fatty liver disease (NAFLD), autoimmune hepatitis , 
hepatitis B virus (unless seroconverted and no positive 
Hepatitis B Virus DNA) and hepatitis C virus 
8.2, 
Exclusion 
Criterion #10 
Moved from Synopsis, Inclusion Criterion # 5, which 
previously read:   
Note 2: Subjects with documented Gilbert’s syndrome 
may be allowed to participate in the study after 
discussion with the medical monitor. 
Known Gilbert’s syndrome or elevations in 
unconjugated (indirect) bilirubin >ULN 
8.2, 
Exclusion 
Criterion #14 
Exclusion criterion inserted. 
Administration of antibiotics is prohibited ≤1 month 
of Day 0. 


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8.2, 
Exclusion 
Criterion #15 
Administration of the following medications is prohibited 
≤6 months of Day 0 and throughout the DB phase of the 
trial: ... or nitrofurantoin). 
Administration of the following medications is prohibited 
≤6 months of Day 0 and throughout the trial: … or 
nitrofurantoin). 
8.2, 
Exclusion 
Criterion #16 
IBD flare during Screening (up to and including Day 0). 
IBD flare during Screening (up to and including Day 0), 
where ‘flare’ is defined as follows: 
• UC flare:  partial Mayo Score ≥5, and  
• CD flare:  CDAI ≥250 
8.4.1, Clinical 
Laboratory 
Values, 2nd 
bullet 
Two consecutive measurements of conjugated (direct) 
bilirubin >2x ULN AND >2x the Baseline value in the 
absence of evidence of new biliary obstruction. 
Two consecutive measurements of total bilirubin >ULN 
AND >2x the Baseline value in the absence of evidence 
of new biliary obstruction.  
8.4.1, IBD 
Flares (new 
section) 
New text inserted into protocol. 
Subjects who experience 3 or more IBD flare-ups in 
one year during the study will be discontinued, where 
‘flare’ is defined as follows: 
• for UC flare: as a partial Mayo Score ≥5, 
and  
• for CD flare:  as a CDAI ≥250 
Section 8.4.2 below describes treatment guidelines for 
managing IBD flares during the study. 
8.4.2, 1st 
paragraph  
The following events are considered appropriate reasons 
for a subject to discontinue from the trial: 
The following events are considered appropriate 
(potential) reasons for a subject to discontinue from the 
trial: 
8.4.2, 
Bactierial 
Cholangitis 
… in conjunction with clinical signs and symptoms and 
positive diagnostic imaging tests.  Subjects should 
temporarily interrupt treatment with IP and receive 
standard of care treatment.  Use of 
amoxicillin/clavulanate is discouraged, but these may 
be used if there are no other treatment options; this 
... in conjunction with clinical signs and symptoms and 
positive diagnostic imaging tests.  Local guidelines 
should be followed for the management of patients 
with acute bacterial cholangitis.  In the absence of 
such local guidelines, the following guidelines should 


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should be discussed with the medical monitor in 
advance of a decision to treat with these medications.  
Discontinuation from the trial is not mandatory in 
cases of bacterial cholangitis unless signs and 
symptoms do not resolve within a clinically reasonable 
timeframe (within 1 month or as agreed upon with the 
medical monitor) or the cholangitis becomes life 
threatening in the opinion of the investigator or 
medical monitor.  In any event, IP should not be 
restarted until signs and symptoms have resolved and 
the subject’s liver biochemistry has returned to pre-
cholangitis levels. 
A subject with frequent (frequency as judged by the 
investigator and with input from the medical monitor) 
bacterial cholangitis events should be discontinued from 
the trial. 
be followed if acute cholangitis is suspected:  
• Diagnosis of acute cholangitis should be 
established based on a combination of 
typical clinical features, laboratory data, 
and imaging findings.  Subsequent to an 
intervention to relieve biliary obstruction 
acute cholangitis may occur with typical 
signs and symptoms including intermittent 
fever with chills, right upper quadrant pain, 
and jaundice (also known as the Charcot 
triad).  Further confirmation of the 
diagnosis should then be made via 
laboratory data (eg, elevated C-reactive 
protein levels and/or leukocytosis) and 
abdominal imaging tests (magnetic 
resonance cholangiopancreatography; 
MRCP).   
• Treatment of acute cholangitis should be 
directed towards treatment of the biliary 
infection and relieving obstruction.  
Therefore, treatment is comprised of 
systemic antibiotic therapy and biliary 
drainage procedures, with appropriate 
supportive care. 
• Antibiotic agents should be administered 
empirically as early as possible.  Blood and 
bile cultures should also be performed at the 
earliest opportunity and prior to initiating 
antibiotic treatment, if possible. 
• The selection of an antibiotic agent should 
be based on likely infecting bacteria, the 


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severity of the disease, and the presence of 
comorbidities.  Empiric antibiotic agents 
may be replaced by directed therapies once 
the blood and bile culture results become 
available.  The use of 
amoxicillin/clavulanate and other antibiotic 
treatments with potential for hepatotoxicity 
should be avoided. 
Subjects should temporarily interrupt treatment 
with IP and receive standard of care treatment.  
Discontinuation from the trial is not mandatory in 
cases of bacterial cholangitis unless signs and 
symptoms do not resolve within a clinically 
reasonable timeframe (typically within 1 month or 
as agreed upon with the medical monitor) or the 
cholangitis becomes life threatening in the opinion 
of the investigator or medical monitor.  In any 
event, IP should not be restarted until signs and 
symptoms have resolved and the subject’s liver 
biochemistry has returned to pre-cholangitis levels.   
A subject with 3 bacterial cholangitis events in one 
year during the study should be discontinued from 
the trial. 
8.4.2, IBD 
Flare 
If a subject experiences an IBD flare during the trial (post-
Day 0), he/she may remain on IP but this should be 
discussed with the medical monitor. 
If a subject experiences an IBD flare during the trial 
(post-Day 0), he/she may remain on IP but this should be 
discussed with the medical monitor and IBD flares 
should be treated as follows (but adjusted based upon 
local guidelines and standards of care, disease severity 
and personal patient preferences, as appropriate): 
aminosalicylates alone (high dose if appropriate) or 
with a topical aminosalicylate and/or topical, oral, or 


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intravenous corticosteroids or immunosuppressant 
therapy, including anti-TNF therapy.  Surgery may be 
required in severe cases that are refractory to 
medicinal treatment.  
Subjects who experience 3 or more IBD flare-ups in 
1 year during the study will be discontinued. 
9.2.3, 1st 
bullet 
New bullet point inserted under 1st bullet point 
Administration of antibiotics within 1 month of Day 0, 
except if administered for acute cholangitis whereby its 
use is prohibited within 3 months of Day 0.  
NOTE:  Antibiotics are permitted as required during 
participation in the trial except amoxicillin/clavulanate 
(Augmentin) which has restrictions as detailed below. 
9.2.3, 3rd 
bullet 
• 
Prohibited from 6 months prior to Day 0 and 
throughout the DB phase of the trial (these are 
not prohibited during the LTSE): … 
 
 -Amoxicillin/clavulanate should not be used unless there 
are no other treatment options (this should be discussed 
with the medical monitor in advance of their use in this 
situation, where possible) 
• 
Prohibited from 6 months prior to Day 0 and 
throughout the LTSE phase of the trial unless 
as noted to discuss with Medical Monitor: 
… 
  
-Amoxicillin/clavulanate (Augmentin) should not be 
used unless there are no other treatment options (this 
should be discussed with the medical monitor in advance 
of their use in this situation, where possible).  Augmentin 
is also discouraged in the treatment of cholangitis but 
is not outright excluded (Section 8.4.2). 
9.4, 1st 
paragraph 
At Day 0, after review … treatment groups in a 1:1:1 ratio 
across sites based on … LTSE phase. 
At Day 0, after review … treatment groups in a 1:1:1 
ratio based on … LTSE phase. 


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9.6.1, 1st 
paragraph 
All trial visits during the DB period are relative to Day 0 
(eg, if the Week 4 visit occurs 4 days late, the Week 8 
visit should still be 8 weeks from Day 0).  The Screening 
visit should occur ≤30 days prior to the Day 0 visit.  All 
visits and contacts during the DB treatment period should 
occur within ± 1 week of the indicated time.  The 
exception to this is the contact at Week 2, which should 
occur within ± 3 days of the indicated time. 
All trial visits during the DB period are relative to Day 0 
(eg, if the Week 6 visit occurs 4 days late, the Week 12 
visit should still be 12 weeks from Day 0).  The 
Screening visit should occur ≤30 days prior to the Day 0 
visit.  All visits during the DB treatment period should 
occur within ±1 week of the indicated time.  The 
exception to this is the Week 2 visit, which should occur 
within ±3 days of the indicated time. 
9.6.3, 9th 
bullet 
New bullet 9. 
For subjects with UC):  provide the diary and request 
subject completes this for each of the 7 consecutive 
days prior to the next scheduled visit. 
9.6.3, 10th 
bullet 
New bullet 10. 
For subjects with CD:  provide the diary and request 
subject completes this for each of the 7 consecutive 
days prior to the next scheduled visit.  
9.6.3, 11th 
bullet 
... no more than 25% of subjects recruited will have a 
bilirubin >1.5x ULN and <2.5x ULN).  In addition, 
subjects with documented Gilbert’s syndrome may be 
allowed to participate in the study after discussion with 
the medical monitor. 
… no more than 25% of subjects recruited will have a 
bilirubin >1.5x ULN and <2.5x ULN).   
9.6.4, 5th 
bullet 
Obtain Partial Mayo Scoring System for Assessment of 
Ulcerative Colitis Activity (partial Mayo score, excluding 
endoscopy).  See Appendix B for details. 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy).  See Appendix B for details. 
9.6.4, 6th 
bullet 
New bullet 6 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score.  See Appendix F for details. 
9.6.4, 7th 
bullet 
Administer pruritus visual analogue scale (VAS) subject 
questionnaire.  See Appendix C for details. 
Administer pruritus visual analogue scale (VAS) subject 
questionnaire and 5-D Itch Questionnaire.  See 
Appendix C for details. 


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9.6.4, 9th 
bullet, 5th 
sub-bullet 
Serum bile acids and 7α-hydroxy-4-cholesten-3-one (C4) 
Plasma bile acids and 7α-hydroxy-4-cholesten-3-one 
(C4) 
9.6.3, 15th 
bullet 
New bullet 15. 
Subjects with UC or CD: provide the diary and request 
this is completed for 7 consecutive days prior to their next 
scheduled visit. 
9.6.4, 16th 
bullet 
Reiterate dosing instructions and advise the subject: 
- All subjects are to … Further details are included in 
Section 9.1. 
Book the date and time for the Week 2 Contact. 
Reiterate dosing instructions and advise the subject: 
-All subjects are to … Further details are included in 
Section 9.1. 
-NOT to take IP on the morning of the next trial 
visit, and  
-To bring the IP bottle(s) and 
-To fast overnight (at least 8 hours) prior to the 
next trial visit.  Fasting is required prior to all 
trial visits, but water is permitted, and the subject 
should dose at the visit after all assessments have 
been performed. 
9.6.5 
Week 2 Contact Procedures 
The Week 2 contact is not a clinic visit however, the site is 
required to contact the subject to assess the following: 
• Assess and record AEs 
• Record current concomitant medications 
• Assess IP compliance 
• Reiterate dosing instructions and advise the 
subject: 
-NOT to take IP on the morning of the next trial visit, 
Week 2 Procedures 
• Assess and record AEs 
• Record current concomitant medications 
• Record vital signs 
• For subjects with UC:  obtain partial Mayo 
score (excluding endoscopy) 
• For subjects with CD:  complete CDAI 
assessments and assign CDAI score 


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and  
-To bring the IP bottle(s) and 
-To fast overnight (at least 8 hours) prior to the next 
trial visit.  Fasting is required prior to all trial visits, 
but water is permitted. 
• Administer pruritus VAS subject 
questionnaire and 5-D Itch Questionnaire 
• Obtain blood samples for serum chemistry 
and hematology  
• 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 trial visits, but water is permitted, and the 
subject should dose at the visit after all 
assessments have been performed. 
• Assess IP compliance and perform 
accountability; retrieve used bottles and 
document returns 
• Record the visit in IWRS and dispense 
indicated bottles of IP 
• Provide the diary and request this is 
completed for 7 consecutive days prior to 
the next scheduled visit. 
• Reiterate dosing instructions and advise the 
subject: 
-NOT to take IP on the morning of the next trial visit, 
and  
-To bring the IP bottle(s); and 
-To fast overnight (at least 8 hours) prior to the next 
trial visit.  Fasting is required prior to all trial visits, 
but water is permitted, and the subject should dose 


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at the visit after all assessments have been 
performed. 
9.6.6, title 
Week 8 Procedures 
Week 6 Procedures 
9.6.6, 4th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.6, 5th 
bullet 
New bullet 5 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.6, 6th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 
9.6.6, 8th 
bullet, 2nd 
sub-bullet 
… fasting is required prior to all trial visits, but water is 
permitted. 
… fasting is required prior to all trial visits, but water is 
permitted, and the subject should dose at the visit after 
all assessments have been performed. 
9.6.6, 11th 
bullet 
New bullet 11 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.6, 12th 
bullet, 3rd 
sub-bullet 
… Fasting is required prior to all trial visits, but water is 
permitted. 
… Fasting is required prior to all trial visits, but water is 
permitted, and the subject should dose at the visit after 
all assessments have been performed. 
9.6.7, 4th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.7, 5th 
bullet 
New bullet 5 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.7, 6th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 


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9.6.7, 7th 
bullet, 5th 
sub-bullet 
Serum bile acids and C4 
Plasma bile acids and C4 
9.6.7, 12th 
bullet, 2nd 
sub-bullet 
… fasting is required prior to all trial visits, but water is 
permitted. 
… fasting is required prior to all trial visits, but water is 
permitted, and the subject should dose at the visit after 
all assessments have been performed. 
9.6.7, 15th 
bullet 
New bullet 15 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.7, 16th 
bullet 
Reiterate dosing instructions  
Book the date and time for the Week 14 contact 
telephone call. 
Reiterate dosing instructions and advise the subject: 
-NOT to take IP on the morning of the next visit, 
and  
-To bring the IP bottle(s) and 
-To fast overnight (at least 8 hours) prior to the 
next visit.  Fasting is required prior to all trial 
visits, but water is permitted, and the subject 
should dose at the visit after all assessments have 
been performed. 
9.6.8, title 
Week 16 Procedures 
Week 14 Procedures 
9.6.8, 4th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.8, 5th 
bullet 
New bullet 5 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.8, 6th 
bullet  
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 


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9.6.8, 8th 
bullet, 2nd 
sub-bullet 
… fasting is required prior to all trial visits, but water is 
permitted. 
… fasting is required prior to all trial visits, but water is 
permitted, and the subject should dose at the visit after 
all assessments have been performed. 
9.6.8, 11th 
bullet 
New bullet 11 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.9, title 
Week 20 Procedures 
Week 18 Procedures 
9.6.9, 4th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.9, 5th 
bullet 
New bullet 5 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.9, 6th 
bullet  
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 
9.6.9, 8th 
bullet, 2nd 
sub-bullet 
… fasting is required prior to all trial visits, but water is 
permitted. 
… fasting is required prior to all trial visits, but water is 
permitted, and the subject should dose at the visit after 
all assessments have been performed. 
9.6.9, 11th 
bullet 
New bullet 11 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.10, 8th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.10, 9th 
bullet 
New bullet 9 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.10, 10th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 


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9.6.10, 12th 
bullet, 5th 
sub-bullet 
Serum bile acids and C4 
Plasma bile acids and C4 
9.6.10, For 
Subjects 
Participating 
in the LTSE, 
5th bullet 
New bullet 5 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.10, For 
Subjects 
Participating 
in the LTSE, 
6th bullet, 3rd 
sub-bullet 
… Fasting is required prior to all trial visits, but water is 
permitted. 
… Fasting is required prior to all trial visits, but water is 
permitted and the subject should dose at each visit after 
all assessments have been performed. 
9.6.10, For 
Subjects 
NOT 
Participating 
in the LTSE, 
3rd bullet 
New bullet 3 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.11, 8th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.11, 9th 
bullet 
New bullet 9 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.11, 10th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 


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9.6.11, 12th 
bullet, 5th 
sub-bullet 
Serum bile acids and C4 
Plasma bile acids and C4 
9.6.11, 13th 
bullet 
New bullet 13 
For sites participating in PK sampling: obtain samples 
for PK analysis (see section 11.5 for sampling 
schedule) 
9.6.11, 19th 
bullet 
New bullet 19 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.12, 4th 
bullet 
New bullet 4 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.12, 5th 
bullet 
New bullet 5 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.12, 5th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 
9.6.14 
See Section 9.6.12 for the LTSE Day 1 (DB Week 24 
visit) procedures. 
See Section 9.6.10 for the LTSE Day 1 (DB Week 24 
visit) procedures. 
9.6.15, 4th 
bullet 
New bullet 4 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.15, 5th 
bullet 
New bullet 5 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.15, 6th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 
9.6.15, 12th 
bullet 
New bullet 12 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 


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9.6.16, 4th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.16, 5th 
bullet 
New bullet 5 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.16, 6th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 
9.6.16, 7th 
bullet, 3rd 
sub-bullet 
Serum bile acids and C4 
Plasma bile acids and C4 
9.6.16, 13th 
bullet 
New bullet 13 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.17, 6th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.17, 7th 
bullet 
New bullet 7 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.17, 8th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 
9.6.17, 9th 
bullet, 5th 
sub-bullet 
Serum bile acids and C4 
Plasma bile acids and C4 
9.6.17, 16th 
bullet 
New bullet 16 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.18, 4th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 


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9.6.18, 5th 
bullet 
New bullet 5 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.18, 6th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 
9.6.18, 13th 
bullet 
New bullet 13 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.19, 8th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.19, 9th 
bullet 
New bullet 9 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.19, 10th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 
9.6.19, 12th 
bullet, 5th 
sub-bullet 
Serum bile acids and C4 
Plasma bile acids and C4 
9.6.19, 19th 
bullet 
New bullet 19 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.20, 8th 
bullet 
Obtain partial Mayo score (excluding endoscopy) 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.20, 9th 
bullet 
New bullet 9 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.20, 10th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 


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9.6.20, 12th 
bullet, 5th 
sub-bullet 
Serum bile acids and C4 
Plasma bile acids and C4 
9.6.20, 13th 
bullet 
New bullet 17 
Subjects with UC or CD: provide the diary and 
request this is completed for 7 consecutive days prior 
to their next scheduled visit. 
9.6.21, 4th 
bullet 
New bullet 4 
For subjects with UC:  obtain partial Mayo score 
(excluding endoscopy) 
9.6.21, 5th 
bullet 
New bullet 5 
For subjects with CD:  complete CDAI assessments 
and assign CDAI score 
9.6.21, 6th 
bullet 
Administer pruritus VAS subject questionnaire 
Administer pruritus VAS subject questionnaire and 5-D 
Itch questionnaire 
11.3, Disease 
Specific 
Symptoms, 
1st paragraph 
Disease-specific symptoms of IBD and pruritus will be 
assessed using the partial Mayo score and as a Pruritus 
VAS respectively. 
 
Disease-specific symptoms of IBD and pruritus will be 
assessed using the partial Mayo score (only for subjects 
with UC), CDAI (only for subjects with CD) and as a 
Pruritus VAS and 5-D itch questionnaire respectively. 
11.3 Disease 
Specific 
Symptoms, 
IBD 
Symptoms, 
CDAI 
New paragraph inserted 
The CDAI will be performed by the investigator at 
specified visits to assess symptoms associated with CD 
(Best 1976) and will be based on the subject’s recount 
of their symptoms in addition to hematocrit and body 
weight measurements.  Details of the CDAI are shown 
in Appendix F. 
To assist sites with recording and calculating the 
partial Mayo score and the CDAI subjects with UC & 
CD, respectively, will be asked to complete a diary in 
the 7 days prior to their next scheduled trial visit to 
record their relevant symptoms.  The PI will 
transcribe relevant information in to the subject’s 


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medical records for SDV and retain the diary cards.  
Pertinent aspects of these data will be recorded in the 
CRF. 
11.3, Disease 
Specific 
Symptoms, 
Pruritus 
Subjects will be asked to complete the Pruritus VA … 
Details of the Pruritus VAS are shown in Appendix C. 
In addition to the assessment of pruritus as an AE with 
mild, moderate and severe categories, pruritus will be 
specifically assessed by patient questionnaires: 
• Pruritus VAS 
Subjects will be asked to complete the Pruritus … Details 
of the Pruritus VAS are shown in Appendix C. 
• 5-D Itch 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).   
11.4, 
paragraph 3 
New paragraph inserted 
Exploratory Analytes 
Blood samples for future analysis related to the effects 
of OCA or FXR activation will be collected at specified 
timepoints during the study and may be assayed on an 
exploratory research basis.  The samples will be stored 
for up to 2 years after the end of the study. 
11.5, 4th 
paragraph 
Subjects should not drink additional water for 1 hour after 
taking the dose of IP 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 nutrition 
information that has been and submitted to and 
approved by the Sponsor in advance. 
Subjects should not drink additional water for 1 hour after 
taking the dose of IP. After approximately 1 hour 
postdose, subjects will be fed a standardized meal 
consisting of a Nutridrink™ (Nutricia).   


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12.1.1.2, 2nd 
paragraph 
2nd paragraph added to this section 
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. 
12.1.5 
Expected Serious Adverse Events 
There are a number of events which are commonly 
associated with PSC and for reporting purposes, these 
events are considered to be ‘Expected’ in this patient 
population: 
Anticipated Serious Adverse Events Associated with 
PSC 
There are a number of events which are commonly 
associated with PSC and for the Sponsor’s Regulatory 
reporting purposes, these events are considered to be 
‘Expected’ in this patient population and are listed 
below.  The investigator remains responsible for 
reporting to the Sponsor all SAEs including the events 
identified here: 
12.2.1 
… Demographic characteristics (age, gender, race, 
ethnicity, etc) will be recorded. 
… Demographic characteristics (age, gender, race, 
ethnicity, etc) will be recorded, as will any historical or 
on study data on colonoscopies (mucosal and 
histological) within the last 3 years and prior and on 
study liver biopsies, hepatic imaging, etc.  Reports 
should be available in the source data. 
12.2.2 
… If clinically significant abnormalities are observed 
before administration of the first dose of IP on Day 1, they 
should be reported in the subject’s medical history.   
… If clinically significant abnormalities are observed 
before administration of the first dose of IP on Day 1, 
they should be reported as adverse events.   


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12.2.4 
Any clinically significant abnormalities on ECGs recorded 
after Day 0 will also be documented as AEs and entered 
on the AE page of the CRF. 
Any clinically significant abnormalities on ECGs 
recorded after Screening will also be documented as AEs 
and entered on the AE page of the CRF. 
12.2.5. 1st 
bullet point 
Hematology (hemoglobin, hematocrit, white blood cell 
[WBC] count with differential, platelets, red blood cell 
[RBC] count) 
Hematology and Coagulation (hemoglobin, hematocrit, 
white blood cell [WBC] count with differential, platelets, 
red blood cell [RBC] count, INR, prothrombin time , 
partial thromboplastin time) 
13.2 
A sample size of 25 subjects per treatment group, a total of 
75 subjects, will provide at least 95% power to detect a 
treatment difference for a change in ALP assuming a 20% 
dropout and the mean percentage changes … alpha level 
of 0.05. 
A sample size of 25 subjects per treatment group, a total 
of 75 subjects, will provide at least 90% power to detect a 
treatment difference for a change in ALP assuming a 20% 
dropout and the mean absolute changes … alpha level of 
0.05. 
13.3 
One of the primary objectives of this proof of concept trial 
is to evaluate the efficacy of OCA in subjects with PSC.  
Accordingly, the primary efficacy analysis will evaluate 
the absolute change from Baseline in ALP with each 
dose of OCA versus placebo.  The primary population for 
efficacy analyses will use the ITT population.  Sensitivity 
analyses will be conducted using the Completer 
populations. 
One of the primary objectives of this proof of concept trial 
is to evaluate the efficacy of OCA in subjects with PSC.  
The primary population for efficacy analyses is the ITT 
population.  Sensitivity analyses will be conducted using 
the Completer populations. 
13.3.1 
The co-primary efficacy endpoints are the absolute 
changes from Baseline in ALP at Week 12 and Week 24.  
The primary efficacy analysis at Week 12 will compare 
the change from Baseline in ALP between OCA 
treatment groups (1.5 mg and 5 mg) and placebo using 
an analysis of covariance (ANCOVA) model with fixed 
effects for treatment group and randomization strata 
and Baseline as a covariate.  The primary efficacy 
analysis at Week 24 will compare the change from 
Baseline in ALP between OCA treatment groups (3 mg 
The primary efficacy endpoint is the Week 24 change 
from Baseline in ALP.  The primary efficacy analysis will 
compare the Week 24 change from Baseline in ALP 
between OCA 10 mg treatment group and placebo 
using an analysis of covariance (ANCOVA) model with 
fixed effects for treatment group and randomization strata 
and Baseline as a covariate. 


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and 10 mg) and placebo using the same ANCOVA 
model as the Week 12 analysis.   
The co-primary endpoints will be tested using a 
hierarchical approach to control the overall 
significance level for multiple visit and dose 
comparisons.  The approach will be detailed in the SAP.   
13.3.2, 1st & 
2nd 
paragraphs 
Secondary efficacy analyses of hepatic biochemistry and 
function parameters (eg, ALT, AST, and GGT) will use 
the same ANCOVA models as the primary endpoints.  
Hepatic biochemistry and function parameters will be 
summarized by treatment group using … of all available 
evaluations prior to treatment.   
Secondary efficacy analyses of hepatic biochemistry and 
function parameters (eg, ALT, AST, and GGT) will be 
summarized by treatment group using … of all available 
evaluations prior to treatment.  Hepatic biochemistry 
and function parameters will be analyzed using the 
same ANCOVA model as specified for the primary 
efficacy analysis. 
A hierarchical approach will be used for multiplicity 
adjustments.  If the primary efficacy analysis is 
statistically significant (p <0.05), the following order 
will be used in the testing procedure to compare the 
change from Baseline in ALP between OCA and 
placebo: 
• Week 12:  OCA 5 mg treatment group 
(randomized to 5 mg for the initial 12 weeks 
followed by 10 mg for the latter 12 weeks) 
vs. placebo 
• Week 24:  OCA 3 mg treatment group 
(randomized to 1.5 mg for the initial 
12 weeks followed by 3 mg for the latter 
12 weeks) vs. placebo  
• Week 12:  OCA 1.5 mg treatment group 
(randomized to 1.5 mg for the initial 


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12 weeks followed by 3 mg for the latter 
12 weeks) vs. placebo 
If at any step a comparison above is not statistically 
significant, then all subsequent comparisons will be 
exploratory rather than confirmatory.   
13.3.2, 3rd 
paragraph 
In addition, secondary efficacy analysis of ALP 
… stratification factor. 
In addition, secondary efficacy analyses of ALP 
… stratification factor. 
13.3.2, 4th 
paragraph 
… The change from Baseline will be analyzed using an 
ANCOVA model with a fixed effect for treatment group 
and the Baseline values as a covariate.   
… The change from Baseline will be analyzed using the 
same ANCOVA model as specified for the primary 
efficacy analysis.  
13.3.2, 5th 
paragraph 
5th paragraph added to this section 
Subgroup analyses will be evaluated as deemed 
appropriate, including but not limited to, those 
subjects who start antibiotics after first dose of 
investigational product. 
13.4, 1st 
paragraph 
PK parameters will be determined for OCA, glyco-OCA, 
tauro-OCA, and total OCA (OCA plus conjugates).  The 
following PK parameters will be calculated using non-
compartmental methods where appropriate: 
PK parameters will be determined for OCA, glyco-OCA, 
tauro-OCA, and total OCA (OCA plus conjugates). PK 
parameters, including the following, will be calculated 
using non-compartmental methods where appropriate: 
13.4, 2nd 
paragraph 
An exploratory exposure-response assessment will be 
made comparing … in this patient population.   
An exposure-response assessment will be made 
comparing ... in this patient population.   
13.5.2 
Baseline values, the values at each visit … assessments by 
treatment.  Baseline is defined as … treatment (except for 
lipoprotein assessments where Baseline will be Day 0).   
Baseline values, the values at each visit … assessments by 
treatment group.  Baseline is defined as … treatment 
(except for lipoprotein assessments where Baseline will be 
the fasted Day 0 assessment).   
13.5.3 
The change from Baseline will also be summarized. 
The absolute change from Baseline will also be 
summarized. 


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13.6 & 13.6.1 
13.6 Interim Analysis 
A formal interim efficacy analysis (eg, at Week 12) is 
not planned.  However, once all subjects have completed 
the DB phase of the study, the DB database will be locked 
and unblinded and analyses will performed.  The 
specific details of the analyses will be documented in the 
SAP.   
13.6 Interim Analyses and Data Monitoring 
13.6.1 Interim Analysis (new section) 
An unblinded interim analysis will be conducted after 
approximately 50% of subjects have completed the 
initial 12-weeks of blinded treatment.  The trial will 
not be terminated early for futility.  The interim 
analysis will compare at Week 12, the same variable as 
will be analyzed for the primary endpoint, the change 
from Baseline in ALP, between OCA treatment groups 
and placebo.  No adjustments to the alpha level will be 
made. 
 
In addition, once all subjects have completed the DB 
phase of the study, the DB database will be locked, 
unblinded, and full analyses will be performed.  The 
specific details of both the interim and end of double-
blind analyses will be documented in the SAP.   


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13.6.2, 1st 
paragraph 
Section 13.6.2 is a new section created to replace the 
previous Section 13.7 (Data Safety Monitoring 
Committee) that includes some of the original text of 
Section 13.7. 
 
13.7 Data Safety Monitoring Committee 
An independent DSMC will review safety data at periodic 
intervals from this and other OCA trials.  Members of 
the DSMC will not be allowed to participate as 
investigators in this trial and will not otherwise consult for 
the Sponsor.   
13.6.2 Data and Safety Monitoring Committee 
An independent DSMC will review safety data at periodic 
intervals from this trial.  The DSMC includes 
internationally recognized hepatologists, 
pharmaceutical physicians and statistician(s).  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 trial and will not 
otherwise consult for the Sponsor.   
13.6.2, 2nd 
paragraph 
The DSMC will review safety data … treatment of 
subjects. 
The DSMC will review data … treatment of subjects. 
13.6.2, 3rd 
paragraph 
The DSMC operates under an appropriate charter … that 
will define its organization … each trial.  
The DSMC operates under an appropriate charter … that 
defines its organization … each trial.   
13.6.2, 4th & 
5th paragraphs 
Two new paragraphs inserted into this section. 
Data listings provided to the DSMC do not contain 
individual patient 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 


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treatment columns with ‘dummy’ labels, ie, the actual 
treatment groups are used, but are not identified. Data 
reviewed during the meetings will include, at a 
minimum, disposition, demographics, exposure, 
clinical laboratory results, MedDRA coded AEs, and 
AEs leading to early withdrawal of study drug. 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.  At a minimum 
the occurrence of two life threatening SAEs or an SAE 
resulting in death will trigger an unscheduled and 
unblinded review of the data by the DSMC. 
19  
New references inserted 
Best WR, Becktel JM, Singleton JW, et al.  
Development of a Crohn's disease activity index. 
National Cooperative Crohn's Disease Study. 
Gastroenterology. 1976 Mar; 70 (3): 439–444. 
 
Elman S, Hynan L, Gabriel V, et al. The 5-D itch scale: 
a new measure of pruritus. British Journal of 
Dermatology. 2010 Dec; 162: 587-593 
Appendix D 
New appendix added 
5-D Itch Questionnaire included. 
Appendix F 
New appendix added  
CDAI included 
 


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APPENDIX H. PROTOCOL VERSION 3 – SUMMARY OF CHANGES 
Background:  Protocol 747-207 has been prepared as a Phase 2 trial to evaluate the potential 
clinical benefit of OCA in PSC. 
Rationale:  Version 3 of the protocol includes changes to clarify eligibility criteria, procedures, 
and minor editorial changes.  
Summary of Changes:  The following revisions were made to the Protocol Version 2 in 
Protocol Version 3.  (Note:  Deletions are stricken and additions are indicated in bold font.)  
Minor grammatical changes are not detailed unless included with other changes 
(eg, capitalizations, punctuation). 
 
 


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Cover Page  
 
Original Version:  06 Jun 2014 
Version 2:  24 September 2014 
Original Version:  06 Jun 2014 
Version 2:  24 September 2014 
Version 3:  26 August 2015 
Investigator’s 
Agreement 
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 747-207 and in accordance with Good 
Clinical Practice (CPMP/ICH/135/95), 21CFR Part 
312 and all applicable regulatory requirements. 
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 747-207 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. 
Contact 
Information 
 
Medical Monitor – 24 hour Emergency Reporting 
Contact: Roya Hoosmand-Rad, MD, PhD 
Executive Director, Clinical Research 
Mobile:  +1 858 880 6485 (Pacific Time Zone) 
Telephone:  +1 858 964 1571 (Pacific Time Zone) 
Email:  rhooshmand-rad@interceptpharma.com 
 
Clinical Operations and Project Management 
Contact:  Tessa Beecher-Jones BSc (Hons) 
Head EU Clinical Operations 
Telephone:  +44 1491 640 710 (GMT) 
Mobile:  +44 7969 621 504 (GMT) 
Email:  tbeecherjones@interceptpharma.com 
Medical Monitor – 24 hour Emergency Reporting 
Contact:  Barbara Scholz, MD, MPH 
Mobile:  +1 844 250 6398 (Pacific Time Zone) 
Email:  barbara.scholz@interceptpharma.com 
 
Clinical Operations and Project Management 
Contact:  Tessa Beecher-Jones BSc (Hons) 
VP, Head of Clinical Operations, EU 
Telephone:  +44 1491 640 710 (GMT) 
Mobile:  +44 7969 621 504 (GMT) 
Email:  tbeecherjones@interceptpharma.com 
 
 


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Synopsis, Long-
Term Safety 
Extension Phase 
(LTSE) 
Following completion of participation in the DB 
phase, subjects will continue in the study in the open-
label long-term safety extension (LTSE) phase for a 
further 24 months, and will be required at this time to 
reconfirm their consent for participation in the trial.   
Upon a subject’s completion of the DB phase, the 
trial blind will be broken in order to assign the 
starting OCA dose for the LTSE phase.  It is intended 
that subjects will commence treatment at 5 mg OCA, 
except those subjects who completed treatment in the 
DB phase with 10 mg OCA who will continue at 
10 mg OCA unless safety and tolerability warrant a 
dose reduction to 5 mg.  If an investigator does not 
wish for a subject to be titrated in line with the below 
schedule, this should be discussed with the medical 
monitor  
• Placebo at end of DB  5 mg OCA in 
LTSE 
• 3 mg OCA at end of DB  5 mg OCA in 
LTSE 
• 10 mg OCA at end of DB  10 mg OCA 
in LTSE 
Those subjects who did not up-titrate their dose at 
Week 12 in the DB phase can remain on their DB 
dose, or commence at 5 mg at the decision of the 
investigator based on safety and tolerability of the 
DB dose at Week 24. 
Following completion of participation in the DB 
phase, subjects will be asked to reconfirm their 
consent for participation in the open-label long-
term safety extension (LTSE) phase (a further 
24 months).   
Upon a subject’s completion of the DB phase, the 
trial blind will be broken in order to assign the 
starting OCA dose for the LTSE phase.  It is intended 
that subjects will commence treatment at 5 mg OCA, 
except those subjects who completed treatment in the 
DB phase with 10 mg OCA who will continue at 
10 mg OCA unless safety and tolerability warrant a 
dose reduction to 5 mg. 
• Placebo at end of DB  5 mg OCA in 
LTSE 
• 3 mg OCA at end of DB  5 mg OCA in 
LTSE 
• 10 mg OCA at end of DB  10 mg OCA 
in LTSE 
Those subjects who did not up-titrate their dose at 
Week 12 in the DB phase can remain on their DB 
dose, or commence at 5 mg at the decision of the 
Investigator based on safety and tolerability of the 
DB dose at Week 24.  If an Investigator does not 
wish for a subject to be titrated in line with the 
above schedules, this may be discussed with the 
Medical Monitor. 


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During the LTSE phase, subjects may titrate to higher 
doses of OCA, at a frequency not greater than 
3 monthly (ie, at each of the scheduled LTSE visits), 
up to a maximum dose of 10 mg daily.  The guideline 
for an increase in the dose of OCA is based on 
tolerability and the goal of achieving an ALP level 
<1.5x the ULN.  Doses of OCA should be titrated as 
follows, unless clinically indicated:  1.5 mg to 3 mg, 
3 mg to 5 mg, and 5 mg to10 mg.    
The investigator may decrease the dose of OCA, or 
dosing frequency, in line with safety and tolerability 
as required for that subject.  Following a change in 
OCA dose or dose frequency, an investigator may be 
permitted to return the subject to a prior dose or 
dosing frequency and this should be discussed with 
the Intercept medical monitor in advance. 
A few Sponsor representatives may be unblinded 
during the trial.  If there are any findings regarding 
safety, tolerability, or efficacy that indicate an 
alternative optimal LTSE starting dose, the starting 
dose in the LTSE may be reduced.  
During the LTSE phase, subjects may titrate to higher 
doses of OCA, at a frequency not greater than 
3 monthly (ie, at each of the scheduled LTSE visits), 
up to a maximum dose of 10 mg daily.  The guideline 
for an increase in the dose of OCA is based on 
tolerability and the goal of achieving an ALP level 
<1.5x ULN.  Doses of OCA should be titrated as 
follows, unless clinically indicated:  1.5 mg to 3 mg, 
3 mg to 5 mg, and 5 mg to10 mg.    
The Investigator may decrease the dose of OCA, or 
dosing frequency, in line with safety and tolerability 
as required for that subject.  Following a change in 
OCA dose or dose frequency, an Investigator may be 
permitted to return the subject to a prior dose or 
dosing frequency and this should be discussed with 
the Intercept Medical Monitor in advance. 
Synopsis 
Methodology, 
Inclusion Criteria 
and  
Section 8.2 Subject 
Inclusion Criteria  
6. For subjects with concomitant IBD:   
a. Colonoscopy within 12 months of Day 0 
confirming no dysplasia or colorectal 
cancer 
6. For subjects with concomitant IBD:   
a. Colonoscopy (if the subject has a colon) 
or other appropriate endoscopic 
procedure within 12 months of Day 0 
confirming no dysplasia or colorectal 
cancer 


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Synopsis 
Methodology, 
Inclusion Criteria 
and  
Section 8.2 Subject 
Inclusion Criteria 
7. For subjects being administered UDCA as part of 
their standard of care, the dose must have been 
stable for ≥3 months prior to, and including, 
Day 0 and must not have exceeded 20 mg/kg/day 
during this time.  
Note 2:  Subjects will be stratified according to 
UDCA use and no more than 50% of subjects 
administering UDCA at Day 0 will be recruited. 
7. For subjects being administered UDCA as part of 
their standard of care, the dose must have been 
stable for ≥3 months prior to, and including, 
Day 0 and must not have exceeded 20 mg/kg/day 
during this time.  
Note 2:  Subjects not taking UDCA at Day 0 
must not have taken UDCA for ≥3 months 
prior to, and including, Day 0 and must not 
take UDCA during the DB period.  Subjects 
will be stratified according to UDCA use, and no 
more than 50% of subjects administering UDCA 
at Day 0 will be enrolled. 
Synopsis 
Methodology, 
Inclusion Criteria 
and  
Section 8.2 Subject 
Inclusion Criteria 
8. For subjects being administered biologic 
treatments (eg, Anti-TNF or anti-integrin 
monoclonal antibodies), immunosuppressants or 
systemic corticosteroids they must have been on a 
stable dose for ≥3 months prior to, and including, 
Day 0 and should plan to remain on a stable dose 
throughout the trial. 
8. Subjects being administered biologic treatments 
(eg, anti-TNF or anti-integrin monoclonal 
antibodies), immunosuppressants, systemic 
corticosteroids, or statins, must have been on a 
stable dose for ≥3 months prior to, and including, 
Day 0 and should plan to remain on a stable dose 
throughout the trial. 
Synopsis 
Methodology 
Inclusion Criteria 
and  
Section 8.2 Subject 
Inclusion Criteria 
9. Contraception:  female subjects of childbearing 
potential must use ≥1 effective method of 
contraception during the trial and until 4 weeks 
following the last dose of IP (including LTSE 
doses). 
9. Contraception:  female subjects of childbearing 
potential must use ≥1 effective method (≤1% 
failure rate) of contraception during the trial and 
until 4 weeks following the last dose of 
investigational product (including LTSE doses).  
Effective methods of contraception are 
considered to be those listed below: 


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• Double barrier method, ie, (a) condom 
(male or female) or (b) diaphragm, with 
spermicide; or 
• Intrauterine device; or 
• Vasectomy (partner), or 
• Hormonal (eg, contraceptive pill, patch, 
intramuscular implant or injection); or 
• Abstinence, if in line with the preferred 
and usual lifestyle of the subject [where 
abstinence is defined as refraining from 
heterosexual intercourse during the 
trial duration (from first administration 
of investigational product until 4 weeks 
after the last dose of investigational 
product)] 
Synopsis 
Methodology 
Exclusion Criteria 
and  
Section 8.3 Subject 
Exclusion Criteria 
4. Presence of clinical complications of chronic liver 
disease or clinically significant hepatic 
decompensation, including:  
• Current Child Pugh classification B or C 
• History of, or current diagnosis or 
suspicion of, cholangiocarcinoma or other 
hepatobiliary malignancy, or biliary tract 
dysplasia. 
• History of liver transplantation, current 
placement on a liver transplant list, or 
current model of end stage liver disease 
(MELD) score ≥12 
5. Presence of clinical complications of chronic liver 
disease or clinically significant hepatic 
decompensation, including:  
• Current Child-Pugh classification B or C 
• History of, or current diagnosis or 
suspicion of, cholangiocarcinoma or other 
hepatobiliary malignancy, or biliary tract 
dysplasia. 
• History of liver transplantation, or current 
model of end stage liver disease (MELD) 
score ≥12 


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Synopsis 
Methodology 
Exclusion Criteria 
and  
Section 8.3 Subject 
Exclusion Criteria 
5. Clinical evidence of dominant stricture (as 
evidenced by cholangiography or other 
appropriate imaging modality within the 
12 months prior to Day 0) 
5. Clinical evidence of dominant stricture (as 
evidenced by cholangiography or other 
appropriate imaging modality within the 
12 months prior to Day 0) or current biliary 
stent 
Synopsis 
Methodology 
Exclusion Criteria  
and  
Section 8.3 Subject 
Exclusion Criteria 
9. History of other chronic liver diseases, including, 
but not limited to, primary biliary cirrhosis 
(PBC), alcoholic liver disease, non-alcoholic 
fatty liver disease (NAFLD), autoimmune 
hepatitis, hepatitis B virus (unless seroconverted 
and no positive Hepatitis B Virus DNA) and 
hepatitis C virus 
9. History of other chronic liver diseases, including, 
but not limited to, primary biliary cirrhosis 
(PBC), alcoholic liver disease, non-alcoholic 
fatty liver disease (NAFLD), autoimmune 
hepatitis, hepatitis B virus (unless seroconverted 
and no positive Hepatitis B Virus DNA), hepatitis 
C virus, and overlap syndrome 
Synopsis 
Methodology 
Exclusion Criteria  
and  
Section 8.3 Subject 
Exclusion Criteria 
12. Currently experiencing, or experienced within 
≤1 month of Screening, moderate to severe 
pruritus requiring systemic or enteral treatment, 
or any history of severe pruritus 
12. Currently experiencing, or experienced within 
≤3 months of Screening, pruritus requiring 
systemic or enteral treatment. 
Synopsis 
Methodology 
Exclusion Criteria  
and  
Section 8.3 Subject 
Exclusion Criteria 
14. Administration of antibiotics is prohibited 
≤1 month of Day 0. 
14. Administration of antibiotics is prohibited 
≤1 month of Day 0 (unless subject is on a stable 
prophylaxis dose for at least 3 months prior to 
Day 0). 


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Synopsis Efficacy 
Analyses 
An unblinded interim analysis for planning purposes 
will be conducted after approximately 50% of 
patients have completed the initial 12-weeks of 
blinded treatment.  The trial will not be terminated 
early for futility.  The interim analysis will compare 
at Week 12, the same variable as will be analyzed for 
the primary endpoint: the change from Baseline in 
ALP, between OCA treatment groups (1.5 mg and 5 
mg) and placebo using an analysis of covariance 
(ANCOVA) model with fixed effects for treatment 
group and randomization strata and Baseline as a 
covariate.  No adjustments to the alpha level will be 
made. 
Text Moved to Synopsis Interim Analysis 
Interim Analysis 
An unblinded interim analysis for planning 
purposes will be conducted after approximately 
50% of subjects have completed the initial 
12-weeks of blinded treatment.  The trial will not 
be terminated early for futility.  The interim 
analysis will compare at Week 12, the same 
variable as will be analyzed for the primary 
endpoint: the change from Baseline in ALP, 
between OCA treatment groups (1.5 mg and 5 mg) 
and placebo using an analysis of covariance 
(ANCOVA) model with fixed effects for treatment 
group and randomization strata and Baseline as a 
covariate.  No adjustments to the alpha level will 
be made. 
List of 
Abbreviations and 
Definitions of 
Terms 
IP   investigational product 
RSI:  Reference Safety Information 
SUSAR:  suspected unexpected serious adverse 
reaction 


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Section 5.3.2 
Nonclinical Effects 
on Cholestasis 
The results of trials performed in rodent models of 
cholestasis involving the administration of chemical 
agents that severely injure bile ducts (such as carbon 
tetrachloride [CCl4] or lithocholic acid [LCA]) 
provide evidence that OCA is effective in preventing 
or reducing cholestasis in vivo.  In the LCA model, 
co-infusion of OCA fully reversed the impairment of 
bile flow and protected against liver cell injury 
(Pellicciari 2002, Vairappan 2009). 
Results of other trials have demonstrated that OCA 
significantly reduces fibrotic collagen synthesis in 
vitro and in various rodent models of chronic liver 
injury that involve fibrosis and eventual cirrhosis, 
consistent with the progression of PSC 
(Albanis 2005, Vairappan 2009).   
The results of trials performed in rodent models of 
cholestasis involving the administration of chemical 
agents that severely injure bile ducts (such as carbon 
tetrachloride [CCl4] or lithocholic acid [LCA]) 
provide evidence that OCA is effective in preventing 
or reducing cholestasis in vivo.  In the LCA model, 
co-infusion of OCA fully reversed the impairment of 
bile flow and protected against liver cell injury 
(Pellicciari 2002). 
Results of other trials have demonstrated that OCA 
significantly reduces fibrotic collagen synthesis in 
vitro and in various rodent models of chronic liver 
injury that involve fibrosis and eventual cirrhosis, 
consistent with the progression of PSC 
(Albanis 2005, Mookerjee 2015).   
Section 5.4 Clinical 
Experience with 
Obeticholic Acid 
To date, OCA has been evaluated in the clinic in a 
total of 17 completed and ongoing trials, including 
patients with PBC and other chronic liver diseases 
(eg, portal hypertension and nonalcoholic 
steatohepatitis [NASH]) and healthy volunteers.  
Additional trials are also planned to further 
characterize the pharmacokinetic (PK) and 
pharmacodynamics (PD) properties of OCA as well 
as the safety and efficacy of OCA in subjects with 
PBC and other chronic liver diseases. 
As of 31 Mar 2014, 1023 subjects have received at 
least one dose of OCA in completed or ongoing trials.  
Of these, 414 (40%) were PBC subjects with 
exposure up to approximately 4.5 years.  Overall, the 
PK profile of OCA is consistent with that expected of 
To date, OCA has been evaluated in the clinic in a 
total of 25 completed and 8 ongoing trials, including 
patients with PBC and other chronic liver diseases 
(eg, portal hypertension and nonalcoholic 
steatohepatitis [NASH]) and healthy volunteers.  
Additional trials are also planned to further 
characterize the pharmacokinetic (PK) and 
pharmacodynamic (PD) properties of OCA as well as 
the safety and efficacy of OCA in subjects with PBC 
and other chronic liver diseases. 
As of 31 Jan 2015, approximately 1650 subjects 
have received at least one dose of OCA in completed 
or ongoing trials.  Overall, the PK profile of OCA is 
consistent with that expected of a bile acid.  Phase 1 
PK trials demonstrated that OCA was rapidly 


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a bile acid.  Phase 1 PK trials demonstrated that OCA 
was rapidly absorbed and extensively conjugated 
with glycine and taurine to form glyco-OCA and 
tauro-OCA, respectively.  OCA and its conjugates 
were 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 peaked shortly after 
meals, consistent with gall bladder emptying into the 
duodenum as expected of a bile acid.   
absorbed and extensively conjugated with glycine 
and taurine to form glyco-OCA and tauro-OCA, 
respectively.  OCA and its conjugates were 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 peaked shortly after meals, 
consistent with gall bladder emptying into the 
duodenum as expected of a bile acid.   
Section 5.5 
Summary of 
Known Potential 
Risks with 
Investigational 
Product 
Pruritus is a common symptom of chronic cholestatic 
diseases such as PBC and PSC.  In subjects with 
PBC, treatment with OCA has been shown to cause a 
dose-dependent exacerbation of this common 
symptom and similar results can be expected in 
subjects with PSC.  Pruritus has also been observed 
in clinical trials with OCA in other indications and in 
healthy volunteers, but at a lower frequency and at 
higher doses than that observed in subjects with 
chronic cholestasis.  Investigator guidance for 
pruritus management strategies are outlined in 
Section 12.1.3.1 of the protocol. 
Other potential risks include liver toxicity, especially 
at higher doses of OCA, which is consistent with 
nonclinical findings and the chemical characteristics 
of OCA as a bile acid and detergent.  An increase in 
liver function tests and hepatic AEs, including 
jaundice, were observed in subjects with PBC and 
NASH who were treated at doses that are several fold 
Investigators are referred to the current IB for a 
thorough presentation of the safety data 
associated with OCA.  An overview is as follows: 
Pruritus is a common symptom of chronic cholestatic 
diseases such as PBC and PSC.  In subjects with 
PBC, treatment with OCA has been shown to cause a 
dose-dependent exacerbation of this common 
symptom and similar results can be expected in 
subjects with PSC.  Pruritus has also been observed 
in clinical trials with OCA in other indications and in 
healthy volunteers, but at a lower frequency and at 
higher doses than that observed in subjects with 
chronic cholestasis.  Investigator guidance for 
pruritus management strategies are outlined in 
Section 12.1.3.1 of the protocol. 
Other potential risks include liver toxicity, especially 
at higher doses of OCA, which is consistent with 
nonclinical findings and the chemical characteristics 
of OCA as a bile acid and detergent.  An increase in 


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higher (primarily 20 to 50 mg daily) than those 
studied in this protocol (1.5 mg, 3 mg, 5 mg, and 
10 mg) doses.  This is an important potential risk in 
subjects with PSC, where there is the possibility of 
dominant strictures of intra- and extra-hepatic bile 
ducts that could restrict bile flow.  In order to monitor 
bile duct patency, the trial protocol requires that sites 
perform an ultrasound at the end of the DB phase and 
thereafter annually in the LTSE.  Consistent with this 
potential risk, the present trial excludes subjects who 
have had, or who are suspected of having, a recent 
dominant stricture (Section 8.3).  In addition, the trial 
calls for mandatory discontinuation of investigational 
product (IP) in those subjects whose liver chemistry 
(AST, ALT and or bilirubin) display clinically 
significant increases following the initiation of 
therapy (Section 8.4.1).  The doses used in the 
present trial (1.5 mg to 10 mg) are amongst the 
lowest doses of OCA tested to date in a clinical 
setting. 
Lipoprotein changes have also been observed with 
OCA dosing in subjects with PBC (including a 
decrease in high density lipoprotein [HDL]).  The 
clinical significance of these lipid findings remains 
unclear and is being studied further.  Notably, despite 
an observed decrease in HDL levels, they generally 
remained within normal limits.  The relevance of 
these findings to subjects with PSC is unclear and 
will be investigated further in this trial.  Investigators 
are referred to the current IB for a thorough 
presentation of the safety data associated with OCA. 
liver function tests and hepatobiliary AEs, including 
jaundice, ascites and acute cholecystitis were 
observed in subjects with PBC and NASH who were 
treated at doses that are several fold higher (primarily 
20 mg to 50 mg daily) than those studied in this 
protocol (1.5 mg, 3 mg, 5 mg, and 10 mg) doses.  
This is an important potential risk in subjects with 
PSC, where there is the possibility of dominant 
strictures of intra- and extra-hepatic bile ducts that 
could restrict bile flow.  In order to monitor bile duct 
patency, the trial protocol requires that sites perform 
an ultrasound at Screening, at the end of the DB 
phase, and annually in the LTSE.  Consistent with 
this potential risk, the present trial excludes subjects 
who have had, or who are suspected of having, a 
recent dominant stricture (Section 8.3).  In addition, 
the trial calls for mandatory discontinuation of 
investigational product in those subjects whose liver 
chemistry (AST, ALT and or bilirubin) display 
clinically significant increases following the initiation 
of therapy (Section 8.4.1).  The doses used in the 
present trial (1.5 mg to 10 mg) are amongst the 
lowest doses of OCA tested to date in a clinical 
setting. 
Lipoprotein changes have also been observed with 
OCA dosing in subjects with PBC (including a 
decrease in high-density lipoprotein [HDL]).  The 
clinical significance of these lipid findings remains 
unclear and is being studied further.  Notably, despite 
an observed decrease in HDL levels, they generally 
remained within normal limits.  The relevance of 


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In addition, the Data Safety Monitoring Committee 
(DSMC) will review safety data from the present trial 
as well as other ongoing OCA trials on a periodic 
basis.  Adjustments to or stopping of the 
protocol-defined doses may be considered based on 
DSMC evaluation of OCA safety and tolerability as 
noted in Section 7.4.3.  A few Sponsor 
representatives may be unblinded during the trial, as 
it is anticipated that this may speed a decision to 
make a dosing change in the study, if necessary.  If 
there are any findings regarding safety, tolerability, 
or efficacy that indicate an alternative optimal LTSE 
starting dose, the starting dose in the LTSE may be 
reduced. 
these findings to subjects with PSC is unclear and 
will be investigated further in this trial. 
In addition, the Data Safety Monitoring Committee 
(DSMC) will review safety data from the present trial 
as well as other ongoing OCA trials at 
approximately quarterly intervals but at least 
every 6 months.  Adjustments to or stopping of the 
protocol-defined doses may be considered based on 
DSMC evaluation of OCA safety and tolerability as 
noted in Section 7.4.3. 
Section 7.1 Overall 
Trial Design 
Long-Term Safety Extension Phase (LTSE) 
Following completion of participation in the DB 
phase at Week 24, subjects will continue in the study 
in the open-label long-term safety extension (LTSE) 
phase for a further 24 months, and will be required at 
this time to reconfirm their consent for participation 
in the trial.  The schedule of trial procedures for the 
LTSE is shown in Table 2. 
Upon a subject’s completion of the DB phase, the 
trial blind will be broken in order to assign the 
starting OCA dose for the LTSE phase.  It is intended 
that subjects will commence treatment at 5 mg OCA, 
except those subjects who completed treatment in the 
DB phase with 10 mg OCA who will continue at 
10 mg OCA unless safety and tolerability warrant a 
dose reduction to 5 mg.  The titration schedule and 
Long-Term Safety Extension Phase (LTSE) 
Following completion of participation in the DB 
phase, subjects will be asked to reconfirm their 
consent for participation in the LTSE phase (a 
further 24 months).  The schedule of trial 
procedures for the LTSE is shown in Table 2. 
Upon a subject’s completion of the DB phase, the 
trial blind will be broken in order to assign the 
starting OCA dose for the LTSE phase.  It is intended 
that subjects will commence treatment at 5 mg OCA, 
except those subjects who completed treatment in the 
DB phase with 10 mg OCA who will continue at 
10 mg OCA unless safety and tolerability warrant a 
dose reduction to 5 mg.  The titration schedule and 
options for the LTSE phase are detailed in 
Section 7.4.2.  If an Investigator does not wish for a 


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options for the LTSE phase are detailed in 
Section 7.4.2.  If an investigator does not wish for a 
subject to be titrated in line with the below schedule 
this should be discussed with the medical monitor:   
A limited number of Sponsor representatives will 
remain unblinded during the DB phase of the study.  
If there are any findings regarding safety, tolerability, 
or efficacy that indicate an alternative optimal LTSE 
starting dose, the starting dose in the LTSE may be 
reduced.  
subject to be titrated in line with Table 4, this may be 
discussed with the Medical Monitor.  
Schedule of Trial 
Procedures, Table 1 
Double-Blind 
Phase 
Screening 
D0 
Hepatic Ultrasound at W24 
Dispense IP at D0, W2, W6, W12, W14, W18, W24 
Serum Chemistry & Hematology 
 
No Text  
 
Footnote d:  The Week 24 visit is the final visit 
during the DB treatment period.  For subjects who 
continue into the LTSE, the Week 24 visit is also 
Day 1 of the LTSE. 
 
 
Screening (Day -30 to Day -1) 
Day 0b 
Hepatic Ultrasound at Screening and W24 
Dispense Investigational Product at Day 0,W12, 
W24 
Serum Chemistry, Hematology, & Coagulation 
Parameters 
Footnote b:  Day 0 must occur by Day 31 for a 
subject to be eligible to continue in the trial. 
Footnote d:  The Week 24 visit is the final visit 
during the DB treatment period.  For subjects who 
continue into the LTSE, the Week 24 visit is also 
Day 1 of the LTSE, and unblinding occurs after the 
Week 24/LTSE Day 1 procedures have been 
completed (except dispensing of open-label 
investigational product). 


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Footnote g:  Height is measured only at the Screening 
Visit. 
 
Footnote i:  TE:  at trial sites where the Fibroscan® 
TE device is available. 
 
 
 
 
 
No Text 
 
 
 
 
Footnote k: Subjects with UC and CD will be asked 
to complete a diary recording details of their 
symptoms in the 7 days prior to their next scheduled 
visit. 
 
 
 
 
Footnote m:  Questionnaire completed with input 
from the subject. 
Footnote h:  Height is measured at the Screening visit 
only. 
 
Footnote j:  TE: at trial sites where the Fibroscan® 
TE device is available.  TE has a 5-day visit 
window.  For the Day 0 assessment, TE should 
occur either on Day 0 or within 5 days prior to 
Day 0.  For the Week 24 assessment, the TE 
should occur within ±5 days of the onsite visit if it 
is not possible to schedule the TE on the same day 
as that visit, but the visit(s) should remain within 
the overall visit window. 
Footnote k:  Hepatic ultrasound has a ±5-day visit 
window (ie, if it is not possible to schedule the 
ultrasound on the same day as the onsite visit, it 
may occur within 5 days on either side of the visit, 
but the visit(s) should remain within the overall 
visit window). 
Footnote m:  Subjects with UC will be asked to 
complete a diary the day prior to their next trial 
visit, recording details since their last scheduled 
visit.  Subjects with CD should complete the diary 
in the 7 days prior to their next clinic visit.  Diary 
card data from the Screening period are collected 
at the Day 0 visit. 
Footnote o:  Questionnaire completed by the subject. 
 
Footnote r:  Investigational product is dispensed only 
for subjects who continue into the LTSE.  


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Footnote r:  Investigational product is dispensed only 
for subjects who continue into the LTSE. 
(Dispensing of open-label investigational product 
occurs after completion of the Week 24/LTSE 
Day 1 procedures and the subsequent unblinding 
of the subject’s treatment allocation.) 
Schedule of Trial 
Procedures, Table 2 
LTSE Phase 
No Text 
Serum Chemistry & Hematology 
 
Footnote c:  The LTSE D1 is also the final visit 
(Week 24) of the DB treatment period. 
 
 
 
No Text  
 
 
Footnote h:  TE:  at trial sites where the Fibroscan® 
TE device is available.  
 
 
No Text 
 
 
 
Contact Wk2 ±3d – Safety Contact 
Serum Chemistry, Hematology, & Coagulation 
Parameters 
Footnote c:  The LTSE D1 is also the final visit 
(Week 24) of the DB treatment period.  For subjects 
continuing into the LTSE, unblinding occurs after 
the Week 24/LTSE Day 1 procedures have been 
completed (except dispensing of open-label 
investigational product). 
Footnote g:  The Safety Contact can be either via 
telephone or email, and does not require an onsite 
visit. 
Footnote i:  TE:  at trial sites where the Fibroscan® 
TE device is available.  The TE should occur within 
±5 days of the onsite visit if it is not possible to 
schedule the TE on the same day as that visit, but 
the visit(s) should remain within the overall visit 
window. 
Footnote j:  Hepatic ultrasound has a ±5-day visit 
window (ie, if it is not possible to schedule the 
ultrasound on the same day as the onsite visit, it 
may occur within 5 days on either side of the visit, 
but the visit(s) should remain within the overall 
visit window). 


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Footnote j:  Subjects with UC and CD will be asked 
to complete a diary recording details of their 
symptoms in the 7 days prior to their next scheduled 
visit. 
 
 
Footnote l:  Questionnaire completed with input from 
the subject. 
No Text 
Footnote l:  Subjects with UC will be asked to 
complete a diary the day prior to their next trial 
visit, recording details since their last scheduled 
visit.  Subjects with CD should complete the diary 
in the 7 days prior to their next clinic visit.  
Footnote n:  Questionnaire completed by the subject. 
 
Footnote o:  Investigational product is dispensed 
only for subjects who continue into the LTSE.  
(Dispensing of open-label investigational product 
occurs after completion of the Week 24/LTSE Day 
1 procedures and the subsequent unblinding of the 
subject’s treatment allocation.)  
Section 7.4.2 LTSE 
Phase 
Upon a subject’s completion of the Week 24 visit, at 
the end of the DB phase, the trial blind will be broken 
in order to assign the starting OCA dose for the LTSE 
phase.  It is intended that subjects will commence 
treatment at 5 mg OCA, except those subjects who 
completed treatment in DB with 10 mg OCA who 
will continue at 10 mg OCA (Table 4) unless safety 
and tolerability warrant a dose reduction to 5 mg.  If 
an investigator does not wish for a subject to be 
titrated in line with the below schedule this should be 
discussed with the medical monitor:   
During the LTSE, phase subjects may titrate to higher 
doses of OCA, at a frequency not greater than 
3 monthly (ie, at each of the scheduled visits), up to a 
maximum dose of 10 mg daily.  The guideline for an 
increase in the dose of open-label OCA is based on 
the goal of achieving ALP <1.5x ULN and 
Upon a subject’s completion of the Week 24 visit, at 
the end of the DB phase, the trial blind will be broken 
in order to assign the starting OCA dose for the LTSE 
phase.  It is intended that subjects will commence 
treatment at 5 mg OCA, except those subjects who 
completed treatment in the DB phase with 10 mg 
OCA who will continue at 10 mg OCA (Table 4) 
unless safety and tolerability warrant a dose reduction 
to 5 mg.   
If an Investigator does not wish for a subject to be 
titrated in line with the above schedules, this may 
be discussed with the Medical Monitor. 
During the LTSE phase subjects may titrate to higher 
doses of OCA, at a frequency not greater than 
3 monthly (ie, at each of the scheduled visits), up to a 
maximum dose of 10 mg daily.  The guideline for an 


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tolerability.  Subjects may be titrated in the order 
1.5 mg to 3 mg, 3 mg to 5 mg, and 5 mg to 10 mg 
unless otherwise clinically indicated.  An increase in 
the dose of OCA may occur at intervals no more 
frequent than once per month. 
increase in the dose of open-label OCA is based on 
the goal of achieving ALP <1.5x ULN and 
tolerability.   Doses of OCA should be titrated as 
follows, unless clinically indicated:  1.5 mg to 3 mg, 
3 mg to 5 mg, and 5 mg to10 mg. 
Section 7.4.3 
Safety Criteria for 
Adjustment or 
Stopping Doses 
The Data Safety Monitoring Committee (DSMC) will 
review safety data from the present trial as well as 
other ongoing OCA trials on a periodic basis.  
Adjustments to or stopping of the protocol-defined 
doses may be considered based on DSMC evaluation 
of OCA safety and tolerability.  At a minimum, the 
occurrence of two life threatening serious adverse 
events (SAEs) or an SAE resulting in death will 
trigger an unscheduled and unblinded review of the 
data by the DSMC to determine if the trial should 
continue.  Section 7.5 details the criteria for trial 
termination.  Reasons for discontinuation of 
individual subjects are noted in Section 8.4.1 and 
Section 8.4.2.  
An independant Data Safety Monitoring Committee 
(DSMC) will review safety data from this trial as 
well as other ongoing OCA trials at approximately 
quarterly intervals but at least every 6 months.  
Adjustments to or stopping of the protocol-defined 
doses may be considered based on DSMC evaluation 
of OCA safety and tolerability.  At a minimum, the 
occurrence of 2 life threatening serious adverse 
events (SAEs) or an SAE resulting in death will 
trigger an unscheduled and unblinded review of the 
data by the DSMC to determine if the trial should 
continue.  Section 7.5 details the criteria for trial 
termination.  Reasons for discontinuation of 
individual subjects are noted in Section 8.4.1 and 
Section 8.4.2. 
Section 7.5 Criteria 
for Trial 
Termination 
The Sponsor reserves the right to terminate the trial at 
any time.  
The Sponsor reserves the right to terminate the trial at 
any time.  Additionally, it is agreed that, for 
reasonable cause, the Investigator may terminate 
the trial at his/her site at any time. 
Section 8.4.2 Other 
Reasons for Study 
Discontinuation 
Other Reasons for Trial or Treatment 
Discontinuation or Potential Discontinuation of 
Subjects 
A reasonable effort must be made to determine the 
reason(s) why a subject fails to return for final visit or 
Other Reasons for Study Discontinuation 
A subject should be discontinued from the study 
if:  


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is discontinued from the trial.  This information and 
date must be recorded on the appropriate case report 
form (CRF).  The following events are considered 
appropriate (potential) reasons for a subject to 
discontinue from the trial: 
• The subject decides that it is in his/her 
best interest.  It is fully understood that all 
subjects volunteer for the trial and that 
they may withdraw their consent to 
continue in the trial at any time. 
• The investigator considers that it is 
advisable or in the best interest of the 
subject  
• There is a major violation of the clinical 
trial protocol for the subject 
• Noncompliance of the subject 
• The development of any exclusion criteria 
(see Section 8.3)  
• An inability to provide blood or urine 
samples 
• The occurrence of clinical or laboratory 
AEs considered by the investigator to be 
clinically important  
• The subject decides that it is in his/her 
best interest.  It is fully understood that all 
subjects volunteer for the trial and that 
they may withdraw their consent to 
continue in the trial at any time. 
• The Investigator considers that it is 
advisable or in the best interest of the 
subject.  
• There is a major violation of the clinical 
trial protocol for the subject that would 
jeopardize the subject’s safety and/or 
data quality. 
• There is significant noncompliance of the 
subject that would jeopardize the 
subject’s safety and/or data quality. 
• The development of any exclusion criteria 
(see Section 8.3) that would jeopardize 
the subject’s safety and/or data quality. 
• The subject is consistently unable to 
provide blood or urine samples. 
• There is an occurrence of clinical or 
laboratory AEs considered by the 
Investigator to be clinically important, 
such that they would jeopardize the 
subject’s safety. 
A reasonable effort must be made to determine 
the reason(s) why a subject fails to return for 
his/her final visit or is discontinued from the trial.  


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This information and date must be recorded on 
the appropriate case report form (CRF).  
Section 8.4.2 Other 
Reasons for Study 
Discontinuation, 
Bacterial 
Cholangitis 
Subjects should temporarily interrupt treatment with 
IP and receive standard of care treatment.  
Discontinuation from the trial is not mandatory in 
cases of bacterial cholangitis unless signs and 
symptoms do not resolve within a clinically 
reasonable timeframe (typically within 1 month or as 
agreed upon with the medical monitor) or the 
cholangitis becomes life threatening in the opinion of 
the investigator or medical monitor.  In any event, IP 
should not be restarted until signs and symptoms 
have resolved and the subject’s liver biochemistry 
has returned to pre-cholangitis levels.   
Investigational product may be interrupted at the 
discretion of the Investigator.  Discontinuation from 
the trial is not mandatory in cases of bacterial 
cholangitis unless signs and symptoms do not resolve 
within a clinically reasonable timeframe (typically 
within 1 month or as agreed upon with the Medical 
Monitor) or the cholangitis becomes life-threatening 
in the opinion of the Investigator or Medical 
Monitor.  In any event, investigational product 
should not be restarted until signs and symptoms 
have resolved and the subject’s liver biochemistry has 
returned to pre-cholangitis levels.   
Section 8.4.2 Other 
Reasons for Study 
Discontinuation, 
Bile Duct Stricture 
and Pruritus 
Bile Duct Stricture 
IP should be interrupted if a subject develops a 
stricture requiring intervention (eg, drainage, ERCP, 
stent) in order to re-establish bile flow.  The medical 
monitor should be contacted to confirm the subject’s 
eligibility to continue in the trial.  Lack of 
improvement (or worsening) within 1 month of 
treatment will require further evaluation by the 
investigator and discussion and agreement with the 
medical monitor before a subject is considered 
eligible to resume IP administration or to continue in 
the trial. 
It is agreed that, for reasonable cause, the investigator 
may terminate the trial at his/her site or the Sponsor 
may decide to terminate the trial. 
Bile Duct Stricture 
Investigational product may be interrupted at the 
discretion of the Investigator if a subject develops a 
stricture requiring intervention (eg, drainage, ERCP, 
stent) in order to re-establish bile flow.  If the 
investigational product has been interrupted and 
the subject does not show improvement within 
1 month of treatment, further evaluation by the 
Investigator and discussion and agreement with the 
Medical Monitor is required before a subject is 
considered eligible to resume investigational 
product administration or to continue in the trial. 
Pruritus 
Pruritus is a common symptom in PBC but less 
common in PSC (Chapman 2011).  Investigator 


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guidance for pruritus management strategies are 
outlined in Section 12.1.3.1 of this protocol.  
Subjects who experience one or more episodes of 
severe pruritus that are not tolerable based on 
Investigator assessment, despite optimal 
supportive treatment as outlined in 
Section 12.1.3.1, should be discontinued from the 
trial. 
Section 9.1 
Investigational 
Product Treatment 
Regimen 
IP will be dispensed in bottles of 100 tablets, and 
subjects will be instructed to take the number of 
tablets indicated by their treatment group.  During the 
first 12 weeks of the DB phase, subjects will be 
instructed to administer two tablets daily:  one 1.5 mg 
(small) tablet and one 5 mg (big) tablet. 
Investigational product will be dispensed in bottles 
of 100 tablets, and subjects will be instructed to take 
the number of tablets indicated by their treatment 
group.  During the first 12 weeks of the DB phase, 
subjects will be instructed to administer 2 tablets 
daily with water:  one 1.5 mg (small) tablet and one 
5 mg (big) tablet. 
Section 9.2 
Concomitant 
Medications 
Relevant information about all concomitant drugs 
(including prescribed, over the counter, or herbal 
preparations) taken prior to (ie, within 30 days of Day 
0) and during the trial must be recorded in the source 
documents and CRF, as well as any dose or dose 
regimen changes that occur during the trial. 
Relevant information about all concomitant drugs 
(including prescribed, over-the-counter, or herbal 
preparations) taken prior to (ie, within 30 days of 
Screening) and during the trial must be recorded in 
the source documents and CRF, as well as any dose 
or dose regimen changes that occur during the trial. 
Section 9.2.1 
Ursodeoxycholic 
Acid 
Subjects taking UDCA at Day 0 should maintain this 
dose and the timing of administration of UDCA for 
the duration of the DB phase of the trial (24 weeks).  
Subjects who were unable to tolerate UDCA prior to 
participating in the trial should not initiate UDCA 
therapy at any time during their participation in the 
DB phase of trial. 
Subjects taking UDCA at Day 0 should maintain this 
dose and the timing of administration of UDCA for 
the duration of the DB phase of the trial (24 weeks).  
Subjects who are not taking UDCA on entry into 
the trial should not initiate UDCA therapy at any time 
during their participation in the DB phase of the trial. 


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Section 9.2.3 
Prohibited 
Medications 
• Systemic or enteral therapy for pruritus in 
the month prior to Screening.  A subject 
may remain in the study if they require 
systemic or enteral therapy for pruritus 
after the initiation of investigational 
product administration 
• Administration of antibiotics within 
1 month of Day 0, except if administered 
for acute cholangitis whereby its use is 
prohibited within 3 months of Day 0.  
 
 
Subjects being administered the following 
medications at Day 0 may enter the trial provided 
they have been on a stable dose for ≥3 months prior 
to, and including, Screening and remain on a stable 
dose throughout the trial:  
• Anti-TNF and anti-integrin antibodies 
• Immunosuppressants (eg, azathioprine, 
colchicine, cyclosporine, methotrexate, 
mycophenolate mofetil, pentoxifylline) 
• Corticosteroids 
• Systemic or enteral therapy for pruritus in 
the 3 months prior to Screening.  A 
subject may remain in the study if they 
require systemic or enteral therapy for 
pruritus after the initiation of 
investigational product administration. 
• Administration of antibiotics within 
1 month of Day 0 (unless subject is on a 
stable prophylaxis dose for at least 
3 months prior to Day 0), except if 
administered for acute cholangitis 
whereby its use is prohibited within 
3 months of Day 0.  
Subjects being administered the following 
medications at Day 0 may enter the trial provided 
they have been on a stable dose for ≥3 months prior 
to, and including, Day 0 and remain on a stable dose 
throughout the trial:  
• Anti-TNF and anti-integrin antibodies 
• Immunosuppressants (eg, azathioprine, 
colchicine, cyclosporine, methotrexate, 
mycophenolate mofetil, pentoxifylline) 
• Corticosteroids 
• Statins 


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Section 9.4 
Randomization and 
Blinding 
A limited number of Sponsor representatives will 
remain unblinded to the treatment allocation during 
the DB phase, for example, to enable evaluation of 
safety and tolerability.  This will not affect the 
scientific integrity of the study or data. 
No Text 
Section 9.4.2 
Unblinding 
Procedures – 
Emergency 
Unblinding 
No Text 
9.4.2  Unblinding Procedures – Emergency 
Unblinding 
For the DB phase of the trial, treatment 
assignment will be made available to the 
Investigator for emergency use only through the 
IWRS.  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 accidental unblinding or 
unblinding due to 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 the purpose 
of evaluating an emergent safety issue, the 
Medical Monitor will document within trial 
documentation the rationale, circumstances, and 


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the person or persons being informed about the 
unblinding. 
The DSMC (refer to Section 13.6.2) will have 
access to the IWRS and will be able to unblind 
individual subjects.  Refer to Section 13.6.2 for 
further details regarding DSMC access to blinded 
and unblinded data.  The DSMC will document, 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), 
details about any unblinded subject data reviews.  
Cases of premature unblinding (as noted above) 
will be reviewed by the DSMC. 
Access to treatment assignments will also be made 
available through the IWRS to the appropriate, 
named individual(s) responsible for reporting 
SAEs and suspected unexpected serious adverse 
reactions (SUSARs) to the regulatory authorities. 
Section 9.6.1 Visit 
Windows 
All trial visits during the DB period are relative to 
Day 0 (eg, if the Week 6 visit occurs 4 days late, the 
Week 12 visit should still be 12 weeks from Day 0).  
The Screening visit should occur ≤30 days prior to 
the Day 0 visit.  All visits during the DB treatment 
period should occur within ± 1 week of the indicated 
time.  The exception to this is the Week 2 visit, which 
should occur within ± 3 days of the indicated time.  
During the LTSE period, visits are relative to LTSE 
Day 1 (which is also the DB Week 24 visit) and all 
visits during this period should occur within 
All trial visits during the DB period are relative to 
Day 0 (eg, if the Week 6 visit occurs 4 days late, the 
Week 12 visit should still be 12 weeks from Day 0).  
The Screening visit should occur ≤30 days (ie, 
Day -30 to Day -1) prior to the Day 0 visit.  All visits 
during the DB treatment period should occur within 
±1 week of the indicated time.  The exception to this 
is the Week 2 visit, which should occur within 
±3 days of the indicated time.  
During the LTSE period, visits are relative to LTSE 
Day 1 (which is also the DB Week 24 visit) and all 


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± 2 weeks of the indicated time, except for the 
Follow-Up visit, which should occur within 
± 1 week.  
visits during this period should occur within 
±2 weeks of the indicated time, except for the 
Week 2 Safety Contact which should occur within 
±3 days and the Follow-Up visit, which should occur 
within ±1 week.  
Section 9.6.3 
Screening 
Procedures (Within 
30 Days of Day 0) 
The Screening Visit assessments must be performed 
within ≤30 days prior to Day 0 to determine whether 
the subject meets all the inclusion criteria and none of 
the exclusion criteria. 
The Screening visit assessments must be performed 
within ≤30 days (ie, Day -30 to Day -1) prior to 
Day 0 to determine whether the subject meets all the 
inclusion criteria and none of the exclusion criteria. 
Section 9.6.3 
Screening 
Procedures (Within 
30 Days of Day 0) 
Screening Visit procedures are as follows: 
• The subject is to review the PIS and sign 
the ICF.  Written informed consent must 
be obtained from the subject before 
performing any trial related procedures, 
including Screening procedures. (Note:  
Collection of AEs commences from the 
point the subject signs the consent form.) 
• Assign subject number 
• Collect medical history 
• Record prior (within 30 days of Day 0) 
and current concomitant medications 
• Verify inclusion and exclusion criteria for 
eligibility 
• Perform a physical examination, including 
height (Screening Visit only) and weight.  
See Section 12.2.2 for physical 
examination requirements. 
Screening visit procedures are as follows: 
• The subject is to review the PIS and sign 
the ICF.  Written informed consent must 
be obtained from the subject before 
performing any trial related procedures, 
including Screening procedures.  (Note:  
Collection of AEs commences from the 
point the subject signs the consent form.) 
• Assign subject number. 
• Collect medical history. 
• Record prior (within 30 days of 
Screening) and current concomitant 
medications. 
• Verify inclusion and exclusion criteria for 
eligibility. 
• Perform a physical examination, including 
height and weight.  See Section 12.2.2 for 
physical examination requirements. 


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• Record vital signs 
• Perform a standard 12-lead 
electrocardiogram (ECG) 
• For subjects with UC:  provide the diary 
and request subject completes this for 
each of the 7 consecutive days prior to the 
next scheduled visit.   
• For subjects with CD:  provide the diary 
and request subject completes this for 
each of the 7 consecutive days prior to the 
next scheduled visit.   
• Obtain blood samples for serum chemistry 
and hematology   
Note:  
If a subject has an ALP value ≤2x ULN, a 
further sample may be taken during the 
Screening period (at least 14 days after the 
initial sample was taken), and provided 
the mean ALP is ≥2x ULN, the subject 
will have met inclusion criterion 4 (ALP 
at Screening ≥2x ULN) 
• Record vital signs. 
• Perform a standard 12-lead 
electrocardiogram (ECG). 
• Perform hepatic ultrasound to assess 
bile duct patency. 
• For subjects with UC:  provide the diary 
and request subject completes this the day 
prior to the Day 0 visit, to reflect their 
symptoms since the Screening visit.  
• For subjects with CD:  provide the diary 
and request subject completes this for 
each of the 7 consecutive days prior to the 
Day 0 visit.   
• Obtain blood samples for serum 
chemistry, hematology, and coagulation. 
Note:  
If a subject has an ALP value <2x ULN, a 
further sample may be taken during the 
Screening period (at least 14 days after the 
initial sample was taken), and provided 
the mean ALP is ≥2x ULN, the subject 
will have met inclusion criterion 4 (ALP 
at Screening ≥2x ULN). 


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Section 9.6.4 Day 0 
Procedures, Bullets 
5, 6 & 15 
• For subjects with UC:  obtain partial 
Mayo score (excluding endoscopy).  See 
Appendix B for details. 
• For subjects with CD:  complete CDAI 
assessments and assign CDAI score.  See 
Appendix F for details. 
• Subjects with UC or CD:  provide the 
diary and request this is completed for 7 
consecutive days prior to their next 
scheduled visit. 
• For subjects with UC:  obtain partial 
Mayo score (excluding endoscopy) using 
the data from the diary card provided 
at the Screening visit.  See Appendix B 
for details. 
• For subjects with CD:  complete CDAI 
assessments using the data from the 
diary card provided at the Screening 
visit.  See Appendix F for details. 
• Subjects with UC or CD:  provide the 
appropriate diary card and request this is 
completed for the 7 consecutive days 
prior to their next scheduled visit (for 
subjects with CD) and the day prior to 
their next scheduled visit (for UC 
subjects). 
Sections 9.6.4–
9.6.12, Sections 
9.6.16–9.6.19, 
9.6.21–9.6.22 Visit 
Procedures 
• Obtain blood samples for serum 
chemistryand hematology 
• Obtain blood samples for serum 
chemistry, hematology, and coagulation 
Sections 9.6.5, 
9.6.6, 9.6.7, 9.6.8, 
9.6.9 Visit 
Procedures 
• Subjects with UC or CD: provide the 
diary and request this is completed for 7 
consecutive days prior to their next 
scheduled visit. 
 
• Subjects with UC or CD:  provide the 
appropriate diary card and request this is 
completed for the 7 consecutive days 
prior to their next scheduled visit (for 
subjects with CD) and the day prior to 
their next scheduled visit (for UC 
subjects).  


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Sections 9.6.5, 
9.6.6, 9.6.8, 9.6.9 
Visit Procedures 
• Record the visit in IWRS and dispense 
indicated bottles of IP 
• Record the visit in IWRS 
Section 9.6.7 Week 
12 (Titration Visit) 
Procedures 
• For sites and subjects participating in PK 
sampling:  obtain samples for PK analysis 
(see Section 11.5 for sampling schedule) 
• For sites and subjects participating in PK 
sampling:  obtain samples for PK analysis 
(see Section 11.5 for sampling schedule).  
Subjects undergoing PK sampling 
should take the currently assigned dose 
(ie, lower dose); the titrated dose should 
be taken by the subject the following 
day. 
Section 9.6.10 
Week 24/LTSE 
Day 1 Procedures; 
Subjects 
Participating in the 
LTSE 
• Unblind the subject’s treatment allocation 
in IWRS (as detailed in the study 
reference manual) and document the dose 
of OCA on which the subject will 
commence the LTSE. 
• Unblind the subject’s treatment allocation 
in IWRS (as detailed in a separate trial 
document) and document the dose of 
OCA on which the subject will commence 
the LTSE. 
Sections 9.6.10, 
9.6.11, 9.6.16, 
9.6.17, 9.6.18, 
9.6.19, 9.6.20, 
9.6.21 Visit 
Procedures 
• Subjects with UC or CD: provide the 
diary and request this is completed for 7 
consecutive days prior to their next 
scheduled visit. 
• Subjects with UC or CD:  provide the 
appropriate diary card and request this is 
completed for the 7 consecutive days 
prior to their next scheduled visit (for 
subjects with CD) and the day prior to 
their next scheduled visit (for UC 
subjects).  


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Section 9.6.15 
LTSE Week 2 
Procedures 
No Text 
9.6.15 LTSE Week 2 Procedures 
The subject will be contacted by the study site 
staff 2 weeks after the start of the LTSE phase to 
assess safety. 
Sections 9.6.20, 
9.6.21 Visit 
Procedures 
• Obtain blood samples for: 
− Serum chemistry and hematology  
− FGF-19  
− CRP 
− ELF markers and other analytes 
− Plasma bile acids and C4 
− Apolipoprotein and NMR lipoprotein 
panel 
− Genetics study (if subject has consented 
to provide a sample for RNA analysis) 
• Obtain blood samples for: 
− Serum chemistry, hematology, and 
coagulation  
− FGF-19  
− CRP 
− ELF markers and other analytes 
− Plasma bile acids and C4 
− Genetics study (if subject has consented 
to provide a sample for RNA analysis) 
Section 9.6.22 
Follow-Up Visit: 
LTSE 
• Obtain blood samples for: 
− Serum chemistry and hematology 
− Apolipoprotein and NMR lipoprotein 
panel 
• Obtain blood samples for: 
− Serum chemistry and hematology 


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Section 10.4 
Investigational 
Product 
Administration 
Subjects will be instructed to begin dosing on the day 
after the Day 0 visit (ie, on Day 1).  IP administration 
should occur at approximately the same time of day 
throughout the duration of the trial.  Subjects must be 
instructed to swallow the indicated number of tablets 
whole; they must not chew, divide, or crush the 
tablets. 
Subjects will be instructed to begin dosing on the day 
after the Day 0 visit (ie, on Day 1).  Investigational 
product administration should occur at 
approximately the same time of day throughout the 
duration of the trial.  Subjects must be instructed to 
swallow the indicated number of tablets whole with 
water; they must not chew, divide, or crush the 
tablets. 
Section 10.4.1 
Investigational 
Product 
Dispensation 
At subsequent clinic visits, IP will be dispensed after 
confirmation of continued subject compliance and 
eligibility.  At the 12 Week Visit during the DB 
phase of the clinical study, subjects will receive 4 
bottles of IP (see Table 6).  
At the 12 Week visit during the DB phase of the 
clinical study, subjects will receive 4 bottles of 
investigational product.  
Section 10.4.3 
Overdose 
The maximum dose of OCA that has been given to 
humans is 500 mg as a single dose and 250 mg as a 
multiple dose.  Reversible increases in 
aminotransferases were seen in most of the healthy 
volunteers who took 250 mg OCA.  If overdose 
occurs in a subject enrolled in the trial, general 
medical supportive measures should be provided, 
including observation and follow-up (eg, serum 
chemistry) as appropriate.  Due to the extensive 
enterohepatic recirculation of OCA it is likely that it 
will take several days before blood (and organ) 
concentrations of the drug will decrease.  Treatment 
with cholestyramine (eg, Questran™), colesevelam 
(eg, Welcol™) and other BAS is recommended given 
that they should bind and eliminate the drug in feces.  
The maximum dose of OCA that has been given to 
humans is 500 mg as a single dose and 250 mg as a 
multiple dose.  Reversible increases in 
aminotransferases were seen in most of the healthy 
volunteers who took 250 mg OCA.  If overdose 
occurs in a subject enrolled in the trial, general 
medical supportive measures should be provided, 
including observation and follow-up (eg, serum 
chemistry) as appropriate.  Due to the extensive 
enterohepatic recirculation of OCA it is likely that it 
will take several days before blood (and organ) 
concentrations of the drug will decrease.  Treatment 
with cholestyramine (eg, Questran™), colesevelam 
(eg, Welcol™) and other BAS is recommended given 
that they should bind and eliminate the drug in feces.  
The Sponsor should be notified immediately in the 


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The Medical Monitor should be notified immediately 
in the event of a significant overdose. 
event of a significant overdose. 
Section 11.3 
Secondary 
Assessments 
Disease-Specific Symptoms 
To assist sites with recording and calculating the 
partial Mayo score and the CDAI subjects with UC 
and CD, respectively, will be asked to complete a 
diary in the 7 days prior to their next scheduled trial 
visit to record their relevant symptoms.  The PI will 
transcribe relevant information into the subject’s 
medical records for SDV and retain the diary cards.  
Pertinent aspects of these data will be recorded in the 
CRF.  
Disease-Specific Symptoms 
To assist sites with recording and calculating the 
partial Mayo score and the CDAI, subjects with UC 
will be asked to complete a diary the day prior to 
the next scheduled visit, recording details since 
their last visit; and subjects with CD should 
complete the diary in the 7 days prior to their next 
clinic visit.  The PI will transcribe relevant 
information into the subject’s medical records for 
SDV and retain the diary cards.  Pertinent aspects of 
these data will be recorded in the CRF.  Data from 
the Screening period diary card will be recorded 
at Day 0. 
Section 11.5 
Pharmacokinetics 
and Bile Acid 
Assessments 
Following collection of the fasted laboratory samples 
(8 hour overnight fast) at Week 12 and Week 24 (as 
noted in Table 1), subjects who are participating in 
the PK/bile acid assessment will each receive a single 
dose of their allocated IP 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.  The trial specific laboratory 
manual will include details of the volume of blood 
required to be drawn during each sampling timepoint 
as well as other logistical details and sample handling 
Following collection of the fasted laboratory samples 
(8 hour overnight fast) at Week 12 and Week 24 (as 
noted in Table 1), subjects who are participating in 
the PK/bile acid assessment will each receive a 
single dose of their allocated investigational 
product with approximately 240 mL of water.  At 
Week 12, subjects will receive their dose assigned 
prior to titration (ie, the lower dose of 
investigational product).  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.  The trial-specific 
laboratory manual will include details of the volume 
of blood required to be drawn during each sampling 
timepoint as well as other logistical details and 


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requirements. 
Subjects should not drink additional water for 1 hour 
after taking the dose of IP.  After approximately 
1 hour post-dose, subjects will be fed a standardized 
meal consisting of a Nutridrink™ (Nutricia).  
sample handling requirements. 
Subjects should not drink additional water for 1 hour 
after taking the dose of investigational product.  
After approximately 1 hour postdose, subjects will be 
fed a meal replacement drink.  
Section 12.1.3.1 
Severity of Pruritus 
Pruritus was the most common AE seen in the 
Phase 2 and Phase 3 PBC trials and thus may occur in 
this trial.  Subjects experiencing, or who have 
experienced within ≤1 month of Screening, moderate 
to severe pruritus requiring systemic or enteral 
treatment, or any history of severe pruritus (as 
defined in Table 9) are excluded from participating 
this trial.  
Pruritus was the most common AE seen in the Phase 
2 and Phase 3 PBC trials and thus may occur in this 
trial.  Subjects experiencing, or who have 
experienced within ≤3 months of Screening, pruritus 
requiring systemic or enteral treatment are excluded 
from participating in this trial.  
Section 12.1.4.2 
Reporting of SAEs 
In agreeing to the provisions of this protocol, the 
investigator accepts all legal responsibilities for 
immediate reporting of SAEs to the medical monitor.  
The medical monitor for this trial is: 
Roya Hooshmand-Rad, MD, PhD 
Telephone:  +1 858 964 1571 (Pacific time zone) 
Mobile:  +1 858 880 6485 (Pacific time zone) 
Email: rhooshmand-rad@interceptpharma.com 
SAE Fax:  + 1 800 497 8521  
SAE Email:  sae@interceptpharma.com  
All SAEs 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 
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.  SAEs are 
reported by entering the SAE data into the study 
specific EDC system.  Entering the SAE data into the 
EDC system will automatically notify the Sponsor of 
the event.  In the event that the EDC system is 
inaccessible, an SAE may reported by: 
• E-mail to the SAE email address:  
sae@interceptpharma.com 
• Fax using a paper SAE report form:  
+1 800 497 8521 
• Telephone:  +1 844 250 6398 


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the EDC system will automatically notify the medical 
monitor of the event.  In the event that the EDC 
system is inaccessible, an SAE may 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 IP.  The Sponsor, Intercept, 
will also assess whether the event is causally related 
to the IP in addition to assessing the overall safety 
profile of the IP.  The Sponsor will notify the 
appropriate regulatory agencies as well as all 
participating investigators of investigational new 
drug (IND) safety reports/expedited safety reports 
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 investigational new 
drug (IND) Safety Reports/Expedited Safety Reports 
that occur during the trial within the time frames 
required by each regulatory agency.  An SAE 
assessed with possible, probable, or definite causal 
relationship to the investigational product and 
unexpected according to the IB Reference Safety 
Information (RSI), is known as a suspected 
unexpected serious adverse reaction (SUSAR).  


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that occur during the trial within the time frames 
required by each regulatory agency.  
The investigator is responsible for submitting 
information on IND safety reports/expedited safety 
reports received from the Sponsor to her/his local 
IRB/IEC.  Documentation of the submissions to 
IRBs/IEC and health authorities must be retained in 
the appropriate trial file(s).  As instructed by the 
Sponsor, IND safety reports/expedited safety reports 
should be retained with the current IB.  
The Investigator must report SUSARs using the 
SAE reporting method described above. 
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 Safety 
Reports/Expedited Safety Reports received from the 
Sponsor to her/his local IRB/IEC, in compliance 
with the local country requirements.  For the 
European Union, the Sponsor will notify the 
regulatory agencies and report SUSARs via the 
Eudra Vigilance database within 7 calendar days 
of a SUSAR involving death or a life-threatening 
SUSAR, and all other SUSARs within 15 calendar 
days.  Documentation of the submissions to 
IRBs/IECs and health authorities (as applicable) 
must be retained in the appropriate trial file(s).  As 
instructed by the Sponsor, Safety Reports/Expedited 
Safety Reports should be retained in the appropriate 
Investigator site trial files, or with the IB.  
Section 12.1.5 
Anticipated Serious 
Adverse Events 
Associated with 
PSC 
There are a number of events which are commonly 
associated with PSC and for the Sponsor’s 
Regulatory reporting purposes, these events are 
considered to be ‘Expected’ in this patient population 
and are listed below.   
There are a number of events which are commonly 
associated with PSC and for the Sponsor’s 
Regulatory reporting purposes, these events are 
considered to be ‘Expected’ in this patient population 
and are listed in the IB.   


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Section 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 
trial.  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 safety data recorded in the CRF represent the 
official record of all AEs and SAEs reported in the 
trial.  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 Sponsor, the 
Investigator should provide input into the SAE 
narrative and provide timely information to ensure 
prompt follow-up and closure of the SAE report. 
Section 12.1.7 
Notification of 
Post-Trial SAEs 
If an investigator becomes aware of an SAE that may 
be attributable to the IP at any time after the end of 
the trial, the medical monitor should be notified 
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 trial, the Sponsor should be 
notified immediately (ie, within 24 hours). 
Section 12.1.8 
Follow-Up of AEs 
and SAEs 
No Text 
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. 


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Section 12.2.5 
Laboratory 
Assessments 
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 test-article 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 trial. 
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 until 
pregnancy outcome.  
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 test-article related AE, 
is identified; or until further follow-up is deemed 
medically unnecessary. 
Urine based β-hCG pregnancy tests will be performed 
in female subjects of childbearing potential per 
protocol specified visits.  Additionally, in 
accordance with local country or site 
requirements, additional urine pregnancy tests 
may be performed.  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 until pregnancy outcome.  
Section 13.6.1 
Interim Analysis 
An unblinded interim analysis will be conducted after 
approximately 50% of subjects have completed the 
initial 12-weeks of blinded treatment.  The trial will 
not be terminated early for futility.  The interim 
analysis will compare at Week 12, the same variable 
as will be analyzed for the primary endpoint, the 
change from Baseline in ALP, between OCA 
treatment groups and placebo.  No adjustments to the 
alpha level will be made. 
An unblinded interim analysis will be conducted after 
approximately 50% of subjects have completed the 
initial 12-weeks of blinded treatment.  The trial will 
not be terminated early for futility.  The interim 
analysis will compare at Week 12, the same variable 
as will be analyzed for the primary endpoint, the 
change from Baseline in ALP, between OCA 
treatment groups (1.5 mg and 5 mg) and placebo 
using an analysis of covariance (ANCOVA) model 
with fixed effects for treatment group and 
randomization strata and Baseline as a covariate.  
No adjustments to the alpha level will be made. 


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Section 13.6.2 Data 
and Safety 
Monitoring 
Committee 
An independent DSMC will review safety data at 
periodic intervals from this trial.   The DSMC 
includes internationally recognized hepatologists, 
pharmaceutical physicians and statistician(s). 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 trial 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 trial.   
An independent DSMC will review safety data from 
this trial, as well as other ongoing OCA trials at 
approximately quarterly intervals, but at least 
every 6 months.  The DSMC includes internationally 
recognized hepatologists, pharmaceutical physicians 
and statistician(s).  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 will 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 trial and will not otherwise 
consult for the Sponsor.   
SAE information will be provided to the DSMC on 
an ongoing basis as SAEs occur.  Adhoc (closed) 
DSMC meetings for review of unblinded data 
from subjects who experience SAEs, as requested 
by the DSMC, will be arranged.  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 trial.   


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Section 16.2 
Ethical Conduct of 
the Trial 
The trial 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. 
The trial will be performed in accordance with ethical 
principles that have their origin in the Declaration of 
Helsinki (64th WMA General Assembly, Fortaleza, 
Brazil, October 2013) and are consistent with 
ICH/GCP, applicable regulatory requirements. 
Section 17.1 AE 
Reporting 
The Investigator is responsible for recording AEs 
reported by the subject or discovered by any other 
means during the trial.  In agreeing to the provisions 
of this protocol, the investigator accepts all legal 
responsibilities for immediate reporting of SAEs to 
the Medical Monitor. 
The Investigator is responsible for recording AEs 
reported by the subject or discovered by any other 
means during the trial.  In agreeing to the provisions 
of this protocol, the Investigator accepts all legal 
responsibilities for immediate reporting of SAEs to 
the Sponsor. 
Section 18 
Publication Policy 
The Sponsor intends to publish the results of all of 
the clinical trials 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 trial 
(http://www.icmje.org/ethical_1author.html, accessed 
May 22, 2013).  Thus, it is anticipated that authorship 
will reflect the contribution made by the Sponsor 
personnel, the Investigators, and others involved, 
such as statisticians.   
The Sponsor intends to publish the results of all of 
the clinical trials that it sponsors consistent with the 
Declaration of Helsinki (64th WMA General 
Assembly, Fortaleza, Brazil, October 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 trial 
(http://www.icmje.org/ethical_1author.html, accessed 
May 22, 2013).  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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Section 19 List of 
References 
Vairappan B. Modulation of the DDAH-ADMA 
pathway with the farnesoid X receptor (FXR) agonist 
INT-747 restores hepatic enos activity and lowers 
portal pressure in cirrhotic rats. Hepatology. 
2009;50(4 Supplement):336A-7A. 
Chapman R. Primary sclerosing cholangitis. 
Autoimmune Liver Disease. 2011; 39(10):558-591. 
Mookerjee RP, Mehta G, Balasubramaniyan V, 
et al, Hepatic dimethylarginine-
dimethylaminohydrolase1 is reduced in cirrhosis 
and is a target for therapy in portal hypertension. 
J Hepatol. 2015 Feb; 62(2):325-331. 
Appendix A List of 
Planned Laboratory 
Analytes 
Hematology 
prothrombin time (PT and INR) 
partial thromboplastin time (PTT) 
Coagulation Parameters 
prothrombin time (PT and INR) 
partial thromboplastin time (PTT) 
 


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APPENDIX I. PROTOCOL VERSION 4 – SUMMARY OF CHANGES 
Background:  Protocol 747-207 has been prepared as a Phase 2 trial to evaluate the potential 
clinical benefit of obeticholic acid (OCA) in PSC. 
Rationale:  Version 4 of the protocol includes changes to clarify eligibility criteria. 
Summary of Changes:  The following revisions were made to the Protocol Version 3 in 
Protocol Version 4.  (Note:  Deletions are stricken and additions are indicated in bold font.)  
Minor grammatical changes are not detailed unless included with other changes (eg, 
capitalizations, punctuation).


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Section 
Original Text (Version 3) 
Revised Text (Version 4) 
Title Page 
Original Version:  06 Jun 2014 
Version 2:  24 September 2014 
Version 3:  26 August 2015 
Original Version:  06 Jun 2014 
Version 2:  24 September 2014 
Version 3:  26 August 2015 
Version 4:  08 February 2016 
Synopsis, 
ExclusionCriterion #5 
Clinical evidence of dominant stricture (as evidenced 
by cholangiography or other appropriate imaging 
modality within the 12 months prior to Day 0) or 
current biliary stent 
Current clinical evidence of dominant strictures 
that are considered clinically relevant in the 
opinion of the Investigator or current biliary 
stent at Screening 
Synopsis, 
ExclusionCriterion #6 
Current cholecystitis or gallstones (identified by hepatic 
imaging) 
Current cholecystitis or evidence of current 
biliary obstruction due to gallstones. 
Asymptomatic gallstones that are not 
considered a safety risk in the opinion of the 
Investigator might be acceptable subject to 
discussion and agreement with the Medical 
Monitor 
Synopsis, 
ExclusionCriterion 
#10 
Known Gilbert’s syndrome or elevations in 
unconjugated (indirect) bilirubin >ULN 
Known Gilbert’s syndrome or history of 
elevations in unconjugated (indirect) bilirubin 
>ULN or unconjugated (indirect) bilirubin 
>ULN at Screening 
8.3. Subject Exclusion 
Criteria, 
ExclusionCriterion #5 
Clinical evidence of dominant stricture (as evidenced 
by cholangiography or other appropriate imaging 
modality within the 12 months prior to Day 0) or 
current biliary stent 
Current clinical evidence of dominant strictures 
that are considered clinically relevant in the 
opinion of the Investigator or current biliary 
stent at Screening 
8.3. Subject Exclusion 
Criteria, 
ExclusionCriterion #6 
Current cholecystitis or gallstones (identified by hepatic 
imaging) 
Current cholecystitis or evidence of current 
biliary obstruction due to gallstones. 
Asymptomatic gallstones that are not 
considered a safety risk in the opinion of the 
Investigator might be acceptable subject to 
discussion and agreement with the Medical 
Monitor 


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8.3. Subject Exclusion 
Criteria, 
ExclusionCriterion 
#10 
Known Gilbert’s syndrome or elevations in 
unconjugated (indirect) bilirubin >ULN 
Known Gilbert’s syndrome or history of 
elevations in unconjugated (indirect) bilirubin 
>ULN or unconjugated (indirect) bilirubin 
>ULN at Screening 
12.2.5 Laboratory 
Assessments 
Lp(a) 
 
Appendix A 
Lp(a) 
 
Appendix A 
Samples will be assessed for the presence/absence of 
Lipoprotein X 
 


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APPENDIX J. PROTOCOL VERSION 5 – SUMMARY OF CHANGES 
Background:  Protocol 747-207 has been prepared as a Phase 2 trial to evaluate the potential 
clinical benefit of obeticholic acid (OCA) in PSC. 
Rationale:  Version 5 of the protocol includes changes to clarify eligibility inclusion criterion #3 
and #9, investigational product storage instructions, clarification for titration adjustments, and 
clarification for summarizing ECG results.  The intention for inclusion criterion #3 is to define 
the evidence required for diagnosis of PSC, which is, as already stated in inclusion criterion #3, 
by cholangiography diagnosed at any point in time.  The requirement for a mandatory 12-month 
cholangiogram to diagnose PSC was included in error in the previous version.  Inclusion 
criterion #9 is changed to provide correct examples of barrier methods in the protocol. 
Summary of Changes:  The following revisions were made to Protocol Version 4 in Protocol 
Version 5.  (Note:  Deletions are crossed out and additions are indicated in bold font.)  Minor 
grammatical changes are not detailed unless included with other changes (eg, capitalizations, 
punctuation). 


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Section 
Original Text (Version 4) 
Revised Text (Version 5) 
Title Page 
Original Version:  06 June 2014 
Version 2:  24 September 2014 
Version 3:  26 August 2015 
Version 4:  08 February 2016 
Version 5:  18 March 2016 
 
Synopsis, Methodology 
Doses of OCA should be titrated as follows, unless 
clinically indicated:  1.5 mg to 3 mg, 3 mg to 5 mg, and 
5 mg to 10 mg. 
Doses of OCA should be titrated as follows, unless 
clinically indicated:  1.5 mg to 3 mg, 3 mg to 5 mg, 
and 5 mg to 10 mg.  Intermediate doses (eg, 6.5 
mg) may be considered as deemed appropriate by 
the Investigator.  Dose should not exceed 10 mg. 
Synopsis, Inclusion 
Criterion #3 
3.  Must have a diagnosis of PSC (based on 
cholangiography at any point in time) and must have 
had a cholangiography within the past 12 months 
Must have a diagnosis of PSC (based on 
cholangiography at any point in time). 
 
Synopsis, Inclusion 
Criterion #9 
• 
Double barrier method, ie, (a) condom (male or 
female) or (b) diaphragm, with spermicide; or 
Barrier method, ie, (a) condom (male or female) 
with spermicide or (b) diaphragm with 
spermicide; or 
Synopsis, 
Investigational 
Product, Dosage and 
Mode of 
Administration 
LTSE Phase:  All subjects will receive open-label OCA 
at a starting dose that is dependent upon their dose at 
completion of DB phase, as well as safety and 
tolerability.  Doses may be 1.5 mg, 3 mg, 5 mg, or 10 
mg, ie, 1 or 2 tablets, once daily.   
LTSE Phase:  All subjects will receive open-
label OCA at a starting dose that is dependent 
upon their dose at completion of DB phase, as 
well as safety and tolerability.  Doses may be 
1.5 mg, 3 mg, 5 mg, or 10 mg, ie, 1 or 2 tablets, 
once daily.  Intermediate doses (eg, 6.5 mg) 
may be considered as deemed appropriate by 
the Investigator.  Dose should not exceed 
10 mg. 
 
Synopsis, Safety 
Analyses 
Laboratory parameters, vital signs, and 
electrocardiograms (ECGs) will be summarized by 
treatment group using descriptive statistics at Baseline 
Laboratory parameters and vital signs will be 
summarized by treatment group using 
descriptive statistics at Baseline and at each 


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and at each scheduled post-Baseline visit.  The change 
from Baseline will also be summarized.   
scheduled post-Baseline visit.  The change from 
Baseline will also be summarized.  
Electrocardiograms (ECGs) will be 
summarized by treatment group using 
frequency at each visit.  The shift from 
baseline will also be summarized.   
7.4.2, LTSE Phase 
…Doses of OCA should be titrated as follows, unless 
clinically indicated:  1.5 mg to 3 mg, 3 mg to 5 mg, and 
5 mg to 10 mg.   
Doses of OCA should be titrated as follows, 
unless clinically indicated:  1.5 mg to 3 mg, 
3 mg to 5 mg, and 5 mg to 10 mg.  
Intermediate doses (eg, 6.5 mg) may be 
considered as deemed appropriate by the 
Investigator.  Dose should not exceed 10 mg. 
8.2 Subject Inclusion 
Criteria, Inclusion 
Criterion #3 
3.  Must have a diagnosis of PSC (based on 
cholangiography at any point in time) and must have 
had a cholangiography within the past 12 months 
Must have a diagnosis of PSC (based on 
cholangiography at any point in time). 
8.2 Subject Inclusion 
Criteria, Inclusion 
Criterion #9 
• 
Double barrier method, ie, (a) condom (male or 
female) or (b) diaphragm, with spermicide; or 
Barrier method, ie, (a) condom (male or female) 
with spermicide or (b) diaphragm with 
spermicide; or 
10.3 Investigational 
Product Storage 
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. 
The investigational product should be stored in 
the containers in which it is received from the 
Sponsor’s supplier, at 15°C to 25°C. 
12.2.4, 
Electrocardiogram 
These ECGs must be clearly labeled with the subject’s 
initials, Subject ID number, date and time. 
These ECGs must be clearly labeled with the 
Subject ID number, date and time. 
13.5.3, Additional 
Safety Analyses 
Additional safety assessments include vital signs and 
ECGs.  Vital signs and ECGs will be summarized by 
treatment group using descriptive statistics at Baseline 
and at each scheduled post-Baseline visit.  The change 
from Baseline will also be summarized.   
Additional safety assessments include vital signs 
and ECGs.  Vital signs will be summarized by 
treatment group using descriptive statistics at 
Baseline and at each scheduled post-Baseline 
visit.  The change from Baseline will also be 
summarized.  ECGs will be summarized by 
treatment group using frequency at each 


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visit.  The shift from baseline will also be 
summarized.   
 

SAP_001.pdf: 
Confidential 
Page 1 of 50 
 
 
 
Statistical Analysis Plan for Protocol 747-207 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, 
Clinical Trial Evaluating the Efficacy and Safety of Obeticholic Acid in 
Subjects with Primary Sclerosing Cholangitis 
 
 
OBETICHOLIC ACID (OCA) 
 
OBETICHOLIC ACID (OCA) 
 
Protocol Version and Date: 
Version 5:  18 March 2016 
Phase: 
Phase 2 
Methodology: 
Double-Blind, Randomized, Placebo-Controlled Study 
Prepared by: 
Greg Platek 
Chiltern International, Ltd. 
Sponsor: 
Intercept Pharmaceuticals, Inc. 
4760 Eastgate Mall 
San Diego, CA 92121 
Tel: 
858-652-6800 
Fax: 
858-558-5961 
Sponsor Representative: 
Courtney Van Biene 
Senior Biostatistician 
Analysis Plan Date: 
05 April 2017 
Analysis Plan Version: 
Final Version 2 




Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
Confidential 
Page 3 of 50 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ......................................................................................................10 
2. 
STUDY OBJECTIVES ..............................................................................................10 
3. 
STUDY DESIGN AND PLAN ..................................................................................10 
4. 
DETERMINATION OF SAMPLE SIZE ...................................................................12 
5. 
STUDY ENDPOINTS ................................................................................................12 
5.1. 
Primary Endpoints ......................................................................................................12 
5.1.1. 
Primary Efficacy Endpoints ........................................................................................12 
5.2. 
Secondary Endpoints ..................................................................................................12 
5.2.1. 
ALP Response Rates ...................................................................................................12 
5.2.2. 
Hepatic Biochemistry and Indices of Hepatic Function .............................................12 
5.2.3. 
Markers of Hepatic Inflammation and Fibrosis ..........................................................13 
5.2.4. 
FXR Activity ..............................................................................................................13 
5.2.5. 
Pharmacokinetic Endpoints ........................................................................................13 
5.2.6. 
Pharmacodynamic Bile Acids .....................................................................................13 
5.2.7. 
Disease Specific Symptoms ........................................................................................13 
5.3. 
Exploratory Endpoints ................................................................................................14 
5.3.1. 
Exploratory Marker of Pruritus ..................................................................................14 
6. 
GENERAL ANALYSIS CONSIDERATIONS .........................................................14 
6.1. 
Data Reporting ............................................................................................................14 
6.2. 
Data Analysis and Summaries ....................................................................................15 
6.2.1. 
Arithmetic Summaries ................................................................................................15 
6.2.2. 
Categorical Methods ...................................................................................................15 
6.2.3. 
Analysis of Covariance ...............................................................................................15 
6.2.4. 
Analysis of Covariance (Repeated Measures) ............................................................16 
6.2.5. 
Median and Confidence Interval Estimation Methods ...............................................17 
6.2.6. 
Geometric (Natural Log Transformed) Summaries ....................................................17 
6.2.7. 
Multiple Comparisons/Multiplicity ............................................................................17 
6.2.8. 
Subgroup Analyses .....................................................................................................17 
6.3. 
Data Handling .............................................................................................................18 


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6.3.1. 
Baseline Values ..........................................................................................................18 
6.3.2. 
Missing Data ...............................................................................................................18 
6.3.3. 
Partial Dates ................................................................................................................18 
6.3.4. 
Data Conventions ........................................................................................................19 
6.3.5. 
Standard Calculations .................................................................................................19 
6.3.6. 
Pruritus 5-D Itch Score Calculations ..........................................................................21 
7. 
ANALYSIS POPULATIONS ....................................................................................22 
7.1. 
Intent-to-Treat (ITT) Population .................................................................................22 
7.2. 
Week 12 Completer Population ..................................................................................22 
7.3. 
Week 24 Completer Population ..................................................................................22 
7.4. 
Per Protocol Population ..............................................................................................22 
7.5. 
Safety Population ........................................................................................................22 
7.6. 
Pharmacokinetic (PK) Population ..............................................................................22 
8. 
STUDY POPULATION .............................................................................................23 
8.1. 
Subject Disposition .....................................................................................................23 
8.2. 
Protocol Deviations ....................................................................................................23 
8.3. 
Demographic and Baseline Characteristics ................................................................23 
8.4. 
PSC Disease History ...................................................................................................24 
8.5. 
General Medical History .............................................................................................25 
8.6. 
Prior and New Concomitant Medications...................................................................26 
9. 
EFFICACY ANALYSES ...........................................................................................27 
9.1. 
Primary Efficacy Analyses .........................................................................................27 
9.2. 
Secondary Efficacy Analyses .....................................................................................28 
9.2.1. 
ALP Responders .........................................................................................................28 
9.2.2. 
Hepatic Biochemistry and Indices of Function ..........................................................28 
9.2.3. 
Markers of Hepatic and GI Inflammation, Disease, and Fibrosis ..............................28 
9.2.4. 
PK and PD Concentrations .........................................................................................29 
9.2.4.1. 
PK Concentrations ......................................................................................................29 
9.2.4.2. 
PK Parameters ............................................................................................................29 
9.2.4.3. 
Bile Acids ...................................................................................................................30 
9.2.5. 
Exposure Response of Total OCA to Biomarkers ......................................................31 
9.2.6. 
Disease-specific symptoms .........................................................................................31 


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11 Apr 2017 
 
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9.3. 
Exploratory Analyses ..................................................................................................32 
9.3.1. 
FXR Activity ..............................................................................................................32 
10. 
SAFETY ANALYSES ...............................................................................................32 
10.1. 
Extent of Exposure .....................................................................................................32 
10.1.1. 
Investigational Product (OCA or Placebo) .................................................................32 
10.2. 
Adverse Events (AEs) .................................................................................................33 
10.3. 
Adverse Events of Special Interest .............................................................................34 
10.3.1. 
Pruritus ........................................................................................................................34 
10.3.2. 
Dyslipidaemia .............................................................................................................35 
10.4. 
Clinical Laboratory Evaluations .................................................................................36 
10.5. 
Vital Signs ..................................................................................................................36 
10.6. 
Electrocardiograms (ECGs) ........................................................................................37 
11. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES AND ENDPOINTS .........37 
12. 
REFERENCES ...........................................................................................................37 
13. 
APPENDICES ............................................................................................................38 
APPENDIX A. LIST OF TABLES, FIGURES, AND LISTINGS ............................................38 
APPENDIX B. DYSLIPIDEMIA PREFERRED TERMS AND ASSOCIATED 
CODES ..............................................................................................................49 
 
LIST OF TABLES 
Table 1. Bile Acids and Their Sub-Components ...........................................................................30 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................11 
 
 
 
 


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Protocol 747-207 
 
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LIST OF ABBREVIATIONS 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANCOVA 
analysis of covariance 
Apo 
apolipoprotein 
ApoA1 
apolipoprotein A-1  
ApoB 
apolipoprotein B 
ApoE 
apolipoprotein E 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC0-6 
area under the concentration-time curve from hour 0 to last 
sampling time (hour 6) 
AUCt 
area under the concentration time curve 
BLQ 
below the limit of quantitation 
BMI 
body mass index  
BP 
blood pressure 
BUN 
blood urea nitrogen 
C4 
7α-hydroxy-4-cholesten-3-one 
CA 
cholic acid 
CDAI 
Crohn’s disease activity index 
CDCA 
chenodeoxycholic acid 
CI 
confidence interval 
CK-18 
cytokeratin 18 
cm 
centimeter(s) 
Cmax 
maximum plasma concentration  
CRP 
C-reactive protein 
CSR 
clinical study report 
Css 
steady state concentration 
CV 
coefficient of variation 
DB 
double-blind 


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Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
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Page 7 of 50 
Abbreviation or Specialist Term 
Explanation 
DCA 
deoxycholic acid 
DOB 
date of birth 
DOIC 
date of informed consent 
eCRFs 
electronic case report forms 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
ELF 
enhanced liver fibrosis 
eq 
equivalents 
ERCP  
endoscopic retrograde cholangiopancreatography 
FGF-19 
fibroblast growth factor-19 
FXR 
farnesoid X receptor 
g 
gram(s) 
GGT 
gamma-glutamyl transferase  
GI 
Gastrointestinal 
Glyco-CA 
glycine 6α-ethyl cholic acid 
Glyco-CDCA 
glycine 6α-ethyl chenodeoxycholic acid 
Glyco-DCA 
glycine 6α-ethyl deoxycholic acid 
Glyco-OCA 
glycine 6α-ethyl chenodeoxycholic acid 
Glyco-LCA 
glycine 6α-ethyl lithocholic acid 
Glyco-UDCA 
glycine 6α-ethyl ursodeoxycholic acid 
H 
High 
HA 
hyaluronic acid 
IBD 
Inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IgA 
Immunoglobulin A 
IgG4 
Immunoglobulin G4 
IgM 
Immunoglobulin M 
IL 
interleukin 
INR 
international normalized ratio 
in 
inch(es) 
ITT 
Intent-to-treat 


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Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
Confidential 
Page 8 of 50 
Abbreviation or Specialist Term 
Explanation 
kg 
kilogram(s) 
KM 
Kaplan-Meier 
L 
low 
lb 
pound(s) 
LCA 
lithocholate acid 
LLN 
lower limit(s) of normal 
LLQ 
lower limit of quantitation 
ln 
natural logarithm 
LOCF 
last observation carried forward 
LS 
least-square 
LTSE 
long-term safety extension  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
mL 
milliliter 
MRCP 
magnetic resonance cholangiopancreatography 
MW 
molecular weight 
ng 
nanogram 
NMR 
nuclear magnetic resonance 
OCA 
obeticholic acid 
ODS 
output delivery system 
P3NP 
procollagen-3 N-terminal peptide 
PD 
pharmacodynamic 
PK 
pharmacokinetic(s) 
PSC 
primary sclerosing cholangitis 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SEM 
standard error of mean 
SI 
international system of units 
tauro-CA 
taurine 6α-ethyl cholic acid 
tauro-CDCA 
taurine 6α-ethyl chenodeoxycholic acid 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
Confidential 
Page 9 of 50 
Abbreviation or Specialist Term 
Explanation 
tauro-DCA 
taurine 6α-ethyl deoxycholic acid 
tauro-LCA 
taurine 6α-ethyl lithocholic acid 
tauro-OCA 
taurine 6α-ethyl chenodeoxycholic acid 
tauro-UDCA 
taurine 6α-ethyl ursodeoxycholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
TGF-β 
transforming growth factor-beta 
TIMP-1 
tissue inhibitor of metalloproteinase 1 
tmax 
time to reach Cmax 
TNF-α 
tumor necrosis factor alpha  
UC  
ulcerative colitis  
UDCA 
ursodeoxycholic acid 
ULN 
upper limit(s) of normal 
VAS 
 
visual analogue scale 
W12C 
Week 12 Completers  
W24C 
Week 24 Completers 
WADD 
Weighted average daily dose 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
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Page 10 of 50 
1. 
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of the 
double-blind (DB) phase data collected within the scope of Intercept Pharmaceuticals, Inc. 
(henceforth referred to as Intercept or the Sponsor) Protocol 747-207 (A Phase 2, Randomized, 
Double-Blind, Placebo-Controlled, Dose-Finding, Clinical Trial Evaluating the Efficacy and 
Safety of Obeticholic Acid in Subjects with Primary Sclerosing Cholangitis).  The purpose of 
this plan is to provide specific guidelines from which the analyses will proceed.  Any deviations 
from these guidelines will be documented in the clinical study report (CSR).  The scope of this 
plan includes the detailed specifications of the statistical analyses for the DB phase only.  A 
separate statistical analysis plan (SAP) will be written for the long-term safety extension (LTSE) 
phase of the study.  The analyses described in this plan are considered a priori, in that they have 
been defined prior to database lock of the DB phase.  Post hoc analyses will be labeled as such 
on the outputs and identified in the CSR.  Further details about study design and procedures can 
be found in the protocol. 
2. 
STUDY OBJECTIVES 
The primary objective of the DB phase is to evaluate the effects of obeticholic acid (OCA) on the 
following in subjects with primary sclerosing cholangitis (PSC): 
• Serum alkaline phosphatase (ALP) 
• Safety 
The secondary objectives are to evaluate the effects of OCA on the following in subjects with 
PSC: 
• Hepatic biochemistry and indices of function  
• Markers of: 
− Hepatic fibrosis and gastrointestinal (GI) inflammation and disease  
− Farnesoid X receptor (FXR) activity 
− Inflammatory bowel disease (IBD) 
• Pharmacokinetics (PK) of OCA and Pharmacodynamic (PD) bile acids 
• Exposure response of total OCA (OCA and its conjugates) to biomarkers (eg, ALP 
and bile acids) 
• Long-term efficacy and safety of OCA  
• Disease-specific symptoms 
3. 
STUDY DESIGN AND PLAN 
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding evaluation of 
the efficacy and safety of OCA in subjects with PSC.  The trial design is shown in Figure 1.  
Approximately 75 subjects who provide written informed consent and meet all of the inclusion 


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Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
Confidential 
Page 12 of 50 
4. 
DETERMINATION OF SAMPLE SIZE 
A sample size of 25 subjects per treatment group, a total of 75 subjects, will provide at least 
90% power to detect a treatment difference for change in ALP assuming 20% dropout and the 
mean absolute change in ALP for OCA and placebo treatment groups are approximately -20 and 
-5, respectively, with a pooled standard deviation of 16, based on a 2-sided independent 2-group 
t-test at an alpha level of 0.05.   
In protocol Version 2, dated 24 Sep 2014, the sample size section was updated to reflect absolute 
change from percent change which was used in protocol Version 1, dated 06 June 2014.  In the 
update, the percentage symbols were not removed.  The percentage symbols have been removed 
in this section of the SAP, in order to accurately reflect what is used in the sample size 
calculation.   
5. 
STUDY ENDPOINTS 
5.1. 
Primary Endpoints 
5.1.1. 
Primary Efficacy Endpoints 
The primary efficacy endpoint is the Week 24 change from Baseline in ALP.  
5.2. 
Secondary Endpoints 
As defined in the protocol the secondary endpoints are ALP response rates, indices of hepatic 
function and GI inflammation, hepatic biochemistry, hepatic inflammation and fibrosis, PK, PD 
bile acids, and disease specific symptoms.  The secondary efficacy endpoints of the DB phase 
are described below. 
5.2.1. 
ALP Response Rates 
The following ALP response rates will be summarized. 
• ALP response, defined as ALP value <1.5 x upper limit of normal, will be evaluated 
at Baseline and all DB post-Baseline visits 
• Percentage change from Baseline ≥10%, ≥15%, ≥20%, ≥25%, ≥30%, ≥35%, and 
≥40% will be evaluated at all DB post-Baseline visits 
5.2.2. 
Hepatic Biochemistry and Indices of Hepatic Function 
The following laboratory parameters will be summarized for hepatic biochemistry and indices of 
hepatic function: ALP, albumin, alanine transaminase (ALT), aspartate aminotransferase (AST), 
total bilirubin, direct bilirubin, gamma-glutamyl transferase (GGT), international normalized 
ratio (INR). 
• Observed values, change from Baseline, and percentage change from Baseline will be 
evaluated at each DB post-Baseline visit 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
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Page 13 of 50 
5.2.3. 
Markers of Hepatic Inflammation and Fibrosis 
The following laboratory parameters will be summarized for markers of hepatic inflammation 
and fibrosis: calprotectin, C-reactive protein (CRP), Cytokeratin-18 (CK-18), Immunoglobulin A 
(IgA), Immunoglobulin G4 (IgG4), Immunoglobulin M (IgM), Interleukin-6 (IL-6), 
Interleukin-12 (IL-12), Interleukin-23 (IL-23), Transforming growth factor-beta (TGF-β), Tumor 
necrosis factor-alpha (TNF-α); and for measures of hepatic stiffness measurements obtained via 
Transient elastography (TE) at participating sites; and enhanced liver fibrosis (ELF) measures of 
hyaluronic acid (HA), procollagen-3 N-terminal peptide (P3NP), tissue inhibitor of 
metalloproteinase 1 (TIMP-1). 
• Observed values, change from Baseline, and percentage change from Baseline will be 
evaluated at each DB post-Baseline visit 
5.2.4. 
FXR Activity 
FXR activity will be assessed by measuring fibroblast growth factor-19 (FGF-19). 
• Observed values, change from Baseline, and percentage change from Baseline will be 
evaluated at each DB post-Baseline visit 
5.2.5. 
Pharmacokinetic Endpoints 
PK parameters will be estimated for plasma OCA (parent) and its conjugates (glycine 6α-ethyl 
chenodeoxycholic acid (glyco-OCA) and taurine 6α-ethyl chenodeoxycholic acid (tauro-OCA), 
total OCA, and potentially other conjugates or metabolites not yet identified.  PK analyses will 
utilize non-compartmental methods.   
The values will be summarized by active treatment group using descriptive statistics.  Only 
samples that have a confirmed fasting of approximately 8 hours or more before their visit will be 
included in the analysis. 
• The PK endpoints include the Week 12 and Week 24 plasma concentrations at all 
collection time points, plasma PK parameters; maximum plasma concentration 
(Cmax), time to reach Cmax (tmax), and area under the concentration-time curve from 
hour 0 to last sampling time (hour 6) (AUC0-6) at steady-state. 
5.2.6. 
Pharmacodynamic Bile Acids 
The following are PD bile acid endpoints: total bile acids, ursodeoxycholic acid (UDCA), 
chenodeoxycholic acid (CDCA), lithocholate acid (LCA), cholic acid (CA), deoxycholic acid 
(DCA), (conjugated and unconjugated forms) and C4 in relation to the average exposure of total 
OCA. 
• Observed values and change from Baseline will be evaluated at each DB 
post-Baseline visit 
5.2.7. 
Disease Specific Symptoms 
The disease specific endpoints include the following: Pruritus Visual Analogue Scale (VAS), 
5-D Itch questionnaire, partial Mayo score assessment for subjects with ulcerative colitis (UC), 
and Crohn’s disease activity index (CDAI). 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
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• Observed values and change from Baseline will be evaluated at each DB 
post-Baseline visit  
5.3. 
Exploratory Endpoints 
5.3.1. 
Exploratory Marker of Pruritus 
Pruritus will be assessed by measuring Autotaxin activity.   
• Observed values, change from Baseline, at Week 12 and Week 24, will be 
summarized 
• Correlation of Autotaxin with 5D and VAS scores at Week 12 and Week 24 will be 
assessed 
6. 
GENERAL ANALYSIS CONSIDERATIONS 
6.1. 
Data Reporting 
The statistical analyses will be reported using summary tables, figures, and data listings.   
Laboratory units will be summarized and presented both in conventional units (CV) and in the 
international system of units (SI).  
Individual subject data obtained from the electronic case report forms (eCRFs), external 
laboratory data, and any derived data (such as change from Baseline and percent change from 
Baseline) will be presented in data listings by subject.  Data from all assessments, whether 
scheduled or unscheduled, will be listed by subject and visit.  Unscheduled visits and visits 
occurring more than one day outside protocol defined window will not be included in the table 
summaries, excluding transient elastography measurements.   
The analyses described in this plan are considered a priori, in that they have been defined prior to 
database lock of the DB phase.  Post hoc analyses will be labeled as such on the outputs and 
identified in the CSR. 
All analyses and tabulations will be performed using SAS Version 9.2 or higher.  PK 
parameters will be estimated using Phoenix WinNonlin Version 6.3.  The following processes 
will be employed to validate statistical outputs: derived datasets (both tabulation datasets and 
analysis datasets), summary tables, and data listings will be verified through independent 
programming; graphical displays will be compared against supporting summary tables; and all 
outputs will undergo a senior-level statistical review.  The process includes confirmation that 
statistically valid methods have been implemented and that all data manipulations and 
calculations are appropriate and accurate.  Checks will be made to ensure accuracy, adherence to 
this SAP, consistency within tables, and agreement between tables and their corresponding data 
listings.  Upon completion of validation/verification and quality review procedures, all 
documentation will be collected and filed in the study master file by the project statistician or 
designee. 


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Protocol 747-207 
 
11 Apr 2017 
 
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6.2. 
Data Analysis and Summaries 
Data distribution characteristics will determine which analysis methods are most appropriate.  If 
methods do not allow for parametric modeling assumptions to be met, then non-parametric 
methods will be implemented.   
6.2.1. 
Arithmetic Summaries 
Continuous variables will be summarized by means, standard deviations (SDs), standard errors 
of the mean (SEMs), medians, interquartile range (IQR), minimums, and maximums.        
6.2.2. 
Categorical Methods 
Categorical variables will be summarized by counts and percentage of subjects in corresponding 
categories.  Percentages will be based on the number of non-missing assessments unless 
otherwise specified.  
6.2.3. 
Analysis of Covariance 
Analysis of covariance (ANCOVA) will be performed to provide least square (LS) mean 
estimates and 95% two-sided confidence intervals (CIs) of the change and percentage change 
from Baseline at each DB post-Baseline visit.  Model covariates include then randomization 
stratification values (ie, UDCA use [yes, no] and screening total bilirubin [≤1.5 x ULN, >1.5 x 
ULN – <2.5 x ULN]) and the Baseline of the parameter being estimated.  The primary analysis 
will exclude the treatment by visit interaction term.   
Normality/Equal Variance Testing 
The assumption of a random error component being normally distributed will be tested by 
examining skewness and kurtosis following D’Agostino et al. (1990) with the residuals pooled 
over treatments.  Additionally, homogeneity of variances across treatment groups will be 
examined using Levene’s Test (Glaser 1982) with significance level of 0.05, based on absolute 
values of the residuals from the residual medians for each treatment.  The data will be 
determined non-normal if the p-value for either the D’Agostino Skewness Test or D’Agostino 
Kurtosis Test is less than 0.05.  If the data do not meet the normality or homogeneity 
assumptions of the parametric analyses, then a RT-2 rank transformation will be applied to the 
data (CFB endpoint and baseline value).  To minimize the effect of differing study site sizes, the 
ranks will be standardized to lie between 0 and 1 using the NPLUS1 option of SAS PROC 
RANK.  Tied values will receive the mean value (midranks) of the corresponding ranks. 
 
 


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Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
Confidential 
Page 16 of 50 
Example SAS code for the primary analysis is as follows:  
ODS graphics on; 
proc mixed data=ADLB noclprint plots=residualpanel; 
 
class udcafl tbilfl trt; 
model change=Baseline udcabl tbilfl trt / ddfm=kr;  
 
lsmeans trt / cl diff alpha=0.05; 
 
title1 "Linear Mixed Effects Model Based Estimates of XXXX Means"; 
 
title2 " Fixed Effects for Visit, Randomization Strata, and Treatment and Baseline as 
           Covariates"; 
run; 
ODS graphics off; 
quit; 
6.2.4. 
Analysis of Covariance (Repeated Measures) 
Analyses of the clinical laboratory values will also be carried out using a restricted maximum 
likelihood (REML) based repeated measures linear mixed model (MMRM) to evaluate the effect 
over time by providing LS mean estimates, 95% CIs of change and percentage change from 
Baseline at each DB post-Baseline visit.  Model covariates include then randomization 
stratification values (ie, UDCA use [yes, no] and pre-randomization total bilirubin [≤1.5 x ULN, 
>1.5 x ULN – <2.5 x ULN]), Baseline of the parameter being estimated, and a treatment by visit 
interaction term.   An unstructured (5×5) covariance model will be used.  If the computational 
algorithm fails to converge, the following structures will be executed:  heterogeneous Toeplitz, 
Toeplitz, heterogeneous First-Order Autoregressive [AR (1)], heterogeneous compound 
symmetry (HCS), and compound symmetry (CS).  The covariance structure converging to the 
best fit, as determined by Akaike’s information criterion (AIC), will be used.  The Kenward and 
Roger method will be used to calculate the denominator degrees of freedom for the test of fixed 
effects. 
Example SAS code for the ANCOVA with repeated measures is as follows: 
ODS graphics on; 
proc mixed data=ADLB noclprint plots=residualpanel; 
 
class subjid week ucdafl tbilfl trt; 
 
model change=week Baseline ucdafl tbilfl trt trt*week/ ddfm=kr;  
    
repeated week / subject=subjid type=uns; 
lsmeans trt trt*week / cl diff alpha=0.05; 
 
title1 "Linear Mixed Effects Model Based Estimates of XXXX Means by Visit"; 
 
title2 " Fixed Effects for Visit, Randomization Strata and Baseline as Covariates, and 
Treatment by Visit Interaction"; 
run; 
ODS graphics off; 
quit; 


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Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
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6.2.5. 
Median and Confidence Interval Estimation Methods 
Hodges Lehmann estimation will be used to provide estimators of the median difference and 
95% CIs for the median difference. 
6.2.6. 
Geometric (Natural Log Transformed) Summaries  
In order to calculate a geometric mean and corresponding 95% CI, the following steps are used: 
• Transform the data by taking natural logarithms (ln = loge) 
• Calculate the mean and 95% CI of the loge-transformed data 
• Exponentiate the mean and the lower and upper CIs back to the original scale in order 
to obtain the geometric mean and corresponding 95% CI. 
The geometric coefficient of variation (geometric CV%) is calculated as 100*sqrt(eSD**2-1) 
where SD is the SD of the loge-transformed data.  
6.2.7. 
Multiple Comparisons/Multiplicity 
A hierarchical approach will be used for multiplicity adjustments.  If the primary efficacy 
analysis is statistically significant (p <0.05), the following order will be used in the testing 
procedure to compare the change from Baseline in ALP between OCA and placebo: 
• Week 12:  OCA 5 mg treatment group (randomized to 5 mg for the initial 12 weeks 
followed by 10 mg for the latter 12 weeks) vs. placebo 
• Week 24:  OCA 3 mg treatment group (randomized to 1.5 mg for the initial 12 weeks 
followed by 3 mg for the latter 12 weeks) vs. placebo  
• Week 12:  OCA 1.5 mg treatment group (randomized to 1.5 mg for the initial 
12 weeks followed by 3 mg for the latter 12 weeks) vs. placebo 
If at any step the comparison is not statistically significant, then all subsequent comparisons will 
be exploratory rather than confirmatory.   
Multiplicity adjustments will not be applied for any other statistical testing. 
6.2.8. 
Subgroup Analyses 
Subgroup analyses will be evaluated as deemed appropriate.  Subgroups are defined as follows: 
• Antibiotic use after first dose (Yes/No) – World Health Organization Anatomical 
Therapeutic Chemical (ATC) codes starting with ‘J01’and the medication start date is 
on or after the first dose of investigational product; for analysis of the primary 
efficacy endpoint. 
• Age (≤65 years, >65 years),  
• BMI (<30 kg/m2 vs ≥30 kg/m2)  
• Baseline UDCA use (Yes vs No) 
• Baseline Total Bilirubin (≤1.5xULN vs >1.5xULN) 
• ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
Confidential 
Page 18 of 50 
• race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White) 
• gender (Male, Female) 
• IBD (Yes vs No) 
• Crohn’s disease (Yes vs No) 
• Ulcerative colitis (Yes vs No)  
• Median TE Score (< vs ≥ Median score for all ITT subjects) 
6.3. 
Data Handling 
6.3.1. 
Baseline Values 
Baseline values are defined as follows:  
• Efficacy, Clinical laboratory, and PD endpoints: the mean of all available 
evaluations prior to first dose of investigational product.  
• Lipoprotein assessments: the last non-missing fasted assessment prior to first dose 
of investigational product. 
• ECG assessment: the last available non-missing assessment prior to first dose of 
investigational product.   
For any other quantitative parameters, Baseline is defined as the mean of all available 
evaluations prior to administration of investigational product on Day 1.  
6.3.2. 
Missing Data 
For secondary efficacy analyses of ALP response rates, missing values will be considered as 
non-responders.   
Additional sensitivity analysis will be performed using LOCF, and it will also be performed 
modifying the handling missing data for ALP response criteria.   For the modified response 
criteria, all OCA treated subjects, missing data will be considered non-responders.  For Placebo 
patients, missing data will be considered responders.     
Otherwise, analysis will be done using observed data only; missing values will not be imputed.   
6.3.3. 
Partial Dates 
If only a partial date is available and is required for a calculation, the following standards will be 
applied: 
• Diagnosis date (eg, PSC diagnosis date) 
− For missing day only: Day will be imputed as the first day of the month (ie, 01). 
− For missing day and month: Day and month will be imputed as the first day of the 
year (ie, 01 January). 
• Start dates (eg, AE onset date or start date of medication) 


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Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
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− For missing start day only: Day will be imputed as the first day of the month (ie, 
01) 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, 01 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 dates should not extend beyond the DB phase (ie, date of completion or 
discontinuation of the DB phase). 
− Imputed stop dates must be on or after the start date. 
6.3.4. 
Data Conventions 
Unless otherwise specified, in summary tables of continuous variables, the minimum and 
maximum values will be displayed to the same number of decimal places as the raw data, the 
mean and median will be presented to one extra decimal place compared to the raw data, and the 
SD and SE of the mean will be displayed to two extra decimal places compared to the raw data.  
Rounding will only occur after all calculations have been incorporated.  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), whereas 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 some form of imputation is defined or a ‘missing’ 
category is presented.  For frequency counts of categorical variables, categories with zero counts 
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%.” 
6.3.5. 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 


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Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
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Page 20 of 50 
• Days: A duration expressed in days between one date (date1) and another later date 
(date2) will be calculated using the following formulas: 
duration (days) = date2 – date1 + 1 
• Months: A duration expressed in months is calculated as the number of days divided 
by 365.25 / 12. 
• Years—A duration expressed in years between one date (date1) and another date 
(date2) is calculated using the following formulas: 
duration (years) = (date2 – date1+ 1) / 365.25 
• 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. 
• Height: Height measured in inches (in) are converted to centimeters (cm) using the 
following formula:  
height (cm) = height (in) × 2.54 
• Weight: Weight measured in pounds (lb) are converted to kilograms (kg) using the 
following formula: 
weight (kg) = weight (lb) / 2.2046 
• Temperature: Temperature measured in degrees Fahrenheit are converted to degrees 
centigrade using the following formula:  
temp (degrees centigrade) = 5 / 9 × (temp [degrees Fahrenheit] – 32) 
• Body Mass Index (BMI): BMI is calculated using height (cm) and weight (kg) using 
the following formula: 
BMI (kg/m2) = weight (kg) / ([height (cm)/100]2) 
• Change from Baseline: Change from Baseline is calculated as:  
change from Baseline = DB post-Baseline value – Baseline value 
• Percentage change from Baseline: Percentage change from Baseline is calculated 
as:  
percentage change from Baseline = 100 × ([DB post-Baseline value – Baseline 
value] / Baseline value) 
• Geometric mean - In order to calculate a geometric mean and corresponding 
95% CI, the following steps are used: 
− Transform the data by taking natural logarithms (loge) 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
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11 Apr 2017 
 
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− Calculate the mean and 95% CI of the loge-transformed data 
− Exponentiate the mean and the lower and upper CIs back to the original scale in 
order to obtain the geometric mean and corresponding 95% CI. 
The geometric coefficient of variation (geometric CV%) is calculated as 100*sqrt(eSD**2-1) 
where SD is the SD of the loge-transformed data.  
• Coefficient of variation - The coefficient of variation (%) will be calculated as the 
ratio of the standard deviation to the arithmetic mean using the following formula: 
Coefficient of variation = standard deviation
arithmetic mean  
6.3.6. 
Pruritus 5-D Itch Score Calculations 
The 5-D questionnaire (Elman 2010) is a specific tool used to quantify the magnitude of pruritus 
in PBC (and other diseases).  It consists of 5 domains:  duration, degree, direction, disability, 
distribution, as well as the total score.  The following rules will be used to calculate the domain 
scores: 
• Single item domain scores (duration, degree, and direction) are equal to the value 
indicated below the response choice (range from 1-5). 
• The disability domain includes 4 items that assess the impact of itching on daily 
activities:  sleep, leisure/social activities, housework/errands, and work/school.  The 
score for the disability domain is achieved by taking the highest score on any of the 
4 items.  The disability domain will only be calculated if at least 3 daily activities are 
documented, otherwise this domain score will be set to missing. 
• For the distribution domain, only the section “Mark whether itching has been present 
in the following parts of your body over the last 2 weeks” will be used.  The 
distribution domain includes 16 potential locations of itch, including 15 body part 
items and one point of contact with clothing.  Points of contact with clothing will only 
count as one point. Missing ticks are interpreted to be absent.  The number of affected 
body parts (‘present’) is tallied (potential sum 0 to 16) and the sum is sorted into 
5 scoring bins:  sum of 0 to 2 = score of 1, sum of 3 to 5 = score of 2, sum of 6 to 
10 = score of 3, sum of 11 to 13 = score of 4, sum of 14 to 16 = score of 5.   
• The total 5D score is obtained by summing up the domain scores and ranges between 
5 (no pruritus) and 25 (most severe pruritus).  The total score will not be calculated if 
any of the domain scores is missing.  
• If multiple answers are given for any item then the most severe one will be used. 


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7. 
ANALYSIS POPULATIONS 
The following analysis populations will be used: 
7.1. 
Intent-to-Treat (ITT) Population 
All randomized subjects who receive any amount of investigational product will be included in 
the ITT population.  Treatment assignment will be based on the randomized treatment.  The ITT 
population will be used for the analysis of all efficacy data.  
7.2. 
Week 12 Completer Population 
The Week 12 Completer (W12C) population will include all ITT subjects who complete the DB 
Phase Week 12 ALP assessment and do not have a major protocol deviations that potentially 
affect the efficacy of the study drug.  Treatment assignment will be based on the randomized 
treatment.   
7.3. 
Week 24 Completer Population 
The Week 24 Completer (W24C) population will include all ITT subjects who complete the DB 
Phase Week 24 ALP assessment and do not have a major protocol deviations that potentially 
affect the efficacy of the study drug.  Treatment assignment will be based on the randomized 
treatment.         
7.4. 
Per Protocol Population 
All randomized subjects without major protocol deviations that potentially affect the efficacy of 
the study drug will be included in the per protocol population.  Subjects who are in the study 
through Week 12 who do not up titrate their dose of IP will be excluded from the per protocol 
population.  Treatment assignment will be based on the randomized treatment. 
7.5. 
Safety Population 
The Safety population will include all subjects who receive any amount of investigational 
product.  Treatment assignment will be based on the treatment actually received.  The Safety 
population will be used for the analysis of all safety data. 
7.6. 
Pharmacokinetic (PK) Population 
The PK Population will include all OCA subjects who consent to participate in the PK 
assessments and have at least one confirmed fasted analyzable sample.  Subjects must have been 
fasting for approximately 8 hours before the visit and must not have any major protocol 
deviations that potentially affect exposure levels. The PK Population will be used for the OCA 
PK and pharmacodynamic (PD) analyses. 


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8. 
STUDY POPULATION 
8.1. 
Subject Disposition 
Subject disposition information will be summarized and listed for all subjects.  Summaries will 
include the following: the number of subjects randomized, the number of subjects in each 
analysis population, the number of subjects at each center, the number of subjects completing the 
DB phase (Week 24) and each scheduled visit (Week 2, 6, 12, 14, and 18), the primary reason 
for discontinuation from the DB phase, and the number of subjects enrolling in the LTSE.  A 
subject will be considered as completing the DB phase (Week 24) and each scheduled visit 
(Weeks 2, 6, 12, 14, and 18) if the subject has a non-missing assessment of ALP at the 
corresponding visit.  Percentages will be based on the ITT Population.   
8.2. 
Protocol Deviations 
Protocol deviations for missed visits, missed assessments, out of window visits or assessments, 
and violations of inclusion/exclusion criteria will be determined based on available data.  All 
other protocol deviations will be collected by the clinical research associates.  Major protocol 
deviations identified during the DB phase that could potentially affect the conclusions of the 
study or result in a subject’s removal from an analysis population will be classified as such prior 
to database lock of the DB phase.  Major protocol deviations will be summarized by deviation 
category and treatment group. All protocol deviations and their classifications will be presented 
in a listing.  Subjects with protocol deviations that result in a subject’s removal from the ITT, 
Safety, W12C, W24C, Per Protocol, or PK Populations will be flagged in a listing. 
8.3. 
Demographic and Baseline Characteristics 
Demographic variables will include the following:   
• Age at informed consent 
• Age at informed consent categorized as <65 years and ≥65 years  
• Sex 
• Race/Ethnicity 
Other Baseline characteristics will include the following:  
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
• BMI categorized as <30 kg/m2 and ≥30 kg/m2 
• Hepatic ultrasound to assess bile duct patency performed (Yes/No) 
• Key liver function test results as a continuous variable and categorized as follows by 
the ULN and the LLN unless otherwise specified: 
− ALP: ≤ 3xULN, >3xULN; and, ≤ median baseline ALP, > median baseline ALP 


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− Total Bilirubin: ≤ ULN, > ULN, > ULN - ≤1.5xULN, >1.5xULN - ≤2xULN,  
>2xULN - ≤2.5xULN 
− International normalized ratio (INR): ≤1.3, >1.3 stratified by subjects on/not on 
anticoagulants at the time of randomization 
Arithmetic summary statistics as described in Section 6.2.1 will be presented for age, weight, 
height, BMI, and key liver function test results.  Frequency counts and percentages will be 
presented for age groups, sex, race/ethnicity, BMI category, key liver function categories, and 
hepatic ultrasound.   
Race and ethnicity will be summarized as follows: 
• Race 
− American Indian or Alaska Native 
− Asian 
− Black or African American 
− Native Hawaiian or Other Pacific Islander 
− White 
• Ethnicity 
− Hispanic or Latino 
− Not Hispanic or Latino 
− Not reported 
− Unknown 
Demographic and Baseline characteristics will be summarized for the ITT, Safety, PK, W12C, 
and W24C populations.  All demographic and Baseline characteristics will be presented in data 
listings.  The subgroup tables will be generated for IBD, UC, and CD regardless of the total 
number of patients in each group.  For the remaining subgroups, the tables will be generated as 
long as each subgroup contains at least 10% of the subjects in the overall population. 
8.4. 
PSC Disease History 
Baseline PSC disease characteristics will be summarized using data collected from the PSC 
Disease History eCRF.  Assessments include the following: 
• Age at first PSC diagnosis 
• Age at first PSC diagnosis categorized as <40 years and ≥40 years  
• Symptomatic at diagnosis (Yes/No) 
• Age at first occurrence of PSC symptoms 
• Age at first occurrence of PSC symptoms categorized as <40 years and ≥40 years 
• Duration of PSC in years at time of informed consent 


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• Duration of PSC categorized as ≤ median years and > median years 
• PSC diagnosis confirmed via cholangiagraphy? 
• Modality of PSC diagnosis (endoscopic retrograde cholangiopancreatography 
[ERCP], magnetic resonance cholangiopancreatography [MRCP], Other) 
• Affected bile ducts (intra-hepatic, extra-hepatic, both, unknown) 
• Symptoms of PSC (Never, Previous, Current) 
− Right upper quadrant abdominal pain 
− Fatigue 
− Weight loss 
− Jaundice 
− Pruritus 
− Other 
• Severity of most recent pruritus event (Mild, Moderate, Severe) 
• UDCA Use (Never/Previous/Current) 
• Total daily dose of UDCA (mg/kg) 
• Inflammatory Bowel Disease (IBD) (No IBD, Ulcerative Colitis, Crohn’s Disease, 
Other) 
Arithmetic summary statistics as described in Section 6.2.1 will be presented for the age at first 
PSC diagnosis, age at first occurrence of PSC symptoms, duration of PSC, and total daily dose of 
UDCA (mg/kg).  All other categorical PSC disease characteristics will be summarized using 
frequency counts and percentages.  PSC disease history will be summarized for the ITT, W12C, 
and W24C Populations. The subgroup tables will be generated for IBD, UC, and CD regardless 
of the total number of patients in each group.  For the remaining subgroups, the tables will be 
generated as long as each subgroup contains at least 10% of the subjects in the overall 
population.  PSC disease history will be presented in a data listing. 
8.5. 
General Medical History 
Verbatim medical history terms on eCRFs will be mapped to preferred terms and system organ 
classes using the Medical Dictionary for Regulatory Activities (MedDRA) version 17.1. 
Frequency counts and percentages of the number of subjects reporting an abnormal Baseline 
medical history will be summarized by MedDRA system organ class and preferred term using 
the ITT Population.   
Summaries that are displayed by system organ class and preferred term will be ordered by 
descending order of incidence of system organ class and preferred terms within each system 
organ class.   
Medical history data will be presented in a data listing. 


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8.6. 
Prior and New Concomitant Medications 
Verbatim terms on eCRFs will be mapped to ATC class and preferred term using the World 
Health Organization Drug Dictionary Enhanced (WHO-DDE June 2014).  
Pretreatment medications are those medications with start and stop dates prior to the first dose of 
investigational product in the DB phase.  Prior concomitant medications are those medications 
that started prior to, and continued after, the first dose of investigational product in the DB phase.  
New concomitant medications are those medications that were started after the first dose of 
investigational product in the DB phase.  If it cannot be determined whether the medication was 
a new concomitant medication due to a partial start or stop date or if the medication is taken on 
the same date as the first OCA dose in the DB phase, then it will be counted as a new 
concomitant medication. 
Pretreatment medications will be presented in listings only.  Prior and new concomitant 
medications will be summarized by World Health Organization ATC class and preferred term 
using the ITT Population.  New concomitant medications will be summarized separately.  These 
summaries will present the number and percentage of subjects using each medication.  Subjects 
may have more than one medication per ATC class and preferred name.  A subject is counted 
once if one or more medication is reported at the ATC class or preferred term level.  Each 
summary will be ordered by descending order of incidence, for all OCA treated patients, of ATC 
class and preferred term within each ATC class. 
Prior and new concomitant medications will be presented a data listing. 


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9. 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will be based on the ITT Population, W12C and 
W24C populations.        
9.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint is the Week 24 change from Baseline in ALP.  Using the ITT 
population, the primary efficacy analysis will compare the Week 24 change from Baseline in 
ALP between OCA 10 mg treatment group and placebo and OCA 3 mg treatment group and 
placebo using an ANCOVA model with treatment group, visit, and randomization strata as fixed 
effects, and Baseline ALP as a covariate.   
In order, to provide estimates of the change from Baseline and corresponding 95% CI, the 
repeated measures ANCOVA methods described in Section 6.2.3 will be applied.  Model fit will 
be assessed in order to determine the validity of the estimates.  The analysis will be repeated with 
percentage change from Baseline as the dependent variable. Estimates of least-square (LS) 
means, SEs, and 95% CIs will be presented by treatment group. 
The values, change from Baseline, and percentage change from Baseline will be summarized 
using observed values by treatment group and visit using arithmetic summary statistics as 
described in Section 6.2.1.   
A hierarchical approach will be used for multiplicity adjustment across the primary efficacy 
endpoint for other visits and doses as described below.  If the primary efficacy analysis is 
statistically significant (p <0.05), the following order will be used in the testing procedure to 
compare the change from Baseline in ALP between OCA and placebo: 
• Week 12:  OCA 5 mg treatment group (randomized to 5 mg for the initial 12 weeks 
followed by 10 mg for the latter 12 weeks) vs. placebo 
• Week 24:  OCA 3 mg treatment group (randomized to 1.5 mg for the initial 12 weeks 
followed by 3 mg for the latter 12 weeks) vs. placebo  
• Week 12:  OCA 1.5 mg treatment group (randomized to 1.5 mg for the initial 
12 weeks followed by 3 mg for the latter 12 weeks) vs. placebo 
If at any step a comparison above is not statistically significant, then all subsequent comparisons 
will be exploratory rather than confirmatory. 
Sensitivity analysis for the primary efficacy analysis will be performed using the W12C and 
W24C Populations.  In addition, the arithmetic summary statistics will be presented by antibiotic 
use, IBD, UC, and CD subgroups as described in Section 6.2.8. 
An unblinded interim analysis of the primary endpoint will be conducted after approximately 
50% of the subjects have completed the initial 12-weeks of blinded treatment.  The interim 
analysis will use the same model described in Section 6.2.3 on the change from Baseline ALP to 
Week 12 in addition to Week 24. 


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9.2. 
Secondary Efficacy Analyses 
Secondary efficacy analyses of hepatic biochemistry and function parameters as described in 
Section 5.2.2 will be summarized by treatment group using descriptive statistics at Baseline and 
at each scheduled DB post-Baseline visit.  The change from Baseline will also be summarized.  
Hepatic biochemistry and function parameters will be analyzed using the same ANCOVA model 
as specified for the primary efficacy analysis.  
9.2.1. 
ALP Responders 
ALP response rates, defined as ALP to <1.5×ULN, will compare OCA treatment groups vs. 
placebo at Baseline and all DB post-baseline visits using a Cochran-Mantel-Haenszel test 
stratified by the randomization stratification factor. For this analysis, missing values will be 
imputed as described in Section 3.2.1. 
The proportion of responders will be summarized by treatment group and visit as described in 
Section 6.2.2 for W24C, W12C, and ITT populations. 
9.2.2. 
Hepatic Biochemistry and Indices of Function 
The secondary efficacy parameters related to hepatic biochemistry and are described in 
Section 5.2.2.  
These parameters will be analyzed using arithmetic summary statistics, ANCOVA, and model 
estimates with independent variables as described Section 6.2.3  for the primary efficacy 
endpoint. 
9.2.3. 
Markers of Hepatic and GI Inflammation, Disease, and Fibrosis 
The secondary efficacy parameters related to markers of hepatic and GI inflammation and 
disease include calprotectin, CRP, CK-18, IgA, IgG, IgM, IL-6, IL-12, IL-23, TGF-β, and TNF-
α.   
The secondary efficacy parameters related to measures of fibrosis include hepatic stiffness 
measurements obtained via TE (at participating sites), the ELF score and its components (HA, 
P3NP, T1MP-1). 
These parameters will be analyzed using arithmetic summary statistics, ANCOVA, and model 
estimates with independent variables as described in Section 6.2.3 for the primary efficacy 
endpoint.  
The proportion of fibrosis improvement based on TE measurement will be summarized using 
arithmetic summary statistics as described in Section 6.2.2  by treatment group at Week 24 of the 
DB phase.  Fibrosis improvement rates, any improvement vs. no improvement or worsening, will 
compare OCA treatment groups vs. placebo at Week 24 using a Cochran-Mantel-Haenszel test 
stratified by the randomization stratification factor. 
Fibrosis improvement will also be defined as follows: 
• Any improvement (Change from Baseline <0) 
• No change or Worsening (Change from Baseline equal to ≥0) 


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Calprotectin will potentially be analyzed.  The details of the analysis will be specified in a 
separate SAP.  
9.2.4. 
PK and PD Concentrations 
Unconjugated OCA, glyco-OCA, and tauro-OCA will be summed to create total OCA 
concentration.  Concentrations will be converted from ng/mL units for each analyte to 
ng-equivalence of OCA/mL units using the following molecular weights (MW):  unconjugated 
OCA = 420.6 g/mol, glyco-OCA = 477.7 g/mol, and tauro-OCA = 527.8 g/mol.  The PK 
Population will be used in the analysis of PK and bile acid data (if performed).  Data will be 
presented to 3 significant figures.  The PK and PD analyses are considered exploratory analyses 
per the protocol. 
9.2.4.1. 
PK Concentrations 
The values at Week 12 and Week 24 for OCA (unconjugated), glyco-OCA, tauro-OCA, total 
OCA, and C4 will be summarized using descriptive statistics as defined in Section 6.2.1 and 
Section 6.2.6 using both arithmetic and geometric statistics.  Plasma concentration data of OCA 
(unconjugated), glyco-OCA, tauro-OCA, total OCA, and C4 will be listed by subject, nominal 
sampling time, actual sampling time, and calculated elapsed time.  Standard summary statistics 
will be calculated for concentrations at each time point.  
Mean (SD) and median plasma concentration versus time data of OCA (unconjugated), 
glyco-OCA, tauro-OCA, total OCA, and C4 will be plotted on a linear and semi-logarithmic 
scale using nominal time. Figures of linear and semi-logarithmic plots will be generated for 
individual subject plasma concentration versus time using the actual sampling times. 
9.2.4.2. 
PK Parameters 
PK parameters will be determined using standard non-compartmental methods.  The PK of OCA 
and its conjugates will be summarized in tabular and graphical forms. The main PK parameters 
estimated in this study are: 
• Cmax, (ng/mL):  the first observed maximum plasma concentration;  
• tmax, (hr[s]):  the time after dosing at which Cmax is observed; and  
• AUC0-6, (hr*ng/mL):  area under the concentration-time curve from hour 0 to last 
post-dose sampling time (hour 6), calculated by the linear trapezoidal method.   
− The linear trapezoidal rule should be used for estimation of AUC  
− Where the clinical pharmacologist identifies that another method is more 
appropriate, the reason for this decision should be documented  
− At least 3 quantifiable concentration-time values must be available to compute 
AUClast 
Additional parameters may be calculated in order to further characterize the PK of OCA and its 
conjugates if deemed necessary. 
Plasma values below the limit of quantitation (BLQ) for OCA, glyco-OCA, tauro-OCA, and C4 
will be imputed to lower limit of quantification (LLOQ)/ 2. 


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Reporting and Significant Figures: The concentration data as reported by the respective 
bioanalytical group should be used without rounding for all analysis. The non-compartmental 
parameters should not be reported to any greater accuracy than that of the concentration data. 
Default significant figures used for reporting in text and tables of the study report is three 
significant figures, except for time related parameters (h) and for geometric least square mean 
ratios. Time related parameters (h) which will be presented with two decimal places. Geometric 
least square ratios will be presented with two decimal places.  
Week 12 and Week 24 AUC0-6 and Cmax for OCA (unconjugated), glyco-OCA, tauro-OCA,  total 
OCA, and C4 will be summarized using descriptive statistics as defined in Section 6.2.1 and 
Section 6.2.6 using both arithmetic and geometric statistics.  Tmax will be summarized using just 
the arithmetic methods described in Section 6.2.1.  All PK parameters will be presented in a 
listing by subject.  
9.2.4.3. 
Bile Acids 
Analysis of conjugated and unconjugated bile acids may be undertaken per the protocol. 
Bile acids include the following:  total bile acids, UDCA (unconjugated-UDCA, glyco-UDCA, 
tauro-UDCA), chenodeoxycholic acid (CDCA) (unconjugated-CDCA, glyco-CDCA, 
tauro-CDCA), LCA (unconjugated-LCA, glyco-LCA, tauro-LCA), cholic acid (CA) 
(unconjugated-CA, glyco-CA, tauro-CA), and deoxycholic acid (DCA) (unconjugated-DCA, 
glyco-DCA, tauro-DCA).   
The bile acid assay comprises 15 sub-component bile acid concentrations that will be used to 
create totals of the individual bile acid concentrations.  Concentrations of the bile acids will be 
converted to molar units using the molecular MWs of the bile acids.  The MWs of the bile acids 
and their conjugates are presented in Table 1.  For each bile acid, the assay will provide 3 
subcomponent values that will need to be summed to produce the total bile acid value, as shown 
below in Table 1.  As an example, the total UDCA concentration would be the sum of the glyco-, 
tauro-, and parent molecules. 
Table 1. Bile Acids and Their Sub-Components 
Derived 
Sub-Components (Molecular Weight) 
Total UDCA 
Glyco-UDCA 
(449.6 g/mol) 
Tauro-UDCA 
(499.7 g/mol) 
UDCA (392.6 g/mol) 
Total CDCA 
Glyco-CDCA 
(449.6 g/mol) 
Tauro-CDCA 
(499.7 g/mol) 
CDCA (392.6 g/mol) 
Total DCA 
Glyco-DCA 
(449.6 g/mol) 
Tauro-DCA 
(499.7 g/mol) 
DCA (392.6 g/mol) 
Total CA 
Glyco-CA 
(465.6 g/mol) 
Tauro-CA 
(515.7 g/mol) 
CA (408.6 g/mol) 
Total LCA 
Glyco-LCA 
(433.6 g/mol) 
Tauro-LCA 
(483.7 g/mol) 
LCA (376.6 g/mol) 


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Individual total bile acids are derived as the sum of all bile acids (total UDCA, total CDCA, total 
DCA, total CA, and total LCA). 
Total endogenous bile acids are derived as the sum of all bile acids, excluding all forms of OCA 
and UDCA. 
Proportions of each bile acid are derived as the individual bile acid total divided by total bile 
acids (eg, total UDCA/total bile acids). 
The PK population will be used to summarize the total bile acid concentrations.  The individual 
bile acids, total endogenous bile acids, and each of the bile acid proportions will be summarized 
by treatment group using descriptive statistics.  Values BLQ will be treated as lower limit of 
quantification (LLOQ)/2.  For total UDCA and total endogenous bile acid, the change from 
Baseline concentrations within each treatment group will be compared using a paired t-test.  
Only samples from subjects that have a confirmed fasting (based on eCRF) of approximately 
8 hours or more prior to the subject’s visit will be included in the analysis.  The final 
determination of subjects included in the PK population and the samples included will be 
determined prior to database lock of the DB phase. 
Reporting and Significant Figures: The concentration data as reported by the respective 
bioanalytical group should be used without rounding for all analysis. The non-compartmental 
parameters should not be reported to any greater accuracy than that of the concentration data. 
Default significant figures used for reporting in text and tables of the study report is three 
significant figures, except for time-related parameters (h) and for geometric least square mean 
ratios. Time-related parameters (h) will be presented with two decimal places. Geometric least 
square ratios will be presented with two decimal places.  
9.2.5. 
Exposure Response of Total OCA to Biomarkers 
Scatter plots of the Week 12 and Week 24 actual values and change from Baseline in biomarkers 
ALP, total bile acids, UDCA, CDCA, LCA, CA, DCA (conjugated and unconjugated forms) and 
C4 will be created versus total OCA plasma AUC0-6. 
9.2.6. 
Disease-specific symptoms 
The Pruritus VAS, Pruritus 5-D Itch questionnaire, Partial Mayo scoring system for assessment 
of UC activity (partial Mayo score), and Crohn’s disease activity index (CDAI) will be compared 
between OCA treatment groups and placebo at Week 12 and Week 24 using a Wilcoxon rank-
sum test.  This analysis will be repeated for change from Baseline and percent change from 
Baseline in these scores. 
The proportion of subjects in remission from Crohn’s disease (CDAI < 150) will be summarized 
by treatment group and visit using statistics as described in Section 6.2.2, and compared between 
treatment groups using Fisher’s exact test.  The analysis will be repeated for the proportions of 
subjects in remission from UC (partial Mayo score of ≤2 with no individual sub-score 
exceeding 1), and the proportion with mild disease (a partial Mayo score ≤3 with no individual 
sub-score exceeding 1 point). 


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9.3. 
Exploratory Analyses 
9.3.1. 
FXR Activity 
FXR activity will be assessed by measuring FGF-19. This parameter will be analyzed using 
arithmetic summary statistics, ANCOVA, and model estimates with independent variables as 
described in Section 6.2.3 for the primary efficacy endpoint. 
10. 
SAFETY ANALYSES 
All safety analyses will be based on the Safety Population.  The evaluation of the effects of OCA 
on safety parameters in the PSC population is a primary objective of this study. 
10.1. 
Extent of Exposure 
10.1.1. 
Investigational Product (OCA or Placebo) 
Subjects will titrate their dose of OCA or placebo at the Week 12 visit according to the criteria 
specified in the protocol.  Frequency counts and percentages of the number of subjects who do 
not up-titrate will be summarized. The duration of investigational product exposure will be 
calculated as Follows: 
• Exposure to investigational product = {[(Date of last investigational product  
dose–Date of 1st investigational product dose) + 1] - Total duration of temporary 
investigational product 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 
investigational product - Date of temporary discontinuation of investigational 
product) + 1. 
The total duration of temporary investigational product discontinuation is the sum duration of 
temporary discontinuation of investigational product over each incidence of discontinuation. 
Total investigational product (mg) exposed to subject will be calculated by adding the doses 
taken by a subject during the study and will be summarized using descriptive statistics. 
Subject’s overall compliance (%) with investigational product will be calculated as follows: 
• (# of days consumed during study)/ (# of days on study drug, excluding drug 
holidays) * 100 
Investigational product compliance will be summarized by treatment group using descriptive 
statistics.     
Additional summaries will present the number and percentage of subjects with any drug 
interruption, subjects with alternate dosing, subjects with reduced dose, subjects who did not 
titrate dose at Week 12, and number of subjects with permanent discontinuation.  Denominators 
for calculating percentages will be based on the number of subjects who received at least one 


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dose in the treatment group summarized.  All exposure data will be presented in a subject data 
listing. 
10.2. 
Adverse Events (AEs) 
All AE summaries will be restricted to treatment-emergent adverse events (TEAEs), which are 
defined as any AEs that newly appear, increase in frequency, or worsen in severity following 
initiation of study medication.  If it cannot be determined whether the AE is treatment emergent 
due to a partial onset date, then it will be counted as treatment emergent.  Verbatim terms on 
eCRFs will be mapped to preferred terms and system organ classes using MedDRA 
(version 17.1).  
Summaries that are displayed by system organ class and preferred terms will be ordered by 
descending order of incidence for all OCA treated patients of system organ class and by 
preferred terms within each system organ class.  Summaries of the following types will be 
presented by treatment group: 
• Overall summary of TEAEs 
• Subject incidence of TEAEs and the total number of entries by MedDRA system 
organ class and preferred term.     
• Subject incidence of drug-related TEAEs by MedDRA system organ class and 
preferred term.  Related AEs are those with relationships reported as “Definite,” 
“Probable,” “Possible,” or with a missing relationship.   
• Subject incidence of serious adverse events (SAEs) by MedDRA system organ class 
and preferred term.  
• Subject incidence of TEAEs leading to investigational product withdrawal or study 
discontinuation by MedDRA system organ class and preferred term.  This is a subset 
of the AEs where Action Taken with Study Medication is checked as “Drug 
Withdrawn” or Subject Discontinued from Study is checked.  
• Subject incidence of TEAEs leading to investigational product withdrawal by 
MedDRA system organ class and preferred term.  This is a subset of the AEs where 
Action Taken with Study Medication is checked as “Drug Withdrawn”. 
• Subject incidence of TEAEs leading to study discontinuation by MedDRA system 
organ class and preferred term.  This is a subset of the AEs where Subject 
Discontinued from Study is checked. 
• Subject incidence of TEAEs by MedDRA system organ class, preferred term, and 
maximum severity will be presented.  At each level of subject summarization, a 
subject is classified according to the maximum severity if the subject reported one or 
more events.  AEs with missing severity will be considered severe for this summary. 
• Subject incidence of follow-up TEAEs and the total number of entries by MedDRA 
system organ class and preferred term.  Follow-up TEAEs are defined as those 
TEAEs with onset after the Week 24 visit, for those subjects not continuing to the 
LTSE phase.   


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The summaries above will be repeated presenting only preferred term ordered by descending 
order of incidence for all OCA treated patients, excluding system organ class.   
The incidence of pre-treatment AEs and pre-treatment SAEs occurring after ICF signoff and 
before the first dosing of investigational product (OCA or placebo) will be tabulated in the same 
manner as above for all subjects participating in the washout period. 
The following listings will be presented by subject: 
• All AEs  
• Serious AEs (subset of the AEs where serious is marked as “Yes”) 
• Death information will be provided in a separate listing, should any deaths occur 
• Severe AEs (subset of AEs where severity is marked as “Severe” or severity is 
missing) 
• Related AEs (subset of AEs where relationship to study medication is marked as 
“Definite”, “Possible” or “Probable”) 
• AE’s leading to withdrawal of investigational product (subset of AEs where action 
taken with study medication is marked as “Drug Withdrawn”) 
• AE’s leading to Study Discontinuation (subset of AEs where subject discontinued 
from study is checked) 
10.3. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are pruritus, and dyslipidaemia.  For each of these 
AESI, subject incidence of TEAEs and the total number of entries by MedDRA system organ 
class and preferred term will be presented.  In addition, for each AESI, the time to first onset and 
time to most severe event will be summarized using descriptive statistics. 
10.3.1. 
Pruritus 
Treatment-emergent pruritus, defined as any preferred term including “Prur,” will be 
summarized separately by the MedDRA system organ class (SOC), treatment group, and 
preferred term (PT) as a subset of all TEAEs.   
An analysis of treatment-emergent pruritus event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  Each individual patient year on study will be derived as the last 
known date during the study minus the first dose date plus 1 divided by 365.25 days/year.   
In order to explore the relationship between pruritus and the investigational product, the 
following time-to-event analyses will be performed: 
• Time to first onset of treatment-emergent pruritus  
− The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 


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Subjects who never report an AE of pruritus will be censored at the date of last 
contact. 
• Time to onset of the first severe treatment-emergent pruritus 
− The time to the start of the first serious pruritus will be calculated by date of onset 
of the first severe pruritus – date of first dose of investigational product + 1. 
− Subjects who never report a severe AE of pruritus will be censored at the date of 
completion or discontinuation. 
• Time to resolution of the most severe treatment-emergent pruritus event  
− The time to resolution of the most severe event of treatment-emergent pruritus 
will be calculated by date of resolution of the most severe event of treatment-
emergent pruritus – start date of the most severe event of treatment-emergent 
pruritus + 1.   
− Subjects whose most severe event of treatment-emergent pruritus is ongoing will 
be censored at the date of completion or discontinuation.  For subjects that are lost 
to follow-up, the last contact date will be used. 
− Only subjects that report a pruritus event are included in this analysis. 
− Separate summaries will be presented for those who discontinue due to pruritus. 
The analysis of time to event will include the number of subjects with the event (first onset, first 
moderate or severe, first severe), the number of subjects without the event (censored), descriptive 
statistics of time for those with an event, and range in days for all subjects.  Kaplan-Meier (KM) 
estimates will be calculated by treatment group.  The quartiles, including the median time-to-
event and their respective 2-sided 95% CIs, will be presented.  KM estimates will be plotted as a 
“survival curve” for each treatment group, with the number at risk identified.  The comparison of 
OCA to placebo will be summarized using a log-rank test stratified by randomization strata 
factor.  The analysis will be repeated on the subset of subjects who experienced a treatment-
emergent pruritus event. 
10.3.2. 
Dyslipidaemia  
AE lipid profile changes, defined in the Dyslipidaemia SMQ, will be reported. See Appendix B 
for a list of the preferred terms and their associated codes.  These events will be summarized 
separately by the MedDRA system organ class (SOC), treatment group, and preferred term (PT) 
as a subset of all TEAEs. 
In order to explore the relationship between dyslipidaemia and the investigational product, the 
following time-to-event analyses will be performed: 
• Time to first onset of treatment-emergent dyslipidaemia  
− The time to the start of the first episode will be calculated by date of onset of first 
episode – date of first dose of investigational product + 1. 
The analysis of time to event will include the number of subjects with the event (first onset) and 
the number of subjects without the event (censored), descriptive statistics of time for those with 


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an event, and range in days for all subjects.  Kaplan-Meier (KM) estimates will be calculated by 
treatment group.  The quartiles, including the median time-to-event and their respective 2-sided 
95% CIs, will be presented.  KM estimates will be plotted as a “survival curve” for each 
treatment group, with the number at risk identified.  The comparison of OCA to placebo will be 
summarized using a log-rank test stratified by randomization strata factor. 
10.4. 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations during the DB phase are assessed at the central laboratory.  A 
listing of available laboratory reference/normal ranges for each laboratory parameter will be 
provided including age, sex, values with units.  All analyses of lipoprotein will include fasted 
samples only. 
Quantitative hematology, coagulation, serum chemistry, apolipoprotein and nuclear magnetic 
resonance (NMR) lipoprotein panel laboratory parameters will be summarized by treatment group 
in SI units using arithmetic summary statistics as described in Section 6.2.1 at Baseline and at 
each scheduled DB post-Baseline visit.  Change from Baseline will also be summarized in the 
same manner.  Re-tests or unscheduled visit results after first dose of investigational product in 
the DB phase will not be summarized but will be included in the data listings.   
In addition, shift tables (ie, low-normal-high at Baseline versus low-normal-high at DB post-
Baseline Visit in a 3-by-3 contingency table) from Baseline to worst value, last value, and at 
each scheduled DB post-Baseline visit will be provided for hematology, coagulation, and serum 
chemistry by treatment group.  
Urinalysis results will not be summarized but will be provided in a data listing. 
Listings of all laboratory values will flag values outside of the normal range as high (H) or low 
(L) and indicate whether or not a value is clinically significant (CS), based on investigator 
judgment. 
For laboratory test results that are below the quantifiable limits: 
Imputed laboratory result = (numeric portion of the result) × 0.9. 
For laboratory test results that are above the quantifiable limits: 
Imputed laboratory result = (numeric portion of the result) × 1.1. 
10.5. 
Vital Signs 
Vital signs (oral temperature, sitting heart rate, respiratory rate, and sitting blood pressure 
[systolic and diastolic]) will be summarized using arithmetic summary statistics as described in 
Section 6.2.1 at Baseline and at each DB post-Baseline visit.  Change from Baseline will also be 
summarized in the same manner.  Re-tests or unscheduled visit results prior to the administration 
time of the first dose in the DB phase will be included in the calculation of Baseline.  Re-tests or 
unscheduled visit results after the first dose of investigational product administration will not be 
summarized but will be included in the data listings.  


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10.6. 
Electrocardiograms (ECGs) 
Overall interpretation results for ECGs and the Investigator interpretation results are collected as 
normal, abnormal-not clinically significant, and abnormal-clinically significant.  Subjects whose 
interpretation shifts from normal at Baseline to abnormal at any DB post-Baseline visit will be 
summarized by treatment group and visit. In addition, these will be listed separately including 
description of the abnormality and any associated comments. 
11. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES AND 
ENDPOINTS 
Gut microbiome and genetic samples will potentially be analyzed.  Details of this analysis will 
be included in a separate SAP.   
12. 
REFERENCES 
D’Agostino R.B., Belanger A, D’Agostino R.B. Jr. A suggestion for using powerful and 
informative tests of normality. The American Statistician; 1990;44(4):316-21. 
Elman S, Hynan L, Gabriel V, et al. The 5-D itch scale: a new measure of pruritus. British 
Journal of Dermatology. 2010;162:587-593. 
Glaser, R.E. Levene’s robust test of homogeneity of variances. Encyclopedia of Statistical 
Sciences. New York: John Wiley and Sons; 1982:608-610. 


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13. 
 APPENDICES 
APPENDIX A. LIST OF TABLES, FIGURES, AND LISTINGS 
List of Tables 
Table Number 
Population 
Table Title 
14.1 
 
Demographic Data 
14.1.1 
All 
Randomized 
Subjects 
Summary of Analysis Populations During 
14.1.2 
ITT 
Summary of Subject Disposition  
14.1.3 
ITT 
Summary of Protocol Deviations  
14.1.4.1 
ITT 
Summary of Demographics and Baseline Characteristics 
14.1.4.2 
PK 
Summary of Demographics and Baseline Characteristics  
14.1.4.3 
Safety 
Summary of Demographics and Baseline Characteristics  
14.1.4.4 
W12C 
Summary of Demographics and Baseline Characteristics  
14.1.4.5 
W24C 
Summary of Demographics and Baseline Characteristics  
14.1.4.6 
ITT 
Summary of Demographics and Baseline Characteristics by IBD 
Status 
14.1.4.7 
ITT 
Summary of Demographics and Baseline Characteristics by UC 
Status 
14.1.4.8 
ITT 
Summary of Demographics and Baseline Characteristics by CD 
Status 
14.1.4.9 
ITT 
Summary of Demographics and Baseline Characteristics by 
Baseline BMI  
14.1.4.10 
ITT 
Summary of Demographics and Baseline Characteristics by 
Baseline UDCA Use 
14.1.4.11 
ITT  
Summary of Demographics and Baseline Characteristics by 
Baseline Total Bilirubin  
14.1.4.12 
ITT 
Summary of Demographics and Baseline Characteristics by Gender 
14.1.4.13 
ITT 
Summary of Demographics and Baseline Characteristics by 
Baseline TE Score 
14.1.5.1 
ITT 
Summary of PSC Disease History 
14.1.5.2 
W12C 
Summary of PSC Disease History 
14.1.5.3 
W24C 
Summary of PSC Disease History 
14.1.5.4 
ITT 
Summary of PSC Disease History by IBD Status 
14.1.5.5 
ITT 
Summary of PSC Disease History by UC Status  


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14.1.5.6 
ITT 
Summary of PSC Disease History by CD Status 
14.1.5.7 
ITT 
Summary of PSC Disease History by Baseline BMI 
14.1.5.8 
ITT 
Summary of PSC Disease History by Baseline UDCA Use 
14.1.5.9 
ITT 
Summary of PSC Disease History by Baseline Total Bilirubin 
14.1.5.10 
ITT 
Summary of PSC Disease History by Gender 
14.1.5.11 
ITT 
Summary of PSC Disease History by Baseline TE Score 
14.1.6 
ITT 
Summary of Abnormal Medical History at Baseline 
14.2 
 
Efficacy Data 
14.2.1.1 
W24C 
Summary of Alkaline Phosphatase by Treatment and Visit  
14.2.1.2 
W12C 
Summary of Alkaline Phosphatase by Treatment and Visit  
14.2.1.3 
ITT 
Summary of Alkaline Phosphatase by Treatment and Visit  
14.2.1.4 
ITT 
Summary of Alkaline Phosphatase by Baseline Antibiotic Use, 
Treatment, and Visit 
14.2.1.5 
ITT 
Summary of Alkaline Phosphatase by IBD Status, Treatment, and 
Visit  
14.2.1.6 
ITT 
Summary of Alkaline Phosphatase by UC Status, Treatment, and 
Visit  
14.2.1.7 
 
ITT 
Summary of Alkaline Phosphatase by CD Status, Treatment, and 
Visit  
14.2.1.8 
ITT 
Summary of Alkaline Phosphatase by Baseline BMI, Treatment 
and Visit 
14.2.1.9 
ITT 
Summary of Alkaline Phosphatase by Baseline UDCA Use, 
Treatment and Visit 
14.2.1.10 
ITT 
Summary of Alkaline Phosphatase by Baseline Total Bilirubin, 
Treatment and Visit 
14.2.1.11 
ITT 
Summary of Alkaline Phosphatase by Gender, Treatment and Visit 
14.2.1.12 
ITT 
Summary of Alkaline Phosphatase by Baseline Median TE Score, 
Treatment and Visit 
14.2.2.1 
ITT 
Summary of Alkaline Phosphatase by Treatment and Visit 
(MMRM)  
14.2.3.1.1 
W24C 
Summary of Subjects with Alkaline Phosphatase < 1.5 x Upper 
Limit of Normal by Treatment and Visit  
14.2.3.1.2 
W12C 
Summary of Subjects with Alkaline Phosphatase < 1.5 x Upper 
Limit of Normal by Treatment and Visit 
14.2.3.1.3 
ITT 
Summary of Subjects with Alkaline Phosphatase < 1.5 x Upper 
Limit of Normal by Treatment and Visit 


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14.2.3.2.1 
W24C 
Summary of Subjects with ≥ 10% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.2.2 
W12C 
Summary of Subjects with ≥ 10% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.2.3 
ITT 
Summary of Subjects with ≥ 10% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit  
14.2.3.3.1 
W24C 
Summary of Subjects with ≥ 15% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.3.2 
W12C 
Summary of Subjects with ≥ 15% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit  
14.2.3.3.3 
ITT 
Summary of Subjects with ≥ 15% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit  
14.2.3.4.1 
W24C 
Summary of Subjects with ≥ 20% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.4.2 
W12C 
Summary of Subjects with ≥ 20% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.4.3 
ITT 
Summary of Subjects with ≥ 20% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit  
14.2.3.5.1 
W24C 
Summary of Subjects with ≥ 25% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.5.2 
W12C 
Summary of Subjects with ≥ 25% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.5.3 
ITT 
Summary of Subjects with ≥ 25% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit  
14.2.3.6.1 
W24C 
Summary of Subjects with ≥ 30% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.6.2 
W12C 
Summary of Subjects with ≥ 30% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.6.3 
ITT 
Summary of Subjects with ≥ 30% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit  
14.2.3.7.1 
W24 
Summary of Subjects with ≥ 35% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.7.2 
W12C 
Summary of Subjects with ≥ 35% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.7.3 
ITT 
Summary of Subjects with ≥ 35% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit  
14.2.3.8.1 
W24C 
Summary of Subjects with ≥ 40% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 
14.2.3.8.2 
W12C 
Summary of Subjects with ≥ 40% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit 


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14.2.3.8.3 
ITT 
Summary of Subjects with ≥ 40% Reduction from Baseline in 
Alkaline Phosphatase by Treatment and Visit  
14.2.4.1 
ITT 
Summary of Hepatic Biochemistry and Indices of Function by 
Treatment and Visit – ANCOVA 
14.2.4.2 
ITT 
Summary of Hepatic Biochemistry and Indices of Function by 
Treatment and Visit – MMRM 
14.2.5.1 
ITT 
Summary of Markers of Hepatic and GI Inflammation and Disease 
by Treatment and Visit – ANCOVA 
14.2.5.2 
ITT 
Summary of Markers of Hepatic and GI Inflammation and Disease 
by Treatment and Visit – MMRM 
14.2.6.1 
ITT 
Summary of Transient Elastography by Treatment and Visit  
14.2.6.2 
ITT 
Summary of Liver Fibrosis Improvement via Transient 
Elastography by Treatment 
14.2.6.3 
ITT 
Summary of Enhanced Liver Fibrosis Score and Components by 
Treatment and Visit 
14.2.7 
ITT 
Summary of Farnesoid X Receptor Activity by Treatment and Visit 
14.2.8.1 
ITT 
Summary of Pruritus Visual Analogue Scale Scores by Treatment 
and Visit 
14.2.8.2 
ITT 
Summary of Pruritus 5-D Itch Scores by Treatment and Visit 
14.2.8.3 
ITT 
Summary of Partial Mayo Score by Treatment and Visit 
14.2.8.4 
ITT 
Summary of Chron’s Disease Activity Index Score by Treatment 
and Visit 
14.2.9.1 
ITT 
Summary of Ulcerative Colitis Remission by Treatment and Visit 
14.2.9.2 
ITT 
Summary of Mild Ulcerative Colitis by Treatment and Visit 
14.2.9.3 
ITT 
Summary of Crohn’s Disease Remission by Treatment and Visit 
14.2.10 
PK 
Summary of Week 12 and 24 Plasma Concentrations for 
Unconjugated OCA, OCA, Glyco-OCA, Tauro-OCA, and Total 
OCA 
14.2.8 
PK 
Summary of Week 12 and 24 Plasma PK Parameters for 
Unconjugated OCA, OCA, Glyco-OCA, Tauro-OCA, and Total 
OCA  
14.2.9.1 
PK 
Summary of Total Bile Acids and Total Endogenous Bile Acids  
14.2.9.2 
PK 
Summary of Bile Acids and Bile Acid Sub-components 
14.2.9.3 
PK 
Summary of Bile Acid Proportions 
14.3 
 
Safety Data 
14.3.1 
ITT 
Summary of Investigational Product Exposure 
14.3.2.1 
ITT 
Summary of Prior Concomitant Medications 


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14.3.2.2 
ITT 
Summary of New Concomitant Medications 
14.3.1 
 
Displays of Adverse Events 
14.3.1.1 
Safety 
Overall Summary of Treatment Emergent Adverse Events 
14.3.1.2.1 
Safety 
Summary of Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term 
14.3.1.2.2 
Safety 
Summary of Treatment Emergent Adverse Events by Preferred 
Term 
14.3.1.3.1 
Safety 
Summary of Investigational product-related Treatment Emergent 
Adverse Events by System Organ Class and Preferred Term 
14.3.1.3.2 
Safety 
Summary of Investigational product-related Treatment Emergent 
Adverse Events by Preferred Term 
14.3.1.4.1 
Safety 
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term 
14.3.1.4.2 
Safety 
Summary of Serious Adverse Events by Preferred Term 
14.3.1.5.1 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to 
Investigational Product Withdrawal or Study Discontinuation by 
System Organ Class and Preferred Term 
14.3.1.5.2 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to 
Investigational Product Withdrawal or Study Discontinuation by 
Preferred Term 
14.3.1.6.1 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to 
Investigational Product Withdrawal by System Organ Class and 
Preferred Term 
14.3.1.6.2 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to 
Investigational Product Withdrawal by Preferred Term 
14.3.1.7.1 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to 
Study Discontinuation by System Organ Class and Preferred 
Term 
14.3.1.7.2 
Safety 
Summary of Treatment-Emergent Adverse Events Leading to 
Study Discontinuation by Preferred Term 
14.3.1.8.1 
Safety 
Summary of Treatment Emergent Adverse Events by Maximum 
Severity, System Organ Class, and Preferred Term 
14.3.1.8.2 
Safety 
Summary of Treatment Emergent Adverse Events by Maximum 
Severity and Preferred Term 
14.3.1.9.1 
Safety 
Summary of Pruritus Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term 
14.3.1.9.2 
Safety 
Summary of Pruritus Treatment Emergent Adverse Events by 
Preferred Term 
14.3.1.9.3 
Safety  
Treatment-Emergent Pruritus Event Days  


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14.3.1.9.4 
Safety  
Time to Onset of First Treatment Emergent Pruritus 
14.3.1.9.5 
Safety  
Time to Onset of Most Severe Treatment Emergent Pruritus 
14.3.1.9.6 
Safety  
Time to Resolution of the Most Severe Treatment Emergent 
Pruritus 
14.3.1.10.1 
Safety 
Summary of Dyslipidaemia Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term 
14.3.1.10.2 
Safety 
Summary of Dyslipidaemia Treatment Emergent Adverse Events 
by Preferred Term 
14.3.1.10.3 
Safety 
Time to Onset of First Treatment Emergent Dyslipidaemia 
14.3.1.11.1 
ITT 
Summary of On-Study Procedures by System Organ Class and 
Preferred Term 
14.3.1.11.2 
ITT 
Summary of On-Study Procedures by Preferred Term 
14.3.4 
 
Clinical Laboratory Evaluations 
14.3.4.1 
Safety 
Summary of Hematology and Coagulation by Treatment and Visit 
14.3.4.1.2 
Safety 
Hematology and Coagulation Shift Analysis by Treatment and 
Visit  
14.3.4.2.1 
Safety 
Summary of Serum Chemistry by Treatment and Visit – SI Units 
14.3.4.2.2 
Safety 
Summary of Serum Chemistry by Treatment and Visit – CV Units 
14.3.4.2.3 
Safety 
Serum Chemistry Shift Analysis by Treatment and Visit 
14.3.4.3 
Safety 
Summary of Apolipoprotein by Treatment and Visit 
14.3.4.4 
Safety 
Summary of Nuclear Magnetic Resonance Lipoprotein Panel by 
Treatment and Visit  
14.3.4.5 
Safety 
NMR Lipoprotein Shift Analysis by Treatment and Visit 
14.3.4.6 
Safety 
Summary of Vital Signs by Treatment and Visit 
14.3.4.7 
Safety 
Electrocardiogram Shift from Baseline by Treatment 
 
 
 


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List of Figures 
Figure Number 
Population 
Figure Title 
14.2 
 
Efficacy Data 
14.2.1.1 
PK 
Individual Plasma Concentration of OCA (Unconjugated) Over 
Time  
14.2.1.2 
PK 
Individual Plasma Concentration of Glyco-OCA Over Time  
14.2.1.3 
PK 
Individual Plasma Concentration of Tauro-OCA Over Time  
14.2.1.4 
PK 
Individual Plasma Concentration of Total OCA Over Time  
14.2.2.1 
PK 
Mean (SD) Plasma Concentration of OCA (Unconjugated) Over 
Time 
14.2.2.2 
PK 
Mean (SD) Plasma Concentration of Total Glyco-OCA Over Time 
14.2.2.3 
PK 
Mean (SD) Plasma Concentration of Total Tauro-OCA Over Time 
14.2.2.4 
PK 
Mean (SD) Plasma Concentration of Total OCA Over Time 
14.2.3.1.1.1 
PK 
Scatter Plot of Week 12 ALP versus Total OCA AUC0-6 
14.2.3.1.1.2 
PK 
Scatter Plot of Week 24 ALP versus Total OCA AUC0-6 
14.2.3.1.2.1 
PK 
Scatter Plot of Week 12 Change from Baseline in ALP versus Total 
OCA AUC0-6 
14.2.3.1.2.2 
PK 
Scatter Plot of Week 24 Change from Baseline in ALP versus Total 
OCA AUC0-6 
14.2.3.2.1.1 
PK 
Scatter Plot of Week 12 Total Bile Acids versus Total OCA AUC0-6 
14.2.3.2.1.2 
PK 
Scatter Plot of Week 24 Total Bile Acids versus Total OCA AUC0-6 
14.2.3.2.2.1 
PK 
Scatter Plot of Week 12 Change from Baseline in Total Bile Acids 
versus Total OCA AUC0-6 
14.2.3.2.2.2 
PK 
Scatter Plot of Week 24 Change from Baseline in Total Bile Acids 
versus Total OCA AUC0-6 
14.2.3.3.1.1.1 
PK 
Scatter Plot of Week 12 UCDA (conjugated) versus Total OCA 
AUC0-6 
14.2.3.3.1.1.2 
PK 
Scatter Plot of Week 12 UCDA (unconjugated) versus Total OCA 
AUC0-6 
14.2.3.3.1.2.1 
PK 
Scatter Plot of Week 24 UCDA (conjugated) versus Total OCA 
AUC0-6 
14.2.3.3.1.2.2 
PK 
Scatter Plot of Week 24 UCDA (unconjugated) versus Total OCA 
AUC0-6  
14.2.3.3.2.1.1 
PK 
Scatter Plot of Week 12 Change from Baseline in UCDA 
(conjugated) versus Total OCA AUC0-6 
14.2.3.3.2.1.2 
PK 
Scatter Plot of Week 12 Change from Baseline in UCDA 
(unconjugated) versus Total OCA AUC0-6 


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14.2.3.3.2.2.1 
PK 
Scatter Plot of Week 24 Change from Baseline in UCDA 
(conjugated) versus Total OCA AUC0-6 
14.2.3.3.2.2.2 
PK 
Scatter Plot of Week 24 Change from Baseline in UCDA 
(unconjugated) versus Total OCA AUC0-6  
14.2.3.4.1.1.1 
PK 
Scatter Plot of Week 12 CDCA (conjugated) versus Total OCA 
AUC0-6 
14.2.3.4.1.1.2 
PK 
Scatter Plot of Week 12 CDCA (unconjugated) versus Total OCA 
AUC0-6 
14.2.3.4.1.2.1 
PK 
Scatter Plot of Week 24 CDCA (conjugated) versus Total OCA 
AUC0-6 
14.2.3.4.1.2.2 
PK 
Scatter Plot of Week 24 CDCA (unconjugated) versus Total OCA 
AUC0-6  
14.2.3.4.2.1.1 
PK 
Scatter Plot of Week 12 Change from Baseline in CDCA 
(conjugated) versus Total OCA AUC0-6 
14.2.3.4.2.1.2 
PK 
Scatter Plot of Week 12 Change from Baseline in CDCA 
(unconjugated) versus Total OCA AUC0-6 
14.2.3.4.2.2.1 
PK 
Scatter Plot of Week 24 Change from Baseline in CDCA 
(conjugated) versus Total OCA AUC0-6 
14.2.3.4.2.2.2 
PK 
Scatter Plot of Week 24 Change from Baseline in CDCA 
(unconjugated) versus Total OCA AUC0-6  
14.2.3.5.1.1.1 
PK 
Scatter Plot of Week 12 LCA (conjugated) versus Total OCA AUC0-
6 
14.2.3.5.1.1.2 
PK 
Scatter Plot of Week 12 LCA (unconjugated) versus Total OCA 
AUC0-6 
14.2.3.5.1.2.1 
PK 
Scatter Plot of Week 24 LCA (conjugated) versus Total OCA AUC0-
6 
14.2.3.5.1.2.2 
PK 
Scatter Plot of Week 24 LCA (unconjugated) versus Total OCA 
AUC0-6  
14.2.3.5.2.1.1 
PK 
Scatter Plot of Week 12 Change from Baseline in LCA (conjugated) 
versus Total OCA AUC0-6 
14.2.3.5.2.1.2 
PK 
Scatter Plot of Week 12 Change from Baseline in LCA 
(unconjugated) versus Total OCA AUC0-6 
14.2.3.5.2.2.1 
PK 
Scatter Plot of Week 24 Change from Baseline in LCA (conjugated) 
versus Total OCA AUC0-6 
14.2.3.5.2.2.2 
PK 
Scatter Plot of Week 24 Change from Baseline in LCA 
(unconjugated) versus Total OCA AUC0-6  
14.2.3.6.1.1.1 
PK 
Scatter Plot of Week 12 CA (conjugated) versus Total OCA AUC0-6 
14.2.3.6.1.1.2 
PK 
Scatter Plot of Week 12 CA (unconjugated) versus Total OCA 
AUC0-6 


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14.2.3.6.1.2.1 
PK 
Scatter Plot of Week 24 CA (conjugated) versus Total OCA AUC0-6 
14.2.3.6.1.2.2 
PK 
Scatter Plot of Week 24 CA (unconjugated) versus Total OCA 
AUC0-6  
14.2.3.6.2.1.1 
PK 
Scatter Plot of Week 12 Change from Baseline in CA (conjugated) 
versus Total OCA AUC0-6 
14.2.3.6.2.1.2 
PK 
Scatter Plot of Week 12 Change from Baseline in CA 
(unconjugated) versus Total OCA AUC0-6 
14.2.3.6.2.2.1 
PK 
Scatter Plot of Week 24 Change from Baseline in CA (conjugated) 
versus Total OCA AUC0-6 
14.2.3.6.2.2.2 
PK 
Scatter Plot of Week 24 Change from Baseline in CA 
(unconjugated) versus Total OCA AUC0-6  
14.2.3.7.1.1.1 
PK 
Scatter Plot of Week 12 DCA (conjugated) versus Total OCA 
AUC0-6 
14.2.3.7.1.1.2 
PK 
Scatter Plot of Week 12 DCA (unconjugated) versus Total OCA 
AUC0-6 
14.2.3.7.1.2.1 
PK 
Scatter Plot of Week 24 DCA (conjugated) versus Total OCA 
AUC0-6 
14.2.3.7.1.2.2 
PK 
Scatter Plot of Week 24 DCA (unconjugated) versus Total OCA 
AUC0-6  
14.2.3.7.2.1.1 
PK 
Scatter Plot of Week 12 Change from Baseline in DCA (conjugated) 
versus Total OCA AUC0-6 
14.2.3.7.2.1.2 
PK 
Scatter Plot of Week 12 Change from Baseline in DCA 
(unconjugated) versus Total OCA AUC0-6 
14.2.3.7.2.2.1 
PK 
Scatter Plot of Week 24 Change from Baseline in DCA (conjugated) 
versus Total OCA AUC0-6 
14.2.3.7.2.2.2 
PK 
Scatter Plot of Week 24 Change from Baseline in DCA 
(unconjugated) versus Total OCA AUC0-6  
14.2.3.2.1.1 
PK 
Scatter Plot of Week 12 C4 versus Total OCA AUC0-6 
14.2.3.2.1.2 
PK 
Scatter Plot of Week 24 C4 versus Total OCA AUC0-6 
14.2.3.8.1.1 
PK 
Scatter Plot of Week 12 Change from Baseline in C4 versus Total 
OCA AUC0-6 
14.2.3.8.1.2 
PK 
Scatter Plot of Week 24 Change from Baseline in C4 versus Total 
OCA AUC0-6 
14.2.3.8.2.1 
PK 
Scatter Plot of Week 12 Change from Baseline in C4 versus Total 
OCA AUC0-6 
14.2.3.8.2.2 
PK 
Scatter Plot of Week 24 Change from Baseline in C4 versus Total 
OCA AUC0-6 
 
 
 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
Confidential 
Page 47 of 50 
List of Data Listings 
Listing 
Number 
Listing Title 
16.2 
Subject Data Listings 
16.2.1 
Discontinued subjects 
16.2.1.1 
Analysis Populations  
16.2.1.2 
Subject Disposition  
16.2.2 
Protocol deviations 
16.2.2.1 
Protocol Deviations 
16.2.2.2 
Inclusion and Exclusion Criteria Findings 
16.2.4 
Demographic data 
16.2.4.1 
Demographics and Baseline Characteristics 
16.2.4.2 
PSC Disease History 
16.2.4.3 
Medical History 
16.2.5 
Compliance and/or drug concentration data 
16.2.5.1 
Investigational Product Accountability 
16.2.5.2 
Investigational Product Exposure 
16.2.5.3 
UDCA Administration 
16.2.5.4 
Concomitant Medications 
16.2.5.5.1 
Plasma Concentration Collection Information 
16.2.5.5.2 
Plasma Concentration Data for OCA, Glyco-OCA, Tauro-OCA, and Total OCA 
16.2.5.5.3 
Plasma PK Parameters for OCA, Glyco-OCA, Tauro-OCA, and Total OCA  
16.2.5.6.1 
Bile Acids and Bile Acid Subcomponents 
16.2.5.6.2 
Total Bile Acids and Total Endogenous Bile Acids 
16.2.6 
Individual efficacy response data 
16.2.6.1 
Alkaline Phosphatase 
16.2.6.2 
Hepatic Biochemistry and Indices of Function 
16.2.6.3 
Markers of Hepatic and GI Inflammation and Disease 
16.2.6.4 
Transient Elastography 
16.2.6.5 
Enhanced Liver Fibrosis Score and Components 
16.2.6.6 
Farnesoid X Receptor Activity 
16.2.6.7.1 
Pruritus Visual Analogue Scale Scores 
16.2.6.7.2 
Pruritus 5-D Itch Scores 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
Confidential 
Page 48 of 50 
16.2.6.8 
Partial Mayo Score 
16.2.6.9 
Chron’s Disease Activity Index Score 
16.2.6.10 
Transient Elastography 
16.2.7 
Adverse events listings 
16.2.7.1 
Adverse Events 
16.2.7.2 
Serious Adverse Events 
16.2.7.3 
Severe Adverse Events 
16.2.7.4 
Adverse Events Leading to Investigational Product Withdrawal or Study 
Discontinuation 
16.2.7.5 
Adverse Events Related to Investigational Product 
16.2.7.6 
Adverse Events Leading to Investigational Product Withdrawal 
16.2.7.7 
Adverse Events Leading to Investigational Study Discontinuation 
16.2.7.8 
Adverse Events Leading to Death 
16.2.8 
Listing of individual laboratory measurements by subject, when required by 
regulatory authorities 
16.2.8.1 
Laboratory Sample Collection 
16.2.8.2 
Hematology and Coagulation  
16.2.8.3.1 
Serum Chemistry – SI Units 
16.2.8.3.2 
Serum Chemistry – CV Units 
16.2.8.4 
Urinalysis 
16.2.8.5 
Apolipoprotein and NMR Lipoprotein  
16.2.8.6.1 
Laboratory Reference/Normal Ranges – SI Units 
16.2.8.6.2 
Laboratory Reference/Normal Ranges – CV Units 
16.2.9 
Additional Safety Listings 
16.2.9.1 
Vital Signs 
16.2.9.2 
12-lead Electrocardiograms (ECGs) 
16.2.9.3 
Pregnancy Test Results 
16.2.9.4 
Historical and On-Study Procedures 
16.2.9.5 
Subject Visit Information 
16.2.9.6 
Subject Reconsent 
16.2.9.7 
Comments 
 
 
 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
Confidential 
Page 49 of 50 
APPENDIX B. DYSLIPIDEMIA PREFERRED TERMS AND 
ASSOCIATED CODES 
Preferred Term 
Code 
Acquired lipoatrophic diabetes 
10073667 
Acquired mixed hyperlipidaemia 
10071236 
Apolipoprotein B/Apolipoprotein A-1 ratio increased 
10065516 
Autoimmune hyperlipidaemia 
10071577 
Blood cholesterol abnormal 
10005423 
Blood cholesterol decreased 
10005424 
Blood cholesterol esterase increased 
10071304 
Blood cholesterol increased 
10005425 
Blood triglycerides abnormal 
10005837 
Blood triglycerides decreased 
10005838 
Blood triglycerides increased 
10005839 
Diabetic dyslipidaemia 
10070901 
Dyslipidaemia 
10058108 
Familial hypertriglyceridaemia 
10059183 
Fat overload syndrome 
10074028 
High density lipoprotein abnormal 
10020051 
High density lipoprotein decreased 
10020060 
High density lipoprotein increased 
10020061 
Hypercholesterolaemia 
10020603 
Hyperlipidaemia 
10062060 
Hypertriglyceridaemia 
10020869 
Hypo HDL cholesterolaemia 
10068961 
Hypotriglyceridaemia 
10021128 
Intermediate density lipoprotein decreased 
10064237 
Intermediate density lipoprotein increased 
10064236 
LDL/HDL ratio decreased 
10052338 
LDL/HDL ratio increased 
10049030 
Lipid metabolism disorder 
10061227 
Lipids abnormal 
10024588 
Lipids decreased 
10024591 


Intercept Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
Protocol 747-207 
 
11 Apr 2017 
 
Confidential 
Page 50 of 50 
Lipids increased 
10024592 
Lipoprotein (a) abnormal 
10054023 
Lipoprotein (a) decreased 
10054021 
Lipoprotein (a) increased 
10054009 
Low density lipoprotein abnormal 
10024901 
Low density lipoprotein decreased 
10024909 
Low density lipoprotein increased 
10024910 
Non-high-density lipoprotein cholesterol decreased 
10064235 
Non-high-density lipoprotein cholesterol increased 
10063967 
Remnant hyperlipidaemia 
10038316 
Remnant-like lipoprotein particles increased 
10073041 
Total cholesterol/HDL ratio abnormal 
10058633 
Total cholesterol/HDL ratio decreased 
10058631 
Total cholesterol/HDL ratio increased 
10058630 
Type I hyperlipidaemia 
10060749 
Type II hyperlipidaemia 
10045254 
Type IIa hyperlipidaemia 
10045261 
Type IIb hyperlipidaemia 
10045263 
Type III hyperlipidaemia 
10060751 
Type IV hyperlipidaemia 
10060753 
Type V hyperlipidaemia 
10060755 
Very low density lipoprotein abnormal 
10047352 
Very low density lipoprotein decreased 
10047360 
Very low density lipoprotein increased 
10047361