Clinical trial NCT03439254
Conditions: Compensated Cirrhosis Nonalcoholic Steatohepatitis
Keywords: Compensated Cirrhosis Nonalcoholic Steatohepatitis Fatty Liver Disease NASH
Sponsor: Intercept Pharmaceuticals
Start date: 2017-08-30; Completion date: 2022-09-08
Enrollment: 919 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate whether obeticholic acid (OCA; INT-747) can lead to histological improvement in fibrosis with no worsening of NASH in adults with compensated cirrhosis due to NASH.

Detailed description:

Arms: arm 1: 10 mg OCA for up to 18 months arm 2: 10 mg OCA for the first 3 months and then may titrate up to 25 mg OCA for the remaining 15 months of the study arm 3: Placebo for up to 18 months
Interventions: intervention 1: Obeticholic acid (10 mg) intervention 2: Obeticholic acid (10 mg to 25 mg) intervention 3: Placebo
Intervention descriptions: intervention 1: Tablets administered orally once daily. intervention 2: Tablets administered orally once daily. intervention 3: Tablets administered orally once daily.

Protocol documents:
Prot_000.pdf: 


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SPONSOR’S APPROVAL OF THE PROTOCOL 
 
Reviewed and Approved by: 
 
 
 
___________________________________   ____________________________ 
MD                     Date  
 Clinical Development 
Intercept Pharmaceuticals, Inc.  
 
 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the current version of the Investigator’s Brochure (IB) for obeticholic 
acid (OCA) and this Protocol 747-304.  Having fully considered all the information available, 
I agree that it is ethically justifiable to give OCA to selected subjects according to this protocol. 
I understand that all information concerning OCA supplied to me by the Sponsor, Intercept 
Pharmaceuticals, Inc., and/or its agents in connection with this study and not previously published 
is confidential information.  This includes the IB, clinical study protocol, electronic case report 
forms (eCRF), and any other preclinical and clinical data provided by the Sponsor. 
I understand that no data are to be made public or published without prior knowledge and written 
approval by the Sponsor. 
By my signature below, I hereby attest that I have read, understood, and agreed to abide by all the 
conditions, instructions, and restrictions contained in Protocol 747-304 and in accordance with 
Good Clinical Practice (CPMP/ICH/135/95), the Declaration of Helsinki, and all regulatory 
requirements for protection of human subjects in clinical studies and privacy requirements for the 
protection of individual and company data. 
I acknowledge that the Sponsor of the study has the right to discontinue the study at any time. 
 
 
 
 
 
 
Investigator’s Name (Printed) 
 
 
 
 
 
 
Investigator’s Signature 
 
Date 


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STUDY PERSONNEL CONTACT INFORMATION 
Emergency Contact Information 
Medical Monitor – 24-hour Emergency Reporting 
 
Primary Contact: 
, MB ChB  
Syneos Health 
1030 Sync Street 
Morrisville, NC 27560 
Telephone: 
  
 
Email:  
Secondary Contact: 
 MD 
 
 Scientific Affairs 
 
Intercept Pharmaceuticals, Inc. 
Email:  
Telephone: 
 
SAE Reporting Information 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product: 
Obeticholic Acid 
Name of Active Ingredient: 
Obeticholic acid (OCA); 6α-ethyl-chenodeoxycholic acid; INT-747; DSP-1747 
Title of Study:  
A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and 
Safety of Obeticholic Acid in Subjects with Compensated Cirrhosis due to Nonalcoholic Steatohepatitis 
Investigators and/or Study Center(s):  
Approximately 300 investigational sites, globally. 
Studied Period:  
The maximum duration of individual subject participation for this study is approximately 
2 years and 9 months, including a Screening Period of up to 12 weeks, an 18-month 
Double-Blind Phase, and an Open-Label Extension (OLE) expected to last approximately 
1 year. 
Phase of 
Development:   
Phase 3 
Objectives:  
Primary Objectives Assessed at the End of the Double-Blind Phase 
To evaluate the effects of OCA treatment compared with placebo on: 
• 
Histological improvement in fibrosis by assessing the percentage of subjects with improvement in fibrosis by 
at least 1 stage with no worsening of nonalcoholic steatohepatitis (NASH) defined as no increase in 
hepatocellular ballooning or lobular inflammation, using the NASH Clinical Research Network (CRN) 
scoring system, from Baseline to the end of the Double-Blind Phase 
Secondary Objectives Assessed at the End of the Double-Blind Phase 
To evaluate the effects of OCA treatment compared with placebo on: 
• 
Resolution of NASH  defined as overall histopathological interpretation of 1) “no fatty liver disease” or 
2) “fatty liver disease (simple or isolated steatosis) without steatohepatitis” AND a nonalcoholic fatty liver 
disease (NAFLD) activity score (NAS) of 0 for ballooning and 0-1 for inflammation, using the NASH CRN 
scoring system, from Baseline to the end of the Double-Blind Phase 
• 
Resolution of NASH based on pathologist’s overall histopathologic interpretation of the presence or absence 
of definite NASH from Baseline to the end of the Double-Blind Phase 
• 
Histological changes in fibrosis status including: (1) improvement, or (2) no change, from Baseline to the 
end of the Double-Blind Phase using the NASH CRN scoring system 
• 
Occurrence of all-cause mortality and liver-related clinical outcomes for the following adjudicated events 
(clinical outcomes composite endpoint):  
− 
Death (all causes)  
− 
Liver transplant 
− 
Model for end-stage liver disease (MELD) score ≥15  
− 
Worsening of Child-Pugh (CP) score (by at least 2 points) 
− 
Hospitalization (as defined by a stay of ≥24 hours) for: 
o 
Variceal bleed 


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o 
Hepatic encephalopathy (as defined by a West Haven score of ≥2) 
o 
Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
− 
Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or paracentesis) 
− 
Hepatocellular carcinoma (HCC) as confirmed by 2 complementary imaging modalities unless already 
confirmed by biopsy  
e 


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Safety Objectives Assessed at the End of the Double-Blind Phase 
• 
To evaluate the safety and tolerability of OCA treatment compared to placebo 
• 
The effect of OCA treatment compared to placebo on the following additional measures and markers: 
− 
Markers of cardiovascular safety 
− 
Incidence of adjudicated cardiovascular events 
− 
Incidence of adjudicated acute kidney injury events (AKI) 
− 
Incidence of adjudicated events of hepatic injury 
Primary Objectives Assessed at the End of the OLE 
• 
To evaluate and summarize the longer-term safety and tolerability of OCA treatment 
• 
To summarize the effects of OCA treatment on the occurrence of all-cause mortality and liver-related clinical 
outcomes for the following adjudicated events (clinical outcomes composite endpoint): 
− Death (all cause) 
− 
Liver transplant 
− 
MELD score ≥15 
− 
Worsening of CP score (by at least 2 points) 
− 
Hospitalization (as defined by a stay of ≥24 hours) for: 
o Variceal bleed 
o Hepatic encephalopathy (as defined by a West Haven score of ≥2) 
o Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
− 
Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or paracentesis) 
− 
HCC as confirmed by 2 complementary imaging modalities unless already confirmed by biopsy  


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Methodology: 
This Phase 3, double-blind, randomized, placebo-controlled, multicenter international study will evaluate the 
efficacy and safety of OCA in subjects with a biopsy-confirmed diagnosis of cirrhosis (based on a fibrosis score 
of 4 using the NASH CRN scoring system) due to NASH (determined by central reading of liver histology).  
Subjects with hepatic decompensation or CP Class B or Class C cirrhosis are excluded.  Subjects who progress to 
CP Class B or Class C during the study will discontinue investigational product but are expected to be followed 
through to study closure (or at the discretion of the Sponsor).  
Double-Blind Phase (18 Months):  Subjects will be screened for a period of up to 12 weeks before entering the 
study.  Subjects who meet the entry requirements will be randomized in a 1:1:1 ratio to one of the three treatment 
arms:  once daily dosing of OCA 10 mg, OCA 10 mg → 25 mg (ie, OCA 10 mg with uptitration to OCA 25 mg 
at Month 3), or placebo, in conjunction with the standard of care.  Uptitration will be determined based on the 
laboratory criteria and safety and tolerability assessments completed prior to Month 3. 
Randomized subjects will be stratified by the presence of type 2 diabetes at enrollment (yes or no).  
Investigational product (ie, OCA or placebo) will be taken orally, with water, once daily.  Efficacy, safety, and 
laboratory assessments will be evaluated at clinical visits at Day 1, monthly for the initial 6 months (Month 1 
through Month 6 Visits), Month 9, Month 12, Month 15, and Month 18. 
Open-Label Extension (up to 12 Months):  Subjects who complete the Double-Blind Month 18 Visit and 
continue to receive investigational product are eligible to enroll into the OLE.  All subjects will receive OCA 
upon entry into the OLE.  Subjects randomized to placebo in the Double-Blind Phase will be re-randomized to 
either OCA 10 mg or OCA 10 mg → 25 mg (ie, OCA 10 mg for the first 3 months of the OLE prior to uptitrating 
to OCA 25 mg at OLE Month 3).  Uptitration will be determined based on the same criteria and assessments as 
employed in the Double-Blind Phase.  Subjects randomized to OCA (10 mg or 10 mg → 25 mg dose) during the 
Double-Blind Phase will continue the same dosing regimen they received at the end of the Double-Blind Phase; 
however, they will undergo dummy titration to maintain study blind until all subjects complete the Double-Blind 
Phase and the database is locked. 
Study Design Diagram 
 
 
CP = Child-Pugh; CRN = clinical research network; NASH = nonalcoholic steatohepatitis; OCA = obeticholic acid; OLE = open-label 
extension; QD = once daily. 
a Subjects who meet the entry requirements will be randomized in a 1:1:1 ratio to one of the three treatment arms:  once daily dosing of OCA 
10 mg, OCA 10 mg → 25 mg (ie, OCA 10 mg with uptitration to OCA 25 mg at Month 3), or placebo, in conjunction with the standard of 
care. 
b All subjects will receive OCA upon entry into the OLE:  Subjects who received placebo during the Double-Blind Phase will be 
re-randomized to either OCA 10 mg or OCA 10 mg → 25 mg (ie, OCA 10 mg with uptitration to OCA 25 mg at OLE Month 3).  Subjects 
who received OCA during the Double-Blind Phase will continue the same dosing regimen they received at the end of the Double-Blind 
Phase. 
c During the OLE period, subjects will return for site visits at Months 1, 2, 3, 4, 5, 6, 9, and 12.   
 
Notes:   
• 
Subjects with cirrhosis (based on a NASH CRN fibrosis score 4) due to NASH (determined by central reading of liver histology) will be 
enrolled in the study.  Subjects with hepatic decompensation or CP Class B or CP Class C cirrhosis are excluded.   
• 
Two screening visit assessments will be performed.  Screening Visit 1 will occur no more than 12 weeks prior to Day 1, and Screening 
Visit 2 will occur at least 4 weeks after Screening Visit 1.  
• 
Randomized subjects will be stratified by the presence of type 2 diabetes at enrollment (yes or no). 
• 
The study will remain blinded until all subjects complete the Double-Blind Phase and the database is locked.  To maintain blinding, all 
investigational product (placebo and OCA) tablets and bottles will be identical.   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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Number of Subjects (planned):  Approximately 900 subjects will be enrolled in the study. 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria 
1. 
Subjects ≥18 years of age  
2. Subjects with a confirmed diagnosis of NASH and a fibrosis score of 4 based upon the NASH CRN scoring 
system determined by central reading of a liver biopsy obtained no more than 12 months before Day 1. 
3. Contraception:  Female subjects of childbearing potential must use ≥1 effective method (≤1% failure rate) of 
contraception during the study until 4 weeks following the last dose of investigational product (including 
OLE doses).  Female subjects are considered as being of childbearing potential, ie, fertile, following 
menarche and until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.   
Effective methods of contraception are 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)  
4. Must provide written informed consent and agree to comply with the study protocol 
Exclusion Criteria 
Criteria with exclusionary laboratory values are to be based on the most recent laboratory result available prior to 
randomization.   
For alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin (conjugated bilirubin for 
subjects with an established diagnosis of Gilbert’s syndrome), if the Screening Visit 2 value is ≥30% higher than 
the Screening Visit 1 value and > the upper limit of normal (ULN), then a third measurement must be obtained at 
an unscheduled visit.  Subjects who satisfy any of the following exclusion criteria will be ineligible for 
enrollment: 
1. Current or past history of a clinically evident hepatic decompensation event, such as ascites, variceal 
bleeding, spontaneous bacterial peritonitis, hepatic encephalopathy (Grade I or greater based on West Haven 
classification), or hepatorenal/hepatopulmonary syndromes 
2. Current or past history of hepatic function impairment with CP score ≥7 points 
3. MELD score >12 
4. Hospitalization within 1 year of Day 1 for complications of cirrhosis 
5. Documented presence of varices based on prior endoscopy performed within 6 months of Day 1  
6. AST ≥5× ULN 
a. 
If a third serum AST measurement is required, and both Screening Visit 2 and unscheduled visit 
AST values are ≥30% higher than the Screening Visit 1 value, the subject is ineligible for 
enrollment 
7. ALT ≥5× ULN 
a. 
If a third serum ALT measurement is required, and both Screening Visit 2 and unscheduled visit 
ALT values are ≥30% higher than the Screening Visit 1 value, the subject is ineligible for 
enrollment 


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8. Calculated creatinine clearance <60 mL/min using Cockcroft-Gault method 
9. Platelet count ≤100 000/mm3 
10. Total bilirubin >2 mg/dL (except for subjects with an established diagnosis of Gilbert’s syndrome, if 
hemoglobin and reticulocyte count are within normal range and conjugated bilirubin is <1.5× ULN) 
a. 
If a third serum total bilirubin measurement is required (conjugated bilirubin for subjects with an 
established diagnosis of Gilbert’s syndrome), and both Screening Visit 2 and unscheduled visit 
values are ≥30% higher than the Screening Visit 1 value, the subject is ineligible for enrollment 
11. Conjugated bilirubin ≥1.5x ULN 
12. Albumin <3.5 g/dL 
13. International normalized ratio (INR) ≥1.7  
14. Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 
1 year before Day 1 (significant alcohol consumption is defined as more than 2 units/day for females and 
more than 4 units/day for males, on average) 
15. Prior (at any point) or planned (during the study period) ileal resection, or prior (within 5 years before 
Screening) or planned (during the study period) bariatric surgery (eg, gastric bands, gastroplasty, Roux-en-Y 
gastric bypass) 
16. Inability to safely undergo a liver biopsy 
17. History of biliary diversion  
18. Evidence of other known forms of chronic liver disease including: 
− 
Positive test result at Screening for hepatitis B surface antigen  
− 
Active hepatitis C virus (HCV) infection (positive for HCV ribonucleic acid [RNA] at Screening) or 
confirmed history of a positive HCV RNA test result(s) except for subjects with evidence of 
spontaneous HCV eradication (defined as positive HCV antibodies at Screening, no history of positive 
HCV RNA result, and documentation that no anti-HCV therapy has been received) 
− 
Primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, or overlap syndrome 
− 
Alcoholic liver disease 
− 
Wilson disease, hemochromatosis, or iron overload 
− 
Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver histology (confirmed 
by A1AT level below the lower limit of normal or exclusion at the Investigator’s discretion) 
− 
Prior known or suspected drug-induced liver injury within 5 years before Day 1 
− 
Known or suspected HCC 
19. History of liver transplant or current placement on a liver transplant waiting list  
20. Hemoglobin A1c (HbA1c) ≥9.5% within 90 days before Day 1 
21. Low-density lipoprotein (LDL) cholesterol ≥190 mg/dL and already on a stable dose of LDL-lowering 
medication for ≥30 days 
22. LDL cholesterol <50 mg/dL in subjects not on LDL-lowering medication 
23. Known positivity for human immunodeficiency virus infection 
24. Subjects with recent history (within 1 year of Day 1) of significant atherosclerotic cardiovascular disease 
(ASCVD; myocardial infarction, unstable angina, acute coronary syndrome, cerebrovascular accident 
[stroke], cerebrovascular ischemia, transient ischemic attack, or peripheral vascular disease requiring 
intervention).  Such subjects may be identified by different means, including, but not limited to, an abnormal 
12-lead electrocardiogram (ECG), a history or planned cardiovascular intervention such as coronary 
revascularization (eg, percutaneous coronary intervention or coronary artery bypass graft), coronary 
angioplasty, stenting, carotid atherectomy, or placement of a cardiac pacemaker or defibrillator 
− 
Controlled hypertension without other recent manifestations of significant ASCVD and placement of 
cardiac pacemaker or defibrillator for reasons other than ASCVD (eg, for treatment of atrial fibrillation 
subsequent to nodal ablation) is not exclusionary 


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25. Current acute cholecystitis or acute biliary obstruction 
26. Other medical conditions that may diminish life expectancy to <2 years, including known cancers (except 
carcinomas in situ or other stable, relatively benign carcinomas) 
27. Known substance abuse in the year before Screening 
28. Chronic use (≥12 months) of drugs historically associated with drug-induced NAFLD within the 5 years 
before Day 1 (eg, amiodarone, methotrexate, systemic glucocorticoids [unless used at physiologic 
replacement doses for the treatment of adrenal insufficiency], tetracyclines, tamoxifen, estrogens at doses 
greater than those used for hormone replacement, anabolic steroids [except for testosterone preparations used 
at physiologic replacement doses for the treatment of documented/confirmed hypogonadism], valproic acid, 
and other known hepatotoxins).  
29. Pregnancy, planned pregnancy, potential for pregnancy (ie, unwillingness to use effective birth control 
during the study), or current or planned breast feeding 
30. Participated in a clinical research study and received any active investigational product being evaluated for 
the treatment of diabetes, weight loss, or NASH in the 6 months before Day 1 
31. Concurrent participation in any other interventional clinical trial. 
32. Received any investigational product from Screening to Day 1, within 30 days before Day 1, or within 
5 half-lives of the compound (whichever was longer) before Day 1 
33. Previous exposure to OCA within 12 months of Day 1 
34. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with 
the study, is uncertain 
35. History of known or suspected clinically significant hypersensitivity to OCA or any of its components 
36. Any other condition that, in the opinion of the Investigator, might confound the results, or would impede 
compliance or hinder completion of the study 
37. Alkaline phosphatase (ALP) ≥1.5x ULN 
38. History of known or suspected hypersensitivity to any ingredient in human albumin preparations (at US sites 
where
will be conducted) 
Liver Histology and Event Adjudication and Data Monitoring Committee Oversight: 
Central Reading of Liver Histology:  All biopsy assessments will be performed centrally, including assessments 
of biopsies to determine study eligibility.  Histological presence of NASH with a fibrosis score of 4 based on the 
NASH CRN scoring system must be confirmed for study eligibility.  For each biopsy, fibrosis will be graded in 
accordance with the NASH CRN scoring system (Kleiner 2005).   
Biopsy samples will be assessed for quantitative collagen in a subset of subjects as an exploratory objective. 
Any extra biopsy tissue may undergo additional histological evaluations such as alpha-smooth muscle actin or 
bile acid transporter analysis. 
Event Adjudication:  Potential liver-related clinical outcomes, and potential events of hepatic injury, AKI, and 
major adverse cardiovascular events (MACE), deaths, and hospitalizations (depending on the cause) that occur 
after administration of the first dose of investigational product will be reviewed by the following blinded 
adjudication committees, depending on event type, before inclusion in any analysis.  The 4 committees that are 
responsible for adjudicating events are as follows: 
• 
Cardiovascular Adjudication Committee:  Adjudicates all potential MACE (including all deaths) and 
hospitalizations (depending on the cause) 
• 
Hepatic Outcomes Committee:  Adjudicates all deaths and potential liver-related clinical outcomes  
• 
Hepatic Safety Adjudication Committee (HSAC):  Adjudicates all potential events of hepatic injury  
• 
Renal Adjudication Committee:  Adjudicates all potential events of AKI 
The adjudication committee members will include experts with relevant adjudication experience; they will not be 
involved in the study as Investigators, Data Monitoring Committee (DMC) members, or consultants.   
Specific details of the events that will be adjudicated by the Cardiovascular Adjudication Committee, Hepatic 
Outcomes Committee, HSAC, and Renal Adjudication Committee are described in the respective adjudication 








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 HCC = hepatocellular carcinoma; HDL = high-density lipoprotein; HE = hepatic encephalopathy; 
HOMA-β = homeostatic model assessment–beta cell; HOMA-IR = homeostatic model assessment – insulin 
resistance; hs-CRP = high-sensitivity C-reactive protein; IL-6 = interleukin-6; INR = international normalized 
ratio; LDL = low-density lipoprotein; Lp(a) = lipoprotein(a); MACE = major adverse cardiovascular events; 
MELD = model for end-stage liver disease; NAFLD = nonalcoholic fatty liver disease; NAS = NAFLD activity 
score; NASH = nonalcoholic steatohepatitis; NFS = NAFLD fibrosis score; OCA = obeticholic acid; 
OLE = open-label extension; PCA = percent collagen area; PCSK9 = proprotein convertase subtilisin/kexin 
type 9; PD = pharmacodynamic; PK = pharmacokinetic; PT = prothrombin time; SAE = serious adverse event; 
SBP = spontaneous bacterial peritonitis; SCORE = systemic coronary risk evaluation; TE = transient 
elastography; TEAE = treatment-emergent adverse event; TNF-α = tumor necrosis factor-α; US = United States; 
VAS = visual analog scale; VLDL = very low-density lipoprotein; WPAI = Work Productivity and Activity 
Index. 
Statistical Methods: 
A detailed statistical analysis plan, providing details about the specific planned analyses and hypothesis tests, will 
be prepared and approved by the Sponsor and its designees.  A separate clinical pharmacology analysis plan will 
be prepared, providing details of PK analysis methods and parameter estimation.  PK/PD analytical methods will 
be detailed in a separate modeling and simulations plan, and all results will be documented separate from the 
clinical study report. Details about these specific planned analyses will be prepared and approved by the Sponsor 
or its designees prior to study database lock. 
Enrollment and Randomization 
Approximately 900 subjects will be enrolled and randomized into the study in a 1:1:1 ratio to OCA 10 mg, OCA 
10 mg → 25 mg, or placebo arms.  Randomized subjects will be stratified by the presence of type 2 diabetes at 
enrollment (yes or no).   
Analysis Populations 
Intent-to-Treat (ITT) Population: 
The ITT Population will include all randomized subjects.  The ITT Population will be the primary population 
used for efficacy analyses.  Treatment assignment will be based on the randomized treatment. 
Modified Intent-to-Treat (mITT) Population: 
The mITT Population will include all ITT subjects except those who are not eligible to dose titrate due to safety 
or tolerability reasons.  Treatment assignment will be based on the randomized treatment. 
Per Protocol (PP) Population: 
The PP Population will include all mITT subjects who do not have any major protocol violations that potentially 
affect the efficacy conclusions.  Treatment assignment will be based on the randomized treatment. 
Safety Population: 
The Safety Population will include all randomized subjects who receive at least 1 dose of investigational product 
(OCA or placebo).  The Safety Population will be the primary population used for safety analyses.  Treatment 
assignment will be based on the treatment actually received. 
Efficacy Analyses 
For the comparison of the primary efficacy endpoint, a Cochran Mantel Haenszel (CMH) test stratified by the 
randomization strata (presence of type 2 diabetes at enrollment [yes/no] will be used.  The overall type I error 
will be controlled at 0.05 for the primary analysis 
Primary efficacy hypothesis testing will be based on the ITT population.  Supportive analyses of the primary 
endpoint will be conducted using the mITT and PP population. 
The primary efficacy analysis will test the following hypotheses: 


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• 
H01:  The percentage of subjects with fibrosis improvement by at least 1 stage and no worsening of NASH 
defined as no increase in hepatocellular ballooning or lobular inflammation using the NASH CRN scoring 
system from Baseline to the end of the Double-Blind Phase is equal between placebo and OCA 10 to 25 mg 
titration. 
• 
H11:  The percentage of subjects with fibrosis improvement by at least 1 stage and no worsening of NASH 
defined as no increase in hepatocellular ballooning or lobular inflammation using the NASH CRN scoring 
system, from Baseline to the end of the Double-Blind Phase is different between placebo and OCA 10 to 
25 mg titration. 
• 
H02:  The percentage of subjects with fibrosis improvement by at least 1 stage and no worsening of NASH 
defined as no increase in hepatocellular ballooning or lobular inflammation using the NASH CRN scoring 
system, from Baseline to the end of the Double-Blind Phase is equal between placebo and OCA 10 mg. 
• 
H12:  The percentage of subjects with fibrosis improvement by at least 1 stage and no worsening of NASH 
defined as no increase in hepatocellular ballooning or lobular inflammation using the NASH CRN scoring 
system, from Baseline to the end of the Double-Blind Phase is different between placebo and OCA 10 mg. 
The type 1 error for the primary efficacy analysis will be controlled at 0.05.  For the comparison of the primary 
and secondary efficacy endpoints, a Cochran–Mantel– Haenszel (CMH) test stratified by the randomization strata 
(presence of type 2 diabetes at enrollment [yes/no] will be used.    
Analyses of the clinical outcomes composite endpoint will evaluate the effect of OCA (10 mg and 25 mg) 
compared to placebo, as listed under the secondary objectives.  Only adjudicated events will be included in 
analyses.  Subjects with none of these events will be censored at the date of last contact.  For the analysis of time 
to first occurrence of adjudicated events, in addition to the CMH test statistics, a log rank test stratified by the 
randomization stratification factor (presence of type 2 diabetes at enrollment [yes/no]) will be used.  Kaplan-
Meier estimates of the distribution of the time-to-event will be tabulated and graphed by treatment group. 
 
Safety Analyses 
Safety evaluations will comprise treatment-emergent AEs, AEs of special interest (including cardiovascular, 
pruritus, renal, urinary tract stones including nephrolithiasis, gallbladder/gallstone-related, pancreatitis, hepatic, 
dyslipidemia, and hyperglycemia/new-onset diabetes mellitus AEs), adjudicated hepatic safety events, 
adjudicated cardiovascular events, adjudicated AKI events, vital signs, electrocardiograms (ECGs), pruritus 
VAS, and clinical laboratory results. 
Safety Analyses (OLE) 


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Safety evaluations conducted during the Double-Blind Phase will also be conducted for the OLE.  For 
quantitative parameters including, but not limited to, vital signs, ECG, and clinical laboratory results, changes 
from double-blind baseline value and OLE baseline value will be presented.  Analyses based on the double-blind 
baseline will be performed using the treatment actually received in the Double-Blind Phase.  Analyses based on 
the OLE baseline will be based on the treatment actually received in the OLE Phase. 
Efficacy Analyses (OLE) 
The occurrence of all-cause mortality and liver-related clinical outcomes will be summarized.  For additional 
exploratory analyses, please refer to SAP for more details. 
Sample Size Justification 
A sample size of 300 subjects per group will provide at least 90% power to detect a statistically significant 
treatment difference of 10% between OCA 25 mg and placebo groups based on a Chi-square test with 2-sided 
type I error at 0.05 level, assuming a responder rate of 10% in the placebo group.  As there was no previous study 
performed using the same endpoint in this disease, the assumption was determined based on data from literature, 
and results from the Farnesoid X receptor Ligand OCA in Nonalcoholic Steatohepatitis Treatment (FLINT) study 
and Study 747-303. 


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C o nfi de ntial a n d Pr o prietar y  
3.  
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F 
FI G U R E S  
T A B L E O F C O N T E N T S  
1.  
TI T L E P A G E  ................................................................................................................ 1 
2.  
S Y N O P SI S  ................................................................................................................... 5 
3.  
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F FI G U R E S  ............... 1 8 
4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  ............................. 2 7 
5.  
I N T R O D U C TI O N ...................................................................................................... 3 1 
5. 1.  
O ver vie w of N o nalc o h olic Steat o he patitis a n d O betic h olic Aci d  .............................. 3 1 
5. 2.  
N o ncli nical E x perie nce wit h O C A  ............................................................................. 3 1 
5. 3.  
Cli nical E x perie nce wit h O betic h olic Aci d  ................................................................ 3 3 
5. 4.  
Rati o nale f or St u d y Desi g n a n d D ose f or I n vesti gati o nal Pr o d uct ............................. 3 5  
5. 4. 1.  
Rati o nale f or St u d y Desi g n ......................................................................................... 3 5  
5. 4. 2.  
Rati o nale f or Place b o C o ntr ol Gr o u p  ......................................................................... 3 5 
5. 4. 3.  
Rati o nale f or O betic h olic Aci d D oses a n d D urati o n  .................................................. 3 6 
5. 5.  
S u m mar y of K n o w n P ot e ntial Ris ks wit h I n vesti gati o nal Pr o d uct ............................ 3 7  
5. 5. 1.  
Ris k/ Be nefit Pr ofile of O C A i n S u bjects wit h N A S H  ................................................ 4 0 
5. 6.  
I m p orta nce of M o nit ori n g of Disease Pr o gressi o n ..................................................... 4 1 
6.  
S T U D Y O BJ E C TI V E S A N D P U R P O S E  .................................................................. 4 2 
6. 1.  
Pri mar y O bjecti ves Assesse d at t he E n d of t he D o u ble- Bli n d P hase ......................... 4 2 
6. 2.  
Sec o n dar y O bjecti ves Assesse d at t he E n d of t he D o u ble- Bli n d P hase ..................... 4 2  
 
 
6. 4.  
P K/ P D O bjecti ves Assesse d at t he E n d of t he D o u ble- Bli n d P hase .......................... 4 3  
6. 5.  
Safet y O bjecti ves Assesse d at t he E n d of t he D o u ble - Bli n d P hase ............................ 4 4 
6. 6.  
Pri mar y O bjecti ves Assesse d at t he E n d of t he O pe n -La bel E xte nsi o n ( O L E)  .......... 4 4 
 
 
7.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 4 5 
7. 1.  
O verall St u d y Desi g n  .................................................................................................. 4 5 
7. 1. 1.  
St u d y Desi g n Dia gra m ................................................................................................ 4 6  
7. 1. 2.  
Sc he d ule of St u d y Pr oce d ures .................................................................................... 4 7  
7. 1. 3.  
St u d y D urati o n ............................................................................................................ 5 4  
7. 2.  
N u m ber of S u bjects  .................................................................................................... 5 4 
7. 3.  
Pla n ne d D osi n g Re gi me n ........................................................................................... 5 4  
D


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Protocol 747-304 
Version 7.0:  16Jun2021 
Page 20 
 
Confidential and Proprietary 
9.2. 
Criteria for Uptitration ................................................................................................78 
9.2.1. 
Double-Blind Phase (Month 3) ...................................................................................78 
9.2.2. 
OLE Phase ..................................................................................................................79 
9.3. 
Criteria for Extension of Double-Blind Treatment with Investigational 
Product ........................................................................................................................80 
9.4. 
Standard of Care and Concomitant Medications ........................................................80 
9.4.1. 
LDL-Lowering Medications .......................................................................................81 
9.4.2. 
Warfarin ......................................................................................................................81 
9.4.3. 
Bile Acid Sequestrants ................................................................................................82 
9.4.4. 
Drug-Drug Interaction ................................................................................................82 
9.4.5. 
Standard of Care: Management of Dyslipidemia .......................................................82 
9.4.6. 
Standard of Care: Management of Hyperglycemia ....................................................83 
9.5. 
Treatment Compliance ................................................................................................84 
9.6. 
Randomization and Blinding ......................................................................................84 
9.6.1. 
Methods of Assigning Subjects to Treatment Groups ................................................84 
9.6.2. 
Blinding ......................................................................................................................85 
9.6.3. 
Emergency Unblinding Procedures ............................................................................85 
9.7. 
Assignment of Site and Subject Numbers ..................................................................86 
9.7.1. 
Site Numbers ..............................................................................................................86 
9.7.2. 
Subject Numbers .........................................................................................................86 
9.8. 
Restrictions .................................................................................................................86 
9.9. 
Highly Effective Contraception ..................................................................................86 
9.10. 
Visit Procedures ..........................................................................................................87 
9.10.1. 
Informed Consent Procedures .....................................................................................87 
9.10.2. 
Fasting Requirement at Study Visits ..........................................................................87 
9.10.3. 
Screening Visit Procedures .........................................................................................87 
9.10.3.1. 
Screening Visit 1 .........................................................................................................88 
9.10.3.2. 
Screening Visit 2 .........................................................................................................89 
9.10.4. 
Day 1 Procedures (Randomization) ............................................................................90 
9.10.5. 
DB Month 1 Procedures .............................................................................................92 
9.10.6. 
DB Month 2, Month 5, Month 9, and Month 15 Procedures ......................................94 
9.10.7. 
DB Month 3 Procedures .............................................................................................95 
9.10.8. 
DB Month 4 Procedures .............................................................................................97 


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Version 7.0:  16Jun2021 
Page 21 
 
Confidential and Proprietary 
9.10.9. 
DB Month 6 and Month 12 Procedures ......................................................................99 
9.10.10. 
DB Month 18/EOT/EOS/OLE Day 1 Visit for Subjects Continuing into the 
OLE ...........................................................................................................................101 
9.10.10.1. Additional Procedures at DB Month 18/OLE Day 1 Visit for Subjects 
Continuing into the OLE ..........................................................................................104 
9.10.11. 
OLE Month 1 ............................................................................................................104 
9.10.12. 
OLE Months 2, 3, 4, 5, 9 ..........................................................................................106 
9.10.13. 
OLE Month 6 ............................................................................................................107 
9.10.14. 
OLE Month 12/EOT/EOS ........................................................................................108 
9.10.15. 
Early Termination Procedures ..................................................................................110 
9.10.16. 
Unscheduled Safety Visit .........................................................................................112 
10. 
STUDY MANAGEMENT DURING COVID-19 ....................................................112 
10.1. 
Alternative Approaches for Study Conduct Due to COVID-19 ...............................113 
11. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT ...........114 
11.1. 
Investigational Product .............................................................................................114 
11.2. 
Investigational Product Packaging and Labeling .....................................................115 
11.2.1. 
Double-Blind Phase ..................................................................................................115 
11.2.2. 
OLE Phase ................................................................................................................115 
11.3. 
Investigational Product Storage ................................................................................115 
11.4. 
Investigational Product Administration ....................................................................115 
11.5. 
Investigational Product Accountability and Disposal ...............................................115 
12. 
OVERVIEW OF ASSESSMENTS ..........................................................................116 
13. 
EFFICACY ASSESSMENTS ..................................................................................119 
13.1. 
Liver Biopsies ...........................................................................................................119 
13.1.1. 
Central Reading of Liver Histology .........................................................................119 
13.2. 
Child-Pugh Assessment ............................................................................................120 
13.3. 
MELD Score .............................................................................................................120 
13.4. 
Prospective Surveillance ...........................................................................................120 
13.5. 
Patient-Reported Outcomes and Healthcare Resource Use ......................................120 
13.6. 
Noninvasive Assessments of Liver Disease .............................................................121 
13.6.1. 
Noninvasive Scores of Liver Fibrosis .......................................................................121 
13.6.2. 
Noninvasive Panel of Liver Fibrosis Markers ..........................................................121 
13.6.3. 
Noninvasive Radiological Liver Fibrosis Measurements .........................................122 


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Page 22 
 
Confidential and Proprietary 
13.7. 
Efficacy Laboratory Assessments .............................................................................122 
14. 
CLINICAL PHARMACOLOGY ASSESSMENTS ................................................122 
14.1. 
Pharmacokinetic Blood Sampling ............................................................................122 
14.2. 
Processing and Handling of Pharmacokinetic Samples ............................................123 
14.3. 
Bioanalysis ................................................................................................................123 
15. 
PHARMACODYNAMIC ASSESSMENTS ............................................................123 
15.1. 
Markers for FXR Activation .....................................................................................124 
 
 
 
 
15.4. 
Additional Assessments ............................................................................................125 
 
 
16. 
SAFETY ASSESSMENTS ......................................................................................125 
16.1. 
Adverse Events and Serious Adverse Events ...........................................................125 
16.1.1. 
Definitions of Adverse Events ..................................................................................125 
16.1.1.1. 
Adverse Event ...........................................................................................................125 
16.1.1.2. 
Treatment-Emergent Adverse Event ........................................................................126 
16.1.1.3. 
Serious Adverse Event ..............................................................................................126 
16.1.2. 
Suspected Unexpected Serious Adverse Reaction ...................................................126 
16.1.3. 
Relationship to Investigational Product ....................................................................127 
16.1.4. 
Relationship to Liver Biopsy ....................................................................................127 
16.1.5. 
Relationship to Study Procedures .............................................................................128 
16.1.6. 
Recording Adverse Event Severity ...........................................................................128 
16.1.6.1. 
Severity of Pruritus (as an Adverse Event) ...............................................................129 
16.1.7. 
Reporting of Adverse Events and Serious Adverse Events ......................................130 
16.1.7.1. 
Reporting of Adverse Events ....................................................................................130 
16.1.7.2. 
Reporting of Serious Adverse Events .......................................................................130 
16.1.8. 
Potential Liver-Related Clinical Outcome Events ....................................................131 
16.1.9. 
Additional Investigator Responsibilities for SAEs ...................................................131 
16.1.10. 
Notification of Post-Treatment SAEs for Subjects Who Continue in the Study ......131 
16.1.11. 
Notification of Post-Study SAEs ..............................................................................132 
16.1.12. 
Follow-Up of AEs and SAEs ....................................................................................132 
16.1.13. 
Pregnancy and Follow-Up ........................................................................................133 


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Confidential and Proprietary 
16.2. 
Other Safety Parameters ...........................................................................................133 
16.2.1. 
Medical History/Demographics ................................................................................133 
16.2.2. 
Physical Examination ...............................................................................................133 
16.2.3. 
Vital Signs ................................................................................................................134 
16.2.4. 
Electrocardiogram .....................................................................................................134 
16.2.5. 
Alcohol Consumption, Smoking Habits, and Caffeine Consumption ......................134 
16.2.6. 
Cardiovascular Risk Scores ......................................................................................134 
16.2.7. 
Laboratory Assessments ...........................................................................................135 
16.2.8. 
Pruritus Assessment ..................................................................................................137 
17. 
STATISTICS ............................................................................................................137 
17.1. 
Analysis Populations ................................................................................................137 
17.2. 
Determination of Sample Size ..................................................................................138 
17.3. 
Primary Efficacy Analysis ........................................................................................138 
17.4. 
Secondary Efficacy Analyses ...................................................................................139 
17.4.1. 
Histology Endpoints .................................................................................................139 
17.4.2. 
Clinical Outcomes ....................................................................................................139 
 
 
 
 
17.5.2. 
Liver Biochemistry and Synthetic Function .............................................................141 
17.5.3. 
Metabolic Parameters ...............................................................................................141 
17.5.4. 
Markers of Inflammation, Apoptosis, and Necrosis .................................................141 
17.5.5. 
Health-Related Quality of Life and Measure of Health Status .................................142 
17.5.5.1. 
Noninvasive Assessments of Liver Disease Assessed by Serum Markers and 
Imaging Tests ............................................................................................................142 
17.5.5.2. 
Noninvasive Radiological Assessment of Liver Fibrosis .........................................142 
17.5.6. 
Disease Progression as Assessed by MELD Score ...................................................142 
 
 
17.6. 
PK Analyses ..............................................................................................................143 
17.7. 
PD Analyses ..............................................................................................................143 
17.8. 
PK/PD Analysis ........................................................................................................143 
17.9. 
Handling of Missing Data .........................................................................................143 
17.9.1. 
Time-to-Event Endpoints ..........................................................................................143 
17.9.2. 
Quantitative Endpoints .............................................................................................144 


Protocol 747-304 
Version 7.0:  16Jun2021 
Page 24 
 
Confidential and Proprietary 
17.9.3. 
Responder Endpoints ................................................................................................144 
17.9.4. 
Incidence Endpoints ..................................................................................................144 
17.10. 
Examination of Subgroups .......................................................................................144 
17.11. 
Safety Analyses ........................................................................................................145 
17.11.1. 
Adverse Events .........................................................................................................145 
17.11.2. 
Hepatic and Renal Safety Adjudication ....................................................................145 
17.11.3. 
Cardiovascular Event Adjudication ..........................................................................145 
17.11.4. 
Cardiovascular Risk Assessment ..............................................................................146 
17.11.5. 
Clinical Laboratory Evaluations ...............................................................................147 
17.11.5.1. Lipoprotein Evaluations ............................................................................................147 
17.11.6. 
Additional Safety Analyses ......................................................................................147 
17.11.6.1. Vital Signs ................................................................................................................147 
17.11.6.2. Electrocardiograms ...................................................................................................147 
17.11.6.3. Pruritus VAS .............................................................................................................148 
17.12. 
Open-Label Extension Analyses ...............................................................................148 
17.12.1. 
Safety Analyses (OLE) .............................................................................................148 
17.12.2. 
Efficacy Analyses (OLE) ..........................................................................................148 
17.13. 
Data Monitoring Committee .....................................................................................148 
17.14. 
Adjudication Committees .........................................................................................149 
18. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................................150 
18.1. 
Study Monitoring ......................................................................................................150 
18.2. 
Audits and Inspections ..............................................................................................150 
19. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................150 
20. 
ETHICS ....................................................................................................................151 
20.1. 
Ethics Review ...........................................................................................................151 
20.2. 
Ethical Conduct of the Study ....................................................................................151 
20.3. 
Written Informed Consent ........................................................................................151 
20.4. 
Subject Confidentiality and Data Protection ............................................................152 
21. 
INVESTIGATOR OBLIGATIONS .........................................................................152 
21.1. 
Adverse Event Reporting ..........................................................................................152 
21.2. 
Protocol Deviations ..................................................................................................153 
21.3. 
Regulatory Documentation .......................................................................................153 


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21.4. 
Ethics Review (IRB/IEC) .........................................................................................153 
21.5. 
Archiving and Record Retention ..............................................................................153 
22. 
PUBLICATION POLICY ........................................................................................154 
23. 
LIST OF REFERENCES ..........................................................................................156 
APPENDIX A. MANAGEMENT OF CHANGES IN CHOLESTEROL ................................159 
APPENDIX B. MANAGMENT OF HYPERGLYCEMIA ......................................................162 
APPENDIX C. EDUCATION AND ASSESSMENT OF SIGNS/SYMPTOMS OF 
INTERCURRENT ILLNESS AND/OR POTENTIAL ADVERSE 
EVENTS AT EACH STUDY VISIT ..............................................................163 
APPENDIX D. COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ........166 
APPENDIX E. STANDARDIZED DEFINITIONS FOR CARDIOVASCULAR 
ENDPOINT EVENTS .....................................................................................247 
APPENDIX F. 
SUMMARY OF CHANGES:  747-304 PROTOCOL VERSION 6.0 
TO PROTOCOL VERSION 7.0 (DATED:  16 JUN 2021) ............................266 
 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures (Double-Blind Phase) ................................................47 
Table 2: 
Schedule of Study Procedures (OLE Phase) ..............................................................51 
Table 3: 
Liver Laboratory Criteria for Monitoring for Potential Hepatic Injury ......................57 
Table 4: 
Child-Pugh Scoring System ........................................................................................61 
Table 5: 
Criteria for Dose Interruption, Discontinuation, Downtitration, and 
Rechallenge .................................................................................................................68 
Table 6: 
NASH CRN Scoring System for Determining Eligibility and Primary 
Histological Endpoint Assessment ...........................................................................119 
Table 7: 
Acceptable Windows for Pharmacokinetic Sample Collection ................................123 
Table 8: 
Relationship of Adverse Events to Investigational Product .....................................127 
Table 9: 
Relationship of Adverse Events to Liver Biopsy .....................................................127 
Table 10: Relationship of Adverse Events to Study Procedures ..............................................128 
Table 11: Severity of Adverse Events ......................................................................................128 
Table 12: Severity of Pruritus ...................................................................................................129 
Table 13: List of Laboratory Scores and Analytes ...................................................................136 
 


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LIST OF FIGURES 
Figure 1: 
Study Design Diagram ................................................................................................46 
Figure 2: 
Potential DILI Management Algorithm for Study 747-304 .......................................56 
Figure 3: 
Algorithm for Monitoring Subjects for Potential Renal Impairment .........................65 
Figure 4: 
Therapeutic Targets for LDLc Based on Subject ASCVD Risk ................................83 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Explanation 
A1AT 
alpha-1-antitrypsin 
ADA 
American Diabetes Association 
AE 
adverse event 
AKI 
acute kidney injury 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ApoA-1 
apolipoprotein A-1 
ApoB 
apolipoprotein B 
ApoE 
apolipoprotein E 
APRI 
aspartate aminotransferase to platelet ratio index 
ASCVD 
atherosclerotic cardiovascular disease 
AST 
aspartate aminotransferase 
AUDIT 
Alcohol Use Disorders Identification Test 
BA 
biliary atresia 
BAS 
bile acid sequestrants 
β-hCG 
beta human chorionic gonadotropin 
BLM 
baseline measurement 
BMI 
body mass index 
BUN 
blood urea nitrogen 
C4 
7α-hydroxy-4-cholesten-3-one 
CAC 
Cardiovascular Adjudication Committee 
CDCA 
chenodeoxycholic acid 
CHI3L1 
chitinase 3-like protein 1 
CI 
confidence interval 
CK-18-M30 
cytokeratin-18 neoepitope M30 
CK-18-M65 
cytokeratin-18 neoepitope M65 
CLDQ 
Chronic Liver Disease Questionnaire 
Col1a1 
Collagen 1a1 
CMH 
Cochran-Mantel-Haenszel 
CRA 
Clinical Research Associate 
CRN 
Clinical Research Network 
CS 
clinically significant 


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Abbreviation or Specialist Term 
Explanation 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
cardiovascular 
CP 
Child-Pugh 
CPMP 
Committee for Medicinal Products for Human Use 
DILI 
drug-induced liver injury 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid  
DSI 
disease severity index 
EASD 
European Association for the Study of Diabetes 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGD 
esophagogastroduodenoscopy 
ELF 
Enhanced Liver Fibrosis 
Emax 
maximum effect 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
FDA 
Food and Drug Administration 
FGF-19 
fibroblast growth factor-19 
FIB-4 
Fibrosis-4 
FLINT 
Farnesoid X receptor Ligand OCA in Nonalcoholic 
Steatohepatitis Treatment 
FRS 
Framingham Risk Score 
FXR 
farnesoid X receptor 
GCP 
Good Clinical Practice 
GGT  
gamma-glutamyl transferase 
glyco-OCA 
glycine conjugate of obeticholic acid 
HA 
hyaluronic acid 
HbA1c 
hemoglobin A1c  
HBsAg 
hepatitis B surface antigen 
HCC 
hepatocellular carcinoma 
HCP 
health care provider 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 


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Abbreviation or Specialist Term 
Explanation 
HE 
hepatic encephalopathy 
HOMA-β 
homeostatic model assessment –beta cell 
HOMA-IR 
homeostatic model assessment –insulin resistance 
HSAC 
Hepatic Safety Adjudication Committee 
hs-CRP 
high-sensitivity C-reactive protein 
HSC 
hepatic stellate cells  
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
 
 
IND 
investigational new drug 
INR 
international normalized ratio  
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent-to-Treat 
KM 
Kaplan-Meier 
LDL 
low-density lipoprotein 
Lp(a) 
lipoprotein(a) 
LS 
least-squares 
MACE 
major adverse cardiovascular events 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCP-1 
monocyte chemoattractant protein-1 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model for end-stage liver disease 
mITT 
modified intent-to-treat 
MRE 
magnetic resonance elastography 
MW 
molecular weight 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
nonalcoholic fatty liver disease activity score 
NASH 
nonalcoholic steatohepatitis 
NCS 
not clinically significant 


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Abbreviation or Specialist Term 
Explanation 
NFS 
nonalcoholic fatty liver disease fibrosis score 
OCA 
obeticholic acid 
OLE 
open-label extension 
P3NP 
procollagen III amino terminal peptide  
PBC 
primary biliary cholangitis 
PCA 
percent collagen area 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTcF 
QT interval corrected by the Fridericia’s formula 
RNA 
ribonucleic acid 
RTSM 
Randomization and trial supply management 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
SCORE 
systemic coronary risk evaluation 
SUSAR 
suspected unexpected serious adverse reaction 
T3 
triiodothyronine 
T4 
thyroxine 
TAA 
thioacetamide  
tauro-OCA 
taurine conjugate of obeticholic acid 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
TIMP-1 
tissue inhibitor of metalloproteinase 1 
 
 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
VLDL 
very low-density lipoprotein 
WPAI 
Work Productivity and Activity Index 


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5. 
INTRODUCTION 
5.1. 
Overview of Nonalcoholic Steatohepatitis and Obeticholic Acid 
Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of 
metabolic syndrome, a cluster of closely related clinical features linked to visceral obesity and 
characterized by insulin resistance, dyslipidemia, and hypertension.  NAFLD is the most common 
cause of chronic liver disease in the western hemisphere.  As the prevalence of obesity and 
metabolic syndrome rises in the industrial world, NAFLD is expected to rise in parallel.  NAFLD 
is thought to be represented by a spectrum of histologically-defined diseases, which progresses 
from simple steatosis to nonalcoholic steatohepatitis (NASH).  Up to one-third of NAFLD 
patients go on to develop NASH, which is characterized by hepatocellular injury, inflammation, 
and progressive fibrosis potentially leading to cirrhosis.  As opposed to simple steatosis, NASH is 
associated with significant morbidity and progression that, if left untreated, can progress to 
advanced fibrosis, cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), and liver-
related death (Vernon 2011).  Of all the histologic features of NASH, fibrosis is considered the 
strongest predictor of adverse clinical outcomes, including liver-related death (Younossi 2011, 
Ekstedt 2015). 
Despite the seriousness of the disease, especially when advanced fibrosis/cirrhosis is present, 
there are currently no approved pharmacologic treatments.  The current treatment strategy for 
NASH patients with cirrhosis becomes largely supportive, focused primarily on managing 
complications and, as a last resort, liver transplant.  It is therefore critical to develop effective 
therapies that can reverse fibrosis or prevent the progression of fibrosis to cirrhosis, with the goal 
of reducing complications secondary to cirrhosis ultimately improving quality of life and 
liver-transplant-free survival. 
In view of the serious nature of the disease, the increasing prevalence, the complications that arise 
from the disease, and the unmet medical need, approved therapy for NASH is warranted.  
Obeticholic acid (OCA) is a modified bile acid and farnesoid X receptor (FXR) agonist that is 
derived from the primary bile acid chenodeoxycholic acid (CDCA), the natural human FXR 
ligand. 
OCA’s potent FXR agonist effects make it an attractive novel therapeutic agent for NASH due to 
its multiple FXR-mediated effects, including prevention and reversal of liver fibrosis, 
anti-inflammatory effects in liver and vasculature, and hepatocyte protection against bile 
acid-induced cytotoxicity.  Specifically, nonclinical studies have shown several potentially 
beneficial properties of FXR agonism in NASH and cirrhosis (Adorini 2012, Mudaliar 2013).   
5.2. 
Nonclinical Experience with OCA 
Non-clinical studies clarifying the anti-inflammatory, anti-fibrotic and anti-cirrhotic mechanisms 
underlying OCA’s effect in NASH include the following: 
• In mice, OCA has been shown to alleviate key histologic hallmarks of NASH in 
high-fat/high-cholesterol diet-induced and biopsy-confirmed disease as reflected by 
improvements in nonalcoholic fatty liver disease activity score (NAS), steatosis, 
ballooning and immunohistochemical markers of fibrosis (eg, collagen 1a1 [Col1a1]) 


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and inflammation (eg, galectin 3; Roth 2017).  These effects were associated with 
regulation of FXR target genes within the gut-liver axis and improvements in genes 
involved in monocyte recruitment and fibrosis (eg, monocyte chemoattractant protein-
1 [MCP-1], Col1a1, collagen type III alpha 1 chain, membrane palmitoylated protein 
2, tissue inhibitor of metalloproteinase 2).  These findings further confirm the benefits 
of FXR agonism by OCA in a rodent model of NASH. 
• Hepatic fibrosis ultimately progresses to cirrhosis.  While it is difficult to induce 
cirrhosis by simple high fat feeding, this stage can be readily induced in rodents by the 
application of thioacetamide (TAA).  Importantly, therapeutic effects have been 
demonstrated when OCA was administered concurrently or following established 
cirrhosis within the rat TAA model (Verbeke 2016).  These benefits were associated 
with: (1) functional hepatic improvements such as a reduction in portal pressure 
through reduced intrahepatic vascular resistance, and (2) a decreased expression of 
pro-fibrotic cytokines (transforming growth factor β, connective tissue growth factor, 
and platelet derived growth factor) and markers of hepatic cell turn-over by blunting 
effects of pro-inflammatory cytokines (MCP-1). 
• To dissect out the contribution of individual cell types, in vitro studies interrogated the 
potential for direct effects of OCA upon isolated hepatic stellate cells (HSCs), Kupffer 
cells, hepatocytes, and liver sinusoidal endothelial cells.  Collectively, these findings 
suggest that the improvements manifest via indirect effects on immune activation and 
hepatic cell turn-over and are linked to a decrease in nuclear factor 
kappa-light-chain-enhancer of activated B cell activation and cytokines promoting 
fibrosis and inflammation within the liver parenchyma (Verbeke 2016).  These effects 
do not appear to be due to a direct effect upon HSCs (Fickert 2009, Verbeke 2016). 
• Although not formally addressed in a cirrhotic model, interactions between the 
intestinal mucosal barrier and liver (the “gut-liver axis”) are recognized as important 
contributors to the clinical pathogenesis of NASH (van Best 2015).  Under healthy 
conditions, the intestinal mucosal barrier is the first line of defense against antigens 
and inflammatory mediators escaping from gut mucosal immune surveillance.  
Disruption results in bacterial translocation to the extra-intestinal space, activating the 
immune system and triggering further hepatic inflammation and damage.  In animal 
models (Garcia-Tsao 1995) and human cirrhosis, bacterial translocation is a prelude to 
hepatic decompensation, further liver impairment, and, ultimately, organ failure.  In 
preclinical models, these effects are attenuated following OCA administration.  
For example, OCA inhibits gastrointestinal inflammation and preserves intestinal 
barrier function in models of inflammatory bowel diseases, upregulating expression of 
anti-bacterial genes and inhibiting bacterial translocation (Gadaleta 2011).  In the bile 
duct ligation model, OCA treatment improves ileal barrier function by attenuating 
intestinal inflammation and reducing bacterial translocation, a key driver in the 
pathogenesis and complications of liver cirrhosis (Verbeke 2015). 
In summary, there is strong rationale to advance OCA for the treatment of NASH based on its 
FXR-mediated hepatoprotective properties. 


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5.3. 
Clinical Experience with Obeticholic Acid 
OCA (Ocaliva) has received marketing authorization in the United States, Europe, Canada, and 
several other countries for the treatment of primary biliary cholangitis (PBC) in combination with 
ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as 
monotherapy in adults unable to tolerate UDCA.  OCA is currently being developed for the 
treatment of multiple chronic nonviral liver diseases, including NASH with fibrosis, NASH with 
cirrhosis, primary sclerosing cholangitis, and biliary atresia. 
The clinical development program for OCA in subjects with NAFLD or NASH includes data 
from the following 6 completed studies: 
• Study 747-203:  A proof-of-concept, Phase 2 study in subjects with type 2 diabetes 
and presumed NAFLD to evaluate the effects of OCA on insulin sensitivity 
(Mudaliar 2013). 
• FXR Ligand OCA in NASH Treatment (FLINT):  A Phase 2 study conducted by the 
National Institute of Diabetes and Digestive and Kidney Diseases and the NASH 
Clinical Research Network (CRN) to evaluate the efficacy and safety of OCA in the 
treatment of NASH (Neuschwander-Tetri 2015). 
• Study D8602001:  A Phase 2 study conducted by Intercept’s Asian development 
partner (Sumitomo Dainippon Pharma Co., Ltd) to evaluate the efficacy and safety of 
3 doses of OCA versus placebo in NASH. 
• Study 747-209:  A Phase 2, double-blind, randomized, placebo-controlled, multicenter 
study evaluating the effect of OCA, and the subsequent addition of statin therapy, on 
lipoprotein metabolism in subjects with NASH with fibrosis stage 1 to 4, but no 
evidence of hepatic decompensation. 
• Study 747-117:  A Phase 1, double-blind, randomized, placebo-controlled study 
evaluating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of OCA in 
subjects with NASH fibrosis. 
• Study 747-118:  A Phase 1, single-center, double-blind, randomized study evaluating 
the safety, pharmacokinetics, and pharmacodynamics of OCA in healthy subjects and 
subjects with compensated Child-Pugh (CP) Class A cirrhosis due to NASH. 
− Including a 747-118 hepatic PK substudy in subjects with cirrhosis due to NASH. 
Study 747-203 showed improved insulin sensitivity in subjects with type 2 diabetes and NAFLD, 
demonstrating the clinical relevance of the FXR agonist pathway and supporting the potential of 
OCA to treat NAFLD and/or NASH.  With the exception of weight loss, OCA 25 mg appeared to 
be at least as effective as OCA 50 mg for the majority of endpoints evaluated.  Pruritus (including 
generalized pruritus) in Study 747-203 occurred at a comparable incidence in OCA-treated and 
placebo-treated subjects with NAFLD; the incidence was approximately 9% to 10% between 
placebo and the highest OCA dose (50 mg).  No subject from Study 747-203 withdrew from the 
study due to pruritus. 
The FLINT study demonstrated that OCA 25 mg was superior to placebo in improving not only 
the key histologic features important in the underlying pathophysiology of the disease 


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(inflammation, ballooning, and steatosis), but notably also fibrosis (35% OCA versus 19% 
placebo; p = 0.004).  Across all fibrosis change categories (fibrosis improvement of ≥1 stage of 
fibrosis, ≥2 stages of fibrosis or resolution of fibrosis), a greater percentage of OCA-treated 
subjects were responders compared to placebo.  Importantly, a significantly greater percentage of 
subjects in the OCA group (17%) showed fibrosis resolution after 72 weeks of treatment 
compared to placebo (5%).  In addition, although the numbers were small (likely due to the 
limited 72-week treatment period), fewer OCA-treated subjects (2%) progressed to cirrhosis 
compared to placebo (5%).  OCA treatment was also associated with improvement in markers of 
hepatocellular injury and some cardiometabolic features, including weight and systolic blood 
pressure.   
Low-density lipoprotein cholesterol (LDLc) demonstrated a modest but significant increase in 
subjects treated with OCA compared to placebo; however, this increase was reversed and LDLc 
cholesterol returned to below baseline levels in subjects who initiated statin therapy.  The general 
adverse event (AE) profile was similar between the OCA 25 mg and placebo groups, with the 
exception of pruritus.  Pruritus occurred more frequently in the OCA-treated subjects (23% OCA 
versus 6% placebo), led to 1 discontinuation, and was generally mild and moderate in severity.  
Otherwise, pruritus was well managed with the use of antipruritic medications and treatment 
interruption. 
Study D8602001 demonstrated a dose-dependent increase in the percentage of OCA-treated 
subjects compared to placebo subjects who achieved the primary endpoint (p = 0.053, not 
significant).  The 40-mg OCA dose group achieved statistical significance for the primary 
endpoint compared to placebo (p = 0.0496).  Dose-dependent trends not reaching statistical 
significance were also observed for several other pre-specified histologic endpoints, including the 
proportion of subjects with steatosis and inflammation improvement, ballooning resolution, and 
NASH resolution.  In the completer analysis, similar dose-dependent effects were observed, with 
51% of patients in the 40-mg dose group compared to 22% in the placebo group meeting the 
primary endpoint (p = 0.0061).  With the exception of dose-dependent pruritus, OCA appeared to 
be generally safe and well tolerated.  The number of pruritus-associated treatment 
discontinuations were 0, 0, 2, and 5 subjects in the placebo, 10-mg, 20-mg, and 40-mg OCA 
groups, respectively.  Changes in lipid parameters were directionally similar to those observed in 
NASH subjects in the FLINT study.  No other meaningful differences in the rate of AEs between 
the OCA and placebo groups were noted. 
Study 747-209 further evaluated the effect of OCA and atorvastatin treatment on LDLc 
metabolism in subjects with NASH and liver fibrosis to better characterize the lipid profile 
changes observed in the FLINT study, as well as their management.  Subjects with 
biopsy-confirmed NASH and fibrosis received placebo or OCA 5 mg, 10 mg, or 25 mg once 
daily, for up to 4 weeks.  Subjects then initiated concurrent treatment with atorvastatin 10 mg 
once daily, and titrated to 20 mg once daily at Week 8 based on tolerability.  At Week 4, prior to 
initiation of statin treatment, subjects experienced an approximately 20% to 25% increase in 
LDLc concentrations across all OCA groups.  By Week 8, atorvastatin treatment effectively 
lowered LDLc to below baseline levels across all treatment groups.  Together, these study results 
suggest that the risk of increases in LDLc with OCA use can generally be managed by statin use.  
Pruritus was the most common AE and was dose dependent.  Two subjects discontinued the study 
due to pruritus.  


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Study 117 demonstrated that the PK profile of OCA in subjects with NASH fibrosis was 
consistent with what has been observed in healthy subjects and largely reflective of enterohepatic 
recirculation with exposure proportional to dose.  Treatment with OCA 10 mg or 25 mg once 
daily for 12 weeks was found to be safe and well tolerated in NASH subjects with fibrosis 
(including fibrosis stage 1 through stage 4).  The PD assessments demonstrated FXR activation 
and positive trends for select markers of fibrosis, inflammation, apoptosis, and liver function.   
Study 747-118 demonstrated that the safety profile of 10 mg and 25 mg doses of OCA in subjects 
with compensated CP Class A cirrhosis due to NASH was similar to the safety observed in 
healthy subjects, supporting their use in longer term efficacy studies.  The hepatic PK substudy 
demonstrated that OCA 25 mg was safe and generally well tolerated, showing improvements in 
the levels of liver biochemistry markers associated with hepatocellular injury when administered 
for 28 days to subjects with CP Class A cirrhosis due to NASH, consistent with results from the 
double blind period. 
The following studies evaluating OCA for the treatment of NASH are currently ongoing: 
• The clinical outcome portion of Study 747-303. 
A complete description of the OCA clinical development program is provided in the 
Investigator’s Brochure. 
5.4. 
Rationale for Study Design and Dose for Investigational Product 
5.4.1. 
Rationale for Study Design 
NASH is a serious, chronic liver disease with a large unmet medical need and no approved 
therapies.  Patients with cirrhosis in the spectrum of NASH disease continuum represent the 
highest unmet medical need and are at the greatest risk of disease progression.  NASH has 
become one of the leading causes of liver transplant (Wong 2020, Younossi 2020), highlighting 
the need for development of effective therapies that may improve steatohepatitis and fibrosis, 
potentially delaying liver transplant or death.  As fibrosis has been consistently shown to be the 
strongest predictor of adverse clinical outcomes, including liver-related death, it is critical to 
prevent further progression of fibrosis and preferably reverse fibrosis.  Results from FLINT and 
the 18-month interim analysis of Study 747-303 have demonstrated that OCA has robust anti-
fibrotic effects and improves underlying disease activity and steatohepatitis in NASH subjects 
with fibrosis at the 18-month assessment.  Study 747-304 will evaluate efficacy (based on 
histological improvement in fibrosis) and safety of OCA in NASH subjects with compensated 
cirrhosis (defined by a NASH Clinical Research Network [CRN] score of 4), and CP score <7. 
5.4.2. 
Rationale for Placebo Control Group  
The use of a randomized placebo control group added to established standard of care, including 
lifestyle modification counseling, provides the best scientific evidence of efficacy and safety.  The 
use of a placebo control provides a concurrent comparator group, accounting for not only a 
placebo effect but a standard of care effect.  As there is no approved or proven pharmacologic 
therapy for NASH, using a placebo for comparative purposes is justified. 


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5.4.3. 
Rationale for Obeticholic Acid Doses and Duration 
In addition to placebo, two dosing regimens of OCA will be evaluated in this study: (1) Titration 
regimen (OCA 10 mg → 25 mg) in which OCA will be initiated at a dose of 10 mg once daily 
followed by uptitration to 25 mg once daily at Month 3; and (2) OCA 10 mg once daily for the 
entire duration of the study. 
This dose titration was selected based upon the known mechanism of FXR and on clinical 
experience in completed Phase 2 studies in subjects with NAFLD (747-203) and NASH (FLINT), 
as well as a clinical pharmacology study in subjects with hepatic impairment (Study 747-103). 
FXR is a nuclear receptor that senses bile acids and regulates their intracellular levels in 
hepatocytes.  FXR activation leads to the reduction of intracellular bile acid levels by increasing 
the export of bile acids from cells, thereby decreasing bile acid uptake and bile acid synthesis.  
After 12 weeks of dosing OCA, FXR activation has been shown to reduce systemic bile acid 
levels while maintaining relatively low OCA levels in the total bile acid pool (<2%). 
Study 747-203, a 6-week study that evaluated the efficacy and safety of OCA 25 mg, 
OCA 50 mg, and placebo in 64 subjects with type 2 diabetes mellitus and NAFLD, demonstrated 
that both OCA 25 mg and 50 mg doses were similarly efficacious in improving insulin sensitivity 
as well as markers of fibrosis such as Enhanced Liver Fibrosis (ELF).   
The efficacy and safety of OCA 25 mg was also evaluated in the FLINT study in which patients 
with NASH fibrosis were treated for a period of 72 weeks.  In this study, OCA-treated patients 
showed significant improvements in histologic parameters, including improvements in features of 
steatohepatitis, improvement of fibrosis, and resolution of NASH.  In both studies, OCA 25 mg 
was well tolerated with pruritus being the most common treatment-emergent adverse event 
(TEAE) in FLINT (23% OCA vs 6% placebo).  In summary, the OCA 25 mg dose has 
demonstrated significant histologic improvement in patients with NASH fibrosis while being well 
tolerated, and has therefore been selected for further evaluation in the population with cirrhosis 
who has not reached CP score ≥7.  
The dedicated hepatic impairment study (747-103) using OCA 10 mg has shown only 10% 
increase in the systemic concentrations of total OCA in subjects with CP Class A compared to 
that of healthy subjects.   
Therefore, the dose of OCA 10 mg will be administered for 3 months to support the lowering of 
bile acid levels in CP Class A subjects.  After 3 months, titration of OCA 25 mg administration is 
introduced to provide clinically proven beneficial doses.  Study 747-209 evaluated a range of 
doses from 5 mg to 25 mg in subjects with NASH and fibrosis, including subjects with 
compensated cirrhosis.  In this study, treatment of NASH subjects with compensated cirrhosis 
with up to 25 mg OCA was found to be safe and well tolerated, and the AE profile of cirrhotic 
subjects was not different from that of precirrhotic subjects.  Guidelines for subjects who progress 
beyond CP Class A are provided in Section 7.4. 
In addition to the titration dosing regimen, an arm evaluating OCA 10 mg once daily will also be 
evaluated.  While OCA 25 mg once daily was well-tolerated overall, there was an increased 
incidence of mostly mild or moderate pruritus in OCA-treated subjects compared to 
placebo-treated subjects in the FLINT and 747-209 studies.  Pruritus was also the most common 
AE associated with OCA in PBC studies, and has been shown to be dose related, warranting 


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evaluation of lower doses as a potential strategy to improve tolerability.  Phase 2 and Phase 3 
studies evaluating OCA for the treatment of PBC have shown that the incidence and severity of 
pruritus with OCA treatment can be mitigated with lower OCA doses.  Therefore, based on the 
therapeutic effect of 10 mg in PBC and to evaluate potential attenuation of effect of OCA on 
pruritus and serum lipid levels, a lower dose of 10 mg daily will be evaluated in this study in 
addition to the titration dosing regimen. 
Rationale for Treatment Duration of 18 Months 
The natural history of NASH with liver fibrosis shows that both progression and regression of 
liver fibrosis are slow processes that may take years to develop as well as to improve.  A 
systematic review and meta-analysis of paired-biopsy studies has shown that a 1-stage change in 
fibrosis occurs over a median of 7.1 years in patients with NASH (Singh 2015).  Regression of 
fibrosis in established NASH cirrhosis is expected to take even longer (Cheung 2019).  To date, 
no clinical trial in subjects with NASH cirrhosis has demonstrated efficacy with respect to 
reversal of cirrhosis and there are no approved treatment options for NASH cirrhosis. 
As presented above, OCA has shown robust anti-fibrotic effects based on histologic endpoints in 
pre-cirrhotic NASH subjects with liver fibrosis.  A treatment duration of 12 months was initially 
selected for the placebo-controlled portion of this study based on non-histological data (using 
serum biomarkers of fibrosis observed in Study 747-203 and FLINT).  However, the effects of 
OCA on liver histology at earlier time points, including 12 months, had not been assessed.  The 
preliminary results of the 18-month interim analysis from Study 747-303 showed that OCA 
25 mg was superior to placebo, demonstrating histological improvement of NASH fibrosis 
without worsening of NASH with an effect size of ~11% over 18 months of treatment 
(Younossi 2019).  However, the results also highlighted the slow process of regression of liver 
fibrosis and the potential challenges of demonstrating efficacy in regression of liver fibrosis 
within a finite time period.  Based on the above considerations, the duration of treatment in the 
Double-Blind Phase has been extended to 18 months. 
5.5. 
Summary of Known Potential Risks with Investigational Product 
The rate of progression and risk of hepatic decompensation is variable and may be rapid in certain 
patients, necessitating closer surveillance of patients at risk.  Investigators should inform 
participating subjects of known and anticipated risks associated with OCA treatment and prompt 
them to communicate with the Investigators in the event of any adverse experiences. 
Post-Marketing Cases of Liver Injury in PBC 
In post-marketing reports, hepatic decompensation and failure, in some cases fatal, have been 
reported in PBC subjects with decompensated cirrhosis or Child-Pugh Class B or C hepatic 
impairment when OCA was dosed more frequently than the recommended starting dosage of 
5 mg once weekly (ie, off-label use).  Subjects who died due to hepatic complications generally 
had decompensated cirrhosis prior to treatment and were started on OCA 5 mg QD, which is 
7-fold greater than the once weekly starting regimen in this population and considered to be a 
medication error. 
Based on a comprehensive review in 2017 of both existing and new clinical information, 
including more than 1300 patient-years of exposure and subjects with advanced disease, multiple 
analyses confirm lack of hepatotoxicity at the current recommended doses of OCA.  The existing 


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post-marketing evidence at that time was considered insufficient to confirm a causal relationship 
between exposure to OCA and the occurrence of hepatic decompensation and/or death.  The 
majority of cases reported were for advanced PBC patients receiving doses inconsistent with 
dosing instructions in the label.  Even in these cases, there is no clear evidence that the higher 
than recommended dosing frequency of OCA led to adverse outcomes.  
PBC is a chronic progressive liver disease, ultimately progressing to hepatic fibrosis and eventual 
cirrhosis, hepatic decompensation, liver transplant, and/or death.  Given that hepatic 
decompensation events are part of the natural history of PBC and patients with end stage disease 
are particularly vulnerable, it is often not possible to distinguish on a case level the hypothesized 
drug effects from the natural history of the disease. 
As a result, a boxed warning was added to the labeling in 2018 providing additional guidance on 
patient management for patients with decompensated cirrhosis as well as stronger dosing 
guidelines.   
A new label, approved on 01 June 2021, states that in the US, OCA is now contraindicated in 
PBC subjects with compensated cirrhosis with evidence of portal hypertension after a Newly 
Identified Safety Signal evaluation. 
Clinical Study Experience 
Liver-related events 
Systemic and hepatic concentrations of OCA increase significantly in patients with moderate to 
severe hepatic impairment.  In PBC clinical studies, a dose-response relationship was observed 
for the occurrence of liver-related adverse reactions with OCA, including jaundice, worsening 
ascites, and PBC flare with dosages of OCA 10 mg to 50 mg once daily.  Most events occurred at 
a dose up to 5-fold higher (50 mg) than the maximum recommended marketed dose (10 mg).  
Clinically relevant increases in AST, ALT, or conjugated bilirubin (markers of liver injury) were 
rarely seen at the intended clinical doses of 5 mg or 10 mg.  Elevated liver enzymes were 
observed in healthy subjects who were treated at doses ≥100 mg in Phase 1, multiple-dose 
studies; however, these elevations were only considered to be of clinical concern at the maximum 
dose of 250 mg daily.  Cases of hepatic decompensation cases have also occurred in PBC.  The 
majority of the cases were considered not related or unlikely related to investigational product by 
the Investigator.  In general, subjects who experienced hepatic decompensation either entered the 
study with more advanced disease, or for those studies where subjects started earlier in disease 
progression, events of hepatic decompensation generally occurred at least 1 year after the 
initiation of treatment or on higher doses. 
In a pooled analysis of 3 completed placebo-controlled clinical trials in subjects with primarily 
early-stage PBC, the exposure-adjusted incidence rates for all serious and otherwise clinically 
significant hepatic adverse reactions and isolated elevations in liver biochemical tests per 
100 patient exposure years were 5.2 in the OCA 10 mg group (highest recommended dosage), 
19.8 in the OCA 25 mg group (2.5 times the highest recommended dosage), and 54.5 in the OCA 
50 mg group (5 times the highest recommended dosage) compared to 2.4 in the placebo group. 
Analyses of liver-related safety information from NASH subjects treated with OCA demonstrate 
an overall hepatic safety profile consistent with PBC.  There is no evidence to indicate a 
consistent, dose-dependent worsening of liver biochemistries at doses up to 25 mg, including 


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ALT, AST or bilirubin.  Modest increases in alkaline phosphatase (ALP) levels have occurred 
following treatment with OCA; however, ALP levels were generally within upper limits of 
normal.  ALP elevations are generally not associated with a rise in gamma-glutamyl transferase 
(GGT), suggesting that these changes are unlikely to be due to cholestatic liver injury. 
In NASH clinical trials 9 cases of hepatic decompensation have been reported as SUSARs, 1 of 
which resulted in death.  The signs of hepatic decompensation included death due to a hepatic 
event; MELD score ≥15; liver transplant; ascites; or a serious adverse event (SAE) of variceal 
bleed, hepatic encephalopathy, or spontaneous bacterial peritonitis.   
Of these events, one was considered unlikely related to OCA and 6 were considered possibly 
related to blinded treatment.  The remaining events were considered possibly related to treatment 
and concerned subjects receiving daily OCA 40 mg.  One case describes a subject with an event 
of DILI, and a second case describes a subject with events of ascites and pruritus.  In the case 
with ascites and pruritus, treatment was discontinued.  Both subjects recovered from the events.  
Key hepatic findings in NASH subjects include the following:   
• In completed NASH clinical studies, cumulative on-study incidence rates for hepatic 
AEs and corresponding hazard ratios indicate that the rates of hepatic SAEs are not 
different across OCA and placebo groups.  Although more events occurred in the OCA 
25 mg group (6 [1%] subjects) than in the OCA 10 mg group (2 [<1%] subjects) or 
placebo group (2 [<1%] subjects), expert reviewers did not identify sufficient evidence 
supporting a consistent pattern of liver injury, and notably, the vast majority of cases 
were associated with confounding concomitant medications or severe intercurrent 
illness.   
• Given that the liver is the primary site of action for OCA safety and efficacy, liver 
concentrations for total OCA were predicted for subjects with hepatic impairment 
based on Child-Pugh Class score.  A 1.1-fold increase in liver OCA exposure is 
predicted in subjects with mild hepatic impairment (Child-Pugh Class A); however, a 
1.5- and 1.7-fold increase in liver concentrations of OCA are predicted for Child Pugh 
Class B and C respectively, when compared to that of healthy subjects (Edwards 
2016).  In a hepatic impairment study (747-118) in NASH subjects with compensated 
liver cirrhosis (Child-Pugh Class A), plasma exposure was approximately 4- to 10-fold 
higher, and liver exposure was approximately 2-fold higher as compared to NASH 
subjects with liver fibrosis.  OCA has not been evaluated in NASH subjects with 
decompensated cirrhosis (Child-Pugh Class B and Child-Pugh Class C). 
Pruritus 
Pruritus is an expected adverse event associated with OCA, particularly in subjects with 
cholestatic liver diseases such as PBC where pruritus is a common symptom of the disease.  In 
PBC clinical studies, the incidence of pruritus was 68% for OCA-treated subjects compared with 
40% in placebo-treated subjects.  The majority of events have been reported as mild to moderate 
in severity and infrequently resulted in early discontinuation.  The majority of subject’s 
experiencing pruritus did not require an intervention for pruritus.  The incidence and severity of 
pruritus have been shown to be dose dependent, but there is no evidence of association with stage 
or progression of underlying disease.   


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Pruritus has also been observed in subjects with NASH.  Across the three, long-term, 
double-blind, placebo-controlled studies in subjects with liver fibrosis due to NASH (747-303, 
FLINT, and D8602001), the incidence of pruritus TEAEs was dose dependent and higher in the 
OCA 25 mg group, as compared to the OCA 10 mg and placebo groups.  The majority of pruritus 
TEAEs were mild to moderate in severity.  The incidence of severe pruritus TEAEs was low, but 
higher in the OCA 25 mg group, as compared to the OCA 10 mg and placebo groups.  The 
incidence of new or worsening pruritus TEAEs was highest early in the course of treatment (ie, 
first 3 months) and subsequently decreased over time.  Consistent with the PBC experience, 
pruritus in subjects with NASH appeared to be manageable with temporary interruption of OCA 
treatment and the use of antipruritic medications.  
Lipids 
In subjects with NASH (FLINT), compared to placebo, treatment with OCA was associated with 
statistically significant elevations in the mean total serum cholesterol and LDLc levels, and a 
decrease in the mean HDL, which remained within normal limits.  These changes developed 
within the first 12-week time point after beginning of treatment, decreased over time after Week 
12, and returned to baseline levels when OCA treatment was withdrawn. 
Withdrawal of OCA treatment reversed the OCA-induced LDLc increase in all groups, including 
subjects who were not on statins (Neuschwander-Tetri 2015).  In Study 747-209, subjects with 
NASH and dyslipidemia received placebo or OCA 5mg, 10 mg, and 25 mg once daily, for up to 
4 weeks.  Subjects then initiated concurrent treatment with 10 mg atorvastatin once daily titrated 
to 20 mg once daily based on tolerability.  At Week 4, subjects experienced approximately 20% 
to 25% increases in LDLc particles across all OCA groups.  By Week 8, atorvastatin treatment 
effectively lowered LDLc to below baseline levels across all OCA groups compared to patients 
not on a statin. 
Together, the small magnitude of OCA mediated cholesterol and LDL changes, coupled with their 
reversibility upon cessation of OCA treatment and/or responsiveness to statin-initiation, suggest 
that this risk can be managed by statins as needed. 
Glycemic Changes 
In NASH clinical studies, treatment with OCA was associated with a generally modest and 
transient rise in glycemic parameters (fasting plasma glucose, fasting serum insulin, and 
hemoglobin A1c (HbA1c), a well-established marker of long-term glycemic control) that 
occurred early (ie, within the first 3 months) and attenuated, returning to levels similar to placebo 
after approximately 6 months of treatment. 
5.5.1. 
Risk/Benefit Profile of OCA in Subjects with NASH 
An independent data monitoring committee (DMC) has performed detailed reviews of individual 
subject and aggregate data from both the Phase 3 clinical outcomes study in subjects with PBC 
(Study 747-302) and the Phase 3 pivotal studies in subjects with NASH fibrosis (Study 747-303) 
and NASH cirrhosis (Study 747-304) on a quarterly basis, in an unblinded fashion, and in closed 
sessions (without the Sponsor’s participation).   
Following a request from the FDA, an ad hoc DMC review was held, and the DMC recommended 
that: 


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• For subjects in Study 747-303, investigational product should be interrupted in 
subjects who experience symptomatic cholelithiasis and/or cholecystitis. 
In a subsequent DMC review, the DMC recommended that: 
• For subjects in Study 747-303, investigational product should be permanently 
discontinued in subjects diagnosed with acute pancreatitis. 
The Sponsor decided to implement the DMC recommendations across the NASH program. 
In summary, based on the robust efficacy of OCA observed in PBC and NASH clinical studies, 
including improvements in liver biochemistry, fibrosis, and key histological features of NASH, as 
well as the overall safety profile of OCA (in >2300 healthy subjects and subjects with chronic 
liver diseases), the benefit-risk profile is favorable. 
Refer to the Investigator’s Brochure for additional information regarding the known potential 
risks with the investigational product. 
5.6. 
Importance of Monitoring of Disease Progression 
NASH is a chronic, progressive liver disease with variable rates of progression to cirrhosis and 
hepatic decompensation, although both may occur rapidly in certain patients.  Subjects with 
NASH cirrhosis have accentuated risks relative to subjects with non-cirrhotic NASH and can 
transition abruptly from a clinically compensated state to decompensated cirrhosis, with the 
manifestations of portal hypertension and impaired synthetic function that characterize end-stage 
liver disease.  Subjects with NASH cirrhosis must, therefore, be closely monitored to ensure early 
identification of signs and symptoms of decompensation and/or liver injury.  In this study, close 
and thorough safety monitoring is paired with appropriate investigational product dosing 
adjustment, interruption, and discontinuation to ensure subject safety. 
Investigators, together with the Sponsor’s Medical Monitor or designee, will consistently and 
frequently assess individual subjects, including careful evaluation of signs, symptoms, and 
laboratory parameters to identify potential hepatic injury and/or decompensation.  Criteria for 
potential hepatic injury and/or progression to decompensation are described in Section 7.4.  
Criteria for implementing dosing adjustments, interruptions, or discontinuations, and close 
monitoring procedures are described in Section 7.4.4 and Section 7.7. 
For subjects randomized to the uptitration arm, special consideration is given to monitoring and 
management of investigational product as discussed in more detail in Section 9.2.  Uptitration 
criteria have been designed to ensure that only subjects with evidence of adequate functional 
hepatic reserve will be exposed to the higher OCA dose (25 mg).  Specifically, subjects may only 
be uptitrated at Month 3 if, in addition to no safety or tolerability concerns being identified, they 
meet strict laboratory criteria (total bilirubin ≤1.2 mg/dL, serum albumin ≥3.5 g/dL, INR <1.5, 
and platelet count >100,000/mm3) at both baseline and all visits prior to Month 3.  Furthermore, 
uptitrated subjects must continue to meet those criteria throughout the study to stay on the 
uptitrated dose; if at any time a subject exceeds these thresholds (including upon retesting), they 
will be downtitrated to the lower OCA dose (10 mg). 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objectives Assessed at the End of the Double-Blind Phase 
The primary objectives are to evaluate the effects of OCA treatment compared with placebo on: 
• Histological improvement in fibrosis by assessing the percentage of subjects with 
improvement in fibrosis by at least 1 stage with no worsening of NASH defined as no 
increase in hepatocellular ballooning or lobular inflammation using the NASH CRN 
scoring system, from Baseline to the end of the Double-Blind Phase 
6.2. 
Secondary Objectives Assessed at the End of the Double-Blind Phase 
The secondary objectives are to evaluate the effects of OCA treatment compared with placebo on: 
• Resolution of NASH defined as overall histopathological interpretation of 1) “no fatty 
liver disease” or 2) “fatty liver disease (simple or isolated steatosis) without 
steatohepatitis” AND a NAS of 0 for ballooning and 0-1 for inflammation, using the 
NASH CRN scoring system, from Baseline to the end of the Double-Blind Phase 
• Resolution of NASH based on pathologist’s overall histopathologic interpretation of 
the presence or absence of definite NASH from Baseline to the end of the Double-
Blind Phase 
• Histological changes in fibrosis status, including:  (1) improvement or (2) no change, 
from Baseline to  the end of the Double-Blind Phase using the NASH CRN scoring 
system 
• Occurrence of all-cause mortality and liver-related clinical outcomes for the following 
adjudicated events (clinical outcomes composite endpoint):  
− Death (all cause) 
− Liver transplant 
− MELD score ≥15 
− Worsening of CP score (by at least 2 points) 
− Hospitalization (as defined by a stay of ≥24 hours) for: 
o Variceal bleed 
o Hepatic encephalopathy (as defined by a West Haven score of ≥2) 
o Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
− Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or 
paracentesis) 
− HCC as confirmed by 2 complementary imaging modalities unless already 
confirmed by biopsy  


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6.5. 
Safety Objectives Assessed at the End of the Double-Blind Phase 
• To evaluate the safety and tolerability of OCA treatment compared to placebo 
• The effect of OCA treatment compared to placebo on the following additional 
measures and markers: 
− Markers of cardiovascular safety 
− Incidence of adjudicated cardiovascular events  
− Incidence of adjudicated acute kidney injury (AKI) events 
− Incidence of adjudicated events of hepatic injury 
6.6. 
Primary Objectives Assessed at the End of the Open-Label Extension 
(OLE) 
• To evaluate and summarize the longer-term safety and tolerability of OCA treatment 
• To summarize the effects of OCA treatment on the occurrence of all-cause mortality 
and liver-related clinical outcomes for the following adjudicated events (clinical 
outcomes composite endpoint): 
− Death (all cause) 
− Liver transplant 
− MELD score ≥15 
− Worsening of CP score (by at least 2 points) 
− Hospitalization (as defined by a stay of ≥24 hours) for: 
o Variceal bleed 
o Hepatic encephalopathy (as defined by a West Haven score of ≥2) 
o Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
− Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or 
paracentesis) 
− HCC as confirmed by 2 complementary imaging modalities unless already 
confirmed by biopsy 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This Phase 3, double-blind, randomized, placebo-controlled, multicenter international study will 
evaluate the efficacy and safety of OCA in subjects with a biopsy-confirmed diagnosis of 
cirrhosis (based on a fibrosis score of 4 using the NASH CRN scoring system) due to NASH 
(determined by central reading of liver histology).  Subjects with hepatic decompensation or CP 
Class B or Class C cirrhosis are excluded.  Subjects who progress to CP Class B or Class C 
during the study will discontinue investigational product but are expected to be followed through 
to study closure (or at the discretion of the Sponsor). 
Double-Blind Phase (18 Months):  Subjects will be screened for a period of up to 12 weeks 
before entering the study.  Subjects who meet the entry requirements will be randomized in a 
1:1:1 ratio to one of the three treatment arms:  once daily dosing of OCA 10 mg, OCA 
10 mg → 25 mg (ie, OCA 10 mg with uptitration to OCA 25 mg at Month 3), or placebo, in 
conjunction with local standard of care.  Uptitration will be determined based on the laboratory 
criteria and safety and tolerability assessments completed prior to Month 3 as described in 
Section 9.2.1. 
Randomized subjects will be stratified by the presence of type 2 diabetes at enrollment (yes or 
no).  Investigational product (ie, OCA or placebo) will be taken orally, with water, once daily.  
Efficacy, safety, and laboratory assessments will be evaluated at clinical visits at Day 1, monthly 
for the initial 6 months (Month 1 through Month 6 Visits), Month 9, Month 12, Month 15, and 
Month 18. 
Open-Label Extension (up to 12 Months):  Subjects who complete the Double-Blind Month 18 
Visit and continue to receive investigational product are eligible to enroll into the OLE.  All 
subjects will receive OCA upon entry into the OLE.  Subjects randomized to placebo in the 
Double-Blind Phase will be re-randomized to either OCA 10 mg or OCA 10 mg → 25 mg 
(ie, OCA 10 mg for the first 3 months of the OLE prior to uptitrating to OCA 25 mg at OLE 
Month 3).  Uptitration will be determined based on the same criteria and assessments as employed 
in the Double-Blind Phase (Section 9.2.1).  Subjects randomized to OCA (10 mg or 10 mg → 
25 mg dose) during the Double-Blind Phase will continue the same dosing regimen they received 
at the end of the Double-Blind Phase; however, they will undergo dummy titration to maintain 
study blind until all subjects complete the Double-Blind Phase and the database is locked (refer to 
Section 9.2). 


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7.1.1. 
Study Design Diagram 
Figure 1: 
Study Design Diagram 
 
CP = Child-Pugh; CRN = clinical research network; NASH = nonalcoholic steatohepatitis; OCA = obeticholic acid; 
OLE = open-label extension; QD = once daily. 
a Subjects who meet the entry requirements will be randomized in a 1:1:1 ratio to one of the three treatment arms:  
once daily dosing of OCA 10 mg, OCA 10 mg → 25 mg (ie, OCA 10 mg with uptitration to OCA 25 mg at 
Month 3), or placebo, in conjunction with the standard of care 
b All subjects will receive OCA upon entry into the OLE:  Subjects who received placebo during the Double-Blind 
Phase will be re randomized 1:1 to either OCA 10 mg or OCA 10 mg → 25 mg (ie, OCA 10 mg with uptitration to 
OCA 25 mg at OLE Month 3).  Subjects who received OCA during the Double-Blind Phase will continue the same 
dosing regimen they received at the end of the Double-Blind Phase. 
c During the OLE period, subjects will return for site visits at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
 
Note: 
• 
Subjects with cirrhosis (based on a NASH CRN fibrosis score 4) due to NASH (determined by central 
reading of liver histology) will be enrolled in the study.  Subjects with hepatic decompensation or CP Class 
B or CP Class C cirrhosis are excluded.   
• 
Two screening visit assessments will be performed.  Screening Visit 1 will occur no more than 12 weeks 
prior to Day 1, and Screening Visit 2 will occur at least 4 weeks after Screening Visit 1.   
• 
Randomized subjects will be stratified by the presence of type 2 diabetes at enrollment (yes or no). 
• 
The study will remain blinded until all subjects complete the Double-Blind Phase and the database is locked.  
To maintain blinding, all investigational product (placebo and OCA) tablets and bottles will be identical. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 














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e The calculations for BMI and waist-to-hip ratio will be performed via EDC:  BMI from weight and height measurements, and waist-to-hip ratio from waist and hip 
circumference measurements.  (Note:  Height will be measured at Screening Visit 1 only.) 
f Body temperature, sitting heart rate, respiratory rate, and seated blood pressure after sitting 3 minutes. 
g For subjects who develop HCC during the study, HCC screening assessments for study visits after onset of HCC are not required. 
h Perform EGD procedure unless data from a recent EGD (within 6 months of OLE Day 1) are available.  Subjects with endoscopic evidence of varices will not continue in the 
OLE Phase. 
i Subjects randomized to placebo during the Double-Blind Phase will be re-randomized to OCA 10 mg or OCA 10 mg → 25 mg arms on OLE Day 1; the placebo subjects in the 
OCA 10 mg → 25 mg arm will receive OCA 10 mg for 3 months followed by OCA 25 mg in the OLE if the uptitration criteria are met (Section 9.2).  Subjects randomized to 
OCA (10 mg or 10 mg → 25 mg dose) during the Double-Blind Phase will continue the treatment they were assigned. 
j Biopsy at Month 18 DB/Day 1 OLE, must be completed prior to receiving investigational product on Day 1 of OLE.  At Month 12 of OLE and ET of OLE, the biopsy procedure 
is optional. 
k All assessments must be completed prior to administration of investigational product.  The first dose of OLE investigational product should be taken the day after the Month 18 
assessments are completed. 
l At the OLE Month 1, 2, 4, and 5 Visits, investigational product dispensed/administered will be from the bottle issued at the previous visit. 
m Glucose only 
n Urine β-hCG pregnancy tests must be performed for females of childbearing potential.  If positive, a confirmatory blood test must be performed.  If the blood test is also positive, 
the subject may not be continued in the study.   
o MRE will be conducted as part of the Month 18 DB EOT Visit. 
 


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7.1.3. 
Study Duration 
The maximum duration of individual subject participation for this study is approximately 2 years 
and 9 months, including a Screening Period of up to 12 weeks, an 18-month Double-Blind Phase, 
and an OLE Phase expected to last approximately 1 year. 
7.2. 
Number of Subjects 
Approximately 900 subjects will be enrolled in the study. 
7.3. 
Planned Dosing Regimen 
Subjects will be randomly assigned in a 1:1:1 ratio to receive OCA 10 mg, 
OCA 10 mg → 25 mg, or placebo.   
For subjects in the OCA 10 mg → 25 mg group, a dose titration to 25 mg will be implemented at 
Month 3 after assessments of liver chemistry and safety at Month 1 and Month 2, unless there are 
safety and tolerability concerns identified by the Medical Monitor/or the Investigator.  Subjects 
randomized to the OCA 10 mg or placebo arms will continue the same dosing (dummy titration) 
(refer to Section 9.2). 
7.4. 
Monitoring and Management of Potential Hepatic Injury and/or 
Disease Progression 
To monitor for potential hepatic injury, disease progression and/or hepatic decompensation, CP 
and MELD scores will be reviewed at each visit (Section 7.1.2).  In addition, adverse events, 
signs and symptoms of potential hepatic injury or decompensation, and laboratory values will 
also be reviewed at regular intervals as described in the following subsections (Section 7.4.1 to 
Section 7.4.3).  Based on the assessments of signs and symptoms of hepatic injury and liver 
biochemistry, the investigational product will be interrupted or discontinued per criteria 
discussed in Section 7.7, and close monitoring procedures will be implemented (refer to 
Section 7.4.4). 
7.4.1. 
Signs and Symptoms of Hepatic Injury or Decompensation 
The Investigator will educate each subject about recognizing the signs and symptoms of potential 
hepatic injury or decompensation and instruct each subject to contact the study site to report the 
onset of any new or worsening signs and symptoms during the study.  The Investigator will 
instruct subjects to seek immediate medical attention if they experience signs or symptoms of 
hepatic injury or decompensation. 
Appendix C provides guidance for review of signs and symptoms of hepatic injury or 
decompensation described below to be evaluated at each study visit, or as frequently as needed 
per Investigator’s discretion. 
Subjects will be evaluated at study visits for potential signs and symptoms of hepatic injury or 
decompensation: 


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Signs and Symptoms of Hepatic Injury or Decompensation: 
• Specific signs and symptoms of liver impairment:  yellowing of the skin or the whites 
of eyes, pale-colored stools, urine color change from pale to deep amber [dark] severe 
fatigue, right upper quadrant pain, rash, eosinophilia 
• More general signs and symptoms of ascites and encephalopathy:  swelling of the 
legs or abdomen, confusion, or abrupt abnormal behavior 
• Non-specific signs and symptoms of impaired health:  nausea, vomiting, abdominal 
pain, diarrhea, weight loss, fever and chills, worsening or new fatigue, weakness, loss 
of appetite 
• Significant intercurrent illnesses such as gastroenteritis may exacerbate hepatic injury 
or decompensation (eg, established severe abdominal pain, vomiting, and diarrhea) 
and should be an indication for prompt investigational product interruption and 
complete subject evaluation 
Other Symptoms: 
• New or worsening pruritus 
• Decreased urine output, urine color change, dizziness, lethargy 
Healthcare Provider (HCP) Interactions: 
• Visits to primary HCP or referral to any specialist for any new symptoms (other than 
ongoing care for stable comorbidities) 
• New medications or changes to current medications prescribed from HCP or any new 
over the counter medications or herbal supplements. 
• Laboratory procedures or assessments performed by an HCP  
Signs and symptoms for potential hepatic injury or decompensation should be followed by 
(1) evaluation of liver biochemistry for potential drug-induced liver injury (DILI) 
(Section 7.4.2), (2) assessment for disease progression (Section 7.4.3), (3) triggering of 
investigational product interruption or discontinuation per criteria (Section 7.7), 
(4) documentation in the AE eCRF or the SAE eCRFs (Section 16.1), and (5) contact with the 
medical monitor. 
7.4.2. 
Potential Drug-Induced Liver Injury 
Events of potential hepatic injury will be reviewed and adjudicated by the Hepatic Safety 
Adjudication Committee (HSAC) as described in Section 17.14.  The specific criteria for 
identification and adjudication of potential hepatic injury events are described in the HSAC 
charter. 
Liver biochemistries will be assessed at each visit to assess biochemical triggers that will prompt 
an immediate reevaluation of subjects.  Thus, these assessments will be performed at: 
• Each protocol-specified visit 
• Unscheduled visits for any safety follow-up as appropriate 


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It is important that the laboratory assessments be completed as required and that the central 
laboratory be used for assessments whenever possible.  In the event that a subject cannot return 
to the clinic for a scheduled or unscheduled visit, or there is an event that triggers a need for an 
immediate assessment, the use of a local laboratory is required.  In these cases, the Investigator 
will obtain the laboratory results and the laboratory normal ranges.  Of note, the Baseline result 
is the average of results from Screening Visits 1 and 2, Day 1, and any unscheduled visit that 
took place between Screening Visit 1 and the Day 1 Visit.  All local laboratory data, including 
the reference ranges, are to be collected and entered in the eCRF within 2 days of receiving the 
results.  For guidance on alternative processes under which subjects may complete the protocol-
specified assessments under COVID-19 restrictions refer to Section 10.  Local laboratory visits 
in conjunction with remote (telemedicine) visits are specifically encouraged in lieu of on-site 
visits where subject’s safety is of concern (eg, adverse event monitoring). 
The process for assessing criteria is presented in Figure 2, and the specific threshold(s) for each 
laboratory analyte to trigger mandatory repeat testing and potentially a complete subject 
evaluation (depending on the repeat result) are summarized in Table 3.  
ALP = alkaline phosphatase; ALT = alanine aminotransferase; BL = baseline; eCRF = Electronic Case Report Form; INR = 
international normalized ratio; IP = Investigational Product; PK = pharmacokinetic; TB = total bilirubin; ULN = upper limit of 
normal. 


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Laboratory assessments include:  
a Signs and symptoms of hepatic injury include severe fatigue, nausea, vomiting, right upper quadrant pain, fever, 
rash, and eosinophilia. Decompensation events include variceal hemorrhage, hepatic encephalopathy, and ascites 
b Lower severity treatment-emergent threshold criteria include the following from Table 3:  In subjects with baseline ALP ≤ULN 
and treatment-emergent ALP ≥2x BL and >ULN but <250 U/L 
c If a subject is unable to return to the site for repeat test, the subject MUST have repeat (or any safety) laboratory tests performed 
at a local laboratory.  All local laboratory results, including reference ranges, should be entered in the eCRF within 2 days of 
receiving results. 
d PK sampling must be conducted within 7 days of IP interruption; close monitoring including physical exams and repeat 
laboratory testing should occur as often as deemed appropriate by the Investigator.  In subjects with signs or symptoms of 
hepatic injury or events of hepatic decompensation, the Medical Monitor should be promptly contacted upon awareness for 
consultation regarding management of the subject. 


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If any subject meets the triggering threshold limits indicated in Table 3 and experiences signs or 
symptoms of hepatic injury (severe fatigue, nausea, vomiting, right upper quadrant pain, fever, 
rash, eosinophilia) or events of decompensation (varices hemorrhage, hepatic encephalopathy, or 
ascites), which can be presenting features of DILI in subjects with cirrhosis, investigational 
product should be immediately interrupted (see Section 7.7 for dosing modifications).  
If no signs or symptoms of hepatic injury or decompensation are present, but liver biochemistries 
are above the triggering threshold limits, the subject should either interrupt investigational 
product or laboratory assessments including creatine phosphokinase (CPK) should be repeated 
within 2-4 days according to the threshold limits specified in Table 3.  If a repeat laboratory test 
cannot be performed within 7 days of receiving results, the subject should be instructed to 
interrupt investigational product until repeat laboratory test results have been reviewed.  


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If investigational product is interrupted, laboratory assessments including CPK should be 
repeated within 2-4 days of receiving results, a PK sample must be collected (within 7 days), and 
close monitoring should be initiated (repeat laboratory testing and physical exam should occur as 
often as deemed appropriate by the Investigator and these data should be entered in the eCRF 
within 2 days of receiving results).  In subjects with signs or symptoms of hepatic injury or 
events of decompensation, the Medical Monitor should be promptly contacted upon awareness 
for consultation regarding management of the subject. 
• If on repeat evaluation, in subjects who did not have investigational product 
interrupted (eg, those that had no signs and symptoms and lower severity), liver 
biochemistries are normal or below threshold values, no dosing modifications are 
required and the subject should continue to be monitored closely. 
• If on repeat evaluation, liver biochemistries remain elevated (see Table 3), 
investigational product must be interrupted for a minimum of 30 days, a PK sample 
(see below for OCA and metabolites) must be collected (within 7 days of receiving 
results), and close monitoring should be initiated (repeat laboratory testing and 
physical exam should occur as often as deemed appropriate by the Investigator and 
these data should be entered in the eCRF within 2 days of receiving results).  The 
medical monitor should be promptly contacted upon awareness for consultation 
regarding management of the subject.   
In any subject for whom investigational product is interrupted for reasons other than the inability 
to promptly repeat laboratory testing (within 7 days) for non-safety reasons, a rechallenge may 
be considered after a minimum of 30 days if liver enzymes return to below threshold values, 
there are no symptoms, lab abnormalities are determined not to be due to DILI, and if approved 
by the Medical Monitor and Investigator.  If investigational product is restarted after 30 days, 
liver biochemistries should be repeated within 2 to 4 days and close monitoring should be 
continued.   
If the liver enzymes do not return to below threshold values after 30 days and the Investigator 
considers that the event has not resolved, the Investigator should consult with the Medical 
Monitor to determine a treatment plan.  This may include continuing close monitoring with 
interruption or discontinuing investigational product. 
For all subjects whose investigational product is interrupted or discontinued, and close 
monitoring is initiated, a follow up assessment of the subject’s status should be performed at 
study completion. 
Subjects should, wherever possible, come back to the site.  It may be difficult for subjects who 
are distant from their study site to return to the site promptly.  Such subjects must have repeat (or 
any safety) laboratory tests performed at a local laboratory, but normal laboratory ranges and the 
results should be made available to the Investigator All local laboratory data, including reference 
ranges, should be entered in the eCRF within 2 days of receiving the results.  For guidance on 
alternative processes under which subjects may complete the protocol-specified assessments 
under COVID-19 restrictions refer to Section 10. 
It should be noted that it is difficult to recognize every potential marker of hepatic deterioration.  
There is no substitute for good medical judgment.  Investigators will be reminded to be cautious 
and mindful in their evaluation of subjects’ symptoms, signs, and laboratory results.  However, 


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for example, a single abnormal laboratory analyte result may be artefactual; accordingly, 
Investigators will be allowed to implement an alternate follow-up procedure if considered 
appropriate based on their medical judgement but only after documented agreement with the 
Sponsor’s medical monitor.  
Specific aspects of the Potential DILI Management Algorithm may be adjusted, in which case 
specific guidelines will be provided to the sites for implementation. 
7.4.3. 
Progression of Disease to Child-Pugh Class B or C 
Investigators will closely monitor subjects for potential progression of cirrhosis to CP Class B or 
Class C at every visit (or at unscheduled visits in the event of signs or symptoms of potential 
hepatic injury or decompensation).  Assessment of CP Scores must be performed at every visit.  
Refer to Section 7.4.3.1 for determination of CP Score.  Investigational product discontinuation 
is required in subjects who progress to CP score of 7 or higher. 
7.4.3.1. 
Child-Pugh Assessment 
CP Score (Pugh 1973, Lucey 1997) is calculated and reported within the EDC system based on 
data entered into the eCRF by adding the scores from the 5 factors outlined in Table 4 and can 
range from 5 to 15.  The investigational product should be discontinued in subjects with CP 
score ≥7.  
Calculation of the CP Score includes Investigator assessments of ascites and hepatic 
encephalopathy, which may be assessed during the adverse event review at the scheduled visits, 
as well as total bilirubin, serum albumin, and prothrombin time, which should be collected at the 
same visit.  The relationship of CP Score to disease progression is as follows: CP score 5-6 = CP 
Class A; CP Score 7-9 = CP Class B; CP Score ≥10 = CP Class C. 


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Table 4: 
Child-Pugh Scoring System 
Factor 
Units 
Points 
1 
2 
3 
Serum total bilirubin 
μmol/L 
<34 
34-50 
>50 
mg/dL 
<2.0 
2.0-3.0 
>3.0 
Serum albumin 
g/L 
>35 
28-35 
<28 
g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
Seconds prolonged 
0-3 
4-6 
>6 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites 
 
None 
Mild 
Moderate-
Severe 
Hepatic encephalopathya 
 
None 
Grade 1 or 2 
Grade 3 or 4 
INR = international normalized ratio 
Child-Pugh criteria:  Pugh 1973, Lucey 1997. 
West Haven criteria:  Vilstrup 2014.  
a Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram 
 Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves 
 Grade 2:  lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
 Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
 Grade 4:  unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity  
7.4.3.2. 
Model for End-Stage Liver Disease (MELD) Scoring 
MELD is a scoring system used to assess the severity of chronic liver disease.  An increasing 
MELD score is associated with increased severity of hepatic dysfunction and increased 3-month 
mortality risk.  MELD scores will be calculated based on creatinine, bilirubin, INR, and serum 
sodium values as appropriate, collected at the same visit with modification by United Network 
for Organ Sharing.  If only 1 component of MELD needs to be repeated, all other components 
should also be repeated.  INR will be calculated based on PT value by the central laboratory.  
The MELD calculation adjusts for subject who have had 2 or more dialysis treatments within the 
prior week and will automatically assign a serum creatinine of 4.0 mg/dL for these subjects.  
7.4.4. 
Close Observation 
The Investigator should consistently and frequently assess individual subjects who meet the 
above criteria to determine on an ongoing basis the totality of a subject’s clinical profile, which 
includes careful evaluation of signs and symptoms of potential hepatic injury or decompensation 
coupled with rules-based laboratory monitoring.  If investigational product is interrupted or 
discontinued as described in Section 7.7, subjects should continue to be closely monitored based 
on the clinical judgement of the Investigator and evaluated for signs and symptoms of potential 
hepatic injury.  In the event of potential hepatic injury, the subject should be promptly brought 
into the clinic and undergo a complete evaluation (laboratory assessments, physical 
examinations, and review of signs and symptoms).  Subjects who permanently discontinue from 
investigational product are not required to undergo additional safety visits provided stabilization 




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7.4.5. 
Pruritus 
Pruritus is already being closely monitored but has not been shown to be a reliable predictor of 
hepatic injury.  However, Investigators should be vigilant in responding to subjects’ complaints 
of new or worsening pruritus symptoms with prompt follow-up.  Pruritus grading (as with all 
adverse events) should be performed in accordance with the current version of the Common 
Terminology Criteria for Adverse Events (CTCAE;Appendix D). 
For subjects with Grade 3 pruritus per the current version of the CTCAE (Section 16.1.6.1), 
instruct the subject to discontinue investigational product (Table 5).  These subjects should 
continue to return for scheduled study visits for safety follow up; however, the subjects will not 
be rechallenged with investigational product.  General guidance for the management of subjects 
experiencing significant pruritus (≤ Grade 2) is provided in Section 16.1.6.1. 
7.5. 
Medical Management of Subjects with Symptomatic Cholelithiasis 
and/or Cholecystitis or Pancreatitis 
7.5.1. 
Symptomatic Cholelithiasis and/or Cholecystitis 
NASH is associated with several known risk factors for cholelithiasis, such as obesity, type 2 
diabetes, and other metabolic abnormalities.  The prevalence of gallstone disease in NASH is 
higher than in the general population.  The majority of gallstones are asymptomatic and may 
never become symptomatic (Sakorafas 2007, Stinton 2012). 
Because symptomatic events of cholelithiasis and/or cholecystitis may develop in subjects with 
or without a known history of gallstones, it is important that all subjects be (1) monitored for 
signs and symptoms suggestive of gallstone disease and (2) counseled to recognize and seek 
immediate medical attention if they experience symptoms suggestive of cholelithiasis and/or 
cholecystitis.  
Subjects who develop signs or symptoms suggestive of symptomatic cholelithiasis (refer to 
Appendix C) and/or complications related to gallstone disease (eg, cholecystitis) should have 
investigational product interrupted while undergoing further evaluation consistent with the local 
standard of care and management until complete resolution, including potential surgical 
intervention.   
Post-cholecystectomy, subjects should be monitored for full resolution and may resume 
investigational product after approval from the Investigator and Medical Monitor (see 
Section 7.7). 
If upon surgical evaluation, it is deemed that the subject does not need to undergo surgery, the 
subject may re-initiate investigational product upon resolution of symptoms and approval from 
the Investigator and Medical Monitor. 
7.5.2. 
Pancreatitis 
Pancreatitis is a serious and potentially fatal condition most commonly caused by gallstones or 
alcohol. 
Because symptoms of acute pancreatitis and acute cholecystitis may be similar, subjects 
presenting with significant upper abdominal pain with nausea, vomiting, fever, or jaundice 


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should be evaluated for both cholecystitis and pancreatitis, consistent with the local standard of 
care (eg, amylase and lipase laboratory tests and/or imaging assessments). 
Investigational product must be permanently discontinued in any subject diagnosed with 
treatment-emergent acute, or nonacute (chronic or recurrent) pancreatitis (see Section 7.7).  
The evidence used to diagnose pancreatitis, including symptoms, laboratory test results, and/or 
imaging results, must be collected.  If a subject is suspected to have acute pancreatitis or 
develops signs and symptoms consistent with acute pancreatitis, amylase and lipase levels should 
be monitored for 3 months after the onset of symptoms per local standard of care.  The 
Investigator should contact the Medical Monitor upon awareness of treatment-emergent acute or 
nonacute pancreatitis.   
Investigational product discontinuation is not required for subjects who have a medical history of 
pancreatitis and have not experienced recurrence of pancreatitis since enrollment into the study.  
Any subject who meets the requirements for investigational product discontinuation should be 
encouraged to remain in the study and complete all protocol‐specific assessments as defined, 
after stopping investigational product. 
7.6. 
Monitoring for Renal Impairment and Nephrolithiasis 
7.6.1. 
Renal Impairment 
AKI is a serious medical condition that may lead to chronic kidney disease or kidney failure; 
therefore, it is important to identify and monitor subjects for signs or symptoms suggestive of 
AKI for appropriate management.  Investigators are instructed to evaluate for symptoms 
suggestive of AKI such as new onset fatigue/asthenia, nausea, or confusion and to assess signs 
such as decreased skin turgor (dehydration), increased heart rate, lower extremity edema, 
decrease urine output or dark urine at each visit.   
As AKI is defined by an abrupt decrease in renal function, the Sponsor recognizes that local labs 
will be required to be recorded as well as all central lab data (scheduled or unscheduled visits) to 
adequately capture events.  Repeat laboratory assessments should include albumin, serum 
chemistry (creatinine, BUN, electrolytes), urinalysis with microscopic examination, and 
assessment of eGFR.  All local lab data, including reference ranges, are required to be entered in 
the eCRF within 2 days of receiving results. 
The threshold criteria used to identify and monitor subjects for potential renal impairment and 
the actions to be taken with investigational product are outlined in Figure 3.  
Baseline serum creatinine values, which will inform the subsequent decisions on monitoring for 
and management of renal injury, are defined as the average of serum creatinine values from the 
two most recent study visits (scheduled and unscheduled), that are not associated with a renal-
related AE or an acute increase. 


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If a subject meets the threshold criteria, a prompt re-evaluation (within 48 hours) should take 
place.  Subjects should, when possible, return to the study site for re-evaluation.  It may be 
difficult for subjects who are distant from their study site to return to the site promptly.  Such 
subjects must have repeat (or any safety) laboratory tests performed at a local laboratory, but the 
laboratory reference ranges and the results should be made available to the Investigator.  All 
local laboratory data, including reference ranges, should be entered into the eCRF within 2 days 
of receiving the results. 


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• If on repeat testing, serum creatinine has returned to below threshold values, no 
dosing modifications are required. 
• If on repeat testing, serum creatinine remains elevated a comprehensive evaluation 
including the subject’s recent medical history, changes in medication, health status, 
and intercurrent illness should be conducted.  If no alternative cause of serum 
creatinine elevation can be identified investigational product should be interrupted 
and close monitoring should be initiated.  Close monitoring includes repeat labs and 
physical exam, which should occur as often as deemed appropriate by the 
Investigator, and these data should be entered in to the eCRF within 2 days of 
receiving results.  If deemed appropriate by the Investigator, the subject may be 
referred to a nephrologist. 
In any subject for whom investigational product is interrupted for reasons other than inability to 
promptly repeat laboratory assessments for non-safety reasons: 
• The event will be treated as a potential case of AKI and will be sent for review and 
adjudication by the Renal Adjudication Committee (described in Section 17.11.2).  
The specific criteria for identification and adjudication of potential AKI events are 
described in the Renal Adjudication Committee charter. 
• A PK sample must be collected within 7 days of investigational product interruption.  
If a PK sample cannot be collected within 7 days, the reason should be recorded in 
the eCRF. 
• A rechallenge may be considered after a minimum of 30 days if serum creatinine 
returns to below threshold values and if approved by the Medical Monitor and 
Investigator.  If serum creatinine remains above threshold values after 30 days, the 
subject should be referred to a nephrologist for further evaluation. 
7.6.2. 
Nephrolithiasis 
The development of signs or symptoms suggestive of kidney stones (nephrolithiasis) should be 
monitored.  Standard of care including adherence to recommended dietary measures, adequate 
fluid intake, and other measures prescribed should be employed to prevent recurrent episodes of 
kidney stones (Pearle 2014).  Subjects should be asked if they have experienced symptoms of 
nephrolithiasis (eg, evidence of hematuria or flank pain).  Nephrolithiasis should be considered 
in subjects with evidence of microscopic hematuria without other symptoms.   
Subjects who develop kidney stones during the study will be further evaluated according to 
guidelines to collect serum electrolytes, uric acid, and a urinalysis with microscopic examination 
(Pearle 2014).  All local laboratory data, including reference ranges, should be entered into the 
eCRF within 2 days of receiving the results.  Every effort should be made to collect the kidney 
stone for analysis.  Subjects should be referred to a urologist or nephrologist for further 
evaluation of the nephrolithiasis, including the etiology as appropriate. 


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7.7. 
Investigational Product Dosage Interruption, Downtitration, 
Discontinuation, and Rechallenge Criteria 
Dosages for investigational product should be maintained constant during the study.  However, 
interruptions, downtitration, discontinuation, and any rechallenge of investigational product 
should be implemented per the criteria outlined in Table 5.  Planned uptitration at Month 3 in the 
OCA 10 mg → 25 mg arm (Double-Blind Phase) and in placebo subjects at OLE Month 3 is 
described in Section 9.2. 
Subjects can be temporarily or permanently discontinued from investigational product by the 
Investigator at any time for clinical safety concerns.  If investigational product is temporarily or 
permanently discontinued, a PK sample must be collected within 7 days.  If a PK sample cannot 
be collected within 7 days, the reason should be recorded in the eCRF. 
• Subjects who are temporarily discontinued from investigational product are expected 
to continue in the study and should follow the regular visit schedule for the duration 
of the study. 
• Subjects who permanently discontinue from investigational product are expected to 
continue in the study and should follow the regular visit schedule for the duration of 
the study.  These subjects will not be rechallenged with investigational product.  
Prior to re-starting investigational product after a prolonged interruption, the subject must be 
re-consented and new baseline visit procedures must be performed (refer to Section 8.2.2) if the 
interval from the last visit was more than 3 months (+2 weeks). 
Investigational product should not be interrupted in the following instances:  1) in subjects who 
experience an event that is not symptomatic (such as an incidental finding of gallstones during an 
ultrasound exam);  2) in subjects who previously experienced an event of symptomatic 
cholelithiasis and/or cholecystitis and have either undergone a cholecystectomy (and have no 
symptoms suggestive of retained or recurrent bile duct stones) or upon surgical consultation does 
not need to undergo surgery, and in whom symptoms have fully resolved at the present time 
while on investigational product;  or 3) in subjects who have a past medical history of 
pancreatitis and have not experienced a recurrence of pancreatitis since enrollment into the study. 


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7.8. 
Criteria for Study Termination 
The Sponsor reserves the right to terminate the study at any time.  It is normal procedure to 
review the emerging clinical and safety data.  As a result of such a review or a recommendation 
by the Data Monitoring Committee (DMC), it may be necessary to stop the study before all 
subjects have completed the study.  In addition, the Sponsor may terminate the study at an 
investigational site at any time (eg, Good Clinical Practice [GCP] noncompliance or 
poorly performing sites, as determined by the number of subjects enrolled or the quality of the 
study data). 
The Investigator and/or Sponsor (or designee) must notify the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) of discontinuation of a site or the study and the 
reason for doing so. 
Investigators will be informed by the Sponsor as to when the final study visit is to be completed 
and should then schedule all subjects for the end of study (EOS) Visit.  
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Population 
This study will be conducted at approximately 300 international study sites with experience in 
treating patients with compensated cirrhosis due to NASH.  Prospective subjects will be 
identified primarily from the hospital and/or physician’s database of patients with NASH or may 
be referred from other physicians.  Subjects may self-refer to an Investigator if they become 
aware of the study through local, national, or international NASH patient societies, forums, or 
networks.  


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8.1.1. 
Subject Inclusion Criteria 
1. Subjects ≥18 years of age 
2. Subjects with a confirmed diagnosis of NASH and a fibrosis score of 4 based upon the 
NASH CRN scoring system determined by central reading of a liver biopsy obtained no 
more than 12 months before Day 1 
3. Contraception:  Female subjects of childbearing potential must use ≥1 effective method 
(≤1% failure rate) of contraception during the study until 4 weeks following the last dose 
of investigational product (including OLE doses).  Female subjects are considered as 
being of childbearing potential, ie, fertile, following menarche and until becoming 
postmenopausal, unless permanently sterile.  Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.  A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause.  A high 
follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a post-menopausal state in women not using hormonal contraception or 
hormonal replacement therapy.  However, in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. 
Effective methods of contraception are listed below (refer to Section 9.9 for highly 
effective contraceptive methods): 
− 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)  
4. Must provide written informed consent and agree to comply with the study protocol 
8.1.2. 
Subject Exclusion Criteria 
Criteria with exclusionary laboratory values are to be based on the most recent laboratory result 
available prior to randomization.  For alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), or total bilirubin (conjugated bilirubin for subjects with an established 
diagnosis of Gilbert’s syndrome), if the Screening Visit 2 value is ≥30% higher than the 
Screening Visit 1 value and > the upper limit of normal (ULN), then a third measurement must 
be obtained at an unscheduled visit.  Subjects who satisfy any of the following exclusion criteria 
will be ineligible for enrollment: 
1. Current or past history of a clinically evident hepatic decompensation event, such as 
ascites, variceal bleeding, spontaneous bacterial peritonitis, hepatic encephalopathy 
(Grade I or greater based on West Haven classification), or hepatorenal/hepatopulmonary 
syndromes 
2. Current or past history of hepatic function impairment with CP score ≥7 points 


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3. MELD score >12 
4. Hospitalization within 1 year of Day 1 for complications of cirrhosis 
5. Documented presence of varices based on prior endoscopy performed within 6 months of 
Day 1. 
6. AST ≥5× ULN 
a. If a third serum AST measurement is required, and both Screening Visit 2 and 
unscheduled visit AST values are ≥30% higher than the Screening Visit 1 value, the 
subject is ineligible for enrollment 
7. ALT ≥5× ULN 
a. If a third serum ALT measurement is required, and both Screening Visit 2 and 
unscheduled visit ALT values are ≥30% higher than the Screening Visit 1 value, the 
subject is ineligible for enrollment 
8. Calculated creatinine clearance <60 mL/min using Cockcroft-Gault method  
9. Platelet count ≤100 000/mm3  
10. Total bilirubin >2 mg/dL (except for subjects with an established diagnosis of Gilbert’s 
syndrome, if hemoglobin and reticulocyte count are within normal range and conjugated 
bilirubin is <1.5× ULN) 
a. If a third serum total bilirubin measurement is required (conjugated bilirubin for 
subjects with an established diagnosis of Gilbert’s syndrome), and both Screening 
Visit 2 and unscheduled visit values are ≥30% higher than the Screening Visit 1 
value, the subject is ineligible for enrollment 
11. Conjugated bilirubin ≥1.5x ULN 
12. Albumin <3.5 g/dL 
13. International normalized ratio (INR) ≥1.7  
14. Current or history of significant alcohol consumption for a period of more than 
3 consecutive months within 1 year before Day 1 (significant alcohol consumption is 
defined as more than 2 units/day for females and more than 4 units/day for males, on 
average) 
15. Prior (at any point) or planned (during the study period) ileal resection, or prior (within 
5 years before Screening) or planned (during the study period) bariatric surgery 
(eg, gastric bands, gastroplasty, Roux-en-Y gastric bypass) 
16. Inability to safely undergo a liver biopsy 
17. History of biliary diversion  
18. Evidence of other known forms of chronic liver disease including: 
− Positive test result at Screening for hepatitis B surface antigen  
− Active hepatitis C virus (HCV) infection (positive for HCV ribonucleic acid 
[RNA] at Screening); or confirmed history of a positive HCV RNA test result(s) 


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except for subjects with evidence of spontaneous HCV eradication (defined as 
positive HCV antibodies at Screening, no history of positive HCV RNA result, 
and documentation that no anti-HCV therapy has been received) 
− PBC, primary sclerosing cholangitis, autoimmune hepatitis, or overlap syndrome 
− Alcoholic liver disease 
− Wilson disease, hemochromatosis, or iron overload 
− Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver 
histology (confirmed by A1AT level below the lower limit of normal or exclusion 
at the Investigator’s discretion) 
− Prior known or suspected drug-induced liver injury within 5 years before Day 1 
− Known or suspected HCC 
19. History of liver transplant or current placement on a liver transplant waiting list  
20. HbA1c ≥9.5% within 90 days before Day 1 
21. LDL cholesterol ≥190 mg/dL and already on a stable dose of LDL-lowering medication 
for ≥30 days 
22. LDL cholesterol <50 mg/dL (in subjects not on LDL-lowering medication) 
23. Known positivity for human immunodeficiency virus infection 
24. Subjects with recent history (within 1 year of Day 1) of significant atherosclerotic 
cardiovascular disease (ASCVD; myocardial infarction, unstable angina, acute coronary 
syndrome, cerebrovascular accident [stroke], cerebrovascular ischemia, transient 
ischemic attack, or peripheral vascular disease requiring intervention).  Such subjects 
may be identified by different means, including, but not limited to, an abnormal 12-lead 
ECG, a history or planned cardiovascular intervention such as coronary revascularization 
(eg, percutaneous coronary intervention or coronary artery bypass graft), coronary 
angioplasty, stenting, carotid atherectomy, or placement of a cardiac pacemaker or 
defibrillator 
− Controlled hypertension without other recent manifestations of significant 
ASCVD and placement of cardiac pacemaker or defibrillator for reasons other 
than ASCVD (eg, for treatment of atrial fibrillation subsequent to nodal ablation) 
is not exclusionary 
25. Current acute cholecystitis or acute biliary obstruction 
26. Other medical conditions that may diminish life expectancy to <2 years, including known 
cancers (except carcinomas in situ or other stable, relatively benign carcinomas) 
27. Known substance abuse in the year before Screening 
28. Chronic use (≥12 months) of drugs historically associated with drug-induced NAFLD 
within the 5 years before Day 1 (eg, amiodarone, methotrexate, systemic glucocorticoids 
[unless used at physiologic replacement doses for the treatment of adrenal insufficiency], 
tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone 


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replacement, anabolic steroids [except for testosterone preparations used at physiologic 
replacement doses for the treatment of documented/confirmed hypogonadism], valproic 
acid, and other known hepatotoxins; see Section 9.4). 
29. Pregnancy, planned pregnancy, potential for pregnancy (ie, unwillingness to use effective 
birth control during the study), or current or planned breast feeding 
30. Participated in a clinical research study and received any active investigational product 
being evaluated for the treatment of diabetes, weight loss, or NASH in the 6 months 
before Day 1 
31. Concurrent participation in any other interventional clinical trial. 
32. Received any investigational product from Screening to Day 1, within 30 days before 
Day 1, or within 5 half-lives of the compound (whichever was longer) before Day 1 
33. Previous exposure to OCA within 12 months of Day 1 
34. Mental instability or incompetence, such that the validity of informed consent or ability 
to be compliant with the study, is uncertain 
35. History of known or suspected clinically significant hypersensitivity to OCA or any of its 
components 
36. Any other condition that, in the opinion of the Investigator, might confound the results, or 
would impede compliance or hinder completion of the study 
37. ALP ≥1.5x ULN 
38. History of known or suspected hypersensitivity to any ingredient in human albumin 
preparations (in the US where 
 is a study procedure). 
8.2. 
Subject Withdrawal Criteria 
Subjects can be discontinued from investigational product by the Investigator at any time for 
clinical safety concerns.  Subjects who are discontinued from investigational product are 
expected to continue in the study and should follow the regular visit schedule for the duration of 
the study phase (Double-Blind or OLE).  Subjects who permanently discontinue from 
investigational product are expected to continue regular visit schedule for safety assessments 
until stabilization of the clinical event has occurred leading to discontinuation (per discretion of 
the Investigator and upon discussion with the medical monitor). 
Refer to Section 7.7 for withdrawal criteria related to potential hepatic injury and/or 
decompensation; progression to cirrhosis with CP score ≥7; treatment-emergent acute or 
nonacute pancreatitis; ≥Grade 3 pruritus, AEs ≥Grade 3 in severity and possibly, probably, or 
definitely related to investigational product; AEs ≥Grade 4 in severity and NOT or unlikely 
related to investigational product; liver transplantation, bariatric surgery, and pregnancy.  Other 
reasons, including withdrawal of consent or lost to follow-up and withdrawal from 
 
substudy, are described in Section 8.2.1 below. 


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8.2.1. 
Other Reasons for Discontinuation of Investigational Product or Study 
Termination 
Subjects who discontinue investigational product are expected to continue in the study until the 
end of the study.  If a subject experiences a suspected clinical outcomes event, he or she should 
continue the regular visit schedule and continue taking investigational product as long as the 
Investigator assesses it as safe.  Subjects who discontinue investigational product prior to 
completion of the study need to also continue to follow the regular visit schedule through study 
completion (Month 18 for the Double-Blind Phase or Month 12 for the OLE phase).  In general, 
subjects should be strongly encouraged to both stay on investigational product and remain in the 
study until study completion.  Early termination procedures should only be conducted if the 
subject withdraws consent (see Section 9.10.15).  
The following events are considered appropriate reasons for a subject to discontinue 
investigational product; however, these subjects are expected to continue in the study until study 
termination (or at the discretion of the Sponsor). 
• The Investigator or Sponsor considers that it is advisable or in the best interest of the 
subject. 
• Modification of consent: 
− Consent may be modified to discontinue study visits but allow periodic telephone 
contact of the subject (in line with the study visit schedule) through completion of 
the study (Month 18 if initiated in the Double-Blind Phase or Month 12 if initiated 
in the OLE phase), through the subject’s primary care physician, or personal 
contacts who can provide information on behalf of the subject by the Investigator 
− Consent may be modified to discontinue study visits but allow continued access to 
medical records through completion of the study (Month 18 if initiated in the 
Double-Blind Phase or Month 12 if initiated in the OLE phase) to assess for 
potential MACE, and liver-related clinical outcomes 
• Lost to Follow-Up 
• Pregnancy 
• The occurrence of clinical or laboratory AEs considered by the Investigator to be 
clinically important 
• There is a major violation of the clinical study protocol  
• The development of any exclusion criteria that might jeopardize safety (Section 8.1.2) 
The Investigator is encouraged to contact the Sponsor prior to discontinuing a subject from 
treatment.  The Investigator must notify the Sponsor study monitor by telephone or email as soon 
as possible if any subject prematurely withdraws from the study. 
It is agreed that, for reasonable cause, either the Investigator or the Sponsor, may terminate this 
study. 


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8.2.1.2. 
Withdrawal of Consent to Continue in the Study 
If the subject decides that it is in his/her best interest to discontinue from the study, he or she 
may withdraw consent.  It is fully understood that all subjects volunteer for the study and that 
they may withdraw their consent to continue in the study at any time. 
A reasonable effort must be made to determine the reason(s) for subject discontinuation.  This 
information and date of contact must be recorded in the appropriate eCRF. 
8.2.1.3. 
Lost to Follow-Up 
If a subject fails to return to the clinic for a study visit, and the Investigator ceases to have 
contact with the subject, he or she will be withdrawn from the study.  Subjects will be considered 
“lost to follow-up” only after reasonable, documented attempts to reach the subject prove 
unsuccessful.   


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A reasonable effort must be made to contact the subject and determine the reason(s) why a 
subject fails to return for a study visit or is lost to follow-up.  This information and date of 
contact must be recorded in the appropriate eCRF. 
8.2.1.4. 
Pregnancy 
Whenever the site is notified of a possible pregnancy, the subject should be asked to come in for 
an unscheduled visit to perform a serum pregnancy test.  If a female subject becomes pregnant, 
the subject must stop taking investigational product immediately but will be encouraged to 
continue study visits until the end of the study.  The subject must be followed by the Investigator 
through pregnancy outcome.  The mother (and infant) will be followed as considered appropriate 
by the Investigator and the Medical Monitor.  As described in Section 16.1.13, a pregnancy is not 
considered an AE for reporting purposes. 
8.2.2. 
Reinitiating Investigational Product After Interruption 
Prior to restarting investigational product after a prolonged interruption (ie, longer than 3 months 
[+2 weeks]), the subject must be reconsented and the procedures listed below must be performed 
before the subject re-starts investigational product regardless of the reason for interruption.   
The following procedures will be performed to reinitiate investigational product: 
• Review Informed Consent Form (ICF) and obtain signatures before performing the 
repeat baseline procedures 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and electronic case report form (eCRF) 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 
• Record current concomitant medications  
• Assess and record AEs 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 
• Record weight and BMI 
• Conduct physical exam 
• Perform standard 12-lead ECG  
• AUDIT, smoking habits, and caffeine consumption 
• Health-related quality of life questionnaires and health status for the assessment of 
health utilities 
• Perform hepatobiliary ultrasound for HCC screening unless data from a recent 
ultrasound (within 3 months) are available 
• Obtain blood samples for: 


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− HCC screening (alpha-fetoprotein [AFP]) 
− Serum chemistry, hematology, and coagulation  
− Metabolic parameters 
− Lipoprotein analysis 
− Markers of inflammation, apoptosis, and necrosis 
− PD assessments 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class 
− Noninvasive scores of liver fibrosis (NAFLD fibrosis score [NFS], Fibrosis-4 
[FIB-4], and aspartate aminotransferase to platelet ratio index [APRI]) 
− Noninvasive panel of liver fibrosis (ELF and FibroMeter) 
− Cardiovascular risk scores (10-year ASCVD Risk, Framingham Risk Score 
[FRS], Reynolds score, SCORE) 
• Noninvasive radiological liver fibrosis measurement (transient elastography [TE]; 
conducted at sites where device is available). 
• Obtain urine sample for urinalysis 
• Perform a urine-based β-hCG pregnancy test for females of childbearing potential 
• Record the visit in the randomized and trial supply management system (RTSM) and 
dispense investigational product 
• Administer investigational product at the study site.  Instruct the subject to swallow 
the tablet whole with water; s/he must not chew, divide, or crush the tablet. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− Take the investigational product at approximately the same time each day  
− NOT to take investigational product on the morning of the next visit  
− To bring the investigational product bottle(s) with them to his/her next visit; s/he 
will dose at the clinic 
− To fast overnight (at least 8 hours) before the next visit, but water is permitted 
8.2.3. 
Subject Discontinuation Notification 
The Investigator must notify the Sponsor as soon as possible if any subject prematurely 
discontinues from the study.  The date when the subject is withdrawn and the primary reason(s) 
for discontinuation must be recorded in the eCRF; additional information may be requested by 
the Sponsor to complete a discontinuation narrative.  Subjects will be considered “lost to 
follow-up” only after reasonable, documented attempts to reach the subject prove unsuccessful.  


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In all cases, a reasonable effort must be made to determine the reason(s) that a subject fails to 
return for required study visits or discontinues from the study.  This information must be 
documented in the eCRF. 
If a subject is withdrawn from the study early (regardless of the cause), all of the early 
termination (ET) evaluations are to be performed at the time of withdrawal, to the extent 
possible. 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Investigational Product Treatment Regimen 
The term investigational product (provided as part of this clinical study) refers to either OCA or 
placebo. 
Three treatment groups will be evaluated: 
• Placebo 
• OCA (10 mg) 
• OCA (10 mg → 25 mg) 
Each dose will be made up of 1 tablet. 
Investigational product will be taken orally with water, once daily for the duration of the study.  
Subjects will be instructed to begin dosing on Day 1 and are to take investigational product at 
approximately the same time each day.  Subjects must be instructed to swallow the tablet whole; 
they must not chew, divide, or crush the tablet. 
At each study visit where the daily dose of investigational product is administered at the site, all 
assessments, except for the post-dose collection of blood samples for the subjects participating in 
the optional serial PK assessment and/or 
, must be completed 
before administration of investigational product. 
Investigational product during the OLE Phase will be provided as open-label OCA tablets.  The 
study will be blinded until the last subject completes the Double-Blind Phase and the database is 
locked. 
9.2. 
Criteria for Uptitration 
9.2.1. 
Double-Blind Phase (Month 3) 
Subjects randomized to the OCA 10 mg → 25 mg arm in the Double-Blind Phase will receive 
OCA 10 mg for the first 3 months.   
Prior to the Month 3 study visit, the Medical Monitor will perform a subject-level consolidated 
review of safety data, including data from the Month 1 and 2 study visits, as well as that from 
any unscheduled visit(s), for all study subjects.  Case review and discussion with the Principal 
Investigator will occur as needed.  The review will include but not be limited to the following: 
• Liver-related adverse events 


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• Safety laboratories:  chemistry panel including glucose, hematology panel, 
coagulation parameters; computed MELD score and CP score 
• Physical examination (development of clinically evident ascites or manifestations of 
hepatic encephalopathy) 
Additional considerations to determine the suitability to uptitrate will include an assessment of 
comorbid conditions, the subject’s overall adverse event profile, concomitant medications with a 
focus on potentially hepatotoxic concomitant medications, and/or any new treatment(s) for 
comorbid condition(s).  A subject may be considered for uptitration to OCA 25 mg if no safety 
and/or tolerability concerns are evident in the clinical judgement of the reviewer(s).  If 
uptitration at Month 3 is not feasible, the window for uptitration may be extended by up to one 
calendar month, after consultation and agreement with the Medical Monitor.  The uptitration 
review process is detailed in the study-specific Medical Management Plan. 
Only those subjects who meet all of the following criteria will be eligible for uptitration at 
Month 3: 
• Total bilirubin ≤1.2 mg/dL, serum albumin ≥3.5 g/dL, INR <1.5, and platelet count 
>100,000/mm3 at baseline, and at all visits prior to Month 3 (including any 
unscheduled visits). 
• Medical Monitor approval following a safety and tolerability assessment as described 
above.  
Subjects who do not meet these criteria will not be uptitrated for the remainder of the study. 
If at any time during the study, a subject who has undergone uptitration has total bilirubin 
>1.2 mg/dL, serum albumin <3.5 g/dL, INR ≥1.5, or platelet count ≤100,000/mm3, the laboratory 
assessment(s) should be repeated within 7 days.  If upon repeat evaluation, value(s) remain 
outside the specified criteria, investigational product should be downtitrated to a maximum daily 
dose of OCA 10 mg and the Medical Monitor should be notified promptly (see Table 5).  
Subjects randomized to the OCA 10 mg or placebo arms will undergo dummy titration to 
maintain study blind.  All uptitration and downtitration will be implemented in a blinded fashion 
within RTSM to maintain the integrity of the study blind. 
Dosing frequency post-titration may be temporarily decreased for tolerability reasons, following 
discussions with the Medical Monitor.   
In addition, investigational product may be interrupted per safety criteria listed in Table 5 and 
Section 7.7.  The procedures for re-initiating investigational product after prolonged interruption 
are provided in Section 8.2.2. 
9.2.2. 
OLE Phase 
Subjects who were randomized to placebo in the Double-Blind Phase will be re-randomized to 
either OCA 10 mg or OCA 10 mg → 25 mg at entry into the OLE.  Uptitration to OCA 25 mg at 
Month 3 in the OLE will be determined based on the same criteria and assessments employed in 
the Double-Blind Phase and described above.  Subjects randomized to OCA (10 mg or 10 mg → 
25 mg dose) during the Double-Blind Phase will continue the same dosing regimen. 


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All dosing, uptitration, and downtitration will be conducted in a blinded fashion in order to 
maintain the integrity of the study blind until all subjects complete the Double-Blind Phase and 
the database is locked. 
9.3. 
Criteria for Extension of Double-Blind Treatment with 
Investigational Product 
With the exception of sites in the Ukraine, for subjects who have been unable to complete the 
liver biopsy procedure at the Month 18 Visit due to the limitations caused by the COVID-19 
pandemic and have or will run out of investigational product, investigational product may be 
extended beyond the Month 18 Visit for a maximum of 3 additional months of the double-blind 
period.  In order for a subject to be eligible for this extension, the following must occur: 
• Assessment of safety laboratory tests (chemistry panel including glucose, hematology 
panel, coagulation parameters; computed MELD score, and CP score) at Month 18, 
with review of results by the Medical Monitor and Investigator.  
• Assessment of subject status at the Month 18 Visit must occur, either via an onsite 
study visit (if possible) or via a telemedicine visit (“virtual visit”) as an alternative 
means of enabling Investigators and site staff to evaluate subject status and record 
any AEs or new medications.  At a minimum, these visits must consist of a direct 
telephone or videocall discussion with the subject by the Investigator or an 
appropriate designee from the Investigator’s team who is currently authorized to 
undertake examinations on the Investigator’s Delegation of Authority Log.  If an 
onsite visit or a telemedicine contact is not feasible (eg, no access to the subject) to 
assess status, investigational product will not be dispensed. 
• If deemed necessary, additional assessment of safety laboratory tests and/or subject 
status may be performed at the discretion of the Investigator or Medical Monitor.  
Based on the individual subject-level safety and tolerability assessment, if both the 
Medical Monitor and the Investigator agree that the benefit-risk profile remains 
favorable, investigational product may be dispensed, which will provide an additional 
3 months of treatment.   
Unless all of the above measures occur, additional investigational product will not be provided. 
9.4. 
Standard of Care and Concomitant Medications 
Concomitant medications will be used at the discretion of the usual care provider (or Investigator 
if also the usual care provider).  Relevant information about all concomitant medications taken 
before (ie, within 12 months of Day 1) and during the study must be recorded in the source 
documents and case report form, as well as any dose or dose regimen changes that occur during 
the study.  All subjects will be questioned about concomitant medications at each clinic visit.  To 
the extent possible, concomitant medications should be maintained at a stable dose throughout 
the study and at a minimum, from Day 1 through the end of the Double-Blind Phase, unless the 
baseline therapy is no longer considered clinically appropriate by the Investigator or the subject’s 
primary care provider.  In general, Investigators will be encouraged to follow guidelines for care 


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based upon local and institutional practice patterns and any relevant published practice 
guidelines.  
Subjects must follow the medication restrictions outlined in the inclusion and exclusion criteria 
(Section 8) during the study.  The restrictions related to use of drugs historically associated with 
drug-induced NAFLD are as follows: 
• Drugs with Potential NASH-modifying Properties 
Subjects should either not be taking any drugs with potential NASH-modifying 
properties (specifically, TZDs/glitazones, vitamin E, or glucagon-like peptide-1 
agonists) or be on a stable dose of these medications for 6 months before Day 1.  
Subjects providing historical biopsies to determine study eligibility should be on a 
stable dose of these medications for 12 months before Day 1 and these medications 
should not have been initiated after the historical liver biopsy was performed.  
Changes to these drugs with potential NASH-modifying properties are not permitted 
for the duration of the Double-blind Phase unless the baseline therapy is no longer 
considered clinically appropriate by the Investigator/or the usual care provider. 
• Drugs with Potential NAFLD-inducing Properties 
Subjects chronically (≥12 months) using the following drugs that are historically 
associated with NAFLD will not be enrolled in the study if used within the 5 years 
before Day 1:  amiodarone, methotrexate, systemic glucocorticoids [unless used at 
physiologic replacement doses for the treatment of adrenal insufficiency], 
tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone 
replacement, anabolic steroids [except for testosterone preparations used at 
physiologic replacement doses for the treatment of documented hypogonadism], 
valproic acid, and other known hepatotoxins (refer to Exclusion Criterion 28; 
Section 8.1.2). 
If a study subject receives a COVID-19 vaccination, the date(s) of vaccination, vaccine name, 
and manufacturer should be recorded as a concomitant medication for each dose (refer to 
Section 10). 
9.4.1. 
LDL-Lowering Medications 
Appendix A provides a general guidance for cholesterol management including monitoring, 
triggers for intervention, and treatment goals.  Use of LDL-lowering medications 
(eg, simvastatin, atorvastatin, PCSK9 inhibitors) should be at a stable dose ≥30 days before 
Day 1.  During the study, changes to LDL-lowering medication regimen are allowed, given the 
potential increase in total and LDL cholesterol following treatment with OCA. 
9.4.2. 
Warfarin 
Taken concomitantly, OCA and warfarin may decrease INR, thus INR should be monitored and 
the dosage of warfarin adjusted, as needed, to maintain the target INR range. 


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9.4.3. 
Bile Acid Sequestrants 
Bile acid sequestrants (BAS) have the potential to bind to fat-soluble vitamins, hormones, or 
medications.  Subjects taking BAS (including colestyramine and its derivatives, colestipol, 
colesevelam, or other BAS) or aluminum hydroxide- or smectite-containing antacids should be 
instructed to stagger their dosing of investigational product in temporal relationship to these 
agents, ensuring at least 4 hours between doses of the BAS and/or these antacids and the 
investigational product (ie, BAS should be administered 4 hours before or 4 hours after 
investigational product administration).  For guidance on using BAS to treat pruritus ≤Grade 2 in 
severity refer to Section 16.1.6.1. 
Due to the potential of BAS to affect the disposition of OCA, long-term use of BAS should be 
avoided where possible while taking investigational product.  In subjects taking long-term BAS 
for other medical conditions (eg, hypercholesteremia), other therapies to replace the BAS should 
be considered.   
9.4.4. 
Drug-Drug Interaction 
The effect of OCA on drug metabolizing enzymes has been evaluated in both in vitro and clinical 
studies.  The PK profile of caffeine, a sensitive CYP1A2 substrate, showed a weak effect of 
OCA on CYP1A2.  Based on these results, OCA may increase the exposure of narrow 
therapeutic index drugs that are substrates for CYP1A2, such as theophylline and tizanidine. 
9.4.5. 
Standard of Care: Management of Dyslipidemia 
Given the prevalence of dyslipidemia in patients with NASH and the potential increase in total 
cholesterol and LDLc following treatment with OCA, it is recommended that Investigators 
proactively monitor and manage lipid levels in all subjects as indicated via appropriate medicinal 
interventions (eg, statins).  Recent guidelines stress the importance of evaluating ASCVD risk in 
all patients to help guide decisions in recommending therapies and reducing LDLc to reduce the 
risk and prevent onset or recurrence of ASCVD.  As such, reducing lipids, particularly LDLc, are 
part of a comprehensive CV risk reduction strategy.  Results from meta-analyses have confirmed 
the dose-dependent reduction in ASCVD with LDLc-lowering agents; the greater the absolute 
LDLc reduction, the greater the CV risk reduction.  Recent guidelines for the management of 
lipids, such as the 2019 ESC/EAS Guidelines (Mach 2020), suggest that LDLc targets should be 
individualized based on available treatments and each subject’s overall ASCVD risk profile.  The 
targeted approach to lipid management is aimed at reducing atherosclerotic risk by substantially 
lowering LDLc to levels that have been achieved in recent large-scale trials (Figure 4). 


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Figure 4: 
Therapeutic Targets for LDLc Based on Subject ASCVD Risk 
 
Adapted from: 2019 ESC/EAS guidelines (Mach 2020). 
9.4.6. 
Standard of Care: Management of Hyperglycemia 
Subjects with type 2 diabetes mellitus and those who are at risk for developing hyperglycemia 
should be closely monitored throughout the study in order to ensure appropriate therapeutic 
interventions based on current guidelines to mitigate potential elevations of serum glucose and 
initiate them when indicated.  The Investigator should proactively consider major risk factors for 
developing hyperglycemia that include family history of type 2 diabetes; obesity; African 
American, Native American, Hispanic or Asian American heritage; hypertension; dyslipidemia; 
or history of gestational diabetes.  Early signs and symptoms of hyperglycemia that include 
polyuria, polydipsia, polyphagia, blurred vision, fatigue and headaches should also be monitored. 
Subjects who experience treatment-emergent hyperglycemia should be closely monitored and 
treatment should be based on current guidelines.  Initiation of therapy should take into 
consideration each subject’s underlying health status and the use of appropriate glycemic targets.   
The management of hyperglycemia depends on several factors including: the duration, frequency 
and severity of hyperglycemia, and the subject’s age, health, and cognitive function.  The 
American Diabetes Association (ADA) and the European Association for the Study of Diabetes 
(EASD) have updated their recommendations on the management of hyperglycemia based on 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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underlying risk factors including underlying cardiovascular and renal disease.  According to 
these guidelines, glycemic treatment targets should be individualized based on patient 
preferences and goals, risk of adverse effects of therapy (eg, hypoglycemia and weight gain), and 
subject characteristics, including frailty and comorbid conditions (Davies 2018).  Glycemic 
management is primarily assessed by measuring HbA1c and the choice of glucose-lowering 
medications should be accompanied by lifestyle management, weight loss, exercise, dietary 
modification, diabetes self-management education and support, and patient-centered care.   
While criteria for initiating therapy requires individualizing HbA1c targets, a reasonable HbA1c 
target is approximately ≤7% (53 mmol/mol) (Davies 2018).  The selection of the appropriate 
individualized therapy is described in current guidelines from ADA and EASD for management 
of hyperglycemia (Appendix B). 
Subjects displaying increasing fasting glucose, HBA1c, or HOMA-IR levels should be referred 
to either their treating physician, if already under care for diabetes, or to their HCP or an 
endocrinologist if they experience new onset type 2 diabetes mellitus. 
9.5. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of investigational product at 
each study visit after Day 1. 
Subjects should be instructed to retain all bottles of investigational product, even if empty, and to 
return them to the Investigator at the indicated visits in Table 1 and Table 2.  The Investigator or 
designee should perform investigational product accountability (ie, count of returned tablets) 
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, he or she should discuss 
this with the subject, assess the reasons for noncompliance and the likelihood that the subject 
will remain noncompliant, and notify the Sponsor accordingly.   
9.6. 
Randomization and Blinding 
9.6.1. 
Methods of Assigning Subjects to Treatment Groups 
This study will be conducted in a double-blind, placebo-controlled manner.  Enrolled subjects 
will be randomized in a 1:1:1 ratio to one of the three treatment arms:  once daily dosing of OCA 
10 mg, OCA 10 mg → 25 mg (ie, OCA 10 mg with uptitration to OCA 25 mg at Month 3), or 
placebo.  Randomization will be done using an RTSM and will be based on a predefined 
randomization code generated by the Sponsor or designee.  Subjects randomized to OCA 
10 mg → 25 mg will initiate dosing at OCA 10 mg for 3 months prior to uptitrating to OCA 
25 mg.  Uptitration will be determined based on the laboratory criteria and safety and tolerability 
assessments completed prior to Month 3 (Section 9.2.1). 
Randomization of subjects will be stratified by the presence of type 2 diabetes at enrollment (yes 
or no).   


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All subjects who enroll into the OLE will receive OCA.  Subjects randomized to placebo in the 
Double-Blind Phase will be re-randomized to OCA 10 mg or OCA 10 mg → 25 mg arms, with 
uptitration at OLE Month 3 in the OCA 10 mg → 25 mg arm (refer to Section 9.2) 
The RTSM will also serve as the investigational product inventory and management system.  
The Investigator or designee will be required to register the subject in the RTSM and may be 
prompted to provide patient data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned and investigational product (OCA or 
placebo) dispensing information will be provided (eg, bottle numbers allocated) while 
maintaining the study blind.   
To maintain blinding, all placebo, OCA 10 mg, and OCA 25 mg tablets and bottles will be 
identical. 
9.6.2. 
Blinding 
The subjects, Investigators, and study site staff will be blinded to the subject’s treatment regimen 
until all subject data have been collected from the study and the database is locked for Double-
Blind Phase.  Using this approach, blinding of the study will be maintained.  
9.6.3. 
Emergency Unblinding Procedures 
Randomization codes and corresponding treatment assignments will be made available to the 
Investigator for emergency use only through the RTSM system.  When possible, the Medical 
Monitor should be consulted in the event that a medical emergency necessitates unblinding 
(ie, in situations where knowledge of the unblinded 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 the case in the subject’s source record.  
Subsequently, the Investigator should contact the Medical Monitor to explain any premature 
unblinding of treatment assignment (eg, accidental unblinding or unblinding due to a 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 or for regulatory reporting purposes, the Medical Monitor will document within 
study correspondence the rationale, circumstances, and the person(s) being informed about the 
unblinding.   
The DMC (refer to Section 17.13) will have access to randomization and will be able to review 
the cases of premature unblinding.  The DMC will document details about any subject who was 
unblinded in the closed session DMC minutes, which will be made available to the Sponsor only 
after the double-blind database is locked and unblinded.  Cases of premature unblinding (as 
noted above) will be reviewed by the DMC. 
Access to randomization codes and corresponding treatment assignments will also be made 
available through the RTSM system to the appropriate, named individual(s) responsible for 
unblinding suspected unexpected serious adverse reactions (SUSARs) for reporting to the 
regulatory authorities. 


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9.7. 
Assignment of Site and Subject Numbers 
9.7.1. 
Site Numbers 
Each study site selected to participate in this study will be assigned a site number by the Sponsor.  
The site number will be used to categorize subject data and to identify the site and/or Investigator 
within study documents.  This number will be recorded in the eCRF. 
9.7.2. 
Subject Numbers 
Subjects are assigned using a unique 10-character, 9-digit identifier (AAA-BBBCCC), 
independent of the randomization number.  The first 3 digits represent the last 3 digits of the 
protocol number, followed by a hyphen (AAA-).  The next 3 digits represent the site number 
(BBB).  The last 3 digits represent a unique screening number that is assigned in sequential order 
at each site starting with 001 (CCC).  Note, in the case of incorrect data entry by a site when 
more than one subject is inadvertently created, the spurious subject numbers will be deleted and 
may not be used again; in this circumstance there may be gaps in the subject numbering scheme 
at a site. 
9.8. 
Restrictions 
No additional restrictions.  
9.9. 
Highly Effective Contraception 
Recent guidelines recommend “highly effective” contraception measures for investigational 
products with limited or no human data available on pregnancies. (HMA CTFG 2014).  Highly 
effective methods of contraception per the CTFG guidelines are those that alone or in 
combination result in a failure rate of less than 1% per year when used consistently and correctly.  
The highly effective contraception measures should be maintained during treatment and until the 
end of relevant systemic exposure.  Women of child-bearing potential, currently enrolled in the 
747-304 study, will employ the highly effective contraception measures during treatment with IP 
for their participation in the study.  
Female subjects must be postmenopausal, surgically sterile, or, if premenopausal (and not 
surgically sterile), be prepared to use at least one highly effective method of contraception during 
the study and for 30 days after the end of treatment.  
Highly effective methods of contraception include the following: 
• Intrauterine device  
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomy (male partner) 
• Combined (estrogen- and progestogen-containing) hormonal contraception (eg, oral, 
intravaginal or transdermal) associated with inhibition of ovulation.  


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• Progestogen-only hormonal contraception (eg, oral, injectable or implantable) 
associated with inhibition of ovulation.  
• Sexual abstinence, if in line with the preferred and usual lifestyle of the subject 
(where abstinence is defined as refraining from heterosexual intercourse during the 
entire period of risk associated with study treatments). 
9.10. 
Visit Procedures 
Visits should be based on Day 1 (not on the prior visit) unless stated otherwise.  The day of the 
first dose from the OLE bottle is considered OLE Day 1.  If Day 1 occurs on January 1st, 
Month 3 should ideally occur on April 1st (±1 week).  This is the definition of a calendar month.  
The visit windows are listed in Table 1 and Table 2.  Acceptable windows for PK sampling 
timepoints are in Table 7. 
9.10.1. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risks, and benefit of the 
study to the subject and will provide him/her with a copy of the informed consent form (ICF).  
The subject will be given sufficient time to consider the study before deciding whether or not to 
participate.  The subject will be informed that participation is voluntary and that her/his future 
medical treatment will not be compromised by participation in the study and that he or she can 
withdraw from the study at any time.  The subject must be willing and able to provide written 
informed consent before entering the study.  The Investigator or a medically qualified designee is 
responsible for administering and documenting the written informed consent of the subject.  The 
subject will be given a copy of his/her signed and dated ICF.  Subjects will also be required to 
provide consent prior to participating in any of the optional assessments, such as providing blood 
samples for serial PK draws.  
9.10.2. 
Fasting Requirement at Study Visits 
Starting with Screening Visit 2, all subjects must arrive to the study site in a fasted state (at least 
8 hours before each visit).  Water is permitted during the fasting period.  If the subject reports 
having eaten within 8 hours of the visit, the nonfasted state will be documented in the source; 
however, scheduled assessments (blood collection) will still be performed during the visit, and 
these subjects will be reminded that fasting is required before all study visits. 
9.10.3. 
Screening Visit Procedures  
Two Screening Visit assessments must be performed to determine whether the subject meets all 
the inclusion criteria and none of the exclusion criteria.  Subjects who do not fulfill all eligibility 
criteria will not be enrolled in the study.  Subjects may be rescreened after 2 months have 
elapsed from the date of their most recent screening visit procedure, or with alternative timing 
approved by the Sponsor’s Medical Monitor; however, all Screening procedures (including 
obtaining informed consent) should be repeated and a new three-digit Screening number 
assigned. 
The 2 Screening visits must occur at least 4 weeks apart to confirm pretreatment serum 
chemistry levels, including ALT, AST, and total bilirubin.   


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• Screening Visit 1 will occur ≤12 weeks prior to Day 1.  
• Screening Visit 2 will occur ≥4 weeks after Screening Visit 1. 
If ALT, AST, or total bilirubin (conjugated bilirubin for subjects with an established diagnosis of 
Gilbert’s syndrome) assessments collected at Screening Visit 2 is are ≥30% higher than the 
Screening Visit 1 value(s) and >ULN, then a third measurement must be obtained at an 
unscheduled visit for eligibility determination. 
9.10.3.1. Screening Visit 1 
The Screening Visit assessments must be performed within ≤12 weeks prior to Day 1 to 
determine whether the subject meets all the inclusion criteria and none of the exclusion criteria.  
Subjects who do not fulfill all eligibility criteria will not be enrolled in the study. 
If an Investigator intends to rescreen a subject <2 months after the initial screening, this decision 
should be discussed with the Sponsor’s Medical Monitor to confirm that early rescreening will 
not affect safety or efficacy for the subject.  When rescreening, all Screening Visit procedures 
should be repeated and a new screening number assigned.  Subjects should be reconsented, as 
appropriate, at this time. 
Screening Visit 1 procedures for all subjects are as follows: 
• Review ICF and obtain signatures before performing any study-related procedures, 
including Screening procedures 
• Collect medical history  
• Assess and record any pretreatment AEs (after the ICF has been signed) 
• Record prior (if within 12 months of Day 1) and current concomitant medications 
• Verify inclusion and exclusion criteria for eligibility 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 
• Measure height.  Record weight and BMI 
• Conduct physical exam  
• Perform standard 12-lead ECG  
• Determine alcohol consumption (Alcohol Use Disorders Identification Test [AUDIT] 
questionnaire) 
• Perform hepatobiliary ultrasound for HCC screening and gallbladder assessment 
unless data from a recent historic ultrasound (within 3 months of Day 1) are available 
• Perform esophagogastroduodenoscopy (EGD) procedure unless data from a recent 
EGD (within 6 months of Day 1) are available.  Subjects with endoscopic evidence of 
varices will not be enrolled in the study. 
• Assess availability of liver biopsy samples obtained ≤12 months prior to Day 1, for 
which unstained slides can be prepared and submitted for central review.  All samples 


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must be submitted for central read such that the report is available prior to Day 1.  For 
subjects without a recent liver biopsy with unstained slides or adequate tissue block, 
an on-study liver biopsy must be performed within the 12-week screening window 
before Day 1 (assuming all other Screening assessments indicate a likelihood that the 
subject will qualify based on biopsy).   
• Obtain blood samples for: 
− HCC screening (AFP) 
− Serum chemistry, hematology, and coagulation  
− Glucose and HbA1c 
− Virology Screen (HCV and hepatitis B surface antigen [HBsAg]) 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
− Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) 
• Noninvasive radiological liver fibrosis measurements (TE and MRE; conducted at 
sites where device is available; MRE only in subjects enrolled prior to Version 5 of 
the protocol and not in newly enrolled subjects) 
Note:  Noninvasive radiological measurements may be completed any time during 
Screening Visit 1 through Day 1 but should be conducted prior to an on-study liver 
biopsy, if one is necessary, and before initiation of investigational product on Day 1. 
• Obtain urine sample for urinalysis 
• Perform a urine-based beta human chorionic gonadotropin (β-hCG) pregnancy test for 
females of childbearing potential 
• Instruct the subject to fast overnight (at least 8 hours) before the next visit (water is 
permitted).  Fasting is required before Screening Visit 2.  
9.10.3.2. Screening Visit 2 
Screening Visit 2 procedures must be performed ≥4 weeks after Screening Visit 1 and are as 
follows: 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and eCRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 
• Medical history 
• Record prior (if within 12 months of Day 1) and current concomitant medications  


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• Assess and record any pretreatment AEs 
• Verify inclusion and exclusion criteria for eligibility 
• Measure circumference of waist and hips  
• If not conducted at Screening Visit 1, noninvasive radiological liver fibrosis 
measurements (TE and MRE; conducted at sites where device is available; MRE only 
in subjects enrolled prior to Version 5 of the protocol and not in newly enrolled 
subjects) 
Note:  Baseline noninvasive radiological measurements should be conducted prior to 
an on-study liver biopsy 
• For subjects without a recent liver biopsy with unstained slides or adequate tissue 
block (≤12 months prior to Day 1), collect liver biopsy sample.  (Procedure may be 
performed within the 12-week screening window, and assuming all other Screening 
assessments indicate a likelihood that the subject will qualify based on biopsy).  
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
• Perform a urine-based beta human chorionic gonadotropin (β-hCG) pregnancy test for 
females of childbearing potential 
• Instruct the subject to fast overnight (at least 8 hours) before the next visit (water is 
permitted) 
9.10.4. 
Day 1 Procedures (Randomization) 
All Day 1 procedures, except for the 
, should be done before 
dosing.  Day 1 Visit procedures for all subjects are as follows: 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and eCRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 
• Record prior and current concomitant medications  
• Assessment of baseline pruritus (via medical history evaluation) 
• Assess and record any pretreatment AEs 
• Assess signs and symptoms of: 
− Hepatic injury or decompensation 


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− Intercurrent illness and/or potential adverse events (Appendix C) 
• Verify inclusion and exclusion criteria for eligibility 
• Randomize the subject only if s/he meets all inclusion criteria and no exclusion 
criteria 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 
• Record weight and BMI  
• Measure circumference of waist and hips 
• Conduct physical exam 
• Perform standard 12-lead ECG  
• AUDIT, smoking habits, and caffeine consumption 
• Health-related quality of life questionnaires and health status for the assessment of 
health utilities 
• Pruritus VAS 
• If a hepatobiliary ultrasound for HCC screening and gallbladder assessment was not 
performed at Screening and the historic ultrasound is >3 months from Day 1, perform 
a hepatobiliary ultrasound  
• Obtain blood samples for: 
− HCC screening (AFP) 
− Serum chemistry, hematology, and coagulation 
− Free fatty acids 
− Thyroid hormones  
− Glucose and HbA1c 
− Insulin, C-Peptide, HOMA-β, and HOMA-IR 
− Lipoprotein analysis 
− Markers of inflammation, apoptosis, and necrosis 
− PD assessments (all subjects) 
− Exploratory biomarkers of disease severity  
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
− Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) 
− Noninvasive panel of liver fibrosis (ELF and FibroMeter) 




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• Assess signs and symptoms of: 
− Hepatic injury or decompensation 
− Intercurrent illness and/or potential adverse events (Appendix C) 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 
• Record weight and BMI  
• Measure circumference of waist and hips 
• Health-related quality of life questionnaires and health status for the assessment of 
health utilities 
• Pruritus VAS 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation  
− Glucose 
− Insulin, C-Peptide, HOMA-β, and HOMA-IR 
− Markers of inflammation, apoptosis, and necrosis 
− Trough PK assessment (all subjects) 
− PD assessments (all subjects) 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
− Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) 
− Potential DILI management algorithm (liver biochemistry) 
• Perform a urine-based β-hCG pregnancy test for females of childbearing potential 
• Record the visit in RTSM; there is no dispensing of investigational product via 
RTSM at this visit. 
• If subject is not participating in serial PK assessments, administer the daily dose of 
investigational product from the bottle dispensed on Day 1 at the study site.  Instruct 
the subject to swallow the tablet whole with water; s/he must not chew, divide, or 
crush the tablet.  Return the same bottle of investigational product to the subject to 
continue daily dosing at home.  
• If subject consented to participate in serial PK assessment, the following procedures 
will be conducted: 
− Dispense/Administer investigational product from the double-blind bottle 
(collected from the subject upon arrival for this visit) with 240 mL (8 oz.) of 


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water.  Instruct the subject to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet.    
− Collect blood samples at:  0.5, 0.75, and 1-hour postdose 
− Immediately following 1-hour post-dose blood draw, administer meal 
replacement drink (to be consumed within 5 – 10 minutes)  
− Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose 
Note:  Subjects should not consume any food for the duration of the 6-hour PK 
assessments except the meal replacement drink.  Subjects should not drink any water 
until at least 1-hour postdose.  Refer to Section 14.1 for complete information and 
instructions regarding serial PK assessments. 
• Return the bottle of investigational product that was dispensed to the subject to 
continue daily dosing at home. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product on the morning of the next visit 
− To bring the investigational product bottle(s) with them to his/her next visit; s/he 
will dose at the clinic 
− To fast overnight (at least 8 hours) before the next visit, but water is permitted 
9.10.6. 
DB Month 2, Month 5, Month 9, and Month 15 Procedures  
All Month 2, Month 5, Month 9, and Month 15 procedures should be done before dosing.  Visit 
procedures for all subjects are as follows: 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and eCRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 
• Collect used bottles of investigational product, assess subject’s investigational 
product compliance, and perform investigational product accountability  
• Review and record current concomitant medications  
• Assess and record any TEAEs  
• Assess signs and symptoms of: 
− Hepatic injury or decompensation 
− Intercurrent illness and/or potential adverse events (Appendix C) 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 


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• Record weight and BMI 
• Measure circumference of waist and hips 
• Pruritus VAS 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation  
− Glucose (Months 2, 5, 9, and 15) and HbA1c (Month 9 and Month 15 only) 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
− Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) 
− Potential DILI management algorithm (liver biochemistry) 
• Perform a urine-based-hCG pregnancy test for females of childbearing potential 
• For Month 2 and Month 5, record the visit in RTSM; there is no dispensing of 
investigational product via RTSM at this visit. 
• For Month 9 and Month 15, record the visit in RTSM and dispense a new bottle of 
investigational product. 
• Administer the daily dose of investigational product at the study site.  Instruct the 
subject to swallow the tablet whole with water; s/he must not chew, divide, or crush 
the tablet.   
• For Month 2 and Month 5, return the bottle of investigational product that was 
dispensed to the subject to continue daily dosing at home.  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− Take the investigational product at approximately the same time each day  
− NOT to take investigational product on the morning of the next visit  
− To bring the investigational product bottle(s) with them to his/her next visit; s/he 
will dose at the clinic 
− To fast overnight (at least 8 hours) before the next visit, but water is permitted 
9.10.7. 
DB Month 3 Procedures  
All Month 3 procedures, except for the 
, should be done before 
dosing, including trough PK sampling.  Visit procedures for all subjects are as follows: 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and eCRF 






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− Glucose only 
− Markers of inflammation, apoptosis, and necrosis 
− Trough PK assessment (all subjects) 
− PD assessments (all subjects) 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
− Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) 
− Potential DILI management algorithm (liver biochemistry) 
• Perform a urine-based β-hCG pregnancy test for females of childbearing potential 
• Record the visit in RTSM; there is no dispensing of investigational product via 
RTSM at this visit. 
• If subject consented to participate in serial PK assessment, the following procedures 
will be conducted: 
− Dispense/Administer investigational product from the double-blind bottle 
(collected from the subject upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the subject to swallow the tablet whole; s/he must not chew, 
divide, or crush the tablet. 
− Collect blood samples at:  0.5, 0.75, and 1-hour post-dose 
− Immediately following 1-hour post-dose blood draw, administer meal 
replacement drink (to be consumed within 5 – 10 minutes) 
− Collect blood samples at: 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose 
Note:  Subjects should not consume any food for the duration of the 6-hour PK 
assessments except the meal replacement drink.  Subjects should not drink any water 
until at least 1-hour postdose.  Refer to Section 14.1 for complete information and 
instructions regarding serial PK assessments. 
• For subjects not participating in serial PK collection, administer the daily dose of 
investigational product at the study site.  Instruct the subject to swallow the tablet 
whole with water; s/he must not chew, divide, or crush the tablet. 
• Return the bottle of investigational product that was dispensed to the subject to 
continue daily dosing at home. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product on the morning of the next visit 
− To bring the investigational product bottle(s) with them to his/her next visit; s/he 
will dose at the clinic 


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− To fast overnight (at least 8 hours) before the next visit, but water is permitted 
9.10.9. 
DB Month 6 and Month 12 Procedures 
All Month 6 and Month 12 procedures, except for the post-dose collection of blood samples for 
subjects participating in the PK and/or 
, should be done before 
dosing, including trough PK sampling.  Visit procedures for all subjects are as follows: 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and eCRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 
• Collect used bottles of investigational product, assess subject’s investigational 
product compliance, and perform investigational product accountability 
• Review and record current concomitant medications 
• Assess and record any TEAEs 
• Assess signs and symptoms of:  
− Hepatic injury or decompensation 
− Intercurrent illness and/or potential adverse events (Appendix C) 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 
• Record weight and BMI 
• Measure circumference of waist and hips 
• AUDIT, smoking habits, and caffeine consumption 
• Health-related quality of life questionnaires and health status for the assessment of 
health utilities 
• Pruritus VAS 
• Noninvasive radiological liver fibrosis measurements (TE and MRE; conducted at 
sites where device is available); Month 6 only (MRE only in subjects enrolled prior to 
Version 5 of the protocol who had baseline MRE and not in newly enrolled subjects) 
• Perform hepatobiliary ultrasounds for HCC screening and gallbladder assessment 
• Obtain blood samples for: 
− HCC screening (AFP) 
− Serum chemistry, hematology, and coagulation 
− Free fatty acids 
− Glucose and HbA1c 




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Note:  Subjects should not consume any food for the duration of the 6-hour PK 
assessments except the meal replacement drink.  Subjects should not drink any water 
until at least 1-hour postdose.  Refer to Section 14.1 for complete information and 
instructions regarding serial PK assessments. 
• For Month 12, if subjects are not participating in serial PK collection, administer the 
daily dose of investigational product at the study site.  Instruct the subject to swallow 
the tablet whole with water; s/he must not chew, divide, or crush the tablet. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product on the morning of the next visit 
− To bring the investigational product bottle(s) with them to his/her next visit; s/he 
will dose at the clinic 
− To fast overnight (at least 8 hours) before the next visit, but water is permitted 
9.10.10. 
DB Month 18/EOT/EOS/OLE Day 1 Visit for Subjects Continuing into the OLE 
For subjects who are unable to complete the liver biopsy procedure at the Month 18 Visit due to 
the limitations caused by the COVID-19 pandemic and have or will run out of investigational 
product, investigational product may be extended beyond the Month 18 Visit for a maximum of 
3 additional months of the double-blind period (refer to Section 9.3 for requirements of this 
extension).  Regardless of whether these subjects are eligible for the additional supply of 
investigational product, they are to return to the site for an unscheduled visit to complete the 
liver biopsy (and other procedures assessments as required) as soon as practical following 
lifting/easing of the COVID-19 restrictions (refer to Section 9.10.16 for details of this visit). 
All Month 18/EOT/EOS procedures, except for the post-dose collection of blood samples for 
subjects participating in the PK and/or 
, should be done before 
dosing, including trough PK sampling.   
Visit procedures for all subjects are as follows: 
• When a subject completes the Double-Blind Month 18 Visit and decides not to 
continue participation in the OLE, the data will be recorded as EOS procedures in the 
eCRF 
• When a subject discontinues investigational product during the Double-Blind Phase 
but continues with regularly scheduled study visits, the visit data will be recorded as 
EOT procedures in the eCRF and the subject’s final study visit will be recorded as 
EOS procedures in the eCRF.  The EOT visit procedures listed below must be 
performed as close as possible to the subject’s last dose of investigational 
product.  Subsequent study visit data will be recorded in the visit-specific eCRF. 
• If a subject will be entering the OLE phase, the Double-Blind Month 18 Visit and the 
Day 1 OLE Visit should be combined as a single visit 
• Verify that the subject has fasted for at least 8 hours 


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− Record fasting status in the source and eCRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 
• Collect used bottles of investigational product, assess subject’s investigational 
product compliance, and perform investigational product accountability 
• Review and record current concomitant medications 
• Assess and record any TEAEs 
• Assess signs and symptoms of: 
− Hepatic injury or decompensation 
− Intercurrent illness and/or potential adverse events (Appendix C) 
• Conduct physical exam 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 
• Record weight and BMI 
• Measure circumference of waist and hips 
• Perform standard 12-lead ECG 
• AUDIT, smoking habits, and caffeine consumption 
• Health-related quality of life questionnaires and health status for the assessment of 
health utilities 
• Pruritus VAS 
• Noninvasive radiological liver fibrosis measurements (TE and MRE; conducted at 
sites where device is available; MRE only in subjects enrolled prior to Version 5 of 
the protocol who had baseline MRE and not in newly enrolled subjects) 
• Perform hepatobiliary ultrasounds for HCC screening and gallbladder assessment 
• Liver biopsy (must be completed prior to dosing with investigational product at Day 1 
OLE).  When a subject completes a liver biopsy as part of the EOT visit during the 
Double-Blind Phase, and remains in the study, a second biopsy is not required at the 
Month 18 Visit.  Refer to Section 9.10.16 for guidance for subjects unable to 
complete the Month 18 biopsy due to COVID-19 restrictions. 
• Obtain blood samples for: 
− HCC screening (AFP) 
− Serum chemistry, hematology, and coagulation 
− Free fatty acids 
− Glucose and HbA1c 




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9.10.10.1. Additional Procedures at DB Month 18/OLE Day 1 Visit for Subjects 
Continuing into the OLE 
Subjects who continue into the OLE Phase after completing the procedures listed for the 
Month 18 Visit (Section 9.10.10) will undergo the following procedures: 
• Review OLE ICF and obtain signatures before performing any OLE-specific 
procedures.  The OLE ICF may be obtained as early as the Month 15 study visit in the 
Double-Blind Phase. 
• Perform EGD procedure unless data from a recent EGD (within 6 months of OLE 
Day 1) are available.  Subjects with endoscopic evidence of varices will not continue 
in the OLE Phase. 
• Subjects randomized to placebo during the DB Phase will be re-randomized to OCA 
10 mg or OCA 10 mg → 25 mg arms on OLE Day 1; the placebo subjects in the 
OCA 10 mg → 25 mg arm will receive OCA 10 mg for 3 months followed by OCA 
25 mg in the OLE, as described in Section 9.2.2.  Subjects randomized to OCA 
(10 mg or 10 mg → 25 mg dose) during the Double-Blind Phase will continue the 
treatment they were assigned. 
• Record the visit in RTSM, and dispense investigational product 
• Administer investigational product from the double-blind bottle issued at previous 
visit (collected from the subject upon arrival for this visit) with 240 mL (8 oz.) of 
water.  Instruct the subject to swallow the tablet whole; s/he must not chew, divide, or 
crush the tablet. 
• Schedule the next visit, reiterate dosing instructions and advise the subject: 
− To take the first dose of OLE investigational product the next day.  The day of the 
first dose from the OLE bottle is considered OLE Day 1. 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product on the morning of the next visit 
− To bring the investigational product bottle(s) with them to his/her next visit; s/he 
will dose at the clinic 
− To fast overnight (at least 8 hours) prior to the next visit but water is permitted. 
9.10.11. 
OLE Month 1 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and eCRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 


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• Collect used bottles of investigational product dispensed at previous visit, assess 
subject’s investigational product compliance, and perform investigational product 
accountability 
• Review and record current concomitant medications 
• Assess and record any TEAEs 
• Assess signs and symptoms of:  
− Hepatic injury or decompensation 
− Intercurrent illness and/or potential adverse events (Appendix C) 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 
• Record weight and BMI 
• Measure circumference of waist and hips 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation 
− Glucose 
− Insulin, C-Peptide, HOMA-β, and HOMA-IR 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
− Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) 
− Potential DILI management algorithm (liver biochemistry) 
• Perform a urine-based β-hCG pregnancy test for females of childbearing potential 
• Record the visit in RTSM; there is no dispensing of investigational product via 
RTSM at this visit. 
• Administer the daily dose of investigational product at the study site.  Instruct the 
subject to swallow the tablet whole with water; s/he must not chew, divide, or crush 
the tablet. 
• Return the bottle of investigational product that was dispensed to the subject at OLE 
Day 1 to continue daily dosing at home. 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− Take the investigational product at approximately the same time each day  
− NOT to take investigational product on the morning of the next visit  
− To bring the investigational product bottle(s) with them to his/her next visit; s/he 
will dose at the clinic 


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− To fast overnight (at least 8 hours) before the next visit, but water is permitted 
9.10.12. 
OLE Months 2, 3, 4, 5, 9 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and eCRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 
• Collect used bottles of investigational product dispensed at previous visit, assess 
subject’s investigational product compliance, and perform investigational product 
accountability 
• Review and record current concomitant medications  
• Assess and record any TEAEs 
• Assess signs and symptoms of:  
− Hepatic injury or decompensation 
− Intercurrent illness and/or potential adverse events (Appendix C) 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 
• Record weight and BMI 
• Measure circumference of waist and hips 
• Obtain blood samples for: 
− Serum chemistry, hematology, and coagulation 
− Glucose at Months 2, 3, 4, 5, and 9 and HbA1c at Months 3 and 9 
− Lipoprotein analysis (Month 2 and Month 5 only) 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
− Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) 
− Noninvasive panel of liver fibrosis (ELF and Fibrometer) (Month 3 only) 
− Potential DILI management algorithm (liver biochemistry) 
• Perform a urine-based β-hCG pregnancy test for females of childbearing potential 
• Record the visit in RTSM and 
− Dispense a new bottle of investigational product (Month 3 and 9). 


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− Return the bottle of investigational product that was previously dispensed to the 
subject to continue daily dosing at home (Months 2, 4 and 5). 
• Administer the daily dose of investigational product at the study site.  Instruct the 
subject to swallow the tablet whole with water; s/he must not chew, divide, or crush 
the tablet.  
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− Take the investigational product at approximately the same time each day  
− NOT to take investigational product on the morning of the next visit  
− To bring the investigational product bottle(s) with them to his/her next visit; s/he 
will dose at the clinic 
− To fast overnight (at least 8 hours) before the next visit, but water is permitted 
9.10.13. 
OLE Month 6  
All procedures should be done before dosing.   
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and eCRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 
• Collect used bottles of investigational product dispensed at previous visit, assess 
subject’s investigational product compliance, and perform investigational product 
accountability 
• Review and record current concomitant medications  
• Assess and record any TEAEs  
• Assess signs and symptoms of: 
− Hepatic injury or decompensation 
− Intercurrent illness and/or potential adverse events (Appendix C) 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 
• Record weight and BMI  
• Measure circumference of waist and hips 
• AUDIT, smoking habits, and caffeine consumption 
• Perform hepatobiliary ultrasound for HCC screening 
• Obtain blood samples for 
− HCC screening (AFP) 


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− Serum chemistry, hematology, and coagulation  
− Free fatty acids 
− Lipoprotein analysis 
− Glucose and HbA1c 
− Insulin, C-Peptide, HOMA-β, and HOMA-IR 
− Thyroid hormones 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
− Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) 
− Noninvasive panel of liver fibrosis (ELF and Fibrometer) 
− Potential DILI management algorithm (liver biochemistry) 
• Obtain urine sample for urinalysis 
• Perform a urine-based β-hCG pregnancy test for females of childbearing potential 
• Noninvasive radiological liver fibrosis measurements (TE; conducted at sites where 
device is available;) 
• Record the visit in RTSM and dispense a new bottle of investigational product 
• Administer the daily dose of investigational product at the study site.  Instruct the 
subject to swallow the tablet whole with water; s/he must not chew, divide, or crush 
the tablet 
• Schedule the next visit, reiterate dosing instructions, and advise the subject: 
− Take the investigational product at approximately the same time each day 
− NOT to take investigational product on the morning of the next visit 
− To bring the investigational product bottle(s) with them to his/her next visit; s/he 
will dose at the clinic 
− To fast overnight (at least 8 hours) before the next visit, but water is permitted 
9.10.14. 
OLE Month 12/EOT/EOS 
• When a subject completes the OLE Month 12 Visit, the data will be recorded in the 
Month 12 and EOS eCRFs.  
• When a subject discontinues investigational product but continues with regularly 
scheduled study visits during the OLE phase, the data will be recorded as EOT 
procedures in the eCRF and the subject’s final study visit will be recorded as EOS 
procedures in the eCRF.  The EOT visit procedures listed below must be performed 


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as close as possible to the subject’s last dose of investigational product.  Subsequent 
study visit data will be recorded in the visit-specific eCRF. 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and eCRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 
• Collect used bottles of investigational product dispensed at previous visit, assess 
subject’s investigational product compliance, and perform investigational product 
accountability  
• Review and record current concomitant medications  
• Assess and record any TEAEs  
• Assess signs and symptoms of: 
− Hepatic injury or decompensation 
− Intercurrent illness and/or potential adverse events (Appendix C) 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 
• Record weight and BMI 
• Measure circumference of waist and hips 
• Conduct physical exam 
• Perform standard 12-lead ECG  
• AUDIT, smoking habits, and caffeine consumption 
• Perform hepatobiliary ultrasound for HCC screening 
• Obtain blood samples for: 
− HCC screening (AFP) 
− Serum chemistry, hematology, and coagulation 
− Free fatty acids 
− Lipoprotein analysis 
− Glucose and HbA1c 
− Insulin, C-Peptide, HOMA-β, and HOMA-IR 
− Thyroid hormones 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 


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− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
− Cardiovascular risk scores (10-year ASCVD Risk, FRS, Reynolds score, and 
SCORE) 
− Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) 
− Noninvasive panel of liver fibrosis (ELF and Fibrometer) 
− Potential DILI management algorithm (liver biochemistry) 
• Obtain urine sample for urinalysis 
• Perform a urine-based β-hCG pregnancy test for females of childbearing potential 
• Noninvasive radiological liver fibrosis measurements (TE; conducted at sites where 
device is available) 
• Liver biopsy (optional) 
9.10.15. 
Early Termination Procedures  
Early Termination procedures will be required whenever a subject discontinues treatment with 
investigational product and will not continue with regularly scheduled study visits.  The ET visit 
and procedures listed below must be performed as close as possible to the subject’s last dose of 
investigational product. 
The data will be recorded as EOS procedures in the eCRF. 
Early Termination procedures for subjects who discontinue during Double-Blind or 
OLE Phase are as follows: 
• Verify that the subject has fasted for at least 8 hours 
− Record fasting status in the source and eCRF 
− If the subject reports having eaten within 8 hours, document accordingly in the 
source and eCRF and remind the subject that fasting is required before all study 
visits 
• Collect used bottles of investigational product, assess subject’s investigational 
product compliance, and perform investigational product accountability 
• Review and record current concomitant medications 
• Assess and record any TEAEs 
• Assess signs and symptoms of 
− Hepatic injury or decompensation 
− Intercurrent illness and/or potential adverse events (Appendix C) 
• Conduct physical exam 
• Record vital signs (body temperature, sitting heart rate, respiratory rate, and seated 
blood pressure after sitting 3 minutes) 


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• Record weight and BMI 
• Measure circumference of waist and hips 
• Perform standard 12-lead ECG 
• AUDIT, smoking habits, and caffeine consumption 
• Perform hepatobiliary ultrasounds for HCC screening 
• Obtain blood samples for 
− HCC screening (AFP) 
− Serum chemistry, hematology, and coagulation  
− Free fatty acids 
− Thyroid hormones 
− Glucose and HbA1c 
− Insulin, C-Peptide, HOMA-β, and HOMA-IR 
• Calculations will be performed by the Sponsor or designee for: 
− MELD Score 
− CP Score/Class (assessment of ascites and hepatic encephalopathy is required) 
− Cardiovascular risk scores (10-year ASCVD Risk, FRS, Reynolds score, and 
SCORE) 
− Potential DILI management algorithm (liver biochemistry) 
• Obtain urine sample for urinalysis 
• Perform a urine-based β-hCG pregnancy test for females of childbearing potential 
• Liver biopsy (optional) 
The following Early Termination procedures will be performed only in Double-Blind 
Phase: 
• Health-related quality of life questionnaires (eg, patient reported outcomes) and 
health status for the assessment of health utilities (eg, healthcare resource use) 
• Pruritus VAS 
• Noninvasive radiological liver fibrosis measurements (TE and MRE; conducted at 
sites where device is available; MRE only in subjects enrolled prior to Version 5 of 
the protocol who had baseline MRE and not in newly enrolled subjects) 
• Obtain blood samples for 
− Lipoprotein analysis 
− Markers of inflammation, apoptosis, and necrosis 
− Trough PK assessment (all subjects) 


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− PD assessments (all subjects) 
− Exploratory biomarkers of disease severity 
• Calculations will be performed by the Sponsor or designee for: 
− Noninvasive panel of liver fibrosis (ELF and FibroMeter) 
− Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) 
9.10.16. 
Unscheduled Safety Visit 
The Investigator may schedule an at-clinic Unscheduled/Safety Visit at any time if clinically 
warranted.  Unscheduled and/or repeat assessments, including additional laboratory tests or 
investigations, may be conducted.  As appropriate, the Medical Monitor should be contacted. 
Additionally, all subjects who were unable to complete the liver biopsy at the Month 18 Visit 
due to the restrictions from the COVID-19 pandemic, regardless of whether they received 
additional supply of investigational product or not as described in Section 9.3, are to return to the 
site for an unscheduled visit to complete the liver biopsy as soon as practical following 
lifting/easing of the COVID-19 restrictions.  At this unscheduled visit, the types of 
procedures/assessments required to be performed, in addition to the liver biopsy, are the 
following: 
• If this unscheduled visit occurs more than 6 weeks since the original Month 18 Visit, 
then all Month 18 study visit procedures are to be performed, including but not 
limited to procedures that could not be performed at Month 18 due to COVID-19 
restrictions. 
• If this unscheduled visit occurs within 6 weeks since the original Month 18 Visit, then 
only the assessments that could not be obtained at the Month 18 Visit and recording 
of any AEs and concomitant medications are to be completed.   
• In addition, for any subject who wishes to enroll in the OLE phase, safety laboratory 
tests (refer to Table 2) as well as any additional assessments required to determine 
eligibility for the OLE (including EGD) are to be completed. 
10. 
STUDY MANAGEMENT DURING COVID-19 
The COVID-19 infection control measures that have been imposed by local and national 
governments to contain the COVID-19 pandemic have resulted in some study sites not being 
able to perform protocol-specified procedures and assessments such as collecting laboratory 
samples.  In addition, some subjects are unable to return to study sites for evaluations and/or to 
receive continued supply of investigational product.  Enforcement of many restrictions by local 
authorities have also affected the site monitor’s ability to perform on-site monitoring during the 
pandemic.   
This section describes the processes under which subjects who are unable or unwilling to return 
to study sites may complete protocol-specified assessments and continue to receive 
investigational product until in-person site visits can resume.  To ensure the continued safety 
monitoring of the participating subject and to minimize the potential adverse impact on 
achieving the objectives of the study due to the restrictions from the COVID-19 pandemic, the 


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following approaches may be applied to the study protocol.  Investigators should document the 
reason for any contingency measures implemented and how restrictions related to COVID-19 led 
to the changes in study conduct, duration of those changes, and how those study participants 
were impacted. 
10.1. 
Alternative Approaches for Study Conduct Due to COVID-19  
For subjects who are unable to attend in-person study visits due to national or local restrictions, 
the following alternative options are deemed acceptable, upon required Ethic Committee or 
Regulatory Agency approval, to satisfy the requirements for continued supply of investigational 
product:   
• Subject Consent:  If re-consent is necessary alternative ways of obtaining re-consent 
should be considered, including obtaining oral consent via phone or video-call 
supplemented with e-mail confirmation.  If the technology is available, then 
electronic methods of obtaining informed consent such as DocuSign® would also be 
considered.  
• Subject Assessment:  In place of in-person visits, assessment of subjects may be 
performed using a "virtual visit" including phone consultation, or video 
(telemedicine) visits by authorized investigators to undertake examinations on the 
study.  All assessments should adhere as closely as possible to the visit windows 
specified in the protocol schedule of visits.  In case this is not possible, please discuss 
with the Medical Monitor or Sponsor. 
• Laboratory Tests:  If central laboratory testing cannot be performed at the study site 
or via homecare visits, every attempt should be made to perform the protocol-
required tests at a local laboratory.  The results and reference ranges of all laboratory 
tests are to be sent to the Investigator and entered in to the eCRF.  Note: 
Investigational product can only be dispensed if central or local laboratory values 
are available.  
− Minimum testing required to support the protocol:  
o Liver safety labs:  Direct and Total bilirubin; AST, ALT, ALP, GGT, INR, 
platelet count, sodium, albumin and creatinine.   
o Non-Liver safety labs:  CBC & Diff; standard electrolytes (sodium & 
potassium only), lipid panel, fasting blood glucose, and urine-based β-hCG 
pregnancy test. 
• Investigational Product Distribution:  Investigational product may be sent directly to 
the subject from either the study site or a third-party vendor via a courier service if 
subjects are not able to attend study site visits.  Direct shipment of investigational 
product from the Investigator site to subjects must adhere to the site’s institutional 
and pharmacy procedures and country specific requirements.  If the Investigator is 
unable to evaluate safety and tolerability and assess the benefit-risk for the individual 
subject, the subject must interrupt investigational product until the assessment can be 
completed. 


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• Home Visits:  If laboratory tests cannot be obtained from local laboratories, qualified 
home nursing support (where available and permitted) is an accepted option that may 
be employed to supplement telemedicine interactions to enable for the collection and 
processing of blood samples for laboratory tests including PK and PD samples, if 
required, and conduct other limited assessments (eg, assessment of vital signs, 
completion of protocol required subject questionnaires).   
• Monitoring:  Cancelling or postponing of on-site monitoring visits and extension of 
the period between monitoring visits may occur per specific local guidelines and 
regulations.  Alternatively, additional off-site monitoring activities such as phone 
calls, video visits, emails may be used to discuss the trial with the Investigator and 
site staff.  Remote source verification also may be performed if it is permissible by 
the local regulations. 
Any other alternative procedures or assessments not listed above must be discussed with the 
Medical Monitor and documented by the Investigator, maintain subject participant confidentiality 
and be compliant with HIPPA/GDPR and 21 CFR Part 11 guidance. 
In addition to regularly collected trial data, available COVID-19 related data such as COVID-19 
testing will also be collected for all subjects.  Any subject that contracts the SARS-CoV-2 virus 
should have this reported as an adverse event under the description “COVID-19” per MedDRA 
23.1.  If a subject is hospitalized for COVID-19 complications an SAE should be reported in 
accordance with the protocol and national requirements.   
COVID-19 Vaccine 
COVID-19 vaccination (with vaccines approved for emergency use in the country where you 
practice) is allowable for participants enrolled in Intercept-sponsored PBC and NASH clinical 
trials.  Of note, as the currently approved COVID-19 vaccines have not been specifically tested 
in the NASH or PBC subject population, nor in the pediatric population suffering from biliary 
atresia (BA), there are no safety data available specific to the use of COVID-19 vaccines in PBC, 
NASH subjects or in children suffering from BA. 
If a subject receives a COVID-19 vaccination, the date(s) of vaccination(s), vaccine name, and 
manufacturer should be recorded as a concomitant medication for each dose. 
11. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
11.1. 
Investigational Product 
Investigational Product will be supplied as white, round, film-coated tablets containing OCA 
10 mg, OCA 25 mg, or placebo.  All tablets will be debossed with “INT” on one side and “3547” 
on the other side, and will be of the same size and appearance.  The tablets contain the following 
inactive ingredients:  microcrystalline cellulose, sodium starch glycolate, and magnesium 
stearate.  The 25-mg tablet also contains silicon dioxide.  The investigational product tablets will 
be provided in high-density polyethylene bottles with a heat induction seal and child-resistant 
closures.  All investigational product will be manufactured according to Good Manufacturing 
Practice. 


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11.2. 
Investigational Product Packaging and Labeling 
11.2.1. 
Double-Blind Phase 
The packaging and labeling of investigational product supplies will be performed according to 
Good Manufacturing Practice standards by a designated qualified vendor.  All investigational 
product for the Double-Blind Phase will be provided as tablets for oral administration and 
provided in high-density polyethylene bottles with heat induction seals and child resistant 
closures, containing 100 tablets.  The bottle packaging will not reveal any information about the 
treatment dose contained in the bottle.  Multiple bottles may be dispensed to the subject 
according to the visit schedule in Table 1 to provide enough tablets for daily dosing until the next 
time investigational product is dispensed. 
The designated investigational product packaging/distribution vendor will also be responsible for 
the distribution of the investigational product to the clinical sites. 
11.2.2. 
OLE Phase 
The packaging and labeling of investigational product supplies will be performed according to 
Good Manufacturing Practice standards by a designated qualified vendor.  All investigational 
product for the OLE Phase will be provided as tablets for oral administration and provided in 
high-density polyethylene bottles with heat induction seals and child resistant closures, 
containing 100 tablets.  Multiple bottles may be dispensed to the subject according to the visit 
schedule in Table 2 to provide enough tablets for daily dosing until the next time investigational 
product is dispensed. 
The designated investigational product packaging/distribution vendor will also be responsible for 
the distribution of the investigational product to the clinical sites. 
11.3. 
Investigational Product Storage 
Investigational product should be stored in the containers in which they are received from the 
Sponsor’s supplier, at 15°C to 25°C. 
11.4. 
Investigational Product Administration 
Refer to Section 9.1 and Section 9.2. 
11.5. 
Investigational Product Accountability and Disposal 
The Sponsor’s representative will send investigational product to the study site under appropriate 
storage conditions.  All shipments of investigational product should be unpacked and the 
contents reviewed immediately upon receipt.  If it is not possible to verify the contents 
immediately, they must be stored under the appropriate storage conditions until verification of 
the contents is possible (ideally, within 1 business day from receipt).  The pharmacist or designee 
should verify the investigational product against the shipment documentation.  The pharmacist or 
designee should contact the Sponsor immediately to report any concerns regarding the shipment. 
All investigational product will be provided for use only in this study and is not to be used for 
any other purpose.  The Investigator or designee will maintain a full record of investigational 








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13. 
EFFICACY ASSESSMENTS 
The assessments supporting the efficacy analyses are as follows: 
13.1. 
Liver Biopsies 
Given that historical biopsies are to be obtained no more than 12 months before Day 1, slides 
should be sent for central reading at least 4 weeks before the end of the 12-month window to 
ensure that the results are available in time for Day 1. 
Liver biopsies will generally be obtained from the right lobe of the liver as described in a 
study-specific histology manual.  Liver biopsies should be performed after the hepatobiliary 
ultrasound for HCC screening.  If the initial biopsy was obtained from the left lobe, then 
subsequent biopsies must be obtained from the left lobe.  For subjects who develop potential 
clinical outcomes or liver-related clinical outcome events during the study, their continued 
participation in the study is encouraged but biopsies scheduled after the diagnosis based on 
central reading may not be required. 
13.1.1. 
Central Reading of Liver Histology 
Full instructions concerning the number and type of samples to be collected at each visit, the 
sample collection methods, sample processing, labeling, and shipping will be provided by the 
Sponsor in a study-specific histology manual.  All necessary collection supplies will be provided 
by the central laboratory and will be appropriately assembled for the specific evaluations 
required at each visit. 
All biopsy assessments will be performed centrally, including assessments of biopsies to 
determine study eligibility.  Histological presence of NASH with a fibrosis score of 4 based on 
the NASH CRN scoring system must be confirmed for study eligibility.  For each biopsy, 
fibrosis will be graded in accordance with the NASH CRN scoring system (Table 6) 
(Kleiner 2005). 
Table 6: 
NASH CRN Scoring System for Determining Eligibility and Primary 
Histological Endpoint Assessment 
NAFLD Activity Score (NAS) 
Fibrosis Staging 
Parameter 
Scoring Criteria 
Parameter 
Staging Criteria 
Steatosis 
0 = <5%  
1 = 5% - 33% 
Stage 0 
No Fibrosis 


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NAFLD Activity Score (NAS) 
Fibrosis Staging 
2 = >33% - 66%  
3 = >66%  
Lobular 
Inflammation 
0 = No Foci 
1 = <2 Foci per 200 × field  
2 = 2 - 4 Foci per 200 × field   
3 = >4 Foci per 200 × field  
Stage 1  
Stage 1a 
Stage 1b 
Stage 1c  
Perisinusoidal or Periportal 
Mild, zone 3, perisinusoidal 
Moderate, zone 3, perisinusoidal 
Portal / periportal   
Table 6: 
NASH CRN Scoring System for Determining Eligibility and Primary 
Histological Endpoint Assessment (Continued) 
NAFLD Activity Score (NAS) 
Fibrosis Staging 
Ballooning 
0 = None  
1 = Few balloon cells  
2 = Many cells / prominent ballooning  
Stage 2 
Perisinusoidal and portal / periportal 
Stage 3 
Bridging fibrosis 
Stage 4 
Cirrhosis  
Biopsy samples will be assessed for quantitative collagen in a subset of subjects as an 
exploratory objective. 
Any extra biopsy tissue may undergo additional histological evaluations such as alpha-smooth 
muscle actin or bile acid transporter analysis. 
13.2. 
Child-Pugh Assessment 
CP score will be calculated as described in Section 7.4.3.1 and according to the frequency listed 
in Table 1 (Double-Blind Phase) and Table 2 (OLE Phase). 
13.3. 
MELD Score 
MELD score will be calculated as described in Section 7.4.3.2 and according to the frequency 
listed in Table 1 (Double-Blind Phase) and Table 2 (OLE Phase). 
13.4. 
Prospective Surveillance 
HCC screening will include a hepatobiliary ultrasound and AFP assessment according to the 
schedule presented in Table 1 (Double-Blind Phase) and Table 2 (OLE Phase). 
For subjects who develop HCC during the study, HCC screening assessments for study visits 
after onset of HCC are not required.  
13.5. 
Patient-Reported Outcomes and Healthcare Resource Use 
Data will be collected to determine the effects of OCA on health-related quality of life.  
Healthcare resource use as well as a general health status assessment (for the purposes of 
generating health utilities) will be used to support subsequent cost-effectiveness analyses that are 
relevant to major health care systems around the world.  Assessments of patient-reported 
outcomes will take place during the visits indicated in Table 1. 
The following patient-reported outcomes will be used to evaluate the effects of OCA compared 
to placebo on improvements in health-related quality of life: 


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• Chronic Liver Disease Questionnaire (CLDQ-NAFLD):  The CLDQ-NAFLD is a 
modified version of the general CLDQ (Younossi 1999).  The CLDQ-NAFLD is a 
36-item validated instrument designed to measure health-related quality of life in 
patients with liver disease (Younossi 2016).  The CLDQ-NAFLD is organized into 
6 domains:  abdominal symptoms, systemic symptoms, fatigue, activity, emotional 
function, and worry.  Each question is answered on a scale from 1 (always) to 
7 (never).  Therefore, a higher score corresponds to a better quality of life while 
conversely a lower score corresponds to a worse quality of life. 
• EQ-5D-5L:  The EQ-5D-5L consists of 2 sections – the descriptive system and the 
visual analog scales (VASs).  The descriptive system is organized into 5 dimensions:  
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  Each 
dimension has 5 levels:  no problems, slight problems, moderate problems, severe 
problems, and extreme problems.  The VAS records the subject’s self-rated health on 
a 20-cm vertical, line with endpoints labelled “the best health you can imagine” and 
“the worst health you can imagine” (Herdman 2011, Oemar 2013). 
• Work Productivity and Activity Index (WPAI):  The WPAI is a validated instrument 
designed to measure impairment in work and activities.  The WPAI is organized into 
4 domains:  absenteeism, presenteesism, work productivity loss, and activity 
impairment.  WPAI outcomes are expressed as impairment percentages, with higher 
numbers indicating greater impairment and less productivity (Prasad 2004). 
Subjects will be asked to complete the questionnaires and initial and date each document.  The 
questionnaires should be filed in the subject’s study records.   
13.6. 
Noninvasive Assessments of Liver Disease 
13.6.1. 
Noninvasive Scores of Liver Fibrosis  
Noninvasive scores of liver fibrosis (NFS, FIB-4, and APRI) will be calculated according to the 
schedule presented in Table 1 (Double-Blind Phase). 
13.6.2. 
Noninvasive Panel of Liver Fibrosis Markers 
FibroMeter (Echosens, Paris, France) combines multiple values including Fibroscan TE liver 
stiffness, age, gender, weight, and blood-based biomarkers (platelets, alpha-2-macroglobulin, 
ALT, urea, GGT, AST, ferritin, glucose level, and prothrombin ratio) to quantify liver fibrosis.  
The test can be conducted by staff who are trained in the use and data interpretation of the 
diagnostic test. 
ELF (Siemens Healthcare, Tarrytown, New York, USA) combines 3 serum markers (HA, P3NP, 
and TIMP-1) to quantify liver fibrosis.  The test can be performed by staff who are trained in the 
use and data interpretation of the diagnostic test. 
Noninvasive panel of liver assessments will be performed according to the schedule presented in 
Table 1 (Double-Blind Phase). 


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13.6.3. 
Noninvasive Radiological Liver Fibrosis Measurements 
At investigational sites where the device is available, TE using the Fibroscan instrument 
(Echosens, Paris, France) and MRE, to assess liver fibrosis will be conducted by staff who are 
trained in the use and data interpretation of the device.  Assessments will be performed according 
to the schedule presented in Table 1 during the Double-Blind Phase only.  MRE will be assessed 
only in subjects enrolled prior to Version 5 of the protocol who had a baseline MRE already 
performed, not in newly enrolled subjects. 
13.7. 
Efficacy Laboratory Assessments 
Refer to Table 13 for a full list of analytes to be tested.  Laboratory assessments will be 
performed according to the schedule presented in Table 1 (Double-Blind Phase) Table 2 (OLE 
Phase). 
HOMA-β and HOMA-IR values will be calculated based on glucose and insulin concentrations. 
Laboratory analyte results may be used to calculate various cardiovascular risk and fibrosis 
measurement scores. 
14. 
CLINICAL PHARMACOLOGY ASSESSMENTS 
Subjects who receive at least one dose of OCA and have measurable plasma PK concentration 
data available will be included in the PK analysis. 
A PK blood sample should be collected in subjects who experience an SAE during the study.  
Blood samples should be collected as soon as possible after the SAE is identified but no later 
than 7 days after the onset of the SAE.  The times of the last dose of investigational product, the 
last meal, and the PK sample collection should be recorded. If a PK sample cannot be collected 
within 7 days, the reason should be recorded in the eCRF. 
14.1. 
Pharmacokinetic Blood Sampling 
Subjects may opt to provide blood samples for serial PK assessments.   
Subjects participating in serial PK assessments will provide blood samples for measurement of 
OCA and its conjugates (glyco-OCA and tauro-OCA) at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 
6 hours post-dose on Month 1, Month 4, Month 12, and Month 18. 
Subjects should be reminded to fast for at least 8 hours prior to the PK assessment; although 
water is allowed during the fasting period.  If the subject reports having eaten within the fasting 
period, this will be documented in the source and the eCRF; however, the PK assessment will 
still be conducted. 
Subjects will then receive a dose of investigational product with approximately 240 mL of water.  
Subjects should not drink additional water for 1 hour after taking the dose of investigational 
product and will remain fasted until after the 1-hour sample is collected.  A meal will be 
provided following collection of the 1-hour PK sample; the meal will be a meal replacement 
drink with nutrition information that has been submitted to and approved by the Sponsor in 
advance.  No other food or drink (water is permitted) will be allowed until after the 6-hour 
sample collection. 


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Trough PK blood samples will be obtained at Month 1, 3, 4, 6, 12, and 18 from all subjects. 
During the Double-Blind Phase: 
• Serial PK samples will be obtained at Month 1, Month 4, Month 12, and Month 18 
from subjects who agree to participate in the assessment. 
• Trough PK blood samples will be obtained from all subjects prior to dose 
administration at Months 1, 3, 4, 6, 12, 18, and ET. 
For each visit with a PK blood draw, the administration time, date, and timing with respect to 
food intake of the investigational product, as well as the last dose of investigational product 
before each visit will be recorded.  The collection date and time of each PK blood sample 
collection will also be recorded.  The acceptable windows for the PK sampling time points are 
listed in Table 7. 
Table 7: 
Acceptable Windows for Pharmacokinetic Sample Collection 
Nominal Sampling Time 
Acceptable Sampling Window 
Before investigational product administration (predose 
or trough) 
Within 30 minutes before dosing 
0.5 to 1.5 hours after investigational product dose  
±10 minutes 
2 to 2.5 hours after investigational product dose 
±20 minutes 
3 to 6 hours after investigational product dose 
±30 minutes 
14.2. 
Processing and Handling of Pharmacokinetic Samples 
Whole blood will be collected at each scheduled sample time point.  Detailed procedures for the 
collection of blood samples (including further processing into plasma), storage, and shipment 
procedures for subsequent bioanalysis will be provided to the investigational site in a separate 
document before the study is initiated. 
14.3. 
Bioanalysis 
Plasma concentrations of OCA and its conjugates (glyco-OCA and tauro-OCA) will be 
determined using a GLP validated liquid-chromatography-mass spectrometry/ mass spectrometry 
method.  A detailed description of validation information and results from the bioanalytical assay 
will be provided in separate reports.  These samples may be used for evaluation of metabolites of 
OCA, for further evaluation of the bioanalytical method, and for analyses that provide 
information on the metabolic pathways used or impacted by OCA.  These data would only be 
used for exploratory purposes and may not be included in the clinical study report. 
Total OCA will be calculated based on OCA, tauro-OCA, and glyco-OCA concentrations. 
15. 
PHARMACODYNAMIC ASSESSMENTS 
Pharmacodynamic markers will be collected during the Double-Blind Phase of the study as 
described in Table 1. 


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15.1. 
Markers for FXR Activation 
Blood samples will be collected from all subjects to measure 7α-hydroxy-4-cholesten-3-one 
(C4), fibroblast growth factor-19 (FGF-19), and plasma bile acids as described in Table 1 
(Double-Blind Phase). 
15.2. 
Markers of Inflammation, Apoptosis and Necrosis 
Blood samples will be collected from all subjects to measure analytes including high-sensitivity 
C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor- α (TNF-α), 
cytokeratin-18 neoepitope M30 (CK-18-M30), and cytokeratin-18 neoepitope M65 (CK-M-65).  
Assessments will be performed according to the schedules presented in Table 1 (Double-Blind 
Phase). 


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15.4. 
Additional Assessments 
16. 
SAFETY ASSESSMENTS 
16.1. 
Adverse Events and Serious Adverse Events 
16.1.1. 
Definitions of Adverse Events 
16.1.1.1. Adverse Event  
AEs are defined as any untoward medical occurrence associated with the use of the 
investigational product in humans, whether or not considered related to investigational product.  
An AE (also referred to an adverse experience) can be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom, or disease temporally associated with any use of 
the investigational product, without any judgment about causality and irrespective of route of 
administration, formulation, or dose, including an overdose. 
AEs include, but are not limited to:  (1) a worsening or change in nature, severity, or frequency 
of condition(s) present at the start of the study; (2) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction.  For reporting purposes, pregnancy is not 
considered an AE. 
Subjects should be questioned in a general way, without leading the subject or asking about the 
occurrence of any specific symptom.  The Investigator should attempt to establish a diagnosis of 
the event based on signs, symptoms, and/or other clinical information.  The diagnosis and not the 
individual signs/symptoms should be documented as the AE.  For example, if the underlying 
disease process is a stroke, it would not be appropriate to record the AE by describing the 
symptoms “sudden numbness, dizziness, and difficulty speaking.”  The AE medical term of 
“stroke or cerebrovascular accident” should be recorded as it more accurately describes the AE. 
Subjects should be instructed to contact the site promptly upon awareness if they develop signs 
and symptoms of potential hepatic decompensation such as:  pale-colored stools, urine color 
from pale to deep amber [dark], nausea, vomiting, abdominal pain, diarrhea, weight loss, fever 
and chills, fatigue, weakness, loss of appetite, confusion, swelling of the legs or abdomen, 
yellowing of the skin or whites of eyes, and bruising easily. 


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16.1.1.2. Treatment-Emergent Adverse Event 
A TEAE is any event not present before the initiation of the investigational product or any event 
already present that worsens in either intensity or frequency following exposure to the 
investigational product. 
16.1.1.3. Serious Adverse Event 
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
• Death 
• Is 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. 
A PK blood sample should be collected in subjects who experience an SAE during the study.  
Blood samples should be collected as soon as possible after the SAE is identified but no later 
than 7 days after the onset of the SAE.  The times of the last dose of investigational product, the 
last meal, and the PK sample collection should be recorded.  If a PK sample cannot be collected 
within 7 days, the reason should be recorded in the eCRF. 
16.1.2. 
Suspected Unexpected Serious Adverse Reaction 
A SUSAR is defined as a suspected adverse reaction that is assessed as serious, causally related 
to the investigational medicinal product, and unexpected per the reference safety information 
(RSI) in the Investigator’s Brochure.  
SUSARs are subject to expedited reporting.  The Sponsor shall ensure that all relevant 
information about SUSARs that are fatal or life-threatening are recorded and reported as soon as 
possible to the relevant competent authorities (either directly or through the Eudravigilance 
Clinical Trials Module, as applicable), and to the Ethics Committees, no later than 7 days after 
knowledge by the Sponsor of such a case.  Relevant follow-up information is subsequently 
communicated within an additional 8 days.  All other SUSARs shall be reported to the competent 
authorities concerned (either directly or through the Eudravigilance Clinical Trials Module) and 
to the Ethics Committees concerned, within a maximum of 15 days of first knowledge by the 
Sponsor.  Each competent authority shall ensure that all SUSARs to an investigational medicinal 


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product that are brought to its attention are recorded.  The Sponsor shall also inform all 
participating Investigators, as applicable to the local regulations. 
16.1.3. 
Relationship to Investigational Product 
The Investigator will document her/his opinion of the relationship of the AE to treatment with 
the investigational product using the criteria outlined in Table 8.  An AE for which there is a 
“reasonable possibility” that the investigational product caused the AE is otherwise referred to as 
suspected adverse reaction (SAR).  “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the investigational product and the AE. 
If the relationship between the AE/SAE and the investigational product is determined to be 
“definite,” “probable,” or “possible” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 
Table 8: 
Relationship of Adverse Events to Investigational Product 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product or in which the investigational product level has been established in 
body fluids or tissue; that follows a known or expected response pattern to the suspected 
investigational product; and that is confirmed by improvement on stopping or reducing the 
dosage of the investigational product, and reappearance of the reaction on repeated 
exposure. 
Probable 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product; that follows a known or expected response pattern to the suspected 
investigational product; that is confirmed by stopping or reducing the dosage of the 
investigational product; and that could not be reasonably explained by the known 
characteristics of the 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 
An event that does not follow a reasonable temporal sequence from administration of the 
investigational product; that does not follow a known or suspected response pattern to the 
suspected investigational product; and that could reasonably be explained by known 
characteristics of the subject’s clinical state. 
Not Related 
Any event that does not meet the above criteria. 
16.1.4. 
Relationship to Liver Biopsy 
The Investigator will document her/his opinion of the relationship of the AE to liver biopsy using 
the criteria outlined in Table 9.   
Table 9: 
Relationship of Adverse Events to Liver Biopsy 
Relationship 
Description 
Related 
A reaction that follows a reasonable temporal sequence from the liver biopsy; that follows 
a known or expected response pattern to the liver biopsy. 
Not Related 
Any event that does not meet the above criteria. 


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16.1.5. 
Relationship to Study Procedures 
The Investigator will document her/his opinion of the relationship of the AE to study procedures 
using the criteria outlined in Table 10. 
Table 10: 
Relationship of Adverse Events to Study Procedures 
Relationship 
Description 
Related 
A reaction that follows a reasonable temporal sequence from the
 
procedure or other study procedures; that follows a known or expected response pattern to 
the administration of cholate or collection of blood samples. 
Not Related 
Any event that does not meet the above criteria. 
16.1.6. 
Recording Adverse Event Severity 
AEs must be graded for severity (ie, intensity) using the current version of the CTCAE 
(Appendix D).  A severity category of mild, moderate, severe, life threatening, or death as 
defined in Table 11, must be entered on the AE eCRF. 
Because a grading (severity) scale is provided for each AE term and not all grades are 
appropriate for all AEs, it may be necessary to refer to (Appendix D) before grading the severity 
of an event. 
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.  When reporting AEs, reference should be made to the CTCAE 
manual for guidance on appropriate grading. 
Table 11: 
Severity of Adverse Events 
Grade 
Clinical Description of Severity 
1 = Mild 
Asymptomatic or mild symptoms, clinical or diagnostic observations only, or 
intervention not indicated.  
2 = Moderate 
Minimal, local or noninvasive intervention indicated; or limiting age-appropriate 
instrumental activities of daily living.a 
3 = Severe 
Medically significant but not immediately life-threatening, hospitalization or 
prolongation of hospitalization indicated, disabling, or limiting self-care activities of 
daily living.b 
4 = Life-threatening 
Urgent intervention indicated. 
5 = Death 
Death related to AE. 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 


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16.1.6.1. Severity of Pruritus (as an Adverse Event) 
To ensure consistency in reporting, pruritus AEs must be graded for severity (ie, intensity) using 
the current version of the CTCAE (Appendix D).  As pruritus is a subjective symptom, clinical 
judgment should be used to determine its severity and management Table 12.  
Table 12: 
Severity of Pruritus 
Pruritus 
Grade 
Clinical Description of Severity for Pruritus and Medical Intervention 
1 = Mild 
Mild or localized; topical intervention indicated. 
2 = Moderate 
Intense or widespread; intermittent; skin changes from scratching (eg, edema, 
papulation, excoriations, lichenification, oozing/crusts); oral intervention indicated; 
limiting instrumental activities of daily living. 
3 = Severe 
Intense or widespread; constant; limiting self-care activities of daily living or sleep; oral 
corticosteroid or immunosuppressive therapy indicated. 
Since pruritus is a subjective symptom and the occurrence and magnitude of which are not 
readily measured by objective tools, clinical judgment needs to be applied in the management of 
each subject.  Managing OCA-related pruritus may help improve tolerance in those subjects who 
experience problematic pruritus and may otherwise discontinue from the study prematurely.  
General guidance for the management of subjects experiencing significant pruritus includes: 
• 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).  Details of drug holidays and/or nondaily dosing regimens 
should be recorded in the eCRF.  Per Section 7.7, subjects with pruritus ≥Grade 3 in 
severity (per CTCAE) must discontinue investigational product but are encouraged to 
continue study visits. 
• Short-term use of BAS  
− Use of BAS may be considered in conjunction with a change in investigational 
product dosing frequency (ie, every other day dosing) for approximately 2 weeks.  
The subject should be evaluated after the 2-week intervention to assess the status 
of pruritus and stop the use of BAS as deemed appropriate by the Investigator.  If 
the Investigator considers that the subject can tolerate investigational product, 
daily dosing may be reinitiated.  
− If the subject cannot tolerate investigational product after stopping BAS due to 
ongoing pruritus, the Investigator should consult with the Medical Monitor to 
determine a treatment plan.  This may include continuing every other day dosing, 
interrupting or discontinuing investigational product.   
− If after 4 to 6 weeks (or up to 3 courses of a 2-week BAS therapy), the subject is 
unable to tolerate investigational product without BAS treatment, the Investigator 
should consider, in consultation with the Medical Monitor, discontinuing 
investigational product.   


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− The subject should make every effort to avoid long-term use of BAS for pruritus 
while taking investigational product.  For additional guidance on BAS refer to 
Section 9.4.3 
• Other medical therapies for the management of pruritus may be considered as deemed 
clinically appropriate and based on current practice guidelines (EASL 2017) or 
literature (Hegade 2015). 
• Less frequent dosing of investigational product (eg, on alternate days) may be tried, 
after which subjects may return to their original daily dose as soon as tolerated. 
16.1.7. 
Reporting of Adverse Events and Serious Adverse Events 
16.1.7.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
fully completes her/his study participation of the study. 
All AEs, whether believed by the Investigator to be related or unrelated to the investigational 
product, must be documented in the subject’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE eCRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product. 
In addition, the Investigator should contact the study Medical Monitor upon awareness when any 
signs or symptoms of hepatic decompensation are observed in any subject. 
Redacted medical record source documentation will be requested for all SAEs.  
16.1.7.2. 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 (including potential liver-related clinical outcome events that qualify as serious) must 
be reported to the Sponsor.  SAEs are reported by entering the SAE data into the study specific 
electronic data capture (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: 
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 
study within the time frames required by each regulatory agency. 
Following the initial report, any additional information obtained by the Investigator about the 
SAE must be reported promptly to the Sponsor in the same manner as described above for the 
initial SAE report.  Any supporting source documentation should be
s soon as possible. 
The Investigator is responsible for submitting information on IND Safety Reports/Expedited 
Safety Reports received from the Sponsor to her/his local IRB/IEC, as directed by the 
local-country requirements. 
Documentation of the submissions to IECs/IRBs must be retained in the appropriate study file(s).  
As instructed by the Sponsor, IND Safety Reports/Expedited Safety Reports should be retained 
in the appropriate investigative site study files, or with the IB. 
16.1.8. 
Potential Liver-Related Clinical Outcome Events 
Specified liver-related clinical outcome events may, by definition, qualify as SAEs (see 
Section 16.1.1.3).  The Sponsor must be notified of any SAEs within 24 hours of the site 
becoming aware of the event (see Section 16.1.7.2).  The Sponsor is responsible for regulatory 
reporting of SAEs, including expeditious reporting of SUSARs, refer to Section 16.1.2 for 
definition of SUSAR. 
16.1.9. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the EDC represent the official record of all AEs and SAEs reported 
in the study.  The Investigator should comply with requests by the Medical Monitor or other 
Sponsor personnel to record the SAE on the subject’s AE eCRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the Sponsor, the Investigator should 
provide input into the SAE narrative and provide timely information to ensure prompt follow-up 
and closure of the SAE report. 
The Investigator and supporting personnel responsible for 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. 
16.1.10. 
Notification of Post-Treatment SAEs for Subjects Who Continue in the Study 
Post-treatment SAEs that occur in subjects who remain in the study after investigational product 
has been discontinued must be reported to the Sponsor within 24 hours by following the 
instructions provided in Section 16.1.7.2. 


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16.1.11. 
Notification of Post-Study SAEs 
All SAEs that occur within 30 days following discontinuation from the study, whether or not 
they are related to the investigational product, must be reported to the Sponsor within 24 hours 
by following the instructions provided in Section 16.1.7. 
If an Investigator becomes aware of an SAE that may be attributable to the investigational 
product at any time after the end of the study, the Sponsor should be notified immediately 
(ie, within 24 hours) by following the instructions provided in Section 16.1.7. 
16.1.12. 
Follow-Up of AEs and SAEs 
All AEs must be followed during the course of the study until the AE resolves, is no longer of 
clinical concern, has stabilized or is otherwise explained, or the subject is lost to follow-up. 
AEs ongoing at the final visit that are deemed to be ‘possibly, probably, or definitely” related or 
of other clinical significance must be followed for as long as necessary to adequately evaluate 
the safety of the subject or until the event stabilizes, resolves, or is no longer of clinical concern.  
If resolved, a resolution date for the AE should be documented on the eCRF.  The Investigator 
must ensure that follow-up includes any supplemental investigations indicated to elucidate the 
nature and/or causality of the AE.  This may include additional laboratory tests or investigations, 
or consultation with other healthcare professionals, as considered clinically appropriate by the 
Investigator. 
All subjects showing possible drug-induced liver injury or disease progression should be 
followed until all abnormalities return to normal or to the baseline state.  Drug-induced liver 
injury may develop or progress even after the causative drug has been stopped.  Results should 
be recorded in the eCRF.  Note that longer follow-up can sometimes reveal an off-drug repetition 
of what had appeared to be drug-induced liver injury, indicating that liver injury was related to 
underlying liver disease. 
If a subject experiences symptoms consistent with symptomatic cholelithiasis and/or 
complications related to gallstone disease or pancreatitis, the subject should have investigational 
product interrupted while undergoing a complete evaluation for both conditions consistent with 
local standards of care.  If symptomatic cholelithiasis and/or cholecystitis is diagnosed, the 
subject should be managed and monitored as described in Section 7.5.1.   
If a subject is suspected to have acute pancreatitis or develops signs and symptoms consistent 
with acute pancreatitis, amylase and lipase levels should be monitored for 3 months after the 
onset of symptoms per local standard of care.  If treatment-emergent acute, or nonacute 
pancreatitis is diagnosed, investigational product must be discontinued, and the subject should be 
managed and monitored as described in Section 7.5.2.  The Investigator should contact the 
Medical Monitor upon awareness of pancreatitis.  Results should be recorded promptly in the 
eCRF. 


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16.1.13. 
Pregnancy and Follow-Up  
Pregnancies are not considered AEs in and of themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical study, she must interrupt treatment with 
investigational product immediately (Section 8.2.1.4) and the Sponsor must be notified within 
24 hours of the Investigator’s awareness of the pregnancy by completing the pregnancy eCRF in 
the EDC system and downloading and completing the Pregnancy Report Form.  Any rechallenge 
of the investigational product should be implemented per the criteria outlined in Table 5. 
The pregnancy Report Form must be emailed to sae@interceptpharma.com or faxed to 
1-800-497-8521. 
In the situation that the EDC is not functioning, the Medical Monitor should be notified by 
telephone.  The investigator remains responsible for entering the pregnancy information into the 
EDC when the EDC becomes functional. 
The subject and neonate must be followed for outcome information and/or as considered 
appropriate by the Investigator and the Sponsor.  The investigator should notify the Sponsor of 
the outcome of the pregnancy by completing Pregnancy Follow-up section in the EDC.  In the 
situation that the EDC is no longer available due to study closure, the outcome of the pregnancy 
should be added to the pregnancy resolution section of the downloaded Pregnancy Outcome 
Form and faxed or emailed to the Sponsor.  Thereafter, the subject and infant must be followed 
as considered appropriate by the Investigator and any new updates should be sent to the Sponsor. 
Completing the pregnancy report form in the EDC is not a substitute for reporting an AE/SAE 
when an AE/SAE has occurred.  In the situation when an AE/SAE has occurred, the AE/SAE 
reporting procedures described in Section 16.1.7 must also be followed. 
16.2. 
Other Safety Parameters 
16.2.1. 
Medical History/Demographics 
A complete medical history will be obtained from the subject at Screening.  Smoking and alcohol 
consumption history and current habits will be recorded.  Demographic characteristics (age, sex, 
race, and ethnicity) will be recorded.  Baseline pruritus by severity will be obtained on Day 1 
using the Pruritus VAS questionnaire. 
16.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the visits specified in the Schedule of Study Procedures, Table 1 (Double-Blind Phase) and 
Table 2 (OLE Phase).  A basic physical examination should be performed, including all body 
systems pertinent to the subject.  Any clinically significant abnormality should be reported on the 
AE eCRF page. 
The physical examination must include the following:  
• General appearance 
• Skin 
• Head, eyes, ears, nose, and throat  


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• Neck 
• Lymph nodes 
• Chest/Respiratory system 
• Cardiovascular system 
• Abdominal region 
• Extremities 
• Musculoskeletal system 
• Mental status 
• Neurological system 
16.2.3. 
Vital Signs 
Vital signs will be assessed at the visits as specified in Table 1 (Double-Blind Phase) and Table 2 
(OLE Phase): temperature, sitting heart rate, respiratory rate, and seated blood pressure after 
sitting 3 minutes.  When taking heart rate, respiratory rate and blood pressure readings, subjects 
should be seated quietly for a minimum of 3 minutes before the readings are taken. 
16.2.4. 
Electrocardiogram  
Standard 12-lead ECGs will be collected as specified in Table 1 (Double-Blind Phase) and 
Table 2 (OLE Phase). 
All ECGs should be performed before blood draws.  12-lead ECG results will be reviewed by the 
Investigator or designee and findings will be recorded in the eCRF as normal, abnormal but not 
clinically significant, or abnormal and clinically significant.  Any clinically significant 
abnormality on ECGs should be reported on the AE eCRF page. 
Investigative sites must retain a copy of all 12-lead ECGs.  These ECGs must be clearly labeled 
with the Subject ID number, date, and time.  Full instructions will be provided for forwarding the 
12-lead ECGs for central reading. 
16.2.5. 
Alcohol Consumption, Smoking Habits, and Caffeine Consumption 
Information about the subject’s alcohol consumption, smoking habits, and caffeine consumption 
will be collected during the visits indicated in Table 1 (Double-Blind Phase) and Table 2 
(OLE Phase) using the AUDIT, smoking habits, and caffeine consumption eCRFs.  AUDIT is a 
10-item questionnaire that uses the domains of alcohol consumption, drinking behavior, and 
alcohol-related problems (Saunders 1993). 
16.2.6. 
Cardiovascular Risk Scores 
Cardiovascular risk scores (10-year ASCVD Risk, FRS, Reynolds score, and SCORE) will be 
calculated according to Table 1 (Double-Blind Phase) and Table 2 (OLE Phase). 


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16.2.7. 
Laboratory Assessments 
Except for Screening, subjects will be instructed to attend each study visit in a fasted state, 
preferably in the morning, and subjects should remain fasted until their blood samples have been 
collected.  For visits that require fasting, the Investigator or designee will verify that the subject 
has fasted for at least 8 hours and record fasting status in the source and eCRF.  If the subject 
reports having eaten (water is permitted) within 8 hours, the Investigator or designee will 
document accordingly in the source and eCRF and remind the subject that fasting is required 
before all study visits. 
Blood and urine samples for laboratory assessments will be collected at the visits specified in 
Table 1 (Double-Blind Phase) and Table 2 (OLE Phase).  Full instructions concerning the 
number and type of samples to be collected at each visit, the required sample volumes, sample 
collection methods, sample processing, labeling, and shipping will be provided in a separate 
procedural manual.  All necessary collection supplies will be provided by the central laboratory 
and will be appropriately assembled for the specific evaluations required at each visit. 
If a subject cannot return to the clinic for a scheduled or unscheduled visit, or there is an event 
that triggers a need for an immediate assessment, the use of a local laboratory is required.  In 
these cases, the Investigator will obtain the laboratory results and the laboratory normal ranges.  
All local laboratory data, including the reference ranges, are to be collected and entered in the 
eCRF within 2 days of receiving the results.  For guidance on alternative processes under which 
subjects may complete the protocol-specified assessments under COVID-19 restrictions refer to 
Section 10. 
All subjects with laboratory tests containing clinically significant abnormal values are to be 
followed regularly until the values return to normal ranges; until a valid reason, other than 
investigational product related AE, is identified; or until further follow-up is deemed medically 
unnecessary.   
The Investigator should proactively monitor and manage lipid levels in all subjects as indicated 
via appropriate medical interventions (eg, statins).  Recent guidelines stress the importance of 
evaluating ASCVD risk in all subjects to help guide decisions in recommending therapies and 
reducing LDLc to reduce the risk and prevent onset or recurrence of ASCVD (refer to 
Section 9.4.5 and Appendix A. 
Urine based β-hCG pregnancy tests will be performed in female subjects of childbearing 
potential per protocol specified visits (Table 1) [Double-Blind Phase] and Table 2 [OLE Phase]).  
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 16.1.13 until pregnancy outcome. 
An assessment of steady-state exposures (on an aggregate level) will be performed by an internal 
Intercept clinical pharmacologist/pharmacometrician or designee who is discrete from the study 
team.  These results may be made available to the DMC as appropriate (see Section 17.13). 
The list of laboratory analytes to be tested is shown in Table 13. 




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AFP = alpha-fetoprotein; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ApoA-1 = apolipoprotein 
A-1; ApoB = apolipoprotein B; ApoE = apolipoprotein E; APRI = aspartate aminotransferase to platelet ratio 
index; ASCVD = atherosclerotic cardiovascular disease; AST = aspartate aminotransferase; aPTT = partial 
thromboplastin time; β-hCG = beta human chorionic gonadotropin; BUN = blood urea nitrogen; C4 = 7α-hydroxy-
4-cholesten-3-one; CHI3L1= chitinase 3-like protein 1; CK-18-M30 = cytokeratin-18 neoepitope M30; 
CK-18-M65 = cytokeratin-18 neoepitope M65; eGFR = estimated glomerular filtration rate; ELF = Enhanced 
Liver Fibrosis; FIB-4 = Fibrosis-4; GGT = gamma-glutamyl transferase; FGF-19 = fibroblast growth factor 19; 
FRS = Framingham Risk Score; glyco-OCA = glycine conjugate of obeticholic acid; HA = hyaluronic acid; HbA1c = 
hemoglobin-specific A1c fraction; HBsAg = hepatitis B surface antigen; HCC = hepatocellular carcinoma; HCV = 
hepatitis C virus; HDL = high-density lipoprotein; HOMA-β = homeostatic model assessment – beta cell; HOMA-
IR = homeostatic model assessment – insulin resistance; hs-CRP = high-sensitivity C-reactive protein; 
IL-6 = interleukin-6; INR = international normalized ratio; LDL = low-density lipoprotein; Lp(a) = lipoprotein(a); 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; NASH = nonalcoholic steatohepatitis; NFS = NAFLD fibrosis score; OCA = obeticholic acid; 
OLE = open-label extension; PD = pharmacodynamics; PCSK9 = proprotein convertase subtilisin/kexin type 9; 
P3NP = procollagen III amino terminal peptide; PK = pharmacokinetic; PT = prothrombin time; SCORE = systemic 
coronary risk evaluation; T3 = triiodothyronine; T4 = thyroxine; tauro-OCA = taurine conjugate of obeticholic acid; 
TIMP-1 = tissue inhibitor of metalloproteinase 1; TNF-α = tumor necrosis factor-α; TSH = thyroid-stimulating 
hormone; US = United States; VLDL = very low-density lipoprotein 
a Overlapping analytes will be analyzed only once. 
16.2.8. 
Pruritus Assessment 
Pruritus Visual Analog Scale (VAS):  The pruritus VAS will be used to assess a subject’s 
experience and severity of pruritus.  This assessment should be captured on the blue pad. 
17. 
STATISTICS 
A detailed statistical analysis plan (SAP), providing details about the specific planned analyses 
and hypothesis tests, will be prepared and approved by the Sponsor and its designees.  A separate 
clinical pharmacology analysis plan will be prepared, providing details of PK analysis methods 
and parameter estimation.  PK/PD analytical methods will be detailed in a separate modeling and 
simulations plan, and all results will be documented separate from the clinical study report.  
Details about these specific planned analyses will be prepared and approved by the Sponsor or its 
designees prior to study database lock. 
17.1. 
Analysis Populations 
• Intent-to-Treat (ITT) Population will include all randomized subjects.  The ITT 
Population will be the primary population used for efficacy analyses.  Treatment 
assignment will be based on the randomized treatment. 
• Modified ITT Population (mITT) will include all ITT subjects except those who are 
not eligible to dose titrate due to safety or tolerability reasons.  Treatment assignment 
will be based on the randomized treatment. 
• The Per Protocol (PP) Population will include all mITT subjects who do not have any 
major protocol violations that potentially affect the efficacy conclusions.  Treatment 
assignment will be based on the randomized treatment.   
• The Safety Population will include all randomized subjects who receive at least 
1 dose of investigational product (OCA or placebo).  The Safety Population will be 


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the primary population used for safety analyses.  Treatment assignment will be based 
on the treatment actually received. 
• The PK Population will consist of all subjects who receive OCA, have at least one 
confirmed analyzable sample, and have no major protocol deviations that may 
potentially affect the PK analysis.  The final determination of subjects included in the 
PK Population and the samples included in the analysis will be determined based on a 
review of data before database lock.  The PK population will be the population used 
for OCA PK and PK/PD analyses. 
Additional analysis population (if any) will be specified in the SAP. 
17.2. 
Determination of Sample Size 
A sample size of 300 subjects per group will provide at least 90% power to detect a statistically 
significant treatment difference of 10% between OCA 25 mg and placebo groups based on a 
Chi-square test with 2-sided type I error at 0.05 level, assuming a responder rate of 10% in the 
placebo group.  As there was no previous study performed using the same endpoint in this 
disease, the assumption was determined based on data from literature, and results from the 
FLINT study and Study 747-303. 
17.3. 
Primary Efficacy Analysis 
The primary efficacy analysis will be conducted using the ITT population and test the following 
hypotheses: 
• H01:  The percentage of subjects with fibrosis improvement by at least 1 stage and no 
worsening of NASH defined as no increase in hepatocellular ballooning or lobular 
inflammation using the NASH CRN scoring system, from Baseline to the end of the 
Double-Blind Phase is equal between placebo and OCA 10 to 25 mg titration. 
• H11:  The percentage of subjects with fibrosis improvement by at least 1 stage and no 
worsening of NASH defined as no increase in hepatocellular ballooning or lobular 
inflammation using the NASH CRN scoring system, from Baseline to the end of the 
Double-Blind Phase is different between placebo and OCA 10 to 25 mg titration.  
• H02:  The percentage of subjects with fibrosis improvement by at least 1 stage and no 
worsening of NASH defined as no increase in hepatocellular ballooning or lobular 
inflammation using the NASH CRN scoring system, from Baseline to the end of the 
Double-Blind Phase is equal between placebo and OCA 10 mg. 
• H12:  The percentage of subjects with fibrosis improvement by at least 1 stage and no 
worsening of NASH defined as no increase in hepatocellular ballooning or lobular 
inflammation using the NASH CRN scoring system, from Baseline to the end of the 
Double-Blind Phase is different between placebo and OCA 10 mg. 
The overall type I error for primary efficacy analysis will be controlled at 0.05.  The primary 
analysis between placebo and OCA 10 to 25 mg titration will be tested first at 5% alpha and the 
hypothesis (H02) between placebo and OCA 10 mg will be tested if the null hypothesis (H01) 
between placebo and OCA 10 to 25 mg titration is rejected at 5% level. 


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For the comparison of the primary efficacy endpoint, a Cochran-Mantel-Haenszel (CMH) test 
stratified by the randomization strata (presence of type 2 diabetes at enrollment [yes/no] will be 
performed.  Additional details regarding analyses with missing values will be provided in the 
SAP.  
Analyses of the primary endpoint will be conducted using the mITT and PP populations and a 
sensitivity analysis will be conducted in the Month 18 biopsy-only population. 
17.4. 
Secondary Efficacy Analyses 
Secondary efficacy analyses will be conducted using mITT and PP populations. 
17.4.1. 
Histology Endpoints 
The following secondary efficacy endpoints will be analyzed: 
• Percentage of subjects with resolution of NASH defined as overall histopathological 
interpretation of 1) “no fatty liver disease” or 2) “fatty liver disease (simple or 
isolated steatosis) without steatohepatitis” as characterized/quantified by a NAS of 0 
for ballooning and 0-1 for inflammation, using the NASH CRN scoring system, at the 
end of the Double-Blind Phase 
• Percentage of subjects with resolution of NASH based on pathologist’s overall 
histopathologic interpretation of the presence or absence of definite NASH at the end 
of the Double-Blind Phase 
• Histological changes in fibrosis status including: (1) improvement, or (2) no change, 
from Baseline to the end of the Double-Blind Phase using the NASH CRN scoring 
system 
Responder endpoints will be analyzed using a CMH test stratified by the randomization strata 
(presence of type 2 diabetes at enrollment [yes/no]).   
Overall shift and frequency tables will be presented for NAS components and fibrosis scores 
(according to NASH CRN criteria). 
17.4.2. 
Clinical Outcomes 
Analyses of the clinical outcomes composite endpoint and occurrence of HCC will evaluate the 
effect of OCA (10 mg and 25 mg) compared to placebo.  Treatment groups will be compared on 
the percentage of subjects who reported any of the following adjudicated events, as well as the 
time to first occurrence:   
• Death (all cause) 
• MELD score ≥15 
• Liver transplant 
• Worsening of CP score by at least 2 points 
• Hospitalization (as defined by a stay of ≥24 hours) for onset of: 
o Variceal bleed 


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o Hepatic encephalopathy (as defined by a West Haven score of ≥2) 
o Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
• Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or 
paracentesis) 
• HCC (as confirmed by 2 complementary imaging modalities unless already 
confirmed by biopsy) will be analyzed as a separate outcome event.   
Only adjudicated events will be included in analyses.  Subjects with none of these events will be 
censored at the date of last contact.  For the analysis of time to first occurrence of adjudicated 
events, a log rank test stratified by the randomization stratification factor (presence of type 2 
diabetes at enrollment [yes/no]) will be used.  Kaplan-Meier (KM) estimates of the distribution 
of the time-to-event will be tabulated and graphed by treatment group.  The tabulation will 
include the KM estimate of the medians and corresponding 95% confidence intervals (CIs), if the 
medians can be estimated.  The number and percent of subjects censored and with events will be 
presented.  The hazard ratio and 95% CI will be determined based on a Cox regression model 
stratified by randomization strata to estimate the magnitude of the effect.  Subjects without any 
documentation of events will be censored at the date of last contact by the end of the Double-
Blind Phase. 
In addition, treatment groups will be compared on each component of the outcome events. 
The percentage of subjects who reported any adjudicated events will be analyzed using a CMH 
test stratified by the randomization strata (presence of type 2 diabetes at enrollment [yes/no]).  
Percentage of subjects who reported each component of the outcome events will also be analyzed 
separately in a similar manner. 


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17.9. 
Handling of Missing Data 
Subjects who discontinue investigational product are expected to continue in the study until 
study termination. 
In order to determine the effect of missing data on the analysis, efficacy endpoints will be 
analyzed using different methods of imputation as described below. 
17.9.1. 
Time-to-Event Endpoints 
For the time-to-event analyses, subjects who do not experience an event will be censored at the 
time of their last contact.   
All time-to-event endpoints include only adjudicated events.  Sensitivity analyses may consider 
all events regardless of adjudication.  Events with discrepant adjudication will be analyzed using 
both results. 


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17.9.2. 
Quantitative Endpoints 
For exploratory efficacy endpoints utilizing an ANCOVA model or the Wilcoxon Rank Sum 
Test, observed cases will serve as the primary analysis.  Sensitivity analyses to assess the effect 
of missing data may be conducted where missing data is imputed using last observation carried 
forward.  The last on-treatment value, scheduled or unscheduled, will be carried forward to the 
missing timepoint. 
Sensitivity analyses of ANCOVA models for exploratory efficacy endpoints will also be 
evaluated using a restricted maximum likelihood based mixed-effect repeated measures model 
where no imputations will be made for missing values. 
17.9.3. 
Responder Endpoints 
For the primary analyses, in which subjects are classified as either a responder or a non-
responder (binary outcome), any subject who does not provide an assessment at the specified 
timepoint for the defining of response will be considered to be a non-responder.  That is, for the 
percentage of responders, the subject will be included in the denominator and will not contribute 
to the numerator.  Additional details regarding the secondary histological endpoints are provided 
in the SAP. 
An “observed cases” analyses will also be conducted as sensitivity analyses, excluding those 
subjects who do not provide an assessment at the specified timepoint for the defining of 
response.  That is, for the percentage of responders, the subject will not be included in the 
numerator or the denominator. 
17.9.4. 
Incidence Endpoints 
For the analyses of the percentage of subjects who reported any of the adjudicated clinical 
outcome events or adjudicated cardiovascular events, all subjects, regardless of whether one has 
reported any adjudicated events will be included in the denominator, and only subjects with 
adjudicated events will contribute to the numerator.  This represents the proportion of subjects 
experiencing events to number of subjects at risk. 
Sensitivity analyses may consider all events regardless of adjudication.  Events with discrepant 
adjudication will be analyzed using both results. 


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17.11. 
Safety Analyses 
Safety evaluations will comprise treatment-emergent AEs, AEs of special interest (including 
cardiovascular, pruritus, renal, urinary tracts stones including nephrolithiasis, 
gallbladder/gallstone-related, pancreatitis, hepatic, dyslipidemia and hyperglycemia/new-onset 
diabetes mellitus AEs), adjudicated CV events, adjudicated AKI events, adjudicated events of 
hepatic injury, vital signs, electrocardiograms (ECGs), pruritus VAS, and clinical laboratory 
results. 
Safety data will be summarized by treatment group using the Safety Population. 
17.11.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Summary tables of treatment-emergent AEs will be provided.  The incidence of TEAEs will be 
tabulated by system organ class and preferred term for each treatment group, and by severity and 
relationship to treatment.  Summaries of TEAEs leading to investigational product 
discontinuation and SAEs will be provided. 
Adverse events of special interest, to be specified in the SAP, will be summarized for each 
treatment group. 
17.11.2. 
Hepatic and Renal Safety Adjudication 
Potential events of hepatic injury and AKI will be adjudicated during the study (Section 17.14).  
The adjudication of the events of hepatic injury will be separate from the adjudication of events 
for the assessment of outcomes in this study.  The adjudication of potential events of hepatic 
injury and AKI will be further defined in the HSAC charter and the Renal Adjudication 
Committee charter, respectively. 
17.11.3. 
Cardiovascular Event Adjudication 
Specific details of the events that will be adjudicated by the Cardiovascular Adjudication 
Committee are described in the respective adjudication charters.  Any changes to either the 
adjudication process or changes to specific events to be adjudicated will be addressed in the 
charters and will be communicated to all study sites. 
Adjudicated cardiovascular events include core MACE (cardiovascular death, nonfatal 
myocardial infarction, and nonfatal stroke) and expanded MACE (unstable angina requiring 
hospitalization, transient ischemic attack, peripheral or coronary revascularization procedures, 
hospitalization for congestive heart failure and arrhythmias).  Any hospitalization (≥24 hours) 
where a cause has not been identified by the Investigator will be considered as a cardiovascular 
event and sent for adjudication.  Other events potentially related to adverse cardiovascular 
outcomes are defined in Appendix E and will be included in the Cardiovascular Adjudication 
Committee Charter for adjudication.   
Summaries of adjudicated cardiovascular events will include the incidence of TEAEs, the 
incidence of serious TEAEs, and a time-to-event analysis as described below.  All summaries of 
incidence will include the associated exact binomial 95% CI. 


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The time-to-event endpoints include: 
• Time from randomization to the first confirmed occurrence of cardiovascular death, 
nonfatal myocardial infarction, nonfatal stroke, or nonfatal unstable angina requiring 
hospitalization 
• Time from randomization to the confirmed occurrence of cardiovascular death 
(including fatal myocardial infarction, fatal stroke) 
• Time from randomization to the first confirmed occurrence of myocardial infarction 
(nonfatal or fatal) 
• Time from randomization to the first confirmed occurrence of stroke (nonfatal or 
fatal) 
• Time from randomization to the confirmed occurrence of death from any cause 
• Time from randomization to the first confirmed occurrence of unstable angina 
requiring hospitalization (nonfatal or fatal) 
• Time from randomization to the first occurrence of coronary revascularization 
procedure 
• Time from randomization to the first occurrence of hospitalization for congestive 
heart failure 
• Time from randomization to the first occurrence of transient ischemic attack 
• Time from randomization to the first occurrence of arrhythmia 
Placebo and OCA will be compared separately using a log rank test stratified by the 
randomization stratification factor.  KM estimates of the distribution of the time-to-event will be 
tabulated and graphed by treatment group.  Subjects without any documentation of events will be 
censored at the date of last contact.  The tabulation will include the KM estimate of the medians 
and corresponding 95% CIs, if the medians can be estimated.  The number and percent of 
subjects censored and with events will be presented.  The hazard ratio and 95% CI will be 
determined based on a Cox regression model stratified by randomization strata to estimate the 
magnitude of the effect. 
17.11.4. 
Cardiovascular Risk Assessment 
The following cardiovascular risk assessments will be calculated: 
• 10-year ASCVD Risk based on Pooled Cohorts Equation 
• FRS 
• Reynolds score 
• SCORE 
Each score is derived from a subject’s age, sex, smoking status, total cholesterol, HDL, and LDL 
levels, systolic blood pressure, diastolic blood pressure, and other factors including family 
history, BMI, ethnicity, and medications. 


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These cardiovascular assessments will be summarized by treatment group using descriptive 
statistics at Baseline and at Month 12 and 18 Visits.  The change and percentage change from 
Baseline and the changes from baseline in risk categories based on these scores will also be 
summarized.  Baseline is defined as the last assessment before treatment. 
17.11.5. 
Clinical Laboratory Evaluations 
Central laboratory parameters will be summarized by treatment group using descriptive statistics 
at Baseline and at each on-study evaluation.  The change from Baseline will also be summarized.  
Baseline is defined as the mean of all available evaluations before treatment.   
In addition, shift tables from Baseline based on normal ranges and CTCAE grade to each 
scheduled post-Baseline visit will be provided for hematology, coagulation, and serum chemistry 
by treatment group to assess changes in laboratory values from Baseline to each on-study 
evaluation. 
17.11.5.1. Lipoprotein Evaluations 
Lipoprotein samples will be obtained, assayed, and analyzed.  The lipoprotein analyte values, 
change from baseline, and percentage change from baseline will be summarized by treatment 
group for the lipoprotein analytes.  Baseline is defined as the last fasting assessment before 
treatment.  This analysis will use only samples that have a confirmed fasting of approximately 
8 hours or more before their visit.  Further analyses of lipoprotein analytes will be specified in 
the SAP. 
Subgroup analyses will also be presented by use of statin medication. 
17.11.6. 
Additional Safety Analyses 
17.11.6.1. Vital Signs 
The results and change from baseline to each on-study evaluation visit will be summarized for 
body temperature, sitting heart rate, respiratory rate, and seated blood pressure after sitting 
3 minutes. 
17.11.6.2. Electrocardiograms 
The ECG data analysis will be conducted based on methodology recommended in the 
International Conference on Harmonisation (ICH) E14 guideline, The Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs. 
Baseline is defined as the mean of all available evaluations prior to treatment.  Descriptive 
statistics of ECG parameters (time between 2 consecutive R waves [RR], PR, QRS, QT, and QT 
interval corrected by Fridericia’s formula [QTcF]) at baseline and at each post-baseline timepoint 
will be summarized by treatment group; absolute changes from baseline will also be 
summarized. 
A categorical summary of abnormal QTcF values will be presented by treatment group.  The 
number of patients with values of >450 msec, >480 msec, and >500 msec will be presented, and 
the number of patients with change from baseline values of >30 msec and >60 msec will also be 
presented. 


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Overall interpretation results for ECGs and the investigator interpretation results are collected as 
normal, abnormal not clinically significant (NCS), and abnormal clinically significant (CS).  
Subjects whose interpretation shifts from normal to abnormal (CS or NCS) will be listed 
separately including description of the abnormality and any associated comments. 
17.11.6.3. Pruritus VAS 
The pruritus VAS will be used to assess a subject’s experience and severity of pruritus and will 
be analyzed as described in Section 16.2.8. 
17.12. 
Open-Label Extension Analyses 
17.12.1. 
Safety Analyses (OLE) 
Safety evaluations conducted during the Double-Blind Phase will also be conducted for the OLE.  
For quantitative parameters including, but not limited to, vital signs, ECG, and clinical 
laboratory results, changes from double-blind baseline value and OLE baseline value will be 
presented.  Analyses based on the double-blind baseline will be performed using the treatment 
actually received in the Double-Blind Phase.  Analyses based on the OLE baseline will be based 
on the treatment actually received in the OLE Phase. 
17.12.2. 
Efficacy Analyses (OLE) 
The occurrence of all-cause mortality and liver-related clinical outcomes (refer to Section 17.4.2) 
will be summarized.  For additional exploratory analyses, please refer to SAP for more details. 
17.13. 
Data Monitoring Committee 
An independent data monitoring committee (DMC) will include hepatologists, pharmaceutical 
physicians, epidemiology/cardiology expert(s), DILI expert(s), and statistician(s); they will not 
be involved in the study as Investigators, adjudication committee members, or consultants.  The 
DMC will have oversight over the study conduct as defined by the DMC charter.  All members 
will have considerable experience with clinical study conduct and DMCs.  Any candidate found 
to have a conflict of interest or whose name is listed on the FDA debarment list will not be 
offered membership.  Conflicts of interest will be assessed regularly, and if members are found 
to have a new conflict of interest they will be replaced. 
The DMC will review the safety data, which will include AE data as well as lab values.  PK 
results will be made available to the DMC as appropriate. 
The DMC will meet approximately quarterly at scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review PK, safety and efficacy data as well as the adjudication 
assessments from the 4 adjudication committees listed in Section 17.14.  Based on review of 
these data, the DMC will advise the Sponsor on the validity and scientific merit of continuing the 
study. 
Written minutes of both the open and closed DMC sessions will be prepared.  The closed 
minutes will be made available to the appointed Sponsor representatives only after the database 
is locked. 


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Summary tables reviewed by the DMC during closed sessions will be unblinded and include an 
overall column containing information regarding all subjects and separate treatment columns 
with fake labels, ie, the actual treatment groups are used but are not identified.  Data reviewed 
during the meetings will include, at a minimum, disposition, demographics, exposure, clinical 
laboratory results, MedDRA-coded AEs, and AEs leading to early withdrawal of investigational 
product.  At each meeting, detailed narratives of interval SAEs (including events resulting in 
death) are reviewed by the DMC in addition to a cumulative list of all SAEs.  In addition, 
specific summary data focused on hepatic and renal safety are reviewed by the DMC, including 
an aggregate unblinded summary of adjudicated cases of suspected hepatic injury and AKI, 
provided on a quarterly basis or ad hoc as appropriate. 
The DMC may agree to adjust meeting frequency based upon actual and projected safety and 
efficacy data availability.  Adjustments to or stopping of the protocol-defined doses may be 
considered based on DMC evaluation of OCA safety and tolerability. 
All Investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DMC relating to subject safety that alter the 
conduct of this study.  The Investigators will inform the subjects of such actions and the 
protocol, patient information sheet, and ICF will be revised, as appropriate. 
17.14. 
Adjudication Committees 
Potential liver-related clinical outcomes and potential events of hepatic injury, AKI, MACE, 
deaths, and hospitalizations (depending on the cause) that occur after administration of the first 
dose of investigational product will be reviewed by the following blinded adjudication 
committees, depending on event type, before inclusion in any analysis.  The 4 committees and 
event types they are responsible for adjudicating are as follows: 
• Cardiovascular Adjudication Committee:  Adjudicates all potential MACE, 
(including all deaths) and hospitalizations (depending on the cause) 
• Hepatic Outcomes Committee:  Adjudicates all deaths and potential liver-related 
clinical outcomes  
• HSAC:  Adjudicates all events of potential hepatic injury 
• Renal Adjudication Committee:  Adjudicates all potential events of AKI 
Each adjudication committee will have a charter that documents the reporting of events by the 
study site, definition of the potential events to be adjudicated, supply of source documentation to 
the committee, entire data flow and process from committee membership, review of the events 
by the committee, reporting of the final assessment, and the working procedures of the 
committee. 
The adjudication committee members will include experts with relevant adjudication experience; 
they will not be involved in the study as Investigators, DMC members, or consultants.  Specific 
details of the events that will be adjudicated by the Cardiovascular Adjudication Committee, 
Hepatic Outcomes Committee, HSAC, and the Renal Adjudication Committee are described in 
the respective adjudication charters.  Any changes to either the adjudication process or changes 
to specific events to be adjudicated will be addressed in the charters and will be communicated to 
all study sites  Any candidate found to have a conflict or whose name is listed on the FDA 


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debarment list is not offered membership.  Conflicts of interest are assessed regularly, and if 
members are found to have a new conflict of interest, they will be replaced. 
The adjudication of potential events will be based on available source documentation, including 
but not limited to individual clinical study data, hospital records, histology, discharge summaries, 
and/or death certificates.  The adjudication committees will not receive any individual subject 
treatment or site-specific information.  All protected health information will remain confidential 
and will not be available to the adjudication committee.  The assessment of events will be 
conducted in compliance with study-specific procedures, manuals, GCP, and all other applicable 
regulatory requirements, including the archiving of essential documents. 
18. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
18.1. 
Study Monitoring 
Study records at each site will be monitored at regular intervals by a representative of the 
Sponsor, the CRA.  The role of the CRA is to aid the Investigator in the maintenance and 
documentation of complete, accurate, legible, well organized, and easily retrievable data.  In 
addition, the CRA will ensure the Investigator's understanding of all applicable regulations 
concerning the clinical evaluation of the investigational product and will ensure an understanding 
of the protocol, reporting responsibilities and the validity of the data.  This will include ensuring 
that full and appropriate essential documentation is available. 
In order to perform this role, the CRA must perform source data verification and as such must be 
given access to the subject’s primary source documentation (eg, paper or electronic medical 
records such as consent to participate in the study, visit dates, screening and randomization 
numbers, demographic information, medical history, disease history, physical examination, vital 
signs, laboratory assessments [copy of laboratory reports], AEs, concomitant medications, dates 
of dispensing investigational product, ECGs, etc.) that support data entries in the eCRF.  The 
eCRF must be completed promptly after each visit to allow the progress and results of the study 
to be closely followed by the Medical Monitor. 
The Investigator may exercise judgment in allowing the CRA access to particular sections of the 
subject's medical records if these are deemed irrelevant to the performance, observations, or 
conduct of this study. 
18.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IEC/IRB, and/or 
regulatory agencies to conduct one or more site audits during or after the study and agrees to 
allow access to all study related documentation and information and be available for discussion 
about the study. 
19. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Logic and consistency checks will be performed on all data entered into the eCRF or ultimately 
transferred into the database to ensure accuracy and completeness.   


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Training sessions, regular monitoring of the study at the study site by the Sponsor or designated 
personnel (eg, CRA), instruction manuals, data verification, cross checking, and data audits will 
be performed to ensure quality of all study data.  Investigators’ meetings and/or onsite study 
initiations will be performed to prepare Investigators and other study site personnel for 
appropriate collection of study data. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit.  Please see Section 18.2 for more details regarding the audit 
process. 
20. 
ETHICS 
20.1. 
Ethics Review 
The final study protocol, including the final version of the ICF and/or other subject information, 
must be approved or given a favorable opinion in writing by an IRB/IEC as appropriate.  The 
Investigator must submit written IRB/IEC approval to Intercept before he or she can enroll any 
subject into the study.  The Investigator is responsible for providing the IB and any other 
available safety information and information about payments and compensation available to 
study subjects to the IRB/IEC for review. 
The Investigator is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements.  A favorable opinion on amendments will be obtained prior 
to implementation, unless the amendment is necessary to reduce immediate risk to study 
participants.  In addition, the IRB/IEC must approve all advertising used to recruit subjects for 
the study.  The protocol must be reapproved by the IRB/IEC upon receipt of amendments and 
annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product, 
according to local regulations and guidelines.  The Sponsor will provide this information to the 
Investigator. 
Progress reports and notifications of SARs will be provided to the IRB/IEC according to local 
regulations and guidelines.  Investigators or the Sponsor or its designee will provide reports to 
the IRB/IEC as requested, at a minimum annually, and after the study is complete. 
20.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the Sponsor’s policies. 
20.3. 
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 risks, and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 


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should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
The subject’s signed and dated ICFs must be obtained before conducting any study procedures. 
The Investigator(s) must maintain the original, signed ICF.  A copy of the ICF must be given to 
the subject. 
20.4. 
Subject Confidentiality and Data Protection 
All information obtained during the conduct of the study with respect to the subject will be 
regarded as confidential, and confidentiality of all subjects will be maintained.  Monitors 
(eg, CRA, Medical Monitor), auditors, and inspectors will require access to a subject’s medical 
notes for the purpose of source document verification, but the subject’s confidentiality will be 
maintained at all times.  An agreement for disclosure of any such information will be obtained in 
writing and is included in the statement of informed consent.  The study data shall not be 
disclosed to a third party (with the exception of auditors and/or regulatory authorities) without 
the written consent of the Sponsor.  All data shall be secured against unauthorized access. 
The Investigator will maintain a list of subjects’ names and identifying information (eg, subject’s 
hospital number, unique subject number).  This list will not be collected by the Sponsor. 
The ICF will explain that study data will be stored in a computer database, maintaining 
confidentiality in accordance with national data protection legislation.  All data computer 
processed by the Sponsor or designee will be identified by unique subject number/randomization 
code/site number only.   
When personal data on subjects are stored or processed by computer, the data must be protected 
to prevent disclosure to unauthorized third parties.  The pertinent sections of the data protection 
laws in the country in which the protocol is being conducted will be complied with in full. 
The ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, regulatory authorities, or IEC/IRBs may require direct access to parts of the hospital or 
study site records relevant to the study, including subject’s medical history. 
21. 
INVESTIGATOR OBLIGATIONS 
The Investigator or a medically trained designee will be responsible for obtaining written 
informed consent and for the care of the subjects for the duration of the study.  If the Investigator 
is not present in the study site during the assessment, he or she will leave instructions for the 
study site staff and a telephone number where he or she can be reached. 
Named physician(s) will be responsible for the medical follow-up of subjects, as applicable. 
21.1. 
Adverse Event Reporting 
The Investigator is responsible for recording AEs reported by the subject or discovered by any 
other means during the study.  In agreeing to the provisions of this protocol, the Investigator 
accepts all legal responsibilities for immediate reporting of SAEs to the Sponsor 
(Section 16.1.7). 


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21.2. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any significant way without 
proper notification to the Sponsor (or designee).  Only the Sponsor may amend the protocol.  
Any change in study conduct considered necessary by the Investigator will be made only after 
consultation with the Sponsor, who will then issue a formal protocol amendment to implement 
the change and obtain regulatory approval.  The only exception is when the Investigator 
considers a subject’s safety to be compromised if immediate action is not taken. 
21.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided and maintained: 
• Approved ICFs (all versions) 
• IRB/IEC approvals (of protocol/amendments, subject questionnaires, etc)  
• Form FDA 1572 (US only); in lieu of 1572 (for ex-US) 
• Current medical license of Investigators 
• Curriculum vitae of Investigators 
• Laboratory certification and reference ranges 
• Financial disclosure forms 
21.4. 
Ethics Review (IRB/IEC) 
Please see Section 20.1 for the Investigator’s responsibilities regarding ethics review. 
21.5. 
Archiving and Record Retention 
The Investigator should retain all correspondence relating to this study in the Investigator Site 
File (ISF).  Any study documents stored elsewhere should have their location referenced in the 
ISF. 
All documents relating to the study including the ISF itself, source documents and subject 
medical files (retained per country specific regulations), completed study subject log and 
confidential subject identification list will be retained by the Investigator until at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the Sponsor.  In the event that storage of records 
becomes a problem at any time during this period, the Sponsor should be consulted for 
assistance.  At the end of the minimum period, the Investigator should obtain written 
authorization from the Sponsor before the destruction of any records.  The Investigator will 
notify the Sponsor if ownership of documents or responsibility for the study site is transferred.  
The Sponsor will inform Investigators should it become aware of any changes in storage 
requirements. 


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22. 
PUBLICATION POLICY 
The Sponsor intends to publish the results of all of the clinical studies that it Sponsors consistent 
with the Declaration of Helsinki.  Consistent with the recommendations of the editors of several 
leading medical journals, the International Committee of Medical Journal Editors (ICMJE), 
authorship of publications resulting from Intercept-sponsored studies should fairly recognize the 
activities of those that have made a significant contribution to the study (http://www.icmje.org).  
Thus, it is anticipated that authorship will reflect the contribution made by the Sponsor 
personnel, the Investigators and others involved, such as statisticians.   
In recent years, issues about conflicts of interest and accuracy of the study data have been raised 
in the medical press.  Accordingly, the Sponsor has developed publication guidelines for clinical 
studies that are appropriate for this study.  Key issues include the following: 
• Clinical Trial Registries (eg, www.clinicaltrials.gov, www.clinicaltrialsregister.eu):  
A description of the study and relevant design elements (eg, basic design, objectives 
and endpoints, sample size, study population, and key inclusion/exclusion criteria) 
and results will be published online in a manner consistent with applicable regulatory 
guidelines. 
• Overview:  Investigators, reviewers, and editors will have the right to audit the data to 
verify its accuracy. 
• Responsibility:  Each Investigator is responsible for the accuracy and completeness of 
all data from her/his site.  The Sponsor (or its representatives) is responsible for the 
accuracy of the data entered into the study databases and the analyses conducted. 
• Data Management:  The Sponsor will establish data management plan and SAP.  The 
Investigators will have the opportunity to provide input into the plans.  The 
Investigators will have the right to review the audit reports and data resolution 
decisions prior to the establishment of a clean file.  The Investigators will have the 
right to appoint appropriately qualified auditors, with GCP experience, to audit the 
Sponsor’s data prior to the establishment of a clean file.  The Investigators must 
provide adequate notice (at least 2 months) to the Sponsor of their intention to audit a 
study.  The audit should be conducted in a timely manner to allow the resolution of 
discrepancies before a clean file is established.  The Investigators will bear all the 
costs for the conduct of audits that they initiate, except those related to the resolution 
of data queries which the Sponsor will bear.  Such audits must be conducted in such a 
manner as to minimize the time to create the clean file. 
• Authorship:  Intercept, in collaboration with the Investigators, will establish the 
appropriate authorship and responsibility for drafting study documents in accordance 
with the principles of the ICMJE.  All manuscripts will be reviewed and agreed upon 
before submission for publication by all authors. 
• Single Center Publication and Additional Publications:  This is a multicenter study 
and is designed to be published with complete data from all the study sites.  Single 
center publications are therefore not considered appropriate.  Any such publications 
should clearly state that the data are “extracted” from a multicenter study and that the 


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study was not intended, or statistically powered, for data presentation by a single 
study site. 
• Intercept Review of External Manuscripts:  Consistent with this, Investigators must 
submit any drafts of any publications or presentations that may arise from this study 
to the Sponsor for review and approval and to ensure consistency with the policy in 
this protocol at least 30 days prior to submission for publication or presentation.  The 
Sponsor will have the right to request appropriate modification to correct facts and to 
represent its, or the Publication Committee’s, opinion if these differ with the proposed 
publication. 
• Confidentiality:  Investigators will conduct all interactions with the company and 
with third parties consistent with the executed confidentiality agreements.  While 
publication, by intention, presents the critical scientific data in a public forum, some 
information (such as future plans, results of preclinical studies or chemical formulae) 
may still need to remain confidential. 
• Medical Journal Review:  Upon request, all pertinent study data and information will 
be made available as supplemental information for journal editors and reviewers to 
evaluate and audit, eg, protocol and amendments, data tabulations, etc.  Arrangements 
will be made to maintain the confidentiality of such supplemental information.  
Arrangements will also be made to maintain the confidentiality of the identity of 
journal reviewers.  Records will be maintained of which documents and datasets were 
reviewed. 


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23. 
LIST OF REFERENCES 
Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic 
steatohepatitis. Drug Discovery Today. 2012;17:988-997. 
Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the primary 
prevention of cardiovascular disease: A report of the American College of Cardiology/American 
Heart Association Task Force on clinical practice guidelines. Circulation. 2019 
Sep;140(11):e596-e646. 
Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: Management of hyperglycemia in type 2 
diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the 
European Association for the Study of Diabetes (EASD). Diabetes Care. 2020 Feb;43(2):487-93. 
Cheung A, Neuschwander-Tetri BA, Kleiner DE, et al. Defining Improvement in Nonalcoholic 
Steatohepatitis for Treatment Trial Endpoints: Recommendations from the Liver Forum. 
Hepatology. 2019 Apr 29. 
Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 
2018. A consensus report by the American Diabetes Association (ADA) and the European 
Association for the Study of Diabetes (EASD). Diabetes care. 2018 Dec;41(12):2669-701. 
Edwards JE, LaCerte C, Peyret T, et al. Modeling and experimental studies of obeticholic acid 
exposure and the impact of cirrhosis stage. Clin Transl Sci. 2016;9:328-336.  
European Association for the Study of the Liver (EASL). EASL clinical practice guidelines:  The 
diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 
2017;67(1):145–72. 
Ekstedt M, Hagstrom H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-
specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 
2015 May;61(5):1547-54. 
Fickert P, Fuchsbichler A, Moustafa T, et al. Farnesoid X receptor critically determines the 
fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and 
periductal myofibroblasts. Am J Pathol. 2009 Dec;175(6):2392-405. 
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;6(4):463-472. 
Garcia-Tsao G. Cirrhotic ascites: pathogenesis and management. The Gastroenterologist. 
1995 Mar;3(1):41-54. 
Hegade VS, Kendrick SF, Jones DE. Drug treatment of pruritus in liver diseases. Clin Med. 2015 
Aug;15(4):351-7. 
Herdman, M, Gudex, C, Lloyd, A, et al. Development and preliminary testing of the new five-
level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727–1736. 


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Human Medicines Agency, Clinical Trial Facilitation Group (2014). Recommendations related 
to contraception and pregnancy testing in clinical trials. Retrieved from: 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf accessed 
27 Jan 2020. 
Kleiner D, Brunt E, Van Natta M, et al. Design and Validation of a Histological Scoring System 
for Nonalcoholic Fatty Liver Disease. Hepatology. 2005;41:1313-1321. 
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver 
transplant waiting list: a report of a national conference organized by the American Society of 
Transplant Physicians and the American Association for the Study of Liver Diseases. Liver 
Transpl Surg. 1997 Nov;3(6):628-37. 
Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of 
dyslipidaemias: lipid modification to reduce cardiovascular risk: The task force for the 
management of dyslipidaemias of the European Society of Cardiology (ESC) and European 
Atherosclerosis Society (EAS). European Heart Journal. 2020 Jan;41(1):111-88. 
Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist 
obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. 
Gastroenterol. 2013;145:574-582.  
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand 
obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, 
randomised, placebo-controlled trial. Lancet. 2015;385(9972):956-65. 
Oemar M, Janssen B. EQ-5D-5L User Guide. EuroQOL.org. 2013.  
Pearle MS, Goldfarb DS, Assimos DG, et al. Medical management of kidney stones: AUA 
Guideline. J Urol. 2014;192:316-24. 
Prasad M, Wahlqvist P, Shikiar R, et al.  A review of self-report instruments measuring health-
related work productivity: a patient-reported outcomes perspective. Pharmacoeconomics. 
2004;22(4):225-44. 
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding 
oesophageal varices. Br J Surg. 1973 Aug;60(8):646-9. 
Roth J, Feigh M, Veidal S, et al. Obeticholic acid improves histological, biochemical and gene 
expression profiles in gubra AMLN mice with diet-induced and biopsy-confirmed 
NASH.  Keystone Symposium: Bile Acid Receptors as Signal Integrators in Liver and 
Metabolism; March 3-7; Monterey, CA 2017. 
Sakorafas GH, Milingos D, Peros G. Asymptomatic cholelithiasis: is cholecystectomy really 
needed? A critical reappraisal 15 years after the introduction of laparoscopic cholecystectomy. 
Dig Dis Sci 2007 May; 52:1313-25. 
Saunders JB, Aasland OG, Babor TF.  Development of the Alcohol Use Disorders Identification 
Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol 
Consumption--II.  Addiction. 1993 Jun;88(6):791-804. 


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Singh S, Allen AM, Wang Z, et al. Fibrosis Progression in Nonalcoholic Fatty Liver vs 
Nonalcoholic Steatohepatitis: A Systematic Review and Meta-analysis of Paired-Biopsy Studies. 
Clinical gastroenterology and hepatology : the official clinical practice journal of the American 
Gastroenterological Association. 2015;13:643-54. 
Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut 
Liver. 2012 Apr;6(2):172-87. 
van Best N, Jansen PL, Rensen SS. The gut microbiota of nonalcoholic fatty liver disease: 
current methods and their interpretation. Hepatology international. 2015 Jul;9(3):406-15.  
Verbeke L, Farre R, Verbinnen B, et al. The FXR Agonist Obeticholic Acid Prevents Gut Barrier 
Dysfunction and Bacterial Translocation in Cholestatic Rats. The American Journal of 
Pathology. 2015;185(2):409-19. 
Verbeke L, Mannaerts I, Schierwagen R, et al. FXR agonist obeticholic acid reduces hepatic 
inflammation and fibrosis in a rat model of toxic cirrhosis. Scientific reports. 
2016 Sep 16;6:33453. 
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history 
of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment 
Pharmacol Ther 2011; 34: 274–285. 
Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 
Practice Guideline by the American Association for the Study of Liver Diseases and the 
European Association for the Study of the Liver. Hepatology. 2014;60(2):715-35. 
Wang W, Li J, Pan R, et al. Association of the Laennec staging system with degree of cirrhosis, 
clinical stage and liver function. Hepatology international. 2015 Oct;9(4):621-6. 
Wong RJ, Singal AK. Trends in liver disease etiology among adults awaiting liver 
transplantation in the United States, 2014-2019. JAMA Netw Open. 2020 Feb;3(2):e1920294. 
Younossi ZM, Guyatt G, Kiwi M, et al. Development of a disease specific questionnaire to 
measure health related quality of life in patients with chronic liver disease. Gut. 1999 Aug; 
45(2):295-300. 
Younossi Z, Stepanova M, Rafiq N, et al. Pathologic Criteria for Nonalcoholic Steatohepatitis: 
Interprotocol Agreement and Ability to Predict Liver-Related Mortality. Hepatology 
2011;53:1874-1882. 
Younossi ZM, Younossi I, Pham, HT, et al. Development and Validation of Disease-Specific 
Health-Related Quality (HRQL) Instrument for Patients with Non-alcholic Fatty Liver Disease 
(NAFLD) and Non-alchoholic Steatohepatitis (NASH):  The CLDQ-NAFLD. Hepatology. 2016 
64 (1), 118A.  
Younossi Z, Ratziu V, Loomba R, et al. Positive Results from REGENERATE: A Phase 3 
International, Randomized, Placebo-Controlled Study Evaluating Obeticholic Acid Treatment for 
NASH. Journal of hepatology. 2019 Apr 2019;70(1 (suppl)):E5. 
Younossi ZM, Stepanova M, Ong J, et al. Nonalcoholic steatohepatitis is the most rapidly 
increasing indication for liver transplantation in the United States. Clin Gastroenterol Hepatol. 
2020 Jun 9. 


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APPENDIX B. MANAGMENT OF HYPERGLYCEMIA 
The selection of the appropriate individualized therapy is described in current guidelines to assess risk of hyperglycemia (Figure B1; 
Buse 2020) 
Figure B1: 
Glucose-Lowering Medication in Type 2 Diabetes: Overall Approach 
 
 
RA = receptor agonist; SU = sulfonylureas; TZD = thiazolidinediones.  
Source: Buse 2020. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 


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APPENDIX C. EDUCATION AND ASSESSMENT OF 
SIGNS/SYMPTOMS OF INTERCURRENT ILLNESS 
AND/OR POTENTIAL ADVERSE EVENTS AT EACH 
STUDY VISIT 
Subjects should be educated to understand and recognize the signs and symptoms of intercurrent 
illnesses and/or potential adverse events listed below.  Investigators should instruct subjects to 
seek immediate medical attention if they experience any of these signs or symptoms.   
At each visit, study site staff should inquire if the subject has developed any of the listed signs 
and symptoms; received any new drug prescriptions, any new over the counter medications, or 
herbal supplements from health care providers (HCPs); or had any laboratory procedures or 
assessments performed by an HCP. 
Events 
Signs and Symptoms 
Cholelithiasis  
(Protocol Section 7.5.1) 
• 
Upper abdominal pain or tenderness (particularly post-prandial), 
abdominal swelling, nausea, vomiting, or fever 
Acute cholecystitis, or 
Acute pancreatitis 
(Protocol Section 7.5.2) 
• 
Symptoms of these events may be similar to symptomatic cholelithiasis 
(see Protocol Section 7.5.1) 
• 
Significant upper abdominal pain with nausea, vomiting, fever, or 
jaundice 
Hyperglycemia 
(Protocol Section 9.4.6) 
• 
Polyuria, polydipsia, polyphagia, blurred vision, fatigue, and headaches 
Renal Impairment 
(Protocol Section 7.6.1) 
• 
New onset fatigue/asthenia, nausea, or confusion and to assess signs 
such as decreased skin turgor (dehydration), increased heart rate, lower 
extremity edema, decreased urine output or dark urine 
Nephrolithiasis 
(Protocol Section 7.6.2) 
• 
Evidence of hematuria, flank or lower abdominal pain, nausea, 
vomiting, fever, or chills 
Hepatic Injury and/or 
decompensation 
(Protocol Section 7.4) 
Questions to ask subjects 
are listed below 
• 
Specific signs and symptoms of liver impairment:  yellowing of the skin 
or the whites of eyes, pale-colored stools, urine color change from pale 
to deep amber [dark], severe fatigue, right upper quadrant pain, rash, 
eosinophilia 
• 
More general signs and symptoms of ascites and encephalopathy:  
swelling of the legs or abdomen, confusion or abrupt abnormal behavior 
• 
Non-specific signs and symptoms of impaired health:  nausea, vomiting, 
abdominal pain, diarrhea, weight loss, fever and chills, worsening or 
new fatigue, weakness, loss of appetite 


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• 
Significant intercurrent illnesses such as gastroenteritis may exacerbate 
hepatic injury or decompensation (eg, established severe abdominal 
pain, vomiting, and diarrhea) and should be an indication for prompt 
investigational product interruption and complete subject evaluation 
Other Symptoms: 
• 
Worsening or new pruritus 
• 
Decreased urine output, dizziness, or lethargy  
Follow up Questions for Positive Response to Signs/Symptoms of Hepatic Injury or 
Decompensation 
1. Example 1:  If subject is experiencing abdominal pain, follow-up questions may include: 
a. For how long? 
b. What is the location? 
c. Is it constant? 
d. What makes it better? Worse? (eg, eating, movement) 
e. Have you ever felt pain or similar discomfort before? 
f. Is it associated with nausea or vomiting or diarrhea? 
g. Are you having fevers? 
2. Example 2:  If subject is experiencing itching, follow up questions may include: 
a. Is this new? 
b. If so, how severe is it? 
c. Is it limiting your daily activities? 
d. Is it limiting your sleep? 
e. Is it constant? 
f. Do you have a rash? Where is it located? 
g. Arms/legs/chest/entire torso/back/face? 
3. Example 3:  If subject is experiencing nausea, vomiting, and/or diarrhea, follow-up 
questions may include: 
a. If so, for how long? 
b.  Which of the three symptoms do you have?  
c. Are they associated with fever? With chills? With yellowing of your eyes? With rash? 
d. Is anyone close to you having similar symptoms? 
4. Example 4:  If subject has noticed that their stool is now pale-colored or urine is darker 
than usual, follow-up question may include: 
a. If so, for how long? 
b. Is your urine darker than usual? 
c. Are the whites of your eyes yellow? 
d. Is your skin yellow?  
5. Example 5:  If subject has noticed feeling dehydrated or is not urinating as often as usual, 
follow up question may include: 


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a. Are you excessively thirsty? 
b. Are you feeling dizzy or lethargic and weak? 


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APPENDIX D. COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS 
 








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Event 
Definitions 
the laboratory should be used.  If the ninety-ninth percentile of the URL or the 
URL for myocardial necrosis is not available, the MI decision limit for the 
particular laboratory should be used as the URL.  Laboratories can also report 
both the ninety-ninth percentile of the upper reference limit and the MI decision 
limit.  Reference limits from the laboratory performing the assay are preferred 
over the manufacturer’s listed reference limits in an assay’s instructions for use.  
In general, troponins are preferred.  Creatine kinase-myocardial band (CK-MB) 
should be used if troponins are not available, and total creatine kinase (CK) may 
be used in the absence of CK-MB and troponin. 
For MI subtypes, different biomarker elevations for CK, CK-MB, or troponin will 
be required.  The specific criteria will be referenced to the URL. 
Since it is not practical to stipulate the use of a single biomarker or assay, the 
locally available results are to be used as the basis for adjudication.  However, if 
possible, using the same cardiac biomarker assay and preferably, a core 
laboratory, for all measurements reduces inter-assay variability. 
Since the prognostic significance of different types of MIs (eg, periprocedural MI 
versus spontaneous MI) may be different, outcomes for these subsets of subjects 
may be evaluated separately. 
c) 
ECG Changes 
Electrocardiographic changes can be used to support or confirm a MI. Supporting 
evidence may be ischemic changes and confirmatory information may be new 
Q waves. 
ECG manifestations of acute myocardial ischemia (in absence of left ventricular 
hypertrophy [LVH] and left bundle branch block [LBBB]) include: 
• 
ST elevation: New ST elevation at the J point in two contiguous leads 
with the cut-points: ≥0.1 mV in all leads other than leads V2-V3 where 
the following cut-points apply: ≥0.2 mV in men ≥40 years (≥0.25 mV in 
men <40 years) or ≥0.15 mV in women 
• 
ST depression and T-wave changes: New horizontal or down-sloping ST 
depression ≥0.05 mV in two contiguous leads and/or new T inversion 
≥ 0.1 mV in two contiguous leads with prominent R wave or R/S ratio 
>1. 
The above ECG criteria illustrate patterns consistent with myocardial ischemia.  
In subjects with abnormal biomarkers, it is recognized that lesser ECG 
abnormalities may represent an ischemic response and may be accepted under the 
category of abnormal ECG findings. 
• 
Criteria for pathological Q-wave 
− 
Any Q-wave in leads V2-V3 ≥0.02 seconds or QS complex in leads 
V2 and V3 
− 
Q-wave ≥0.03 seconds and ≥0.1 mV deep or QS complex in leads I, 
II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead 
grouping (I, aVL; V1-V6; II, III, and aVF)c 
• 
ECG changes associated with prior MI 
− 
Pathological Q-waves, as defined above 


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− 
R-wave ≥0.04 seconds in V1-V2 and R/S ≥1 with a concordant 
positive T-wave in the absence of a conduction defect 
• 
Criteria for prior MI:  Any one of the following criteria meets the 
diagnosis for prior MI: 
− 
Pathological Q waves with or without symptoms in the absence of 
non-ischemic causes 
− 
Imaging evidence of a region of loss of viable myocardium that is 
thinned and fails to contract, in the absence of a non-ischemic cause 
Pathological findings of a prior myocardial infarction 
Hospitalization for Unstable 
Angina 
Unstable angina requiring hospitalization is defined as: 
6. Ischemic discomfort (angina, or symptoms thought to be equivalent) 
≥10 minutes in duration occurring 
• 
at rest, or 
• 
in an accelerating pattern with frequent episodes associated with 
progressively decreased exercise capacity. 
AND 
7. Prompting an unscheduled hospitalization within 24 hours of the most 
recent symptoms.  Hospitalization is defined as an admission to an 
inpatient unit or a visit to an emergency department that results in at least 
a 24 hour stay (or a change in calendar date if the hospital admission or 
discharge times are not available). 
AND 
8. At least one of the following: 
a. 
New or worsening ST or T wave changes on resting ECG (in the 
absence of confounders, such as LBBB or LVH) 
• 
Transient ST elevation (duration <20 minutes) New ST 
elevation at the J point in two contiguous leads with the cut-
points: ≥0.1 mV in all leads other than leads V2-V3 where the 
following cut-points apply: ≥0.2 mV in men ≥40 years 
(≥0.25 mV in men <40 years) or ≥0.15 mV in women. 
• 
ST depression and T-wave changes 
• 
New horizontal or down-sloping ST depression ≥0.05 mV in 
two contiguous leads and/or new T inversion ≥0.3 mV in two 
contiguous leads with prominent R wave or R/S ratio >1. 
b. Definite evidence of inducible myocardial ischemia event as 
demonstrated by: 
• 
an early positive exercise stress test, defined as ST elevation or 
≥2 mm ST depression prior to 5 mets OR 
• 
stress echocardiography (reversible wall motion abnormality) 
OR 
• 
myocardial scintigraphy (reversible perfusion defect), OR 
• 
magnetic resonance imaging (MRI; myocardial perfusion deficit 
under pharmacologic stress). 


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• 
And believed to be responsible for the myocardial ischemic 
symptoms/signs. 
c. 
Angiographic evidence of new or worse ≥70% lesion (≥50% for left 
main lesion) and/or thrombus in an epicardial coronary artery that is 
believed to be responsible for the myocardial ischemic 
symptoms/signs. 
d. Need for coronary revascularization procedure (PCI or CABG) for 
the presumed culprit lesion(s).  This criterion would be fulfilled if 
revascularization was undertaken during the unscheduled 
hospitalization, or subsequent to transfer to another institution 
without interceding home discharge. 
AND 
Negative cardiac biomarkers and no evidence of acute MI 
Transient Ischemic Attack 
(TIA) 
TIA is defined as a transient episode of focal neurological dysfunction caused by 
brain, spinal cord, or retinal ischemia, without acute infarction. 
Stroke (Includes Ischemic 
Stroke, Hemorrhagic Stroke, 
Undetermined Stroke, or 
Stroke Disability) 
Stroke is defined as an acute episode of focal or global neurological dysfunction 
caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage 
or infarction. 
A. Ischemic Stroke: Ischemic stroke is defined as an acute episode of focal 
cerebral, spinal, or retinal dysfunction caused by infarction of central 
nervous system tissue. 
Hemorrhage may be a consequence of ischemic stroke.  In this situation, 
the stroke is an ischemic stroke with hemorrhagic transformation and not 
a hemorrhagic stroke. 
B. Hemorrhagic Stroke: Hemorrhagic stroke is defined as an acute episode 
of focal or global cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or subarachnoid hemorrhage. 
C. Undetermined Stroke: Undetermined stroke is defined as an acute 
episode of focal or global neurological dysfunction caused by presumed 
brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction but with insufficient information to allow categorization as A 
or B.  
Stroke Disability: Disability should be measured by a reliable and valid scale in 
all cases, typically at each visit and 90 days after the event.  For example, the 
modified Rankin Scale may be used to address this requirement: 
Scale Disability 
0 
No symptoms at all 
1 
No significant disability despite symptoms; able to carry out all 
usual duties and activities 
2 
Slight disability; unable to carry out all previous activities, but 
able to look after own affairs without assistance 
3 
Moderate disability; requiring some help, but able to walk without 
assistance 


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4 
Moderately severe disability; unable to walk without assistance 
and unable to attend to own bodily needs without assistance 
5 
Severe disability; bedridden, incontinent and requiring constant 
nursing care and attention 
6 
Dead 
Heart Failure (A HF event 
includes hospitalization for 
HF and may include urgent 
outpatient visits) 
A HF hospitalization is defined as an event that meets ALL of the following 
criteria: 
1. The subject is admitted to the hospital with a primary diagnosis of HF 
2. The subject’s length-of-stay in hospital extends for at least 24 hours (or a 
change in calendar date if the hospital admission and discharge times are 
unavailable) 
3. The subject exhibits documented new or worsening symptoms due to HF 
on presentation, including at least ONE of the following: 
• 
Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, 
paroxysmal nocturnal dyspnea) 
• 
Decreased exercise tolerance 
• 
Fatigue 
• 
Other symptoms of worsened end-organ perfusion or volume 
overload (must be specified and described by the protocol) 
4. The subject has objective evidence of new or worsening HF, consisting 
of at least TWO physical examination findings OR one physical 
examination finding and at least ONE laboratory criterion), including: 
a. 
Physical examination findings considered to be due to HF, including 
new or worsened: 
i. Peripheral edema 
ii. Increasing abdominal distention or ascites (in the absence of 
primary hepatic disease) 
iii. Pulmonary rales/crackles/crepitations 
iv. Increased jugular venous pressure and/or hepatojugular reflux 
v. S3 gallop 
vi. Clinically significant or rapid weight gain thought to be related to 
fluid retention 
b. Laboratory evidence of new or worsening HF, if obtained within 
24 hours of presentation, including: 
i. 
Increased B-type natriuretic peptide (BNP)/ N-terminal pro-
BNP (NT pro-BNP) concentrations consistent with 
decompensation of HF (such as BNP >500 pg/mL or NT-
proBNP >2,000 pg/mL).  In subjects with chronically elevated 
natriuretic peptides, a significant increase should be noted 
above baseline. 
ii. Radiological evidence of pulmonary congestion 




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b. Objective signs of ischemia at rest (electrocardiographic changes) or 
during exercise test (or equivalent), presumably related to the target 
vessel 
c. 
Abnormal results of any invasive functional diagnostic test [eg, 
coronary flow reserve (CFR) or fractional flow reserve (FFR)]  
Comment:  Target lesion revascularization of a >70% diameter stenosis by QCA 
in the absence of the above signs or symptoms may be considered clinically-
driven. 
Comment:  In the absence of QCA data or if a ≤50% stenosis is present, TLR may 
be considered clinically-driven by the Adjudication Committee (AC) if severe 
ischemic signs and symptoms attributed to the target lesion are present. 
Non-Target Lesion and 
Non-Target Lesion 
Revascularization: 
A lesion for which revascularization is not attempted or one in which 
revascularization is performed using a non-study device, respectively. 
Non-Target Vessel and Non-
Target Vessel 
Revascularization: 
A vessel for which revascularization is not attempted or one in which 
revascularization is performed using a non-study device, respectively. 
Percutaneous Coronary 
Intervention (PCI) Status: 
a. 
Elective: The procedure can be performed on an outpatient basis or during a 
subsequent hospitalization without significant risk of MI or death.  For stable 
inpatients, the procedure is being performed during this hospitalization for 
convenience and ease of scheduling and NOT because the subject's clinical 
situation demands the procedure prior to discharge. 
b. Urgent: The procedure should be performed on an inpatient basis and prior to 
discharge because of significant concerns that there is risk of myocardial 
ischemia, MI, and/or death.  Subjects who are outpatients or in the 
emergency department at the time that the cardiac catheterization is requested 
would warrant hospital admission based on their clinical presentation. 
c. 
Emergency:  The procedure should be performed as soon as possible because 
of substantial concerns that ongoing myocardial ischemia and/or MI could 
lead to death.  "As soon as possible" refers to a subject who is of sufficient 
acuity that one would cancel a scheduled case to perform this procedure 
immediately in the next available room during business hours, or one would 
activate the on-call team were this to occur during off-hours. 
d. Salvage:  The procedure is a last resort. The subject is in cardiogenic shock 
when the PCI begins (ie, the time at which the first guide wire or 
intracoronary device is introduced into a coronary artery or bypass graft for 
the purpose of mechanical revascularization) OR within the last ten minutes 
prior to the start of the case or during the diagnostic portion of the case, the 
subject has also received chest compressions or has been on unanticipated 
circulatory support (eg, intra-aortic balloon pump, extracorporeal membrane 
oxygenation, or cardiopulmonary support). 
Percutaneous Coronary 
Intervention (PCI): 
Placement of an angioplasty guide wire, balloon, or other device (eg, stent, 
atherectomy catheter, brachytherapy delivery device, or thrombectomy catheter) 
into a native coronary artery or coronary artery bypass graft for the purpose of 
mechanical coronary revascularization.  In the assessment of the severity of 
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(CFR), or fractional flow reserve (FFR), insertion of a guide wire will NOT be 
considered PCI. 
Procedural Success: 
Achievement of <30 % residual diameter stenosis of the target lesion assessed by 
visual inspection or QCA and no in-hospital major adverse cardiac events 
(MACE, a composite of death, MI, or repeat coronary revascularization of the 
target lesion).  Ideally, the assessment of the residual stenosis at the end of the 
procedure should be performed by an angiographic core laboratory. 
Comment: For some device interventions (eg, balloon angioplasty), achievement 
of <50% diameter stenosis by visual inspection or QCA is an acceptable 
definition for procedural success. 
Target Lesion: 
Any lesion treated or attempted to be treated during the PCI with the study device.  
The target lesion includes the arterial segment treated with the study device (stent, 
in most cases) plus 5 mm proximal and 5 mm distal to the treatment site. 
Target Lesion Failure 
(TLF): 
The composite of ischemia-driven revascularization of the target lesion, MI 
related to the target vessel, or cardiac death related to the target vessel.  If it 
cannot be determined with certainty whether the MI or death was related to the 
target vessel, it is considered a TLF. 
Target Lesion 
Revascularization (TLR): 
Any repeat percutaneous intervention of the target lesion (including 5 mm 
proximal and 5 mm distal to the target lesion) or surgical bypass of the target 
vessel performed for restenosis or other complication involving the target lesion.  
In the assessment of TLR, angiograms should be assessed by an angiographic 
core laboratory (if designated) and made available to the AC for review upon 
request. 
Target Vessel: 
A major native coronary artery (eg, left main coronary artery, left anterior 
descending coronary artery, left circumflex coronary artery, or right coronary 
artery) or bypass graft containing the target lesion.  A native coronary artery 
target vessel includes the arterial segments upstream and downstream to the target 
lesion plus major side branches. 
Target Vessel Failure 
(TVF): 
The composite of ischemia-driven revascularization of the target vessel, MI 
related to the target vessel, or cardiac death related to the target vessel.  If it 
cannot be determined with certainty whether the MI or death was related to the 
target vessel, it is considered a TVF. 
Target Vessel, Non-Target 
Lesion, and Target Vessel, 
Non-Target Lesion 
Revascularization: 
Any lesion or revascularization of a lesion in the target vessel other than the target 
lesion, respectively. 
Target Vessel 
Revascularization (TVR): 
Any repeat percutaneous intervention or surgical bypass of any segment of the 
target vessel. In the assessment of TVR, angiograms should be assessed by an 
angiographic core laboratory (if designated) and made available to the CEC for 
review upon request. 
Vascular Complications: 
• 
Access site hematoma:  Development of a new, localized collection of blood 
at a vascular access site sufficient to produce a palpable mass within 
72 hours of a procedure. 




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Posterolateral segmental 
artery 
In right dominant circulations, the distal 
continuation of the right coronary artery in the 
posterior atrioventricular groove after the origin 
of the right posterior descending artery (PLSA) 
First right posterolateral 
branch 
In right dominant circulations, the first 
posterolateral branch originating from the right 
posterior atrioventricular artery (RPL1) 
Second right 
posterolateral branch 
In right dominant circulations, the second 
posterolateral branch originating from the right 
posterior atrioventricular artery (RPL2) 
Third right posterolateral 
branch 
In right dominant circulations, the third 
posterolateral branch originating from the right 
posterior atrioventricular artery (RPL3) 
Posterior descending 
septal perforator 
Septal perforator vessel originating from the 
posterior descending artery 
Right ventricular branch 
Branch arising from the right coronary artery to 
supply the right ventricular wall (RV) 
Left main coronary artery 
ostium 
Origin of the left coronary artery, including the 
first 3 mm of the artery 
Left main coronary artery 
body 
Body of the left main coronary artery, from the 
ostium to the bifurcation (LM) 
Left main coronary artery 
bifurcation 
Distal end of the left main, including the 
terminal 3 mm through the bifurcation of the left 
main into the left anterior descending and left 
circumflex arteries 
Left anterior descending 
artery ostium 
Origin of the left anterior descending coronary 
artery, including the first 3 mm of the artery 
Proximal left anterior 
descending 
artery 
Proximal portion of the left anterior descending 
coronary artery, from the ostium to the origin of 
the first septal (pLAD) 
Mid left anterior 
descending artery 
Middle portion of the left anterior descending 
coronary artery, from the origin of the first 
septal artery to the origin of the third septal 
artery (mLAD) 
Distal left anterior 
descending artery 
Distal portion of the left anterior descending 
coronary artery, from the origin of the third 
septal artery to the terminus (dLAD) 
First diagonal branch 
First of the three longest branches originating 
from the left anterior descending artery to supply 
the anterolateral wall of the left ventricle (D1) 
First diagonal lateral 
branch 
Branch of the first diagonal branch 


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Second diagonal branch 
Second of the three longest branches originating 
from the left anterior descending artery to supply 
the anterolateral wall of the left ventricle (D2) 
Second diagonal lateral 
branch 
Branch of the second diagonal branch 
Third diagonal branch 
Third of the three longest branches originating 
from the left anterior descending artery to supply 
the anterolateral wall of the left ventricle (D3) 
Third diagonal lateral 
branch 
Branch of the third diagonal branch 
Anterior descending 
septal perforator 
Septal perforator vessel originating from the left 
anterior descending artery to supply the 
interventricular septum 
Left circumflex artery 
ostium 
Origin of the left circumflex coronary artery, 
including the first 3 mm of the artery 
Proximal left circumflex 
artery 
Proximal portion of the left circumflex coronary 
artery, from the ostium to the origin (or the 
nominal location of) the first marginal branch 
(pLCX) 
Mid left circumflex artery 
Middle portion of the left circumflex coronary 
artery, from the origins of (or nominal locations 
of) the first marginal to the second marginal 
(mLCX) 
Distal left circumflex 
artery 
Distal portion of the left circumflex coronary 
artery, from the origin of (or the nominal 
location of) the second marginal to the terminus 
(in right dominant systems), or to the origin of 
the 1st left posterolateral in all other dominance 
systems (dLCX) 
First obtuse marginal 
branch 
First of the three longest branches originating 
from the left circumflex artery to supply the 
lateral wall of the left ventricle (OM1) 
First obtuse marginal 
lateral branch 
Branch of the first marginal branch 
Second obtuse marginal 
branch 
Second of the three longest branches originating 
from the left circumflex artery to supply the 
lateral wall of the left ventricle (OM2) 
Second obtuse marginal 
lateral branch 
Branch of the second marginal branch 
Third obtuse marginal 
branch 
Third of the three longest branches originating 
from the left circumflex artery to supply the 
lateral wall of the left ventricle (OM3) 
Third obtuse marginal 
lateral branch 
Branch of the third marginal branch 


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Left atrioventricular 
artery 
In left dominant and mixed circulations, the 
distal continuation of the left circumflex 
coronary artery in the posterior atrioventricular 
groove 
Left posterior descending 
artery 
In left dominant circulations, the vessel that 
arises from the distal continuation of the left 
atrioventricular artery, travels in the posterior 
interventricular groove, and supplies septal 
perforator branches (LPDA) 
First left posterolateral 
branch 
In left dominant and mixed circulations, the first 
posterolateral branch originating from the 
posterior atrioventricular left circumflex artery 
(LPL1) 
Second left posterolateral 
branch 
In left dominant and mixed circulations, the 
second posterolateral branch originating from 
the posterior atrioventricular left circumflex 
artery (LPL2) 
Third left posterolateral 
branch 
In left dominant and mixed circulations, the 
third posterolateral branch originating from the 
posterior atrioventricular left circumflex artery 
(LPL3) 
Ramus intermedius 
branch 
Branch vessel whose origin bisects the origins of 
the left anterior descending and circumflex 
arteries (RI) 
Ramus intermedius lateral 
branch 
Branch of the ramus intermedius branch 
Dissection: 
Based on the National Heart, Lung, and Blood Institute (NHLBI) Dissection 
Classification System: 
• 
Grade A: Minor radiolucencies within the lumen during contrast injection 
with no persistence after dye clearance  
• 
Grade B: Parallel tracts or double lumen separated by a radiolucent area 
during contrast injection with no persistence after dye clearance 
• 
Grade C: Extraluminal cap with persistence of contrast after dye clearance 
from the lumen 
• 
Grade D: Spiral luminal filling defect with delayed but complete distal flow 
• 
Grade E: New persistent filling defect with delayed antegrade flow 
• 
Grade F: Non-A-E types with total coronary occlusion and no distal 
antegrade flow 
Note: Grade E and F dissections may represent thrombus 
Late Loss: 
Minimum lumen diameter (MLD) assessed at follow-up angiography minus the 
MLD assessed immediately after the index procedure.  MLDs are measured by 
QCA. 


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Minimum Lumen Diameter 
(MLD): 
The mean minimum lumen diameter (typically measured in-lesion, in-stent, and 
in-segment) derived from two orthogonal views by QCA. 
No Reflow: 
An acute reduction in coronary flow (TIMI grade 0-1) in the absence of 
dissection, thrombus, spasm, or high-grade residual stenosis at the original target 
lesion. 
Percent Diameter Stenosis 
(% DS): 
The value calculated as 100 x (1 – MLD/RVD) using the mean values determined 
by QCA from two orthogonal views (when possible). 
Reference Vessel Diameter 
(RVD): 
Defined as the average of normal segments within 10 mm proximal and 10 mm 
distal to the target lesion from two orthogonal views using QCA. 
Restenosis: 
Re-narrowing of the vessel following the treatment of a prior stenosis  
• 
Binary restenosis: A diameter stenosis of > 50% at the previously treated 
lesion site, including the originally treated site plus the adjacent vascular 
segments 5 mm proximal and 5 mm distal to the site. 
• 
In-stent restenosis (ISR): A previously stented lesion with a > 50% diameter 
stenosis. 
Thrombus (Angiographic): 
A discrete, mobile, intraluminal filling defect with defined borders with or 
without associated contrast staining. 
TIMI (Thrombolysis in 
Myocardial Infarction) Flow 
Grades: 
• 
Grade 0 (no perfusion): There is no antegrade flow beyond the point of 
occlusion. 
• 
Grade 1 (penetration without perfusion): The contrast material passes 
beyond the area of obstruction but “hangs up” and fails to opacify the entire 
coronary bed distal to the obstruction for the duration of the 
cineangiographic filming sequence. 
• 
Grade 2 (partial perfusion): The contrast material passes across the 
obstruction and opacifies the coronary bed distal to the obstruction. 
However, the rate of entry of contrast material into the vessel distal to the 
obstruction or its rate of clearance from the distal bed (or both) is 
perceptibly slower than its entry into or clearance from comparable areas 
not perfused by the previously occluded vessel (eg, the opposite coronary 
artery or the coronary bed proximal to the obstruction). 
• 
Grade 3 (complete perfusion): Antegrade flow into the bed distal to the 
obstruction occurs as promptly as antegrade flow into the bed proximal to 
the obstruction and clearance of contrast material from the involved bed is 
as rapid as from an uninvolved bed in the same vessel or the opposite artery. 
Vessels 
• 
Left main coronary artery (LMCA) 
• 
Left anterior descending artery (LAD) with septal and diagonal branches 
• 
Left circumflex artery (LCX) with obtuse marginal branches 
• 
Ramus intermedius artery 
• 
Right coronary artery (RCA) and any of its branches 
• 
Posterior descending artery 




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subject who has been stabilized following initial treatment of 
acute limb ischemia, and there is clinical consensus that a 
definitive procedure should occur within the next 24 hours). 
b. 
Elective: An elective procedure is one that is scheduled and is performed 
on a subject with stable disease, or in whom there is no urgency and/or 
increased morbidity or mortality associated with a planned procedure.  
Target Lesion: 
A target lesion is any vascular segment treated or attempted to be treated during 
the trial procedure with the index device.  The target lesion is the treated segment 
starting 10 mm proximal and ending 10 mm distal to the index device or therapy 
(stent, balloon, atherectomy catheter, or aortic stent-graft). 
Target Vessel: 
A target vessel is any vessel (eg, non-cardiac or non-intracranial) that contains the 
target lesion treated with the study device.  The target vessel includes the target 
lesion as well as the entire length of native vessel upstream and downstream from 
the target lesion, including side branches.  For the arteries of the leg, the 
vasculature is divided into 3 vessel “levels:” aorto-iliac, femoral-popliteal, and 
tibial-crural. 
Non-Target Lesion and 
Non-Target Lesion 
Revascularization: 
A lesion for which revascularization is not attempted or one in which 
revascularization is performed using a non-study device, respectively. 
Non-Target Vessel and Non-
Target Vessel 
Revascularization: 
A vessel for which revascularization is not attempted or one in which 
revascularization is performed using a non-study device, respectively. 
Target Vessel, Non-Target 
Lesion and Target Vessel, 
Non-Target Lesion 
Revascularization: 
Any lesion or revascularization of a lesion in the target vessel other than the target 
lesion, respectively. 
Target Lesion 
Revascularization (TLR): 
Target lesion revascularization is any repeat intervention of the target lesion 
(including 10 mm proximal and 10 mm distal to the index device, as target lesion 
is defined above) or surgical intervention/bypass of the target vessel performed 
for restenosis or other complication involving the target lesion.  In the assessment 
of TLR, angiograms should be assessed by an angiographic core laboratory (if 
designated).  Angiograms (and core laboratory assessment thereof) and other 
source documentation should be made available to the CEC for review upon 
request. 
Target Vessel 
Revascularization (TVR): 
Target vessel revascularization is any repeat intervention or surgical bypass of 
any segment of the target vessel. In the assessment of TVR, angiograms should be 
assessed by an angiographic core laboratory (if designated).  Angiograms (and 
core laboratory assessment thereof) and other source documentation should be 
made available to the CEC for review upon request. 
Clinically-Driven Target 
Lesion Revascularization: 
Clinically-driven target lesion revascularization is defined as target lesion 
revascularization performed due to target lesion diameter stenosis >50% AND 
either evidence of clinical or functional ischemia (eg, recurrent/progressive 
intermittent claudication, critical limb ischemia) OR recurrence of the clinical 
syndrome for which the initial procedure was performed.  Clinically-driven target 




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− 
Typical rise and fall in cardiac biomarkers (refer to definition of 
spontaneous MI) 
− 
Nonocclusive thrombus:  Intracoronary thrombus is defined as a 
(spheric, ovoid, or irregular) noncalcified filling defect or 
lucency surrounded by contrast material (on 3 sides or within a 
coronary stenosis) seen in multiple projections, or persistence of 
contrast material within the lumen, or a visible embolization of 
intraluminal material downstream 
− 
Occlusive thrombus:  TIMI 0 or TIMI 1 intrastent or proximal 
to a stent up to the most adjacent proximal side branch or main 
branch (if originates from the side branch). 
b. Pathological Confirmation of Stent Thrombosis:  Evidence of recent 
thrombus within the stent determined at autopsy or via examination 
of tissue retrieved following thrombectomy. 
2. Probable Stent Thrombosis:  Clinical definition of probable stent 
thrombosis is considered to have occurred after intracoronary stenting in 
the following cases: 
a. 
Any unexplained death within the first 30 daysg 
b. Irrespective of the time after the index procedure, any MI that is 
related to documented acute ischemia in the territory of the 
implanted stent without angiographic confirmation of stent 
thrombosis and in the absence of any other obvious cause 
3. 
Possible Stent Thrombosis:  Clinical definition of possible stent 
thrombosis is considered to have occurred with any unexplained death 
from 30 days after intracoronary stenting until end of trial follow-up. 
a The 30-day cut-off is arbitrary. 
b 2012 Third Universal Definition of Myocardial Infarction. 
c The same criteria are used for supplemental leads V7-V9, and for the Cabrera frontal plane lead grouping. 
d Peripheral vascular disease includes veins, arteries, and lymphatics.  However, for simplicity, this definition 
focuses on peripheral artery and venous interventions. 
e The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not 
considered a confirmed stent thrombosis (silent occlusion). 
f Intracoronary thrombus. 
g For studies with ST-elevation MI population, one may consider the exclusion of unexplained death within 30 days 
as evidence of probable stent thrombosis. 
Source:  “Standardized Definitions for Cardiovascular and Stroke Endpoint Events in Clinical Trials,” dated 
August 20, 2014, and available at the CDISC website 
(http://www.cdisc.org/system/files/all/standard/Draft%20Definitions%20for%20CDISC%20August%2020,%2020
14.pdf). 
 


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APPENDIX F. SUMMARY OF CHANGES:  747-304 PROTOCOL VERSION 6.0 TO PROTOCOL 
VERSION 7.0 (DATED:  16 JUN 2021) 
Protocol 747-304 was revised to include the following information: 
1) Reorganization and updates to the study objectives and related sections on overall assessments and statistics 
2) Inclusion of Hepatic Safety Adjudication Committee and Renal Adjudication Committee for the adjudication of all events of 
potential hepatic injury and acute kidney injury, respectively.  The protocol was updated to ensure these events will be 
provided to the DMC for inclusion in their review as well as added to the Safety Objectives to be assessed at the End of Study. 
3) Updated process for the monitoring and management of potential DILI and updated the DILI algorithm and laboratory triggers 
to monitor hepatic injury 
4) Clarification of language on PK sample collection following investigational product interruption or discontinuation and within 
7 days of experiencing a serious adverse event.   
5) Additional sections added to address monitoring and management of renal impairment and nephrolithiasis, hyperglycemia, and 
dyslipidemia.  Additional education and assessments to identify intercurrent illness and/or potential adverse events was added.   
6) Inclusion of local laboratory results and reference ranges into the eCRF 
7) COVID-19-related changes to the protocol 
8) The use of “suspected” was globally updated to “potential” throughout the protocol 
9) Interactive web response system (IWRS) was updated to randomized and trial supply management system (RTSM) to align 
with new vendor terminology 
10) Previous Summary of Changes for each protocol amendment removed.  Moving forward, only the current Summary of 
Changes with be included. 
The text deleted from Protocol Version 6.0 is crossed out and revised text in Version 7.0 is indicated in bold font in the following 
table.  Each revision also includes a reason or justification for the change.  Section numbers refer to Version 7.0 unless otherwise 
stated.  Sections with extensive changes that are discussed elsewhere have been summarized rather than highlighting exact changes.  
Minor changes including typos or editorial revisions are not listed individually in the following table. 
 
 






































































































































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APPENDIX H. SUMMARY OF CHANGES:  PROTOCOL VERSION 5.0 
TO PROTOCOL VERSION 6.0 (DATED:  06 MAR 2020) 
Protocol 747-304 was revised to include the following information: 
1) DMC recommendation for treatment-emergent acute or nonacute pancreatitis 
2) Highly effective contraception language per CTFG guidance 
3) SUSAR definition per ICH guidance 
The text deleted from Protocol Version 5.0 is crossed out and revised text in Version 6.0 is 
indicated in bold font in the following table.  Each revision also includes a reason or justification 
for the change.  Section numbers refer to Version 6.0 unless otherwise stated.  Sections with 
extensive changes that are discussed elsewhere have been summarized rather than highlighting 
exact changes.  Minor changes including typos or editorial revisions are not listed individually in 
the following table. 
 
























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APPENDIX G. SUMMARY OF CHANGES:  PROTOCOL VERSION 4.0 
TO PROTOCOL VERSION 5.0 (DATED:  19 JULY 2019) 
Protocol 747-304 was revised to include the following information: 
1. The Double-Blind Phase was extended from 12 months to 18 months, with the addition 
of study visits at Month 15 and Month 18. 
2. Total enrollment was expanded from 540 subjects to 900 subjects 
 
4. Additional criteria for uptitration at Month 3 were included 
The text deleted from Protocol Version 4.0 is crossed out and revised text in Version 5.0 is 
indicated in bold font in the following table.  Each revision also includes a reason or justification 
for the change.  Section numbers refer to Version 5.0 unless otherwise stated.  Sections with 
extensive changes that are discussed elsewhere have been summarized rather than highlighting 
exact changes.  Minor changes including typos or editorial revisions are not listed individually in 
the following table. 
 


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Section 
Original Text (Version 4.0, 14 Jan 2019) 
Revised Text (Version 5.0, 19 July 2019) 
Key Change 
Reasons/ 
Justification for 
Change 
Study Personnel 
Contact 
Information 
 MD 
Intercept Pharmaceuticals, Inc. 
 MD 
Intercept Pharmaceuticals, Inc. 
Change in study 
personnel contact 
information. 
Synopsis: 
Studied 
Period/Duration 
of 
Treatment/Crite
ria for 
Evaluation/Effi
cacy Analysis 
and 
Section 6 
Study 
Objectives and 
Purpose 
and 
Section 7.1.3 
Study Duration 
and 
Section 11 
Overview of 
Assessments 
and 
Section 16.3 
Primary 
Efficacy 
Analysis 
The maximum duration of individual subject participation 
for this study is approximately 2 years and 3 months, 
including a Screening Period of up to 12 weeks, a 1 year 
Double-Blind Phase, and an optional Open-Label Extension 
(OLE) expected to last approximately 1 year. 
The maximum duration of individual subject 
participation for this study is approximately 2 years and 
6 months, including a Screening Period of up to 12 
weeks, an 18-month Double-Blind Phase, and an Open-
Label Extension (OLE) expected to last approximately 
1 year. 
EOS/EOT extended 
from Month 12 to 
Month 18 
 
While a treatment 
duration of 
12 months had 
initially been 
selected, emerging 
evidence suggests 
that 12 months may 
not be optimal to 
evaluate histological 
reversal of NASH 
cirrhosis. As such, 
the 18-month 
duration of the 
treatment period for 
Study 747-304 has 
been selected. 
 
“optional” removed 
as a redundancy 


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Section 
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Revised Text (Version 5.0, 19 July 2019) 
Key Change 
Reasons/ 
Justification for 
Change 
Synopsis: 
Objectives/Crit
eria for 
evaluation/Effic
acy Analysis 
and 
Section 6.1: 
Primary 
Objectives  
and 
Section 11: 
Overview of 
Assessments 
and 
Section 16.3: 
Primary 
Efficacy 
Analysis 
Histological improvement in fibrosis by assessing the 
percentage of subjects with improvement in fibrosis by at 
least 1 stage with no worsening of Nonalcoholic 
Steatohepatitis (NASH) defined as no increase in 
hepatocellular ballooning or lobular inflammation, using 
the NASH Clinical Research Network (CRN) scoring 
system, from Baseline to Month 12 
Histological improvement in fibrosis by assessing the 
percentage of subjects with improvement in fibrosis by 
at least 1 stage with no worsening of Nonalcoholic 
Steatohepatitis (NASH) defined as no increase in 
hepatocellular ballooning or lobular inflammation, using 
the NASH Clinical Research Network (CRN) scoring 
system, from Baseline to Month 18 
EOS/EOT extended 
from Month 12 to 
Month 18 
Synopsis: 
Objectives 
and 
Section 6.2 
Secondary 
Objectives 
and 
Section 11 
Overview of 
Assessments 
and 
Addition of a secondary objective 
• 
NASH resolution based on overall pathologist 
interpretation (resolution of definite NASH) 
from Baseline to Month 18 
Emerging evidence 
suggests that overall 
pathologist 
interpretation is a 
more consistent and 
reproducible way to 
evaluate NASH 


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Section 
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Revised Text (Version 5.0, 19 July 2019) 
Key Change 
Reasons/ 
Justification for 
Change 
Section 16.5.1 
Other Histology 
Endpoints 
Synopsis: 
Objectives/ 
Criteria for 
evaluation 
and 
Section 6.2: 
Secondary 
Objectives 
and 
Section 11: 
Overview of 
Assessments 
and 
Section 16.5.2: 
Clinical 
Outcomes 
• 
Occurrence of all-cause mortality and liver-related 
clinical outcomes for the following adjudicated events 
(clinical outcomes composite endpoint):  
− 
Death (all causes)  
− 
Liver transplant 
 
Hepatocellular carcinoma (HCC) as confirmed by 
2 complementary imaging modalities unless 
already confirmed by biopsy 
− 
Model for end-stage liver disease (MELD) score 
≥15  
− 
Worsening of Child-Pugh (CP) score (by at least 
2 points) 
− 
Hospitalization (as defined by a stay of ≥24 hours) 
for: 
o 
Variceal bleed 
o 
Hepatic encephalopathy (as defined by a West 
Haven score of ≥2) 
o 
Spontaneous bacterial peritonitis (confirmed 
by diagnostic paracentesis) 
− 
Ascites secondary to cirrhosis and requiring 
medical intervention (eg, diuretics or paracentesis) 
• 
Occurrence of individual components of outcome 
events  
• 
Occurrence of all-cause mortality and liver-related 
clinical outcomes for the following adjudicated 
events (clinical outcomes composite endpoint):  
− 
Death (all causes)  
− 
Liver transplant 
− 
Model for end-stage liver disease (MELD) 
score ≥15  
− 
Worsening of Child-Pugh (CP) score (by at 
least 2 points) 
− 
Hospitalization (as defined by a stay of 
≥24 hours) for: 
o 
Variceal bleed 
o 
Hepatic encephalopathy (as defined by a 
West Haven score of ≥2) 
o 
Spontaneous bacterial peritonitis 
(confirmed by diagnostic paracentesis) 
− 
Ascites secondary to cirrhosis and requiring 
medical intervention (eg, diuretics or 
paracentesis) 
• 
Occurrence of individual components of outcome 
events  
• 
Occurrence of hepatocellular carcinoma (HCC) 
as confirmed by 2 complementary imaging 
modalities unless already confirmed by biopsy 
HCC is not 
considered part of 
the composite 
endpoint so it was 
listed separately 
Synopsis: 
Objectives/Crit
The effect of OCA treatment compared to placebo on the 
following additional measures and markers: 
The effect of OCA treatment compared to placebo on the 
following additional measures and markers: 
To differentiate 
from liver function 


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Revised Text (Version 5.0, 19 July 2019) 
Key Change 
Reasons/ 
Justification for 
Change 
eria for 
Evaluation 
and 
Section 6.2 
Secondary 
Objectives 
and 
Section 11 
Overview of 
Assessments 
• 
Liver biochemistry and function 
• 
Liver biochemistry and synthetic function 
Synopsis: 
Objectives 
and 
Section 6.2: 
Secondary 
Objectives 
• 
The PK/pharmacodynamic (PD) relationships of OCA 
and its conjugates 
• 
Safety and tolerability 
• 
The PK/pharmacodynamic (PD) relationships of 
OCA and its conjugates 
• 
The effect of OCA treatment on liver function 
using 
 (conducted at US sites 
where capable) 
• 
Safety and tolerability 
 
was added as a 
substudy at US sites 
where capable 
Synopsis: 
Open-Label 
Extension 
and 
Section 7.1 
Overall Study 
Design 
and 
Section 9.2.2 
OLE Phase 
Subjects who complete the Double-Blind Month 12 Visit 
(and continue to receive investigational product) are eligible 
to enroll into the OLE.  All subjects will receive OCA upon 
entry into the OLE.  Subjects randomized to placebo in the 
Double-Blind Phase will be re-randomized to either OCA 
10 mg or OCA 10 mg → 25 mg (ie, OCA 10 mg for the first 
3 months of the OLE prior to uptitrating to OCA 25 mg at 
OLE Month 3).  Uptitration will be based on the safety and 
tolerability assessments completed prior to Month 3.  
Subjects randomized to OCA (10 mg or 25 mg dose) during 
the Double-Blind Phase will continue the same dosing 
regimen they received at the end of the Double-Blind Phase; 
however, they will undergo dummy titration to maintain 
study blind until all subjects complete the Double-Blind 
Phase and the database is locked. 
Subjects who complete the Double-Blind Month 18 Visit 
and continue to receive investigational product are 
eligible to enroll into the OLE.  All subjects will receive 
OCA upon entry into the OLE.  Subjects randomized to 
placebo in the Double-Blind Phase will be re-randomized 
to either OCA 10 mg or OCA 10 mg → 25 mg (ie, OCA 
10 mg for the first 3 months of the OLE prior to 
uptitrating to OCA 25 mg at OLE Month 3).  Uptitration 
will be determined based on the same criteria and 
assessments as employed in the Double-Blind Phase.  
Subjects randomized to OCA (10 mg or 10 mg → 25 mg 
dose) during the Double-Blind Phase will continue the 
same dosing regimen they received at the end of the 
Double-Blind Phase; however, they will undergo dummy 
titration to maintain study blind until all subjects 
 
 
 
 
 
 
Edited for clarity 




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Section 
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Revised Text (Version 5.0, 19 July 2019) 
Key Change 
Reasons/ 
Justification for 
Change 
Section 7.1.1 
Study Design 
Diagram: 
Overall Study 
Design 
• 
Two screening visit assessments will be performed.  
Screening Visit 1 will occur no more than 12 weeks 
prior to Day 1, and Screening Visit 2 will occur at least 
4 weeks after Screening Visit 1.  
• 
Subjects without a liver biopsy obtained ≤12 months 
prior to Day 1 must have a biopsy completed during the 
screening period.   
• 
Randomized subjects will be stratified by the presence 
of type 2 diabetes at enrollment (yes or no). 
• 
Subjects who received placebo during the Double Blind 
Phase will be re randomized to either OCA 10 mg or 
OCA 10 mg → 25 mg (ie, OCA 10 mg for the first 
3 months of the OLE prior to uptitrating to OCA 25 mg 
at OLE Month 3).  Subjects who received OCA during 
the Double Blind Phase will continue the same dosing 
regimen they received at the end of the Double Blind 
Phase. 
• 
The study will remain blinded until all subjects 
complete the Double-Blind Phase and the database is 
locked.  To maintain blinding, all investigational 
product (placebo and OCA) tablets and bottles will be 
identical.   
 
• 
Two screening visit assessments will be performed.  
Screening Visit 1 will occur no more than 12 weeks 
prior to Day 1, and Screening Visit 2 will occur at 
least 4 weeks after Screening Visit 1.  
• 
Randomized subjects will be stratified by the 
presence of type 2 diabetes at enrollment (yes or 
no). 
• 
The study will remain blinded until all subjects 
complete the Double-Blind Phase and the database 
is locked.  To maintain blinding, all investigational 
product (placebo and OCA) tablets and bottles will 
be identical.   
 
 
 
 
Removed bullet 
points are addressed 
other places in the 
protocol. 
 
 
 
Note added to 
footnote of Diagram 
Synopsis: 
Number of 
Subjects 
(planned)/ 
Enrollment and 
Randomization 
and 
Section 7.2 
Number of 
Subjects 
Approximately 540 subjects will be enrolled in the study 
Approximately 900 subjects will be enrolled in the study 
Enrollment 
expanded to 
900 subjects 


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Key Change 
Reasons/ 
Justification for 
Change 
Synopsis 
Exclusion 
Criteria 
and 
Section 8.1.2 
Subject 
Exclusion 
Criteria 
and 
Section 9.3 
Concomitant 
Medications 
and 
Section 9.8.3  
Screening 
Procedures 
Criteria with exclusionary laboratory values are to be based 
on the most recent laboratory result available prior to 
randomization.  For alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), and total bilirubin for 
which if Screening Visit 1 and Visit 2 values differ by 
≥30% and either of the lab values is > upper limit of normal 
(ULN), then a third sample will be collected at an 
unscheduled visit as a confirmatory sample.  Subjects who 
satisfy any of the following exclusion criteria will be 
ineligible for enrollment: 
 
 
 
1. Current or past history of hepatic decompensation such 
as clinically significant ascites (requiring medical 
intervention), variceal bleeding, spontaneous bacterial 
peritonitis, hepatic encephalopathy (Grade I or greater 
based on West Haven classification), or 
hepatorenal/hepatopulmonary syndromes 
 
6. AST ≥5× upper limit of normal (ULN) 
 
 
 
 
 
7. ALT ≥5× ULN 
 
 
 
Criteria with exclusionary laboratory values are to be 
based on the most recent laboratory result available prior 
to randomization.  For alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), or total bilirubin 
(conjugated bilirubin for subjects with an established 
diagnosis of Gilbert’s syndrome), if the Screening 
Visit 2 value is ≥30% higher than the Screening Visit 
1 value and > the upper limit of normal (ULN), then 
a third measurement must be obtained at an 
unscheduled visit.  Subjects who satisfy any of the 
following exclusion criteria will be ineligible for 
enrollment: 
 
1. Current or past history of a clinically evident hepatic 
decompensation event, such as ascites, variceal 
bleeding, spontaneous bacterial peritonitis, hepatic 
encephalopathy (Grade I or greater based on West 
Haven classification), or hepatorenal/hepatopulmonary 
syndromes 
 
6. AST ≥5× ULN  
a. If a third serum AST measurement is required, 
and both Screening Visit 2 and unscheduled 
visit AST values are ≥30% higher than the 
Screening Visit 1 value, the subject is ineligible 
for enrollment 
 
7. ALT ≥5× ULN  
a. If a third serum ALT measurement is required, 
and both Screening Visit 2 and unscheduled visit 
ALT values are ≥30% higher than the Screening 
Visit 1 value, the subject is ineligible for 
enrollment 
Edited to clarify 
when a third 
measurement is 
necessary 
 
 
 
 
 
 
 
Edited for clarity  
 
 
 
 
 
 
Edited for clarity 
 
 
 
 
 
Edited for clarity 
 
 
 


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Key Change 
Reasons/ 
Justification for 
Change 
 
8. Calculated creatinine clearance <60 mL/min using 
Cockcroft-Gault method at Screening 
 
9. Platelet count ≤100 000/mm3 at Screening 
 
10. Total bilirubin >2 mg/dL (subjects with an established 
diagnosis of Gilbert’s syndrome and a normal hemoglobin 
and reticulocyte count may be enrolled despite a total 
bilirubin level >2 mg/dL if their conjugated (direct) 
bilirubin is <2× ULN) 
 
 
 
 
 
 
 
 
13. International normalized ratio (INR) ≥1.7 (subjects with 
a known inherited blood disorder and INR ≥1.7 may be 
enrolled, and subjects on anticoagulant/anti aggregant 
treatment and INR ≥1.7 may be enrolled by approval of 
Medical Monitor) 
 
 
18. Evidence of other known forms of chronic liver disease 
including: 
− 
Positive test result at Screening for hepatitis B 
surface antigen  
8. Calculated creatinine clearance <60 mL/min using 
Cockcroft-Gault method  
 
9. Platelet count ≤100 000/mm3  
 
10. Total bilirubin >2 mg/dL (except for subjects with 
an established diagnosis of Gilbert’s syndrome, if 
hemoglobin and reticulocyte count are within the 
normal range and conjugated  bilirubin is <1.5× 
ULN)  
a. If a third serum total bilirubin measurement is 
required (conjugated bilirubin for subjects with an 
established diagnosis of Gilbert’s syndrome), both 
Screening Visit 2 and unscheduled visit values are 
≥30% higher than the Screening Visit 1 value, the 
subject is ineligible for enrollment. 
 
 
 
13. International normalized ratio (INR) ≥1.7  
 
 
 
 
 
 
18. Evidence of other known forms of chronic liver 
disease including: 
− 
Positive test result at Screening for hepatitis B 
surface antigen  
− 
Active hepatitis C virus (HCV) infection 
(positive for HCV ribonucleic acid [RNA] at 
 
“at Screening” is 
redundant in this 
section 
 
Exceptions for 
subjects with 
Gilbert’s syndrome 
added to clarify that 
bilirubin entry 
criteria should be 
based on conjugated 
bilirubin levels 
rather than total 
bilirubin levels 
 
 
 
 
Removed allowance 
for enrollment of 
subjects on 
anticoagulants with 
INR >/= 1.7 due to 
potential artificial 
inflation of 
MELD/CP scores 
 
 
 
 


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Key Change 
Reasons/ 
Justification for 
Change 
− 
Active hepatitis C virus (HCV) infection (positive 
for HCV ribonucleic acid [RNA] at Screening) or 
confirmed history of a positive HCV RNA test 
result(s) 
− 
Primary biliary cholangitis, primary sclerosing 
cholangitis, autoimmune hepatitis, or overlap 
syndrome 
− 
Alcoholic liver disease 
− 
Wilson disease, hemochromatosis, or iron overload 
− 
Alpha-1-antitrypsin (A1AT) deficiency as defined 
by diagnostic features in liver histology 
(confirmed by A1AT level below the lower limit 
of normal or exclusion at the Investigator’s 
discretion) 
− 
Prior known drug-induced liver injury within 5 
years before Day 1 
− 
Known or suspected HCC  
 
 
 
 
 
 
 
19. History of liver transplant, current placement on a liver 
transplant list  
 
20. Hemoglobin A1c ≥9.5% within 60 days before Day 1 
 
 
Screening) or confirmed history of a positive 
HCV RNA test result(s) except for subjects 
with evidence of spontaneous HCV 
eradication (defined as positive HCV 
antibodies at Screening, no history of 
positive HCV RNA result, and 
documentation that no anti-HCV therapy 
has been received) 
− 
Primary biliary cholangitis, primary sclerosing 
cholangitis, autoimmune hepatitis, or overlap 
syndrome 
− 
Alcoholic liver disease 
− 
Wilson disease, hemochromatosis, or iron 
overload 
− 
Alpha-1-antitrypsin (A1AT) deficiency as 
defined by diagnostic features in liver histology 
(confirmed by A1AT level below the lower 
limit of normal or exclusion at the 
Investigator’s discretion) 
− 
Prior known or suspected drug-induced liver 
injury within 5 years before Day 1 
− 
Known or suspected HCC  
 
 
 
 
19. History of liver transplant, or current placement on 
a liver transplant waiting list  
 
20. Hemoglobin A1c (HbA1c) ≥9.5% within 90 days 
before Day 1 
 
Exception added to 
allow enrollment of 
subjects with a 
history of 
spontaneous HCV 
eradication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Edited for clarity 
 
 
 
Changed to align 
with 747-303 
protocol 
 


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Key Change 
Reasons/ 
Justification for 
Change 
 
21. Low-density lipoprotein (LDL) cholesterol ≥190 
mg/dL and already on a stable dose of statin and/or 
proprotein convertase subtilisin/kexin type 9 (PCSK9) 
inhibitor for ≥30 days at Screening 
 
22. LDL cholesterol <50 mg/dL (irrespective of statin use) 
 
28. Chronic use (≥12 months) of drugs historically 
associated with drug-induced NAFLD within the 5 years 
before Day 1 (eg, amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at 
doses greater than those used for hormone replacement, 
anabolic steroids, valproic acid, and other known 
hepatotoxins).  
 
 
 
 
 
Addition of criteria 37 and 38 
 
21. Low-density lipoprotein (LDL) cholesterol 
≥190 mg/dL and already on a stable dose of LDL-
lowering medication for ≥30 days 
 
 
22. LDL cholesterol <50 mg/dL in subjects not on 
LDL-lowering medication 
 
28. Chronic use (≥12 months) of drugs historically 
associated with drug-induced NAFLD within the 5 
years before Day 1 (eg, amiodarone, methotrexate, 
systemic glucocorticoids [unless used at physiologic 
replacement doses for the treatment of adrenal 
insufficiency], tetracyclines, tamoxifen, estrogens at 
doses greater than those used for hormone replacement, 
anabolic steroids [except for testosterone 
preparations used at physiologic replacement doses 
for the treatment of documented/confirmed 
hypogonadism], valproic acid, and other known 
hepatotoxins). 
 
37. Alkaline phosphatase ≥1.5x ULN 
 
 
 
 
 
 
38. History of known or suspected hypersensitivity to 
any ingredient in human albumin preparations (at 
US sites where 
will be conducted) 
Expanded to any 
LDL-lowering 
medication 
 
 
Expanded to any 
LDL-lowering 
medication 
 
 
Exception added for 
adrenal 
insufficiency 
 
Exception added for 
hypogonadism 
 
 
Added ALP 
exclusion based on 
FDA draft guidance 
for NASH cirrhosis 
(June 2019) 
 
Synopsis 
Clarification added 
Specific details of the events that will be adjudicated 
by the Cardiovascular Adjudication Committee and 
Added for clarity 


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Key Change 
Reasons/ 
Justification for 
Change 
Event 
Adjudication 
and 
Section 16.11.2 
Adjudicated 
Cardiovascular 
Events 
and 
Section 16.14 
Adjudication 
Committees 
Hepatic Outcomes Committee are described in the 
respective adjudication charters.  Any changes to 
either the adjudication process or changes to specific 
events to be adjudicated will be addressed in the 
charters and will be communicated to all study sites.  
Synopsis 
Criteria for 
Evaluation 
and 
Section 11: 
Overview of 
Assessments 
and 
Table 13 
And 
Section 16 
Statistics 
Markers of cardiovascular safety 
Lipoproteins (LDL, HDL, VLDL, ApoB, ApoA-1, ApoE, 
Lp[a]), total cholesterol, triglycerides, PCSK9, 
cardiovascular risk scores (FRS, Reynolds score, and 
SCORE) 
 
Noninvasive assessments of liver disease assessed by serum 
markers and imaging tests: 
:  NFS, FIB-4, and 
APRI 
Noninvasive panel of circulating fibrosis markers:  ELF, 
FibroMax, and FibroMeter 
Noninvasive radiological liver fibrosis measurements 
(conducted at sites where device is available): TE 
Fibroscan®, MRE 
 
 
PK/PD of OCA and conjugates 
Markers of cardiovascular safety 
Lipoproteins (LDL, HDL, VLDL, ApoB, ApoA-1, 
ApoE, Lp[a]), total cholesterol, triglycerides, PCSK9, 
cardiovascular risk scores (10-year ASCVD Risk, 
FRS, Reynolds score, and SCORE) 
 
Noninvasive assessments of liver disease assessed by 
serum markers and imaging tests: 
Noninvasive scores of liver fibrosis:  NFS, FIB-4, 
and APRI 
Noninvasive panel of circulating fibrosis markers:  
ELF, and FibroMeter 
Noninvasive radiological liver fibrosis measurements 
(conducted at sites where device is available): TE 
Fibroscan® and/or MRE (only in subjects enrolled 
prior to Version 5 of the protocol who already 
had baseline MRE; not in newly enrolled 
subjects) 
 
PK/PD of OCA and conjugates 
10-year ASCVD 
Risk was added to 
the markers of 
cardiovascular 
safety 
 
 
 
 
Fibromax marker 
removed 
 
MRE will only be 
continued for 
subjects with a 
baseline 
measurement 
 
 
Edited for clarity 
 
 
 


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Key Change 
Reasons/ 
Justification for 
Change 
The exposure response relationships between OCA PK and 
PD biomarkers of FXR activation and NASH  
 
 
 
Addition of HepQuant procedure 
 
Exposure-response relationships between OCA 
PK and efficacy endpoint(s) along with PD 
markers of FXR activation 
 
 
Liver function assessment using HepQuant-SHUNT 
DSI, a marker of liver function, as assessed by 
HepQuant-SHUNT measures (conducted at US 
sites where capable) 
 
 
 
HepQuant Shunt 
was added as a 
substudy at US sites 
where capable 
Synopsis 
Efficacy 
Analysis 
And 
Section 16.4 
Secondary 
Efficacy 
Analysis 
The type 1 error for the primary efficacy analysis will be 
controlled at 0.01. 
The type 1 error for the primary efficacy analysis will be 
controlled at 0.05. 
 
As the study is 
testing a single 
hypothesis, a 2-
sided type I error at 
0.05 level is 
assumed with no 
multiplicity 
adjustment.  Given 
Study 747-304 is 
designed to support 
a single study 
approval, the 
Sponsor 
acknowledges that 
the p value for the 
primary endpoint 
will need to be 
robust.  Of note, this 
sample size will 
provide at least 80% 
probability to 
achieve a p-value < 
0.01. 
 
-


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Key Change 
Reasons/ 
Justification for 
Change 
Synopsis 
Pharmacodyna
mic Analyses 
and 
Section 16.5.8 
HepQuant-
Shunt 
Addition of HepQuant-SHUNT analysis 
HepQuant Shunt 
was added as a 
substudy at US sites 
where capable 
Synopsis: 
Pharmacokineti
c/Pharmacodyn
amic Analyses 
A sequential approach will be used to perform the 
population PK/PD analysis.  The Bayesian estimates of 
individual PK parameters from the final population PK 
model will be used to generate PK profiles for each subject.  
The change in each PD assessment (eg, C4, FGF 19) over 
time will be incorporated into a maximum effect (Emax) 
model with OCA dose level as an independent variable.  
Estimated model parameters for each individual will be 
derived from prior Emax, and the half maximal effective 
concentration values, and baseline measures of each PD 
assessment.  The appropriate structure of the variance
covariance matrix will also be evaluated.  Fixed and 
random effect parameter estimates and associated 
asymptotic standard errors will be estimated.  Descriptive 
statistics will be used to summarize Bayesian estimates of 
PK/PD parameters obtained from individual assessments in 
the population PK/PD model.  These PK/PD analyses will 
be reported in a separate document outside of the clinical 
study report. 
Exploratory plots for efficacy endpoints and markers 
of FXR activation versus plasma exposure of total 
OCA will be generated.  A locally estimated 
scatterplot smoothing (LOESS) line will be used to 
assess potential relationships.  Additional analyses, 
including maximum effect (Emax) models, may also be 
performed based on the exploratory results.  Details 
of these analyses will be specified in the statistical 
analysis plan and/or clinical pharmacology analysis 
plan.   
 
PK/PD analysis 
updated 
Synopsis 
Sample Size 
Justification 
and 
Section 16.2: 
A sample size of 180 subjects per group with an assumed 
5% discontinuation rate will provide 90% power to 
demonstrate a statistically significant treatment difference 
between OCA 25 mg and placebo groups based on 
Chi square test with 2 sided type I error at 0.01 level.  This 
assumes a responder rate of 23% and 8% in the OCA and 
A sample size of 300 subjects per group will provide 
at least 90% power to detect a statistically significant 
treatment difference of 10% between OCA 25 mg 
and placebo groups based on a Chi-square test with 
2-sided type I error at 0.05 level, assuming a 
responder rate of 10% in the placebo group.  As 
Enrollment 
expanded to 
900 subjects and 
adjustment of type 1 
error 


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Determination 
of Sample Size 
placebo groups, respectively, based on data from literature, 
observed effect size on fibrosis improvement in advanced 
fibrosis subjects in the Farnesoid X receptor Ligand OCA 
in Nonalcoholic Steatohepatitis Treatment (FLINT) study 
and practical consideration. 
there was no previous study performed using the 
same endpoint in this disease, the assumption was 
determined based on data from literature, and 
results from the Farnesoid X receptor Ligand OCA 
in Nonalcoholic Steatohepatitis Treatment (FLINT) 
study and Study 747-303. 
 
 
 
 
 
Section 5.1 
Overview of 
Nonalcoholic 
Steatohepatitis 
and Obeticholic 
Acid 
Despite the seriousness of the disease, there are currently no 
approved therapies for the treatment of NASH nor an 
accepted standard of care.  The therapeutic options for 
NASH are largely limited to lifestyle modifications and 
treatment of concurrent conditions such as diabetes 
(Neuschwander Tetri 2003, Belfort 2006, Sanyal 2010, 
Chalasani 2012).  For patients with NASH without diabetes, 
practice guidelines from the American Association for the 
Study of Liver Diseases recommend the use of vitamin E as 
first line therapy (Chalasani 2012).  
However, there are currently no approved treatments 
targeting the underlying pathophysiology, of progressive 
fibrosis or cirrhosis. 
 
Obeticholic acid (OCA) is a modified bile acid and 
farnesoid X receptor (FXR) agonist that is derived from the 
primary bile acid chenodeoxycholic acid (CDCA). 
OCA’s potent FXR agonist effects make it an attractive 
novel therapeutic agent for NASH due to its multiple FXR-
mediated effects including an increase in insulin sensitivity, 
glucose and lipid metabolism, hepatocyte protection against 
bile acid induced cytotoxicity, anti inflammatory effects in 
Despite the seriousness of the disease,especially when 
advance fibrosis/cirrhosis is present, there are 
currently no approved pharmacologic treatments. 
 
 
 
 
 
 
 
 
 
 
Obeticholic acid (OCA) is a modified bile acid and 
farnesoid X receptor (FXR) agonist that is derived from 
the primary bile acid chenodeoxycholic acid (CDCA), 
the natural human FXR ligand. 
OCA’s potent FXR agonist effects make it an attractive 
novel therapeutic agent for NASH due to its multiple 
FXR-mediated effects, including prevention and reversal 
of liver fibrosis, anti-inflammatory effects in liver and 
vasculature, and hepatocyte protection against 
bile-acid-induced cytotoxicity.  Specifically, 
Edited for 
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liver and vasculature, and prevention and reversal of liver 
fibrosis (Adorini 2012, Mudaliar 2013).  Specifically, 
nonclinical studies have shown several potentially 
beneficial properties of FXR agonism in NASH. 
nonclinical studies have shown several potentially 
beneficial properties of FXR agonism in NASH and 
cirrhosis (Adorini 2012, Mudaliar 2013). 
Section 5.2 
Nonclinical 
Experience with 
OCA 
In addition, OCA plays a broad role in improving glycemic, 
metabolic, and cardiovascular parameters: 
• 
FXR plays a role in bile acid homeostasis, 
metabolism, and clearance (Cariou 2006, 
Ma 2006, Zhang 2008). 
• 
FXR controls glucose metabolism through 
regulation of gluconeogenesis and 
glycogenolysis in the liver, as well as 
regulation of peripheral insulin sensitivity in 
striated muscle and adipose tissue (Zhang 
2006). 
• 
In nonclinical models, FXR agonism is 
associated with beneficial effects on body 
weight and composition (Fu 2004, Xu 2009). 
• 
The absence of endogenous intact FXR 
signaling results in dyslipidemia and a hepatic 
phenotype similar to NASH patients (Zhang 
2008).  Conversely, FXR agonists lower 
plasma triglycerides by repressing hepatic 
sterol regulatory element binding protein 1 c 
(Watanabe 2004) and increased hepatic fatty 
acid oxidation (Savkur 2005). 
In summary, there is strong rationale to advance OCA 
for the treatment of NASH based on its FXR-mediated 
hepatoprotective properties. 
Edited for 
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• 
In addition, OCA and other FXR agonists are 
anti atherogenic and cardioprotective in 
animal models (Miyazaki Anzai 2010, 
Hartman 2009). 
In summary, there is strong rationale to advance OCA for 
the treatment of NASH based on its FXR-mediated 
hepatoprotective properties, anti fibrotic effects in a NASH 
model, and results indicating that OCA improves glycemia 
by increasing peripheral glucose uptake, enhancing glucose
stimulated insulin secretion, and inhibiting hepatic lipid 
synthesis and content while inducing lipid uptake by 
adipocytes. 
Section 5.3 
Clinical 
Experience with 
Obeticholic 
Acid 
OCA is under investigation for the treatment of multiple 
chronic liver diseases, including the treatment of NASH, 
primary biliary cholangitis (PBC, also called primary 
biliary cirrhosis) [Beuers 2015a, Beuers 2015b, Beuers 
2015c]), primary sclerosing cholangitis, biliary atresia, and 
other chronic liver diseases.  OCA was granted accelerated 
approval by the United States Food and Drug 
Administration (FDA) on 27 May 2016.  Conditional 
approvals were obtained on 12 Dec 2016 in the European 
Union (EU), and by Health Canada on 24 May 2017 under 
the trademark Ocaliva for the treatment of PBC in 
combination with ursodeoxycholic acid (UDCA) in adults 
with an inadequate response to UDCA, or as monotherapy 
in adults unable to tolerate UDCA. 
 
OCA (Ocaliva) has received marketing authorization 
in the United States, Europe, Canada, and several 
other countries for the treatment of primary biliary 
cholangitis (PBC) in combination with ursodeoxycholic 
acid (UDCA) in adults with an inadequate response to 
UDCA, or as monotherapy in adults unable to tolerate 
UDCA.  OCA is currently being developed for the 
treatment of multiple chronic non-viral liver 
diseases, including the treatment of NASH with 
fibrosis, NASH with cirrhosis, primary sclerosing 
cholangitis, and biliary atresia. 
 
 
 
Edited for clarity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The clinical development program for OCA in subjects with 
NAFLD or NASH includes data from the following 4 
completed studies: 
• 
Double Blind Phase of Study 747-209: A Phase 2, 
double-blind, randomized, placebo-controlled, 
multicenter study evaluating the effect of OCA, and the 
subsequent addition of statin therapy, on lipoprotein 
metabolism in subjects with NASH with fibrosis stage 
1 to 4, but no evidence of hepatic decompensation. 
Addition of studies 747-117 and 747-118 
 
 
 
 
 
 
 
 
 
 
Low-density lipoprotein (LDL) cholesterol demonstrated a 
modest but significant increase in subjects treated with 
The clinical development program for OCA in subjects 
with NAFLD or NASH includes data from the following 
6 completed studies:  
• 
Study 747-209: A Phase 2, double-blind, 
randomized, placebo-controlled, multicenter study 
evaluating the effect of OCA, and the subsequent 
addition of statin therapy, on lipoprotein metabolism 
in subjects with NASH with fibrosis stage 1 to 4, but 
no evidence of hepatic decompensation. 
• 
Study 747-117: A Phase 1, double-blind, 
randomized, placebo-controlled study evaluating 
the safety, pharmacokinetics, and 
pharmacodynamics of OCA in subjects with 
NASH fibrosis. 
• 
Study 747-118: A Phase 1, single-center, double-
blind, randomized study evaluating the safety, 
pharmacokinetics, and pharmacodynamics of 
OCA in healthy subjects and subjects with 
compensated Child-Pugh (CP) Class A cirrhosis 
due to NASH. 
− 
Including a 747-118 hepatic PK 
substudy in subjects with cirrhosis 
due to NASH. 
 
Low-density lipoprotein (LDL) cholesterol 
demonstrated a modest but significant increase in 
 
 
 
 
Study 209 has been 
completed 
 
 
 
 
 
747-117 and 
747-118 have been 
completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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OCA compared to placebo; however, this increase was 
reversed and LDL cholesterol returned to below baseline 
levels in subjects who initiated statin therapy.  The change 
in lipid profile, which was attenuated with continued 
treatment and reversed post treatment, needs to be further 
investigated mechanistically and with respect to clinical 
management with standard of care statin therapy.  The 
general adverse event (AE) profile was similar across both 
groups, with the exception of pruritus. 
 
Study 747 209 enrolled subjects with histological evidence 
of definite or probable NASH confirmed by liver biopsy 
and a nonalcoholic fatty liver disease activity score (NAS) 
of 4 or greater, randomized in a 1:1:1:1 ratio to receive 
OCA 5 mg, OCA 10 mg, OCA 25 mg or placebo, orally 
once daily, for 16 weeks.  Randomization was stratified by 
LDL concentration (fasting serum low density lipoprotein 
(LDL) cholesterol at Screening Visit 2; ≤125 mg/dL or 
>125 mg/dL) and baseline fibrosis stage (stage 1, 2 or 
stage 3, 4).  Statin free subjects as well as statin treated 
subjects (following a 4 week statin washout) were eligible 
for enrollment.  All subjects initiated treatment with 
atorvastatin at a dose of 10 mg once daily after 4 weeks of 
OCA treatment.  After 4 weeks of 10 mg atorvastatin 
treatment, dosing was increased to 20 mg once daily, and 
continued for an additional 4 weeks.  After 4 weeks of 
treatment at 20 mg daily dose, atorvastatin dosing could be 
titrated up or down as clinically indicated.   
subjects treated with OCA compared to placebo; 
however, this increase was reversed and LDL 
cholesterol returned to below baseline levels in subjects 
who initiated statin therapy.  The general adverse event 
(AE) profile was similar between the OCA 25 mg and 
placebo groups, with the exception of pruritus. 
 
 
 
 
Study 747-209 further evaluated the effect of OCA 
and atorvastatin treatment on LDL metabolism in 
subjects with NASH and liver fibrosis to better 
characterize the lipid profile changes observed in the 
FLINT study, as well as their management.  Subjects 
with biopsy-confirmed NASH and fibrosis received 
placebo or OCA 5mg, 10 mg, or 25 mg once daily, for 
up to 4 weeks.  Subjects initiated concurrent 
treatment with atorvastatin 10 mg once daily, 
titrated to 20 mg once daily at Week 8 based on 
tolerability.  At Week 4, subjects experienced an 
approximately 20% to 25% increase in LDLc 
concentrations across all OCA groups.  By Week 8, 
atorvastatin treatment effectively lowered LDLc to 
below baseline levels across all treatment groups.  
Together, these study results suggest that the risk of 
increases in LDLc with OCA use can generally be 
managed by statin use.  Pruritus was the most 
Description of 
effects of OCA on 
lipid metabolism 
from study 747-209 
edited for clarity 
 
 
 
 
 
 
 
 
Replaced with an 
updated summary of 
Study 747-209 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A total of 84 subjects were randomized into the study, with 
baseline cirrhosis status being pre cirrhotic in 62 (74%) 
subjects and cirrhotic in 22 (26%) subjects.  Seventy nine 
(94%) subjects completed the Double Blind Phase.  An 
increase in LDL cholesterol was observed following 
treatment with OCA and the addition of low dose 
atorvastatin (10 mg) reversed OCA associated changes in 
LDL cholesterol back to baseline levels and lower within 4 
weeks. 
Three subjects discontinued due to AEs: 1 subject on OCA 
5 mg for Stage 4 breast cancer, and 2 subjects on OCA 25 
mg for pruritus. 
 
 
 
 
 
 
 
 
 
 
 
common AE and was dose dependent.  Two subjects 
discontinued the study due to pruritus.  
 
Study 117 demonstrated that the PK profile of OCA 
in subjects with NASH fibrosis was consistent with 
what has been observed in healthy subjects and 
largely reflective of enterohepatic recirculation with 
exposure proportional to dose.  Treatment with OCA 
10 mg or 25 mg once daily for 12 weeks was found to 
be safe and well tolerated in NASH subjects with 
fibrosis (including fibrosis stage 1 through stage 4).  
The PD assessments demonstrated FXR activation 
and positive trends for select markers of fibrosis, 
inflammation, apoptosis, and liver function.   
Study 747-118 demonstrated that the safety profile of 
10 mg and 25 mg doses of OCA in subjects with 
compensated CP Class A cirrhosis due to NASH was 
similar to the safety observed in healthy subjects, 
supporting their use in longer term efficacy studies. .  
The hepatic PK substudy demonstrated that OCA 25 
mg was safe and generally well tolerated, showing 
improvements in the levels of liver biochemistry 
markers associated with hepatocellular injury when 
administered for 28 days to subjects with CP Class A 
cirrhosis due to NASH, consistent with results from 
the double blind period. 
 
 
 
 
 
Description of 
newly completed 
studies added 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In addition, the following studies evaluating OCA for the 
treatment of NASH are currently ongoing: 
• 
The open label extension portion of Study 
747 209. 
• 
A Phase 3, double blind, randomized, long
term, placebo controlled, multicenter 
international study (Study 747 303) evaluating 
the safety and efficacy of OCA in precirrhotic 
subjects with NASH. 
 
The following studies evaluating OCA for the treatment 
of NASH are currently ongoing: 
• 
The clinical outcome portion of Study 
747-303. 
A complete description of the OCA clinical 
development program is provided in the 
Investigator’s Brochure. 
 
 
 
 
747-209 has been 
completed 
 
Update to 747-303 
ongoing study 
Section 5.4.1 
Rationale for 
Study Design 
NASH is a serious, chronic liver disease with a large unmet 
medical need and no approved therapies.  The incidence of 
NASH is increasing, and NASH is likely to be the leading 
cause of liver transplant by 2020, highlighting the need for 
development of effective therapies that may improve 
steatohepatitis and fibrosis, potentially delaying liver 
transplant or death.  The FLINT study has demonstrated 
that OCA can improve individual features of steatohepatitis 
as well as fibrosis (Neuschwander Tetri 2015).  As fibrosis 
has been consistently shown to be the strongest predictor of 
adverse clinical outcomes, including liver-related death, it 
is critical to prevent further progression of fibrosis and 
preferably reverse fibrosis.  The effects of OCA on fibrosis 
are currently being evaluated in a Phase 3 study in subjects 
with NASH and liver fibrosis.  Patients with cirrhosis in the 
spectrum of NASH disease continuum represent the highest 
NASH is a serious, chronic liver disease with a large 
unmet medical need and no approved therapies.  
Patients with cirrhosis in the spectrum of NASH 
disease continuum represent the highest unmet 
medical need and are at the greatest risk of disease 
progression.  NASH is likely to be the leading cause of 
liver transplant by 2020, highlighting the need for 
development of effective therapies that may improve 
steatohepatitis and fibrosis, potentially delaying liver 
transplant or death.  As fibrosis has been consistently 
shown to be the strongest predictor of adverse clinical 
outcomes, including liver-related death, it is critical to 
prevent further progression of fibrosis and preferably 
reverse fibrosis.  Results from FLINT and the 
18-month interim analysis of Study 747-303 have 
demonstrated that OCA has robust anti-fibrotic 
Rationale expanded 
and clarified. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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unmet medical need and are at greatest risk of disease 
progression.  Thus, Study 747-304 will evaluate efficacy 
and safety of OCA in subjects with histological evidence of 
NASH with cirrhosis (defined by a NASH Clinical 
Research Network [CRN] score of 4), with the exception of 
subjects with hepatic decompensation or Child-Pugh 
(CP) score ≥7.  The efficacy of OCA in this study will be 
evaluated based on histological improvement in fibrosis. 
effects and improves underlying disease activity and 
steatohepatitis in NASH subjects with fibrosis at the 
18 month assessment.  .  Study 747-304 will evaluate 
efficacy (based on histological improvement in 
fibrosis) and safety of OCA in NASH subjects with 
compensated cirrhosis (defined by a NASH Clinical 
Research Network [CRN] score of 4), and C 
(CP) score <7.   
 
 
 
 
 
 
Section 5.4.3 
Rationale for 
Obeticholic 
Acid Doses and 
Duration 
Removal of a paragraph 
The duration of the 12 week titration is based upon results 
seen in the prior PBC program which effectively 
demonstrated titration for biologically altering the FXR 
signaling pathways thus inducing bile acid levels.  Overall 
study duration was determined based on findings in prior 
NASH studies ranging from 6 months to 72 weeks.  While 
the largest Phase 2 study of OCA in NASH patients was 
conducted over a period of 72 weeks, recent reports suggest 
that fibrosis improvement can be observed earlier than 
72 weeks (Sanyal 2016, Loomba 2016).  Modest decreases 
of serum markers of fibrosis (hyaluronic acid [HA], 
procollagen III amino terminal peptide [P3NP], and tissue 
inhibitor of metalloproteinase 1 [TIMP 1]) were seen after 
only 6 weeks of OCA 25 mg treatment (Study 747 203).  
Furthermore, in FLINT, OCA demonstrated reductions in 
fibrosis scores as early as 6 months after treatment with 
OCA, and these reductions were associated with histologic 
fibrosis improvement at 72 weeks.  Therefore, it is 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale updated to 
reflect new 
information from 
the program 


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reasonable to expect that a 12 month placebo controlled 
treatment period is sufficient to demonstrate an OCA 
treatment effect and a pattern of responses in this study 
population (Chalasani 2012). 
Addition of 18 Month treatment duration rationale 
 
 
 
 
Rationale for Treatment Duration of 18 Months 
The natural history of NASH with liver fibrosis 
shows that both progression and regression of liver 
fibrosis are slow processes that may take years to 
develop as well as to improve.  A systematic review 
and meta-analysis of paired-biopsy studies has 
shown that a 1-stage change in fibrosis occurs over a 
median of 7.1 years in patients with NASH (Singh 
2015).  Regression of fibrosis in established NASH 
cirrhosis is expected to take even longer (Cheung 
2019).  To date, no clinical trial in subjects with 
NASH cirrhosis has demonstrated efficacy with 
respect to reversal of cirrhosis and there are no 
approved treatment options for NASH cirrhosis. 
As presented above, OCA has shown robust anti-
fibrotic effects based on histologic endpoints in pre-
cirrhotic NASH subjects with liver fibrosis. A 
treatment duration of 12 months was initially 
selected for the placebo-controlled portion of this 
study based on non-histological data (using serum 
biomarkers of fibrosis observed in Study 747-203 
and FLINT). However, the effects of OCA on liver 
histology at earlier time points, including 12 months, 
had not been assessed. The preliminary results of the 
18-month interim analysis from Study 747-303 
showed that OCA 25 mg was superior to placebo, 


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demonstrating histological improvement of NASH 
fibrosis without worsening of NASH with an effect 
size of ~11% over 18 months of treatment (Younossi 
2019). However, the results also highlighted the slow 
process of regression of liver fibrosis and the 
potential challenges of demonstrating efficacy in 
regression of liver fibrosis within a finite time period. 
To reduce the chance of a false negative study, based 
on the above considerations, the duration of 
treatment in the double-blind phase has been 
extended to 18 months. 
Section 5.5.1 
Risk/Benefit 
Profile of OCA 
in Subjects with 
NASH 
An independent data monitoring committee (DMC) has 
performed detailed reviews of several studies including the 
Phase 3, clinical outcomes study in PBC (747 302) and the 
Phase 3, pivotal study in NASH with fibrosis (747 303).  
The DMC reviewed data (unmasked for PBC and unblinded 
by treatment group for NASH with a total of approximately 
1000 subjects) in closed sessions, which excluded 
participation of the Sponsor.  Based on these reviews, the 
DMC recommended that both studies continue without 
modification providing further support for the lack of safety 
concern and positive benefit risk profile of OCA. 
An independent data monitoring committee (DMC) 
has performed detailed reviews of individual subject 
and aggregate data from both the Phase 3 clinical 
outcomes study in subjects with PBC (Study 747-302) 
and the Phase 3 pivotal studies in subjects with 
NASH fibrosis (Study 747-303) and NASH cirrhosis 
(Study 747-304) on a quarterly basis, in an unblinded 
fashion, and in closed sessions (without the Sponsor’s 
participation).  In the quarterly DMC meetings to 
date, the DMC has recommended the studies 
continue without modification. 
Following a request from the FDA to provide an up 
to date DMC report analyzing unblinded data on 
respective incidence of cholecystitis, cholelithiasis, 
and pancreatitis by treatment group across all 
Updated based on 
recent 
communication with 
the DMC 


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ongoing clinical studies, an ad hoc DMC review was 
held and the DMC recommended that: 
• 
As it concerned pancreatitis, all studies 
continue without changes. 
• 
For subjects in Study 747-303, 
investigational product should be 
uninterrupted in subjects who experience 
symptomatic cholelithiasis and/or 
cholecystitis. 
The Sponsor decided to implement the DMC 
recommendations across the NASH program 
Section 5.6 
Importance of 
Monitoring of 
Disease 
Progression 
NASH is a chronic, progressive liver disease; therefore, it is 
important that subjects with NASH are closely monitored to 
ensure early identification of potential disease progression 
to cirrhosis, decompensation and/or liver injury.  The rate 
of progression and risk of decompensation is variable and 
may be rapid in certain patients necessitating closer 
surveillance of patients at risk.  Therefore, more extensive 
safety monitoring and appropriate dosing adjustments, 
interruptions, and discontinuations will be implemented to 
improve subject oversight and safety.  Investigators 
together with the Sponsor’s Medical Monitor or designee 
will consistently and frequently assess individual subjects 
to determine on an ongoing basis the totality of a subject’s 
clinical profile, which includes careful evaluation of signs 
and symptoms of potential hepatic injury and/or 
NASH is a chronic, progressive liver disease with 
variable rates of progression to cirrhosis and hepatic 
decompensation, although both may occur rapidly in 
certain patients. Subjects with NASH cirrhosis have 
accentuated risks relative to subjects with non-
cirrhotic NASH and can transition abruptly from a 
clinically-compensated state to decompensated 
cirrhosis, with the manifestations of portal 
hypertension and impaired synthetic function that 
characterize end-stage liver disease. Subjects with 
NASH cirrhosis must therefore be closely monitored 
to ensure early identification of signs and symptoms 
of decompensation and/or liver injury. In this study, 
close and thorough safety monitoring is paired with 
appropriate investigational product dosing 
adjustment, interruption, and discontinuation to 
improve subject oversight and safety. 
Edited to provide  
rationale of 
uptitration criteria 


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decompensation coupled with rules based laboratory 
monitoring. 
Subjects will be monitored for potential hepatic injury 
and/or progression to decompensation (Section 7.4).  
Criteria for implementing dosing adjustments, interruptions, 
or discontinuations, and close monitoring procedures 
postdose adjustment are described in Section 7.6and 
Section 7.7.  The more extensive monitoring is important 
given the elevated risk of decompensation and potential for 
higher hepatic exposure to OCA in this population. 
Investigators, together with the Sponsor’s Medical 
Monitor or designee, will consistently and frequently 
assess individual subjects, including careful 
evaluation of signs, symptoms, and laboratory 
parameters to identify potential hepatic injury 
and/or decompensation. Criteria for potential 
hepatic injury and/or progression to decompensation 
are described in Section 7.4. Criteria for 
implementing dosing adjustments, interruptions, or 
discontinuations, and close monitoring procedures 
are described in Section 7.6 and Section 7.7. 
For subjects randomized to the uptitration arm, 
special consideration is given to monitoring and 
management of investigational product as discussed 
in more detail in Section 9.2.  Uptitration criteria 
have been designed to ensure only subjects with 
evidence of adequate functional hepatic reserve will 
be exposed to the higher OCA dose (25 mg). 
Specifically, subjects may only be uptitrated at 
Month 3 if, in addition to no safety or tolerability 
concerns being identified, they meet strict laboratory 
criteria ( total bilirubin ≤1.2 mg/dL, serum albumin 
≥3.5 g/dL, INR <1.5, and platelet count 
>100,000/mm3) at both baseline and all visits prior to 
Month 3. Furthermore, uptitrated subjects must 
continue to meet those criteria throughout the study 
to stay on the uptitrated dose; if at any time a subject 
exceeds these thresholds (including upon retesting), 


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they will be downtitrated to the lower OCA dose (10 
mg). 
Section 7.1.2 
Schedule of 
Study 
procedures 
Table 1 
And 
Table 2 
And 
Section 9.8 
Visit 
Procedures 
Addition of Month 15 and Month 18 visits and procedures, 
EOT/EOS moved to Month 18 
Additional study visit days added to Pruritus VAS 
“Other Metabolic Parameters” replaced with Insulin, C-
Peptide, HOMA-β, and HOMA-IR, Month 2, Month 3, 
Month 4, Month 5, and Month 9 assessments removed.  
Free Fatty Acids assessment moved into separate row 
Footnotes edited 
Section 9.8 was updated to match Table 1 and Table 2 
The following study visits were added to Table 1 Ver. 5: 
Month 15 and Month 18 
 
The following assessments were added to Table 1 
Ver. 5: 
Pruritus VAS: Day 1, Month 1, Month 2, Month 
3,Month 4, Month 5, Month 6, Month 9, Month 12, 
Month 15, Month 18,  and ET 
Glucose and HbA1c: SV1, Day 1, Month 1, Month 2, 
Month 3, Month 4, Month 5, Month 6, Month 9, 
Month 12, Month 15, Month 18, and ET 
Insulin, C-Peptide, HOMA-β, and HOMA-IR: Day 1, 
Month 1, Month 6, Month 12, Month 18, and ET  
Free Fatty Acids: Day 1, Month 6, Month 12, Month 
18, and ET 
HepQuant-SHUNT: Day 1, Month 3, Month 6, and 
Month 18 
 
The following footnotes were added in Table 1 Ver. 5: 
w. Blood samples will be collected at predose of 
cholate and 5, 20, 45, 60 and 90 minutes after 
administration of stable label cholate used to assess 
liver function in the HepQuant-SHUNT test.  
 
Given the onset of 
pruritus usually 
occurs within the 
first 6 months 
pruritus VAS will be 
assessed at every 
visit 
 
“Other metabolic 
parameters” was 
clarified and 
schedule of glucose 
testing was made to 
match HbA1c 
 
 
 
 
HepQuant Shunt 
was added as a 
substudy at US sites 
where capable 
 
 
Footnote for 
HepQuant-SHUNT 
procedure 
 


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Subjects enrolled at the selected US sites that are 
capable of administering the 
test 
will participate in this mandatory assessment.  The 
test should not be administered if the diastolic blood 
pressure is 110 mmHg or higher. The test can be 
rescheduled once the blood pressure is controlled.  β-
blockers, angiotensin II receptor blockers, or 
angiotensin-converting enzyme inhibitors should be 
delayed on the morning of testing until after the 
SHUNT test administration. 
The following footnotes were edited in Table 1 Ver. 5: 
a Screening Visit 2 must occur at least 4 weeks after 
Screening Visit 1 to confirm pretreatment serum 
chemistry levels, including ALT, AST, and total 
bilirubin. Biopsy, EGD, ultrasound, TE, and MRE 
do not have to be performed on the same day as 
Screening Visit 1 or Screening Visit 2 
h At Screening Visit 1, only AUDIT will be conducted.  
At D1, M6, M12, M18/EOT/EOS, and ET, all 
3 assessments (AUDIT, smoking habit, and caffeine 
consumption) will be done. 
m Perform EGD procedure unless data from a recent 
EGD (within 6 months of Day 1) are available. 
Subjects with endoscopic evidence of varices will not 
be enrolled in the study. 
p All assessments, except for the post-dose collection of blood 
samples for the subjects participating in the PK and/or 
 must be completed prior 
to administration of investigational product.   
r In the event any of the 2 ALT, AST, or total bilirubin 
assessments collected at Screening Visit 1 and 
 
 
 
 
Edits for clarity 


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Screening Visit 2 differ by ≥30% and either lab value is 
>ULN, a third sample will be collected at an 
unscheduled visit as a confirmatory sample. In the 
event the Screening Visit 2 value for 
, or 
total bilirubin (conjugated bilirubin for subjects with 
an established diagnosis of Gilbert’s syndrome) is 
≥30% higher than the Screening Visit 1 value and > 
ULN, then a third measurement must be obtained at 
an unscheduled visit. 
s. Other metabolic parameters include fasting plasma 
glucose, insulin, C peptide, HOMA β, and HOMA IR. 
Glucose only 
u TE by Fibroscan® and MRE will be conducted at sites 
where device is available.  Baseline TE should be 
performed once at Screening Visit 1, Screening 
Visit 2, or Day 1 (prior to first study drug 
administration).  It is encouraged that TE is conducted 
prior to on-study liver biopsy(-ies). MRE will be 
conducted only in subjects enrolled prior to 
Version 5 of the protocol who had baseline MRE 
and not in newly enrolled subjects. 
The following footnotes were edited in Table 2 Ver. 5: 
a  If the procedure indicated was performed at the end of 
the Double-Blind Phase, it is not necessary to repeat, 
unless the Investigator determines otherwise.  The day 
of the first dose from the OLE bottle is considered 
OLE Day 1.  OLE visit windows are based on the 
OLE Day 1 Visit 


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g Perform EGD procedure unless data from a recent 
EGD (within 6 months of OLE Day 1) are available. 
Subjects with endoscopic evidence of varices will not 
continue in the OLE Phase. 
h Subjects randomized to placebo during the Double-
Blind Phase will be re-randomized to OCA 10 mg or 
OCA 10 mg → 25 mg arms on OLE Day 1; the placebo 
subjects in the OCA 10 mg → 25 mg arm will receive 
OCA 10 mg for 3 months followed by OCA 25 mg in 
the OLE if the uptitration criteria are met 
(Section 9.2 ).  Subjects randomized to OCA (10 mg or 
10 mg → 25 mg dose) during the Double-Blind Phase 
will continue the treatment they were assigned. 
All assessments must be completed prior to administration of 
investigational product.  The first dose of OLE 
investigational product should be taken the day after the 
Month 18 assessments are completed. 
l Other metabolic parameters include fasting plasma glucose, 
insulin, C-peptide, HOMA-β, and HOMA-IR. Glucose only 
The following footnotes were removed from Table 2 
Ver  5; 
n Whichever modality/ies used at Double-Blind Phase 
Baseline must be collected consistently at each OLE visit. 
Section 7.4.2 
Suspected 
Drug Induced 
Liver Injury 
It is important that the laboratory assessments be completed 
as required and that the central laboratory be used for 
assessments whenever possible.  In the event that a subject 
cannot return to the clinic for a scheduled or unscheduled 
visit, or there is an event that triggers a need for an 
It is important that the laboratory assessments be 
completed as required and that the central laboratory be 
used for assessments whenever possible.  In the event 
that a subject cannot return to the clinic for a scheduled 
or unscheduled visit, or there is an event that triggers a 
Baseline 
calculations 
specified 


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immediate assessment, the use of a local lab is permissible 
at the discretion of the Investigator. In these cases, the 
investigator will obtain the laboratory results and the 
laboratory normal ranges. 
need for an immediate assessment, the use of a local lab 
is permissible at the discretion of the Investigator. In 
these cases, the investigator will obtain the laboratory 
results and the laboratory normal ranges. Of note, the 
Baseline result is the average of results from 
Screening visits 1 and 2, Day 1, and any unscheduled 
visit which took place between Screening visit 1 and 
the Day 1 visit.   
Table 3 
Criteria Resulting in Immediate Interruption of 
Investigational Product Upon First Observation added 
 
Footnote added 
Conj. Bilirubin >ULN: ≥1.5x baseline: None 
 
 
a Baseline result is the average of results from 
Screening visits 1 and 2, Day 1, and any 
unscheduled visit which took place between 
Screening Visit 1 and the Day 1 Visit.  This will 
remain the Baseline for the remainder of the study 
(including the OLE).  
Criteria added for 
subjects with 
baseline conjugated 
bilirubin >ULN 
 
 
 
Baseline 
calculations 
specified 
Table 5 
 
Dose Downtitration Criteria added 
Uptitrated subject no longer meets uptitration 
criteria: Downtitrate after confirmation by repeat 
testing (within 7 days): Not applicable 
To allow OCA 
25 mg to a subset of 
subjects who meet 
additional specific 
criteria as outlined 
Section 7.6 
Investigational 
Product Dosage 
Interruption, 
Downtitration, 
Discontinuation
, and 
Investigational Product Dosage Interruption and 
Discontinuation Criteria 
 
Investigational Product Dosage Interruption, 
Downtitration, Discontinuation, and Rechallenge 
Criteria 
 
Edited to match 
Table 5 


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Rechallenge 
Criteria 
Section 8.2.1 
Other Reasons 
for 
Discontinuation 
• Withdrawal of consent: 
− 
Consent may be fully withdrawn 
− 
Consent may be modified to discontinue study visits 
but allow semi-annual telephone contact  
• Withdrawal of consent: 
− 
Consent may be fully withdrawn 
Consent may be modified to discontinue study visits but 
allow semi-annual telephone contact of subject, 
subject’s primary care physician, or personal 
contacts who can provide information on behalf of 
the subject by the Investigator 
Additional details 
added for follow-up 
of subjects given the 
extended study 
period 
Section 8.2.1.1 
Reasons for 
Subject 
Withdrawal 
from the 
HepQuant 
Substudy 
Addition of section 
Subject Discontinuation 
In the event of an allergic or anaphylactic reaction to 
albumin, investigators must suspend administration 
of the cholates and manage the subject according to 
standard of care.  Any subject with a hypersensitivity 
reaction to any component of the HepQuant-SHUNT 
kit will be withdrawn from the HepQuant substudy 
and will not undergo any further HepQuant 
procedure. Subjects that are withdrawn from the 
HepQuant-SHUNT substudy may continue in the 
study 


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Circumstances that may warrant termination or 
suspension include, but are not limited to: 
• Determination of unexpected, significant, 
or unacceptable risk to participants 
• Demonstration of efficacy that would 
warrant stopping 
• Insufficient compliance to protocol 
requirements 
• Data that are not sufficiently complete 
and/or evaluable 
• Determination of futility 
  
Use of the kit in the study may resume once concerns 
about safety, protocol compliance, and data quality 
are addressed, and satisfy the Sponsor, IRB and/or 
FDA. 
Section 9.2.1 
Double-Blind 
Phase 
Subjects randomized to the OCA 10 mg → 25 mg arm in 
the Double-Blind Phase will receive OCA 10 mg for the 
first 3 months.  Uptitration to 25 mg may occur at Month 3, 
following review of individual subject safety and 
tolerability data.   
Prior to the Month 3 study visit, the Medical Monitor will 
perform a review of consolidated safety data, including data 
Subjects randomized to the OCA 10 mg → 25 mg arm 
in the Double-Blind Phase will receive OCA 10 mg for 
the first 3 months.   
Prior to the Month 3 study visit, the Medical Monitor 
will perform a subject-level consolidated review of 
safety data, including data from the Month 1 and 2 study 
visits, as well as that from any unscheduled visit(s), for 
To allow uptitration 
to a subset of 
subjects who meet 
additional specific 
criteria as outlined 


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from the Month 1 and 2 study visits, as well as that from 
any unscheduled visit(s), for all study subjects.  Case 
review and discussion with the Principal Investigator will 
occur as needed.  A subject may proceed with uptitration to 
OCA 25 mg (or matching placebo), if no safety and/or 
tolerability concerns are evident in the clinical judgement of 
the reviewer(s).  The review will include but not be limited 
to the following: 
• 
Liver-related adverse events 
• 
Safety laboratories: chemistry panel including 
glucose, hematology panel, coagulation 
parameters; computed MELD score and Child-
Pugh score 
• 
Physical examination (development of clinically 
evident ascites or manifestations of hepatic 
encephalopathy) 
Additional considerations to determine the suitability to 
uptitrate will include an assessment of comorbid conditions, 
the subject’s overall adverse event profile, concomitant 
medications with a focus on potentially hepatotoxic 
concomitant medications, and/or any new treatment(s) for 
comorbid condition(s).  The uptitration review process is 
detailed in the study specific Medical Management Plan. 
If uptitration at Month 3 is not feasible due to special 
circumstances, the window for uptitration may be extended 
by up to one calendar month, after consultation and 
agreement with the Medical Monitor.  
all study subjects.  Case review and discussion with the 
Principal Investigator will occur as needed.  The review 
will include but not be limited to the following: 
• 
Liver-related adverse events 
• 
Safety laboratories: chemistry panel including 
glucose, hematology panel, coagulation 
parameters; computed MELD score and CP 
score 
• 
Physical examination (development of 
clinically evident ascites or manifestations of 
hepatic encephalopathy) 
Additional considerations to determine the suitability to 
uptitrate will include an assessment of comorbid 
conditions, the subject’s overall adverse event profile, 
concomitant medications with a focus on potentially 
hepatotoxic concomitant medications, and/or any new 
treatment(s) for comorbid condition(s).  A subject may 
be considered for uptitration to OCA 25 mg if no 
safety and/or tolerability concerns are evident in the 
clinical judgement of the reviewer(s).  If uptitration at 
Month 3 is not feasible, the window for uptitration may 
be extended by up to one calendar month, after 
consultation and agreement with the Medical Monitor.  
The uptitration review process is detailed in the 
study-specific Medical Management Plan. 


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Subjects randomized to the OCA 10 mg or placebo arms 
will undergo dummy titration to maintain study blind. 
In addition, dosing frequency post titration may be 
temporarily decreased for tolerability reasons, following 
discussions with the Medical Monitor.  In addition, 
investigational product may be interrupted per safety 
criteria listed in Table 5 and Section 7.6.  The procedures 
for re initiating investigational product after prolonged 
interruption are provided in Section 8.2.2. 
 
Only those subjects who meet all of the following 
criteria will be eligible for uptitration at Month 3: 
• 
Total bilirubin ≤1.2 mg/dL, serum 
albumin ≥3.5 g/dL, INR <1.5, and 
platelet count >100,000/mm3 at baseline, 
and at all visits prior to Month 3 
(including any unscheduled visits). 
• 
Medical Monitor approval following a 
safety and tolerability assessment as 
described above.  
Subjects who do not meet these criteria will not be 
uptitrated for the remainder of the study. 
If at any time during the study, a subject who has 
undergone uptitration has total bilirubin 
>1.2 mg/dL, serum albumin <3.5 g/dL, INR ≥1.5, or 
platelet count ≤100,000/mm3, the laboratory 
assessment(s) should be repeated within 7 days.  If 
upon repeat evaluation, value(s) remain outside the 
specified criteria, investigational product should be 
downtitrated to a maximum daily dose of OCA 
10 mg and the Medical Monitor should be notified 
promptly (see Table 5).  Subjects randomized to the 
OCA 10 mg or placebo arms will undergo dummy 
titration to maintain study blind.  All uptitration and 
downtitration will be implemented in a blinded 
fashion within IWRS to maintain the integrity of the 
study blind. 


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Dosing frequency post-titration may be temporarily 
decreased for tolerability reasons, following 
discussions with the Medical Monitor.   
In addition, investigational product may be 
interrupted per safety criteria listed in Table 5 and 
Section 7.6.  The procedures for re-initiating 
investigational product after prolonged interruption 
are provided in Section 8.2.2. 
Section 9.2.2 
OLE Phase 
Subjects who were randomized to placebo in the Double-
Blind Phase will be re-randomized to either OCA 10 mg or 
OCA 10 mg → 25 mg at entry into the OLE.  Uptitration to 
OCA 25 mg at Month 3 in the OLE will be conducted in the 
same manner applied in the Double Blind Phase and 
described above.  Subjects randomized to OCA (10 mg or 
25 mg dose) during the Double-Blind Phase will continue 
the same dosing regimen. 
All dosing will be conducted in a dummy titration fashion 
in order to maintain the blind until all subjects complete the 
Double-Blind Phase and the database is locked. 
Subjects who were randomized to placebo in the 
Double-Blind Phase will be re-randomized to either 
OCA 10 mg or OCA 10 mg → 25 mg at entry into the 
OLE.  Uptitration to OCA 25 mg at Month 3 in the OLE 
will be determined based on the same criteria and 
assessments employed in the Double-Blind Phase and 
described above.  Subjects randomized to OCA (10 mg 
or 10 mg → 25 mg dose) during the Double-Blind Phase 
will continue the same dosing regimen. 
All dosing, uptitration, and downtitration will be 
conducted in a blinded fashion in order to maintain 
the integrity of the study blind until all subjects 
complete the Double-Blind Phase and the database is 
locked. 
Edited for clarity 
Section 9.3 
Concomitant 
Medications 
Drugs with Potential NASH-modifying Properties 
Subjects should either not be taking any drugs with 
potential NASH-modifying properties (specifically, 
Drugs with Potential NASH-modifying Properties 
Subjects should either not be taking any drugs with 
potential NASH-modifying properties (specifically, 
TZDs/glitazones, vitamin E, or glucagon-like peptide -
GLP-1 agonists 
added to list of 
potential NASH-
modifiers 


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TZDs/glitazones or vitamin E) or be on a stable dose of 
these medications for 6 months before Day 1. 
1 agonists) or be on a stable dose of these medications 
for 6 months before Day 1. 
Section 9.3.1 
LDL-Lowering 
Medications 
Statins 
Given the prevalence of dyslipidemia in patients with 
NASH and the potential increase in total and LDL 
cholesterol following treatment with OCA, it is 
recommended that Investigators proactively monitor and 
manage lipid levels via appropriate medicinal interventions 
(eg, statins).  Appendix A provides a general guidance for 
cholesterol management including monitoring, triggers for 
intervention, and treatment goals.  Use of statins (eg, 
simvastatin, atorvastatin) should be at a stable dose 
≥30 days before Day 1.  During the study, changes to statin 
doses or initiation of statin therapies are allowed, given the 
potential increase in total and LDL cholesterol following 
treatment with OCA. 
LDL-Lowering Medications 
Given the prevalence of dyslipidemia in patients with 
NASH and the potential increase in total and LDL 
cholesterol following treatment with OCA, it is 
recommended that Investigators proactively monitor and 
manage lipid levels via appropriate medicinal 
interventions.  Appendix A provides a general guidance 
for cholesterol management including monitoring, 
triggers for intervention, and treatment goals.  Use of 
LDL-lowering medications (eg, simvastatin, 
atorvastatin, PCSK9 inhibitors) should be at a stable 
dose ≥30 days before Day 1.  During the study, changes 
to LDL-lowering medication regimen are allowed, 
given the potential increase in total and LDL cholesterol 
following treatment with OCA. 
 
Section 9.5.3 
Emergency 
Unblinding 
Procedures 
The DMC (refer to Section 16.13) will have access to the 
IWRS and will be able to unblind individual subjects.  The 
DMC will document details about any subject who was 
unblinded in the closed session DMC minutes, which will 
be made available to the Sponsor only after the 
double-blind database is locked and unblinded.  Cases of 
premature unblinding (as noted above) will be reviewed by 
the DMC. 
The DMC (refer to Section 16.13) will have access to 
randomization and will be able to review the cases of 
premature unblinding.  The DMC will document 
details about any subject who was unblinded in the 
closed session DMC minutes, which will be made 
available to the Sponsor only after the double-blind 
database is locked and unblinded.  Cases of premature 
unblinding (as noted above) will be reviewed by the 
DMC. 
DMC access 
corrected 


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Section 9.6.2 
Subject 
Numbers 
Subjects are assigned using a unique 10-character, 9-digit 
identifier (AAA-BBBCCC), independent of the 
randomization number. The first 3 digits represent the last 
3 digits of the protocol number, followed by a hyphen 
(AAA-). The next 3 digits represent the site number (BBB). 
The last 3 digits represent a unique screening number that is 
assigned in sequential order at each site starting with 001 
(CCC). 
Subjects are assigned using a unique 10-character, 
9-digit identifier (AAA-BBBCCC), independent of the 
randomization number. The first 3 digits represent the 
last 3 digits of the protocol number, followed by a 
hyphen (AAA-). The next 3 digits represent the site 
number (BBB). The last 3 digits represent a unique 
screening number that is assigned in sequential order at 
each site starting with 001 (CCC).  Note, in the case of 
incorrect data entry by a site when more than one 
subject is inadvertently created, the spurious subject 
numbers will be deleted and may not be used again; 
in this circumstance there may be gaps in the subject 
numbering scheme at a site. 
Some sites may not 
have sequential 
numbering 
Section 9.8 
Visit 
Procedures 
and 
Table 2 
Visits should be based on Day 1 (not on the prior visit) 
unless stated otherwise.  If Day 1 occurs on January 1st, 
Month 3 should ideally occur on April 1st (±1 week).  This 
is the definition of a calendar month.  The visit windows are 
listed in Table 1 and Table 2 .  Acceptable windows for PK 
sampling timepoints are in Table 7 
Visits should be based on Day 1 (not on the prior visit) 
unless stated otherwise.  The day of the first dose from 
the OLE bottle is considered OLE Day 1.  .  If Day 1 
occurs on January 1st, Month 3 should ideally occur on 
April 1st (±1 week).  This is the definition of a calendar 
month.  The visit windows are listed in Table 1 and 
Table 2 2 .  Acceptable windows for PK sampling 
timepoints are in Table 7 
Edited for clarity 
Section 9.8.3.1 
Screening Visit 
1 
Perform EGD procedure unless data from a recent EGD 
(within 6 months of Day 1) are available. Subjects with 
varices will not be enrolled in the study. 
Perform EGD procedure unless data from a recent EGD 
(within 6 months of Day 1) are available. Subjects with 
endoscopic evidence of varices will not be enrolled in 
the study. 
Only endoscopic 
evidence of varices 
will be considered 
for exclusion 


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Section 12.6.2 
Noninvasive 
Panel of Liver 
Fibrosis 
Markers 
FibroMeter (Echosens, Paris, France) combines multiple 
values including Fibroscan TE liver stiffness, age, gender, 
and blood-based biomarkers (platelets, 
alpha-2-macroglobulin, ALT, urea, gamma glutamyl 
transferase (GGT), AST, ferritin, glucose level, HA, and 
prothrombin ratio) to quantify liver fibrosis.  The test can 
be conducted by staff who are trained in the use and data 
interpretation of the diagnostic test. 
FibroMax (BioPredictive, Paris, France) combines up to 10 
serum markers (alpha 2 macroglobulin, haptoglobin, 
apolipoprotein A 1, total bilirubin, GGT, ALT, AST, 
fasting glucose, triglycerides, and total cholesterol) with the 
age, sex, height, and weight of a subject to quantify liver 
fibrosis.  The test can be performed by staff who are trained 
in the use and data interpretation of the diagnostic test. 
FibroMeter (Echosens, Paris, France) combines multiple 
values including Fibroscan TE liver stiffness, age, 
gender, weight, and blood-based biomarkers (platelets, 
alpha-2-macroglobulin, ALT, urea, gamma- GGT, AST, 
ferritin, glucose level, and prothrombin ratio) to quantify 
liver fibrosis.  The test can be conducted by staff who 
are trained in the use and data interpretation of the 
diagnostic test. 
 
Weight is included 
as a value of the 
FibroMeter 
measurement 
 
 
 
 
 
Fibromax was 
removed as a marker 
Section 13: 
Clinical 
Pharmacology 
Assessments 
Subjects who receive at least one dose of OCA and have 
bioanalytical concentration data available will be included 
in the PK analysis.  Subjects with at least one PD 
assessment after dosing will be included in the combined 
PK/PD analyses.  Any missing samples will be removed 
from the analyses, and no imputation will be performed. 
 
Subjects who receive at least one dose of OCA and have 
measurable plasma PK concentration data available 
will be included in the PK analysis.   
 
Edited for clarity 
Section 13.1: 
Pharmacokineti
c Blood 
Sampling 
Subjects may opt to provide blood samples for serial PK 
assessments.  Serial blood samples will be used to 
characterize the PK at steady state for a cohort of subjects 
at both OCA 10 mg and (when titrated) 25 mg doses.  An 
Subjects may opt to provide blood samples for serial PK 
assessments.   
 
The plans no longer 
apply 
 
 


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assessment of steady state exposures (on an aggregate 
level) will be performed by an internal Intercept clinical 
pharmacologist/pharmacometrician or designee who is 
discrete from the study team.  These results may be made 
available to the DMC as appropriate (see Section 16.13). 
 
Subjects participating in serial PK assessments will provide 
blood samples for measurement of OCA and its conjugates 
(glyco-OCA and tauro-OCA). 
 
 
 
Subjects will then receive a dose of investigational product 
with approximately 240 mL of water.  Serial PK blood 
samples will be obtained at 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 
and 6 hours post dose.  Subjects should not drink additional 
water for 1 hour after taking the dose of investigational 
product and will remain fasted until after the 1-hour sample 
is collected.  A meal will be provided following collection 
of the 1-hour PK sample; the meal will be a meal 
replacement drink with nutrition information that has been 
submitted to and approved by the Sponsor in advance.  No 
other food or drink (water is permitted) will be allowed 
until after the 6-hour sample collection. 
 
 
 
 
 
 
Subjects participating in serial PK assessments will 
provide blood samples for measurement of OCA and its 
conjugates (glyco-OCA and tauro-OCA) at 0.5, 0.75, 1, 
1.5, 2, 2.5, 3, 4, 5, and 6 hours post-dose on Month 1, 
Month 4, Month 12, and Month 18.   
 
Subjects will then receive a dose of investigational 
product with approximately 240 mL of water.  Subjects 
should not drink additional water for 1 hour after taking 
the dose of investigational product and will remain 
fasted until after the 1-hour sample is collected.  A meal 
will be provided following collection of the 1-hour PK 
sample; the meal will be a meal replacement drink with 
nutrition information that has been submitted to and 
approved by the Sponsor in advance.  No other food or 
drink (water is permitted) will be allowed until after the 
6-hour sample collection. 
 
Trough PK blood samples will be obtained at Month 1, 
3, 4, 6, 12, and 18 from all subjects. 
 
 
 
 
 
 
 
Timing of PK 
assessments moved 
from lower 
paragraph 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Trough PK blood samples will be obtained from all 
subjects. 
During the Double-Blind Phase: 
• 
Serial PK samples will be obtained at Month 
1, Month 4, and Month 12 from subjects who 
agree to participate in the assessment. 
• 
Trough samples will be obtained from all 
subjects prior to dose administration at 
Months 1, 3, 4, 6, 12, and ET. 
During the Double-Blind Phase: 
• 
Serial PK samples will be obtained at 
Month 1, Month 4, Month 12, and 
Month 18 from subjects who agree to 
participate in the assessment. 
• 
Trough PK blood samples will be 
obtained from all subjects prior to dose 
administration at Months 1, 3, 4, 6, 12, 18, 
and ET. 
Updated due to the 
extension of the DB 
phase to 18 months 
Section 14.3 
HepQuant-
SHUNT 
Assessments 
Addition of section 
HepQuant-SHUNT Assessments 
An assessment of liver function using the HepQuant-
SHUNT assessment will be performed as described 
in Table 1. 
Detailed instructions for HepQuant-SHUNT testing 
will be described in a study operational manual 
(HepQuant SHUNT Test Instructions for Use) that 
will be provided to sites offering this procedure in 
the US.  For those US sites that participate in the 
mandatory HepQuant SHUNT sub-study, all 
subjects will be required to provide consent prior to 
participating.  Failure of a subject to agree to 
participate in the sub-study will be a cause for 
screen-failure at these sites. 
In brief, the test involves placement of an indwelling 
peripheral venous catheter (usually in the antecubital 


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Change 
vein of the arm), an injection of 20 mg 13C-cholate 
(cold, stable label, NOT RADIOACTIVE) 
intravenously and a drink of flavored solution of 
40 mg d4-cholate (again, cold, stable label, NOT 
RADIOACTIVE), with 3 mL blood sampling at 
predose and 5, 20, 45, 60, 90 minutes post-


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Reasons/ 
Justification for 
Change 
Section 15.1.4: 
Relationship to 
Study 
Procedures 
and  
Table 10 
Table 14: Relationship of Adverse Events to Liver Biopsy 
and Other Study Procedures 
Relations
hip 
Description 
Related 
A reaction that follows a reasonable 
temporal sequence from the required 
procedure (eg, liver biopsy); that follows a 
known or expected response pattern to the 
required study procedure. 
Not 
Related 
Any event that does not meet the above 
criteria. 
 
Table 15: Relationship of Adverse Events to Study 
Procedures 
Relation
ship 
Description 
Related 
A reaction that follows a reasonable 
temporal sequence from the 
HepQuant-SHUNT procedure or other 
study procedures; that follows a known 
or expected response pattern to the 
administration of cholate or collection 
of blood samples. 
Not 
Related 
Any event that does not meet the above 
criteria. 
HepQuant Shunt 
was added as a 
substudy at US sites 
where capable 
 
Section 15.1.12  
Pregnancies are not considered AEs in and of themselves; 
however, if a female study participant becomes pregnant 
Pregnancies are not considered AEs in and of 
themselves; however, if a female study participant 
Subjects may re-
start treatment when 
they are no longer 


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Key Change 
Reasons/ 
Justification for 
Change 
Pregnancy and 
Follow-up 
while she is enrolled in the clinical study, she must 
discontinue investigational product immediately 
(Section 8.2.1.4) and the Sponsor must be notified within 
24 hours of the Investigator’s awareness of the pregnancy 
by completing the pregnancy eCRF in the EDC system and 
downloading and completing the Pregnancy Report Form. 
 
 
 
 
 
The subject and neonate must be followed for outcome 
information and/or as considered appropriate by the 
Investigator and the Sponsor.  The investigator should 
notify the Sponsor of the outcome of the pregnancy by 
completing Pregnancy Follow-up section in the EDC.  In 
the situation that the EDC is no longer available due to 
study closure, a Pregnancy Outcome Form should be 
completed and faxed or emailed to the Sponsor.  Thereafter, 
the subject and infant must be followed as considered 
appropriate by the Investigator and any new updates should 
be sent to the Sponsor. 
becomes pregnant while she is enrolled in the clinical 
study, she must interrupt treatment with 
investigational product immediately (Section 8.2.1.4) 
and the Sponsor must be notified within 24 hours of the 
Investigator’s awareness of the pregnancy by 
completing the pregnancy eCRF in the EDC system and 
downloading and completing the Pregnancy Report 
Form.  Any rechallenge of the investigational product 
should be implemented per the criteria outlined in 
Table 5. 
 
 
The subject and neonate must be followed for outcome 
information and/or as considered appropriate by the 
Investigator and the Sponsor.  The investigator should 
notify the Sponsor of the outcome of the pregnancy by 
completing Pregnancy Follow-up section in the EDC.  
In the situation that the EDC is no longer available due 
to study closure, the outcome of the pregnancy should 
be added to the pregnancy resolution section of the 
downloaded Pregnancy Outcome Form and faxed or 
emailed to the Sponsor.  Thereafter, the subject and 
infant must be followed as considered appropriate by the 
Investigator and any new updates should be sent to the 
Sponsor. 
pregnant or 
breastfeeding  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Edited for clarity 


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Key Change 
Reasons/ 
Justification for 
Change 
Section 15.2.6 
Cardiovascular 
Risk Score 
and 
Section 8.2.2 
Reinitiating 
Investigational 
Product After 
Interruption 
Cardiovascular risk scores (Framingham Risk Score [FRS], 
Reynolds score, and SCORE) will be calculated according 
to Table 1 (Double-Blind Phase) and Table 2 (OLE Phase). 
Cardiovascular risk scores (10-year ASCVD Risk, 
FRS, Reynolds score, and SCORE) will be calculated 
according to Table 1 (Double-Blind Phase) and Table 2 
(OLE Phase). 
10-year ASCVD 
Risk was added to 
the markers of 
cardiovascular 
safety 
 
Section 15.2.7 
Laboratory 
Assessments 
Addition of paragraph 
An assessment of steady-state exposures (on an 
aggregate level) will be performed by an internal 
Intercept clinical 
pharmacologist/pharmacometrician or designee who 
is discrete from the study team.  These results may 
be made available to the DMC as appropriate (see 
Section 16.13). 
Edited for clarity 
Section 16.1 
Analysis 
Populations 
and 
Synopsis: 
Analysis 
Populations 
• 
Intent-to-Treat (ITT) Population will include all 
randomized subjects who receive at least 1 dose of 
investigational product (OCA or placebo).  The ITT 
Population will be the primary population used for 
efficacy analyses.  Treatment assignment will be based 
on the randomized treatment. 
Intent-to-Treat (ITT) Population will include all 
randomized subjects.  The ITT Population will be the 
primary population used for efficacy analyses.  
Treatment assignment will be based on the randomized 
treatment. 
Edited for 
compliance with 
ICH guideline 
Section 16.5.1 
Other 
Histological 
Endpoints 
Addition of endpoints 
• 
Changes in fibrosis score from Baseline to 
Month 18 
• 
Percentage of subjects with resolution of NASH 
defined as overall histopathological interpretation 
of 1) “no fatty liver disease” or 2) “fatty liver 
Added to clarify 
analyses in line with 
SAP 


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Justification for 
Change 
disease (simple or isolated steatosis) without 
steatohepatitis” as characterized/quantified by a 
NAS of 0 for ballooning and 0-1 for inflammation, 
using the NASH CRN scoring system, at 
Month 18. 
• 
Percentage of subjects with resolution of NASH 
based on overall pathologist interpretation 
(resolution of definite NASH) at Month 18. 
Section 16.7  
PD Analyses 
PD assessments will be performed on FXR activation 
biomarkers (C4, FGF-19, and bile acids). 
C4, FGF 19, and bile acids will be summarized by 
treatment group using descriptive statistics at Baseline and 
at each on-study evaluation.  The absolute change from 
Baseline and percent change from Baseline will also be 
summarized.  Baseline is defined as the mean of all 
available evaluations before treatment. 
 
PD assessments will be performed on FXR activation 
biomarkers (C4, FGF-19, and plasma bile acids) and 
markers of inflammation, apoptosis and necrosis. 
PD assessments will be summarized by treatment group 
using descriptive statistics at Baseline and at each on-
study evaluation.  The absolute change from Baseline 
and percent change from Baseline will also be 
summarized.  Baseline is defined as the mean of all 
available evaluations before treatment. 
Edited to include all 
PD assessments 
Section 16.8 
PK/PD 
Analysis 
 
A sequential approach will be used to perform the 
population PK/PD analysis.  The Bayesian estimates of 
individual PK parameters from the final population PK 
model will be used to generate PK profiles for each subject.  
The change in each PD assessment (eg, C4, FGF 19) over 
time will be incorporated into a maximum effect (Emax) 
model with OCA dose level as an independent variable.  
Estimated model parameters for each individual will be 
derived from prior Emax, and the half maximal effective 
The relationship between the PD markers and 
plasma exposure of OCA will be assessed.  Details 
regarding the evaluation of PK/PD analyses to 
characterize exposure-response relationships in this 
NASH population will be specified in the statistical 
analysis plan and/or a separate Clinical 
Pharmacology Analysis Plan the clinical study report. 
 
Details regarding 
the PK/PD analyses 
were removed and 
will be described in 
the statistical 
analysis plan and/or 
a clinical 
pharmacology 
analysis plan 


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Justification for 
Change 
concentration values, and baseline measures of each PD 
assessment.  The appropriate structure of the variance
covariance matrix will also be evaluated.  Fixed and 
random effect parameter estimates and associated 
asymptotic standard errors will be estimated.  Descriptive 
statistics will be used to summarize Bayesian estimates of 
PK/PD parameters obtained from individual assessments in 
the population PK/PD model.  Further details regarding the 
evaluation of population PK and PK/PD analyses to 
characterize exposure-response relationships in this NASH 
population will be specified in a modeling and simulation 
plan.  Results from these PK/PD analyses will be reported 
separate from the clinical study report. 
Section 20.3 
Regulatory 
Documents 
• 
Form FDA 1572 
• 
Form FDA 1572 (US only); in lieu of 
1572 (for ex-US) 
Edited for clarity 
Section 22 
List of 
References 
References removed 
 
Removed due to 
removal of use 
within text 


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APPENDIX F. SUMMARY OF CHANGES:  PROTOCOL VERSION 3.0 
TO PROTOCOL VERSION 4.0 (DATED:  14 JAN 2019) 
The revisions to Protocol 747-304 Version 4.0 summarized in this appendix include the 
following: 
The text deleted from Protocol Version 3.0 is crossed out and revised text in Version 4.0 is 
indicated in bold font in the following table.  Each revision also includes a reason or justification 
for the change.  Section numbers refer to Version 4.0 unless otherwise stated.  Sections with 
extensive changes that are discussed elsewhere have been summarized rather than highlighting 
exact changes.  Minor changes including typos or editorial revisions are not listed individually in 
the following table. 


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Section 
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Revised Text (Version 4.0, 14 Jan 2019) 
Key Change 
Reasons/ 
Justification for 
Change 
Study Personnel 
Contact 
Information 
Primary Contact:   
MBChB  
INC Research/ 
inVentiv Health 
3201 Beechleaf Court,  
Suite 600 
Raleigh NC 27604 
Email
Primary Contact:   
 MB ChB  
Syneos Health 
1030 Sync Street 
Morrisville, NC 27560 
 
 
Email:
Change in study 
personnel contact 
information. 
Synopsis, 
Investigators 
and/or Study 
Center(s) 
Approximately 225 investigational sites, globally. 
Approximately 300 investigational sites, globally. 
The number of 
study sites has 
been increased to 
meet enrollment 
goals for this 
study. 
Synopsis, 
Inclusion 
Criteria 
3. Contraception:  Female subjects of childbearing potential 
must use ≥1 effective method (≤1% failure rate) of 
contraception during the study until 4 weeks following the 
last dose of investigational product (including OLE doses).  
Effective methods of contraception are listed below: 
3. Contraception:  Female subjects of childbearing 
potential must use ≥1 effective method (≤1% failure 
rate) of contraception during the study until 4 weeks 
following the last dose of investigational product 
(including OLE doses).  Female subjects are 
considered as being of childbearing potential, ie, 
fertile, following menarche and until becoming 
postmenopausal, unless permanently sterile. 
Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. A postmenopausal state is defined as 
no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be 
used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 
12 months of amenorrhea, a single FSH 
measurement is insufficient. 
Updated 
definition of 
woman of 
childbearing 
potential. 


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Synopsis, 
Exclusion 
Criteria 
18. Evidence of other known forms of chronic liver disease 
including: 
− 
Positive test result at Screening for hepatitis B 
surface antigen  
− 
Active hepatitis C virus (HCV) infection (positive 
for HCV ribonucleic acid [RNA] at Screening) or 
history of positive HCV RNA test result  
− 
Primary biliary cirrhosis, primary sclerosing 
cholangitis, autoimmune hepatitis, or overlap 
syndrome 
− 
Alcoholic liver disease 
− 
Wilson disease, hemochromatosis, or iron 
overload 
− 
Alpha-1-antitrypsin (A1AT) deficiency as defined 
by diagnostic features in liver histology 
(confirmed by A1AT level below the lower limit 
of normal or exclusion at the Investigator’s 
discretion) 
− 
Prior known drug-induced liver injury within 
5 years before Day 1 
− 
Known or suspected HCC 
 
31. Concurrent participation in any other interventional or 
noninterventional clinical trial. 
18. Evidence of other known forms of chronic liver 
disease including: 
− 
Positive test result at Screening for hepatitis B 
surface antigen  
− 
Active hepatitis C virus (HCV) infection 
(positive for HCV ribonucleic acid [RNA] at 
Screening) or confirmed history of a positive 
HCV RNA test result(s) 
− 
Primary biliary cholangitis, primary 
sclerosing cholangitis, autoimmune hepatitis, 
or overlap syndrome 
− 
Alcoholic liver disease 
− 
Wilson disease, hemochromatosis, or iron 
overload 
− 
Alpha-1-antitrypsin (A1AT) deficiency as 
defined by diagnostic features in liver 
histology (confirmed by A1AT level below 
the lower limit of normal or exclusion at the 
Investigator’s discretion) 
− 
Prior known drug-induced liver injury within 
5 years before Day 1 
− 
Known or suspected HCC 
31. Concurrent participation in any other interventional 
clinical trial. 
Changes were 
made for 
clarification 
purposes 
(exclusion 
criterion #18). 
 
 
 
 
 
 
 
 
 
Change was made 
for clarification 
that subjects will 
not be excluded 
for participating 
in 
noninterventional 
clinical trials 
(exclusion 
criterion #31). 




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7.4.3.1. 
Child-Pugh 
Assessment 
Table 4: 
Child-Pugh Scoring System 
Factor 
Units 
Points 
1 
2 
3 
Serum total 
bilirubin 
μmol/L 
<35 
35-50 
>50 
mg/dL 
<2.0 
2.0-3.0 
>3.0 
Serum albumin 
g/L 
>35 
28-35 
<28 
g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin 
time 
Seconds 
prolonged 
0-3 
4-6 
>6 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites 
 
None 
Mild 
Modera
te-
Severe 
Hepatic 
encephalopath
ya 
 
No 
Grade 1 
or 2 
Grade 
3 or 4 
 
Table 4: 
Child-Pugh Scoring System 
Factor 
Units 
Points 
1 
2 
3 
Serum total 
bilirubin 
μmol/L 
<34 
34-50 
>50 
mg/dL 
<2.0 
2.0-3.0 
>3.0 
Serum albumin 
g/L 
>35 
28-35 
<28 
g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin 
time 
Second
s 
prolong
ed 
0-3 
4-6 
>6 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites 
 
None 
Mild 
Moder
ate-
Severe 
Hepatic 
encephalopathy
a 
 
None 
Grade 
1 or 2 
Grade 
3 or 4 
Changes were 
made for 
clarification and 
consistency 
purposes. 


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7.5, Medical 
Management of 
Subjects with 
Symptomatic 
Cholelithiasis 
and/or 
Cholecystitis 
NA (new section added, Medical Management of 
Subjects with Symptomatic Cholelithiasis and/or 
Cholecystitis) 
NASH is associated with several known risk factors 
for cholelithiasis, such as obesity, type 2 diabetes, 
and other metabolic abnormalities. The prevalence 
of gallstone disease in NASH is higher than in the 
general population.  The majority of gallstones are 
asymptomatic and may never become symptomatic. 
Because symptomatic events of cholelithiasis and/or 
cholecystitis may develop in subjects with or 
without a known history of gallstones, it is 
important that all subjects be (1) monitored for 
signs and symptoms suggestive of gallstone disease 
and (2) counseled to recognize and seek immediate 
medical attention if they experience symptoms 
suggestive of cholelithiasis and/or cholecystitis.  
If a subject experiences symptoms suggestive of 
cholelithiasis and/or cholecystitis, s/he should 
undergo a complete evaluation consistent with the 
local standard of care, be assessed for appropriate 
treatment, including potential indication for 
surgery (e.g., cholecystectomy), and be monitored 
until resolution of clinical signs and symptoms. 
If symptomatic cholelithiasis and/or cholecystitis is 
diagnosed, IP should be interrupted (see 
Section 7.6). 
The Sponsor is 
implementing 
new rules for 
implementing and 
monitoring of IP 
in cases of 
symptomatic 
cholelithiasis 
and/or cholestasis. 


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7.6, 
Investigational 
Product 
Adjustment, 
Interruption, 
and 
Discontinuation 
Criteria 
New language added.  
Investigational product should not be 
interrupted in the following instances: 1) in 
subjects who previously experienced an event 
of symptomatic cholelithiasis and/or 
cholecystitis, and in whom symptoms have 
fully resolved at the present time while on IP; 
2) in subjects who experience an event that is 
not symptomatic (such as an incidental finding 
of gallstones during an ultrasound exam); or 3) 
in subjects who have already undergone a 
cholecystectomy following a prior event of 
cholelithiasis or cholecystitis (and who have no 
symptoms suggestive of retained or recurrent 
bile duct stones). 
The following row was added to Table 5: 
Symptomatic 
cholelithiasis 
and/or 
cholecystitis 
Interrupt 
Subjects who meet the  
requirements for IP  
interruption for  
symptomatic cholelithiasis  
and/or cholecystitis  
may not  
resume IP until approval  
from the Medical Monitor  
is received or further  
guidance from the Sponsor i
Subjects should remain  
in the study  
and complete all  
protocol- 
specified assessments,  
as defined in Table 1, while  
off IP. In subjects  
undergoing  
cholecystectomy following  
an event of cholelithiasis or  
cholecystitis, IP may be  
resumed after the  
procedure,  
provided there are no signs 
symptoms suggestive of  
retained or recurrent bile  
duct stones. 
The Sponsor is 
implementing 
new rules for 
implementing and 
monitoring of IP 
in cases of 
symptomatic 
cholelithiasis 
and/or cholestasis. 


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8.1, Subject 
Population 
This study will be conducted at approximately 
225 international study sites with experience in treating 
patients with compensated cirrhosis due to NASH.  
Prospective subjects will be identified primarily from the 
hospital and/or physician’s database of patients with NASH 
or may be referred from other physicians.  Subjects may 
self-refer to an Investigator if they become aware of the 
study through local, national, or international NASH patient 
societies, forums, or networks. 
This study will be conducted at approximately 
300 international study sites with experience in treating 
patients with compensated cirrhosis due to NASH.  
Prospective subjects will be identified primarily from 
the hospital and/or physician’s database of patients 
with NASH or may be referred from other physicians.  
Subjects may self-refer to an Investigator if they 
become aware of the study through local, national, or 
international NASH patient societies, forums, or 
networks. 
The number of 
study sites has 
been increased to 
meet enrollment 
goals for this 
study. 
8.1.1, Subject 
Inclusion 
Criteria 
3. Contraception:  Female subjects of childbearing potential 
must use ≥1 effective method (≤1% failure rate) of 
contraception during the study until 4 weeks following the 
last dose of investigational product (including OLE doses).  
Effective methods of contraception are listed below: 
3. Contraception:  Female subjects of childbearing 
potential must use ≥1 effective method (≤1% failure 
rate) of contraception during the study until 4 weeks 
following the last dose of investigational product 
(including OLE doses).  Female subjects are 
considered as being of childbearing potential, ie, 
fertile, following menarche and until becoming 
postmenopausal, unless permanently sterile. 
Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. A postmenopausal state is defined as 
no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be 
used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal 
replacement therapy. However ,in the absence of 
12 months of amenorrhea, a single FSH 
measurement is insufficient. 
Updated 
definition of 
woman of 
childbearing 
potential. 


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8.1.2, Subject 
Exclusion 
Criteria 
18. Evidence of other known forms of chronic liver disease 
including: 
− 
Positive test result at Screening for hepatitis B 
surface antigen  
− 
Active hepatitis C virus (HCV) infection (positive 
for HCV ribonucleic acid [RNA] at Screening) or 
history of positive HCV RNA test result  
− 
PBC, primary sclerosing cholangitis, autoimmune 
hepatitis, or overlap syndrome 
− 
Alcoholic liver disease 
− 
Wilson disease, hemochromatosis, or iron 
overload 
− 
Alpha-1-antitrypsin (A1AT) deficiency as defined 
by diagnostic features in liver histology 
(confirmed by A1AT level below the lower limit 
of normal or exclusion at the Investigator’s 
discretion) 
− 
Prior known drug-induced liver injury within 
5 years before Day 1 
− 
Known or suspected HCC 
 
31. Concurrent participation in any other interventional or 
noninterventional clinical trial. 
18. Evidence of other known forms of chronic liver 
disease including: 
− 
Positive test result at Screening for hepatitis B 
surface antigen  
− 
Active hepatitis C virus (HCV) infection 
(positive for HCV ribonucleic acid [RNA] at 
Screening) or confirmed history of a positive 
HCV RNA test result(s) 
− 
PBC, primary sclerosing cholangitis, 
autoimmune hepatitis, or overlap syndrome 
− 
Alcoholic liver disease 
− 
Wilson disease, hemochromatosis, or iron 
overload 
− 
Alpha-1-antitrypsin (A1AT) deficiency as 
defined by diagnostic features in liver 
histology (confirmed by A1AT level below 
the lower limit of normal or exclusion at the 
Investigator’s discretion) 
− 
Prior known drug-induced liver injury within 
5 years before Day 1 
− 
Known or suspected HCC 
31. Concurrent participation in any other interventional 
clinical trial. 
Changes were 
made for 
clarification 
purposes 
(exclusion 
criterion #18). 
 
 
 
 
 
 
 
 
 
Change was made 
for clarification 
that subjects will 
not be excluded 
for participating 
in 
noninterventional 
clinical trials 
(exclusion 
criterion #31). 


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9.8.12, OLE 
Months 2, 3, 4, 
5, 9 
• 
Calculations will be performed by the Sponsor 
or designee for: 
− 
MELD Score 
− 
CP Score/Class (assessment of ascites and 
hepatic encephalopathy is required) 
− 
Noninvasive scores of liver fibrosis (NFS, 
FIB-4, and APRI) 
− 
Noninvasive panel of liver fibrosis (ELF, 
FibroMax, and Fibrometer) 
(Month 9 only) 
− 
DILI management algorithm (liver 
biochemistry) 
• 
Calculations will be performed by the 
Sponsor or designee for: 
− 
MELD Score 
− 
CP Score/Class (assessment of 
ascites and hepatic encephalopathy is 
required) 
− 
Noninvasive scores of liver fibrosis 
(NFS, FIB-4, and APRI) 
− 
Noninvasive panel of liver fibrosis 
(ELF, FibroMax, and Fibrometer) 
(Month 3 only) 
− 
DILI management algorithm (liver 
biochemistry) 
Correction of 
error. 
15.1.10, 
Follow-Up of 
AEs and SAEs 
New paragraph added to section.  
If a subject experiences signs and symptoms 
consistent with cholelithiasis and/or cholecystitis, 
the subject should be managed and monitored as 
described in Section 7.5. The Investigator should 
contact the Medical Monitor upon awareness.  
Results should be recorded promptly in the eCRF. 
The Sponsor is 
implementing 
new rules for 
implementing and 
monitoring of IP 
in cases of 
symptomatic 
cholelithiasis 
and/or cholestasis. 
15.2.3, Vital 
Signs 
Vital signs will be assessed at the visits as specified in 
Table 1 (Double-Blind Phase) and Table 2 (OLE Phase): 
oral temperature, sitting heart rate, respiratory rate, and 
seated blood pressure after sitting 3 minutes.  When taking 
heart rate, respiratory rate and blood pressure readings, 
subjects should be seated quietly for a minimum of 
3 minutes before the readings are taken. 
Vital signs will be assessed at the visits as specified in 
Table 1 (Double-Blind Phase) and Table 2 (OLE 
Phase): temperature, sitting heart rate, respiratory rate, 
and seated blood pressure after sitting 3 minutes.  
When taking heart rate, respiratory rate and blood 
pressure readings, subjects should be seated quietly for 
a minimum of 3 minutes before the readings are taken. 
Change was made 
for clarification 
purposes. 


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APPENDIX E. SUMMARY OF CHANGES:  PROTOCOL VERSION 2.0 
TO PROTOCOL VERSION 3.0 (DATED:  05 DEC 2017) 
The previous version of this protocol (747-304 Version 2.0, 17 May 2017) was amended to 
create Version 3.0 on 05 Dec 2017.  Key updates made to the protocol Version 2 are summarized 
below: 
1. The study design has been updated as follows: Subjects who meet the entry requirements 
will be randomized in a 1:1:1 ratio to one of the three treatment arms:  once daily dosing 
of OCA 10 mg, OCA 10 mg → 25 mg (ie, OCA 10 mg with uptitration to OCA 25 mg at 
Month 3), or placebo, in conjunction with local standard of care. 
2. The primary efficacy endpoint has been changed to improvement in fibrosis AND no 
worsening of Nonalcoholic Steatohepatitis (NASH). 
3. Subjects with a diagnosis of cryptogenic cirrhosis and presence of metabolic risk factor 
are no longer eligible to enroll in the study. 
4. The Introduction was revised to highlight the need for close monitoring specifically for 
patients who progress to have clinical evidence of hepatic decompensation and other 
complications due to advanced cirrhosis.  Reference is made to sections describing 
specific criteria for investigational product adjustment, interruption, or discontinuation 
based on adverse events or laboratory values. This language also emphasizes the need for 
careful observation and evaluation of the entire clinical picture over and above system-
generated alerts and flags for lab values. The importance of continued monitoring and 
appropriate referrals are highlighted in the event of potential diagnostic dilemmas and 
mandate follow-up until such dilemmas are stabilized. 
5. Guidance was added that subjects should be instructed to contact the site promptly upon 
awareness of signs and symptoms of potential hepatic decompensation such as:  pale-
colored stools, urine color from pale to deep amber [dark], nausea, vomiting, abdominal 
pain, diarrhea, weight loss, fever and chills, fatigue, weakness, loss of appetite, 
confusion, swelling of the legs or abdomen, yellowing of the skin or the whites of eyes, 
and bruising easily. 
6. Guidance was added that the Investigator should contact the study Medical Monitor upon 
awareness when any signs and symptoms of hepatic decompensation are observed in any 
subject. 
7. Pancreatitis. Subjects who are diagnosed with pancreatitis or develop symptoms 
consistent with pancreatitis, will be monitored for 3 months after the onset of symptoms 
per standard of care, including amylase and lipase enzyme levels. 
8. The visit windows for the 2 screening visits are clarified to allow for sufficient time to 
complete screening procedures.  
9. The gallbladder ultrasound will be performed at Screening to obtain baseline status.  
10. Subjects with known evidence of varices or with MELD score >12 will not be enrolled 
in the study. 
11. The duration of OLE phase is changed from 24 months to 12 months.  


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12. SF-36, microbiome/metabolome assessments, and genetic analyses have been 
removed. 
The text deleted from Protocol Version 2.0 is crossed out and revised text in Version 3.0 is 
indicated in bold font in the table below.  Minor changes including typos or editorial revisions 
are not listed individually in the summary table below. 
 


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Section 
Original Text (Version 2.0, 17 May 2017) 
Revised Text (Version 3.0, 05 Dec 2017) 
Key Change 
Reasons/Justification for 
Change 
Title Page 
Added Study Name (Acronym) 
The REVERSE Study 
Randomized phase 3 study EValuating the 
Efficacy and safety of obeticholic acid in subjects 
with compensated ciRrhosis due to nonalcoholic 
StEatohepatitis 
To help the study sites, 
Investigators, and subjects 
in referencing the study 
easily during verbal or 
written communications 
Study Personnel 
Contact Information 
PhD 
Clinical Development 
 
Primary 
Contact: 
MD 
 Drug Safety 
Intercept Pharmaceuticals, Inc. 
(Intercept) 
Telephon
e: 
 
Email: 
 
 
 
 
 
 
 
 
 
Safety Contact Information 
PhD  
Clinical Development 
 
Primary 
Contact: 
MBChB  
 Drug Safety  
INC Research/inVentiv Health 
3201 Beechleaf Court, Suite 600 
Raleigh NC 27604 
Telephone: 
Email: 
 
Secondary 
Contact: 
MD  
Intercept Pharmaceuticals, Inc. 
Email: 
 
SAE Reporting Information 
Updated Sponsor 
information 
 
 
Change of personnel 


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Synopsis, 
Investigators and/or 
Study Center(s),  
and 
Section 8.1, Subject 
Population 
Approximately 150 investigational sites, globally. 
 
 
 
This study will be conducted at approximately 
150 international study sites with experience in 
treating patients with compensated cirrhosis due 
to NASH. 
Approximately 225 investigational sites, globally. 
 
 
 
This study will be conducted at approximately 225 
international study sites with experience in treating 
patients with compensated cirrhosis due to NASH. 
Number of study sites have 
been increased to meet 
enrollment goals for this 
study. 
Synopsis, Studied 
Period 
 
 
 
 
Synopsis, Duration of 
the Treatment 
and 
Section 7.1.3, Study 
Duration 
The maximum duration of individual subject 
participation for this study is approximately 
3 years and 2 months, including a Screening 
Period of up to 8 weeks, a 1-year Double-Blind 
Phase, and an optional Open-Label Extension 
(OLE) expected to last approximately 2 years. 
 
The maximum duration of treatment is 
approximately 3 years including a 1-year Double-
Blind Phase, and an optional OLE expected to 
last approximately 2 years. 
The maximum duration of individual subject 
participation for this study is approximately 2 years 
and 3 months, including a Screening Period of up to 
12 weeks, a 1-year Double-Blind Phase, and an 
optional Open-Label Extension (OLE) expected to 
last approximately 1 year. 
 
The maximum duration of treatment is 
approximately 2 years including a 1-year Double-
Blind Phase, and an optional OLE expected to last 
approximately 1 year. 
The screening period has 
been increased from 
8 weeks to 12 weeks to 
provide sufficient time for 
screening procedures. The 
OLE Phase has been 
decreased to 1 year. 
Synopsis, Primary 
Objectives. 
and 
Section 6.1 Primary 
Objectives 
• Histological improvement in fibrosis by 
assessing the percentage of subjects with 
improvement in fibrosis by at least 1 stage using 
the Nonalcoholic Steatohepatitis (NASH) Clinical 
Research Network (CRN) scoring system from 
Baseline to Month 12 
• Safety and tolerability 
• Histological improvement in fibrosis by assessing 
the percentage of subjects with improvement in 
fibrosis by at least 1 stage with no worsening of 
Nonalcoholic Steatohepatitis (NASH) defined as 
no increase in hepatocellular ballooning or 
lobular inflammation, using the NASH Clinical 
Research Network (CRN) scoring system, from 
Baseline to Month 12 
The primary efficacy 
endpoint has changed to 
include no worsening of 
NASH in addition to 
fibrosis improvement. 
“Safety and tolerability” is 
now one of the secondary 
objectives of the study 


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Synopsis, Secondary 
Objectives. 
and 
Section 6.2 Secondary 
Objectives 
• Histological changes in fibrosis including 
improvement, no worsening, and progression 
from Baseline to Month 12 using the following 
criteria, as appropriate: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Occurrence of all-cause mortality and liver-
related clinical outcomes for the following 
adjudicated events (clinical outcomes composite 
endpoint):  
- Death (all cause) 
- Liver transplant (if model for end stage liver 
disease [MELD] <15 at Baseline) 
- MELD score ≥15 (if MELD ≤12 at Baseline) 
 
• The effect of OCA treatment compared to 
placebo on the following additional measures and 
markers: 
̶ Health-related quality of life 
• Histological changes in fibrosis including (1) 
improvement, (2) no worsening, and (3) progression 
from Baseline to Month 12 using the following 
criteria, as appropriate: 
 
• Resolution of NASH defined as overall 
histopathological interpretation of 1) “no fatty 
liver disease” or 2) “fatty liver disease (simple or 
isolated steatosis) without steatohepatitis” AND 
a nonalcoholic fatty liver disease (NAFLD) 
activity score (NAS) of 0 for ballooning and 0-1 
for inflammation, using the NASH CRN scoring 
system, from Baseline to Month 12 
• Histological improvement in fibrosis by at least 
1 stage and improvement in NAS by at least 
2 points with at least 1 point improvement each 
for hepatocellular ballooning and lobular 
inflammation, using the NASH CRN scoring 
system, from Baseline to Month 12 
• Improvement in each key histological feature 
of NASH by at least 1 point (steatosis, lobular 
inflammation, and hepatocellular ballooning), 
using the NASH CRN scoring system, from 
Baseline to Month 12 
 
• Occurrence of all-cause mortality and liver-related 
clinical outcomes for the following adjudicated 
events (clinical outcomes composite endpoint):  
- Death (all causes) 
- Liver transplant 
- MELD score ≥15 
 
• The effect of OCA treatment compared to placebo 
on the following additional measures and markers: 
̶ Health-related quality of life (eg, patient 
reported outcomes) 
Clarification. 
Changes in histological 
parameters of fibrosis will 
be individually assessed. 
 
Additional secondary 
objectives added to the 
study that are relevant to 
the population being 
studied. 
 
 
 
 
 
 
 
 
 
 
 
 
This objective was updated 
since subjects with MELD 
score >12 are excluded 
from the study. 
 
 
 
 
Clarifications 
 


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- Hepatic function as assessed by MELD and CP 
scores 
- Disease progression as assessed by MELD and 
CP scores 
 
• Safety and tolerability 


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Synopsis, 
Methodology. 
and 
Section 7.1, Overall 
Study Design 
Up to approximately 30% of total enrolled 
subjects may have a diagnosis of cryptogenic 
cirrhosis and presence of metabolic risk factor.   
Subjects who progress to CP Class B or Class C 
during the study will discontinue investigational 
product, but should be encouraged to continue 
study visits.  
 
Double-Blind Phase (12 Months):  Subjects will 
be screened for a period of up to 8 weeks before 
entering the study.  Subjects who meet the entry 
requirements will be randomized in a 1:1 ratio to 
receive placebo or OCA daily in conjunction with 
local standard of care.  Subjects will receive OCA 
10 mg for the first 3 months.  At Month 3, all 
subjects will titrate to OCA 25 mg once daily 
unless there are safety concerns.   
Randomized subjects will be stratified by the 
presence of type 2 diabetes at enrollment (yes or 
no) and by cryptogenic cirrhosis (yes or no).   
 
 
 
Open Label Extension (up to 24 Months):  
Subjects who complete the Double-Blind Month 
12 Visit are eligible to enroll into the OLE for the 
evaluation of safety.  All subjects will receive 
OCA upon entry into the OLE.  Subjects who 
received placebo during the Double-Blind Phase 
will receive OCA 10 mg daily for 3 months and 
titrate to OCA 25 mg daily in the same manner 
that was applied during the Double Blind Phase.  
Subjects who received OCA during the Double
Blind phase will continue the same dosing 
regimen they received at the end of the Double-
Blind Phase. 
 
 
Subjects who progress to CP Class B or Class C 
during the study will discontinue investigational 
product, but are expected to be followed through 
to study closure (or at the discretion of the 
Sponsor). 
 
Double-Blind Phase (12 Months):  Subjects will 
be screened for a period of up to 12 weeks before 
entering the study.  Subjects who meet the entry 
requirements will be randomized in a 1:1:1 ratio to 
one of the three treatment arms: once daily 
dosing of OCA 10 mg, OCA 10 mg → 25 mg (ie, 
OCA 10 mg with uptitration to OCA 25 mg at 
Month 3), or placebo, in conjunction with the 
standard of care.  Uptitration will be determined 
based on the safety and tolerability assessments 
completed prior to Month 3. 
Randomized subjects will be stratified by the 
presence of type 2 diabetes at enrollment (yes or 
no).   
 
Open Label Extension (up to 12 Months):   
Subjects who complete the Double-Blind Month 12 
Visit (and continue to receive investigational 
product) are eligible to enroll into the OLE.  All 
subjects will receive OCA upon entry into the OLE.  
Subjects randomized to placebo in the Double-
Blind Phase will be re-randomized to either 
OCA 10 mg or OCA 10 mg → 25 mg (ie, OCA 
10 mg for the first 3 months of the OLE prior to 
uptitrating to OCA 25 mg at OLE Month 3).  
Uptitration will be based on the safety and 
tolerability assessments completed prior to 
Month 3.  Subjects randomized to OCA (10 mg 
or 25 mg dose) during the Double-Blind Phase will 
continue the same dosing regimen they received at 
Subjects with cryptogenic 
cirrhosis will not be 
enrolled under Version 3 of 
the protocol. 
 
 
 
 
The new study design 
includes 3 treatment arms. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarification of OCA 
treatment assignment 
during OLE Phase for 
subjects who were 
randomized to placebo arm 
during the Double-Blind 
Phase. 


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the end of the Double-Blind Phase; however, they 
will undergo dummy titration to maintain study 
blind until all subjects complete the Double-
Blind Phase and the database is locked. 
 
Note: In Section 7.1, hyperlink to Section 9.2 is also 
included for the titration scheme at Month 3 
(Double-Blind Phase) or at OLE Month 3. 
Synopsis, Study 
Design Diagram 
and 
Section 7.1.1, Study 
Design Diagram 
The study diagram was updated per changes in 
study design 
Diagram was updated as follows:  
− 
Change from 2 groups (Placebo, and OCA 10 
mg) to 3 groups (Placebo, and OCA 10 mg, and 
OCA 10 mg→25mg) during the Double-Blind 
Phase. 
− 
1:1 randomization at D1 changed to 1:1:1 
randomization 
− 
Screening period: “≤8 weeks” changed to 
“≤1  weeks” 
− 
Change in OLE from “up to 2 years” to “up to 
1 year”. 
Clarifications 


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Synopsis, Study 
Design Diagram - 
Footnotes 
and 
Section 7.1.1, Study 
Design Diagram - 
Footnotes 
CP = Child Pugh; NASH = nonalcoholic 
steatohepatitis; OCA = obeticholic acid; OLE = 
open-label extension; QD = Once Daily. 
Note:  
Subjects with cirrhosis (based on a NASH CRN 
fibrosis score 4) due to NASH or cryptogenic 
cirrhosis with metabolic factors assumed to be 
due to NASH will be enrolled in the study.  
Subjects with CP Class B or CP Class C 
cirrhosis are excluded.   
• a Two screening visit assessments will be 
performed at least 4 weeks apart.  Screening 
Visit 1 will occur 8 weeks prior to Day 1, and 
Screening Visit 2 will occur 4 weeks ± 2 days 
prior to Day 1.  
Subjects without a liver biopsy obtained 
≤12 months prior to Day 1 will have a biopsy at 
Screening Visit 2.   
b During the double blind period, all subjects will 
titrate to OCA 25 mg ( or matching placebo) at 
Month 3 unless safety concerns dictate 
otherwise.  A blinded review of Month 1 and 
Month 2 safety data, including liver 
biochemistry and adverse events by the medical 
monitor will be conducted prior to a subject’s 
Month 3 visit. 
c All subjects who enroll into the OLE will 
receive OCA.  Subjects randomized to placebo 
in the Double-Blind Phase will initiate 
investigational product of OCA 10mg for the 
first 3 months of the OLE prior to uptitrating to 
OCA 25 mg.  Uptitration will be based on 
safety and tolerability assessments completed at 
Month 1, Month 2, and Month 3 of the OLE.  
Subjects randomized to OCA will continue the 
same dosing regimen they received at the end 
of the Double-Blind Phase. 
d The study will remain blinded until all subjects 
complete the Double-Blind Phase.  To maintain 
CP = Child Pugh; CRN = clinical research 
network; NASH = nonalcoholic steatohepatitis; 
OCA = obeticholic acid; OLE = open-label 
extension; QD = once daily. 
a All subjects will receive OCA upon entry into 
the OLE. 
b During the OLE period, subjects will return 
for site visits at Months 1, 2, 3, 4, 5, 6, 9, and 
12.   
Notes: 
• Subjects with cirrhosis (based on a NASH CRN 
fibrosis score 4) due to NASH (determined by 
central reading of liver histology) will be 
enrolled in the study.  Subjects with hepatic 
decompensation or CP Class B or CP Class C 
cirrhosis are excluded.   
• Two screening visit assessments will be 
performed.  Screening Visit 1 will occur no more 
than 12 weeks prior to Day 1, and Screening 
Visit 2 will occur at least 4 weeks after 
Screening Visit 1.  
• Subjects without a liver biopsy obtained 
≤12 months prior to Day 1 must have a biopsy 
completed during the screening period.   
• Randomized subjects will be stratified by the 
presence of type 2 diabetes at enrollment (yes 
or no). 
• Subjects who received placebo during the 
Double-Blind Phase will be re randomized to 
either OCA 10 mg or OCA 10 mg → 25 mg (ie, 
OCA 10 mg for the first 3 months of the OLE 
prior to uptitrating to OCA 25 mg at OLE Month 
3).  Subjects who received OCA during the 
Double-Blind Phase will continue the same 
dosing regimen they received at the end of the 
Double-Blind Phase. 
• The study will remain blinded until all subjects 
complete the Double-Blind Phase and the 
Clarifications 


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blinding, all placebo, OCA 10 mg, and OCA 25 
mg tablets and bottles will be identical.  Once 
all subjects have titrated to the 25 mg dose in 
the OLE, subjects may receive investigational 
product with an open label identifying the 
product as OCA 25 mg. 
database is locked.  To maintain blinding, all 
investigational product (placebo and OCA) 
tablets and bottles will be identical.   
Synopsis, Number of 
Subjects (Planned) 
and 
Section 7.2, Number 
of Subjects 
Approximately 360 subjects will be enrolled in 
the study. 
Approximately 540 subjects will be enrolled in the 
study. 
Number of subjects have 
been increased to meet the 
goal of sufficiently powered 
primary objective of the 
study. 


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Synopsis, Inclusion 
Criteria 
and 
Section 8.1.1, Subject 
Inclusion Criteria 
2. Subjects with confirmed diagnosis of NASH 
with a fibrosis score of 4 based on NASH CRN 
scoring system determined by central reading 
of a liver biopsy obtained no more than 
12 months before Day 1, OR 
Subjects with cryptogenic cirrhosis assumed to 
be due to NASH as determined by central 
reading of a liver biopsy obtained no more than 
12 months before Day 1 accompanied by TWO 
of the following risk factors 
 Obesity (body mass index ≥30 kg/m2) 
 Type 2 diabetes diagnosed per 2013 American 
Diabetes Association criteria (hemoglobin A1c 
≥6.5%, fasting plasma glucose ≥126 mg/dL, 2
hour plasma glucose ≥200 mg/dL during oral 
glucose tolerance test, or random plasma 
glucose ≥200 mg/dL) or on any prescription 
glucose lowering agent for Type 2 diabetes 
 Abdominal obesity (waist circumference >102 
cm [>40 in] for men and >88 cm [>35 in] for 
women) with no evidence of ascites by imaging 
unless obvious on physical exam  
 Dyslipidemia (triglyceridemia ≥150 mg/dL 
and low high density lipoprotein [<40 mg/dL in 
men and <50 mg/dL in women]) or using a 
prescription lipid lowering medication due to 
dyslipidemia 
3. Contraception:  Female subjects of 
childbearing potential must use ≥1 effective 
method (≤1% failure rate) of contraception 
during the study until 4 weeks following the 
last dose of investigational product (including 
OLE doses).  Effective methods of 
contraception are considered to be those listed 
below: 
2. Subjects with a confirmed diagnosis of NASH 
and a fibrosis score of 4 based upon the NASH 
CRN scoring system determined by central 
reading of a liver biopsy obtained no more than 
12 months before Day 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Contraception:  Female subjects of 
childbearing potential must use ≥1 effective 
method (≤1% failure rate) of contraception during 
the study until 4 weeks following the last dose of 
investigational product (including OLE doses).  
Effective methods of contraception are listed 
below: 
Subjects with cryptogenic 
cirrhosis will not be 
enrolled under Version3 of 
the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Editorial 


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Synopsis, Exclusion 
Criteria 
and 
Section 8.1.2, Subject 
Exclusion Criteria 
 
 
 
 
 
 
 
 
8.Total bilirubin >2 mg/dL (subjects with 
Gilbert’s syndrome may be enrolled despite a 
total bilirubin level >2 mg/dL if their conjugated 
(direct) bilirubin is <2× ULN) 
 
 
 
9. Albumin <3.2 g/dL 
 
 
 
 
 
 
 
 
 
 
 
28. Previous exposure to OCA within 12 months 
For alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and total bilirubin for 
which if Screening Visit 1 and Visit 2 values 
differ by ≥30% and either of the lab values is > 
upper limit of normal (ULN), then a third 
sample will be collected at an unscheduled visit 
as a confirmatory sample.   
3. MELD score >12 
5. Documented presence of varices based on prior 
endoscopy performed within 6 months of Day 1 
10. Total bilirubin >2 mg/dL (subjects with an 
established diagnosis of Gilbert’s syndrome and 
a normal hemoglobin and reticulocyte count 
may be enrolled despite a total bilirubin level 
>2 mg/dL if their conjugated (direct) bilirubin is 
<2× ULN) 
11. Conjugated bilirubin ≥1.5x ULN 
12. Albumin <3.5 g/dL 
22. LDL cholesterol <50 mg/dL (irrespective of 
statin use) 
28. Chronic use (≥12 months) of drugs 
historically associated with drug-induced 
NAFLD within the 5 years before Day 1 (eg, 
amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, 
estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, 
valproic acid, and other known hepatotoxins). 
31. Concurrent participation in any other 
interventional or noninterventional clinical 
trial. 
33. Previous exposure to OCA within 12 months of 
Day 1 
 
Note: Exclusion criteria 28 in main protocol 
(Section 8.1.2) also refers to Section 9.3 
28. Chronic use (≥12 months) of drugs 
historically associated with drug-induced 
Clarification 
 
 
 
 
Additional exclusion 
criteria are added to the 
protocol as follows: 
Subjects with MELD >12, 
presence of varices, 
conjugated bilirubin ≥1.5x 
ULN, low LDL cholesterol, 
or chronic use of drugs 
historically associated with 
drug-induced NAFLD will 
not be enrolled in the study. 
 
Other criteria have been 
clarified as indicated 
 


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NAFLD within the 5 years before Day 1 (eg, 
amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, 
estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, 
valproic acid, and other known hepatotoxins; 
see Section 9.3). 
Synopsis, Liver 
Histology and Event 
Adjudication and Data 
Monitoring 
Committee Oversight 
 
 
 
and 
Section 16.14, 
Adjudication 
Committees 
Histological presence of NASH with a fibrosis 
score of 4 based on the NASH CRN scoring 
system, or cryptogenic cirrhosis with metabolic 
factors assumed to be due to NASH must be 
confirmed for study eligibility. 
All suspected liver-related clinical outcomes, and 
major adverse cardiovascular events (MACE), 
and drug related hepatic injury events that occur 
after administration of the first dose of 
investigational product will be reviewed by the 
following blinded adjudication committees, 
depending on event type, before inclusion in any 
analysis.  The 3 committees and event types they 
are responsible for adjudicating events are as 
follows:. 
• Hepatic Safety Committee:  Adjudicates all 
suspected drug related hepatic injury events 
The DMC will include hepatologists, 
pharmaceutical physicians, epidemiology/ 
cardiology expert(s), and statistician(s); they will 
not be involved in the study as Investigators, 
adjudication committee members, or consultants.  
All members will have considerable experience 
with clinical study conduct and DMCs before 
joining the DMC. 
Histological presence of NASH with a fibrosis 
score of 4 based on the NASH CRN scoring system 
must be confirmed for study eligibility. 
 
All suspected liver-related clinical outcomes, and 
major adverse cardiovascular events (MACE), and 
drug-related hepatic injury events that occur after 
administration of the first dose of investigational 
product will be reviewed by the following blinded 
adjudication committees, depending on event type, 
before inclusion in any analysis.  The 2 committees 
that are responsible for adjudicating events are as 
follows: 
 
 
The DMC will include hepatologists, 
pharmaceutical physicians, epidemiology/ 
cardiology expert(s), drug-induced liver injury 
(DILI) expert(s) and statistician(s); they will not be 
involved in the study as Investigators, adjudication 
committee members, or consultants.  All members 
will have considerable experience with clinical 
study conduct and DMCs 
Subjects with cryptogenic 
cirrhosis will not be 
enrolled under Version 3 of 
the protocol. 
 
 
 
 
 
Clarification 
 
 
 
 
Clarification 








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Synopsis, Statistical 
Methods  
(and subsections) 
 
 
and 
Section 16.12.1, 
Safety Analyses 
(OLE) 
 
 
 
A total of approximately 360 subjects will be 
enrolled and randomized into the study in a 1:1 
ratio to placebo or OCA.  Randomized subjects 
will be stratified by the presence of type 2 
diabetes at enrollment (yes or no) and 
cryptogenic cirrhosis (yes or no). 
 
The mITT Population will include all ITT 
subjects who dose titrate at Month 3 per protocol. 
 
Primary and key secondary efficacy hypothesis 
testing will be based on the ITT population.  
Exploratory analyses of the primary endpoint will 
be conducted using the mITT and PP population. 
The primary efficacy analysis will test the 
following hypotheses: 
• H0:  The percentage of subjects with fibrosis 
improvement by at least 1 stage using the NASH 
CRN score from Baseline to Month 12 is equal 
between placebo and OCA. 
• H1:  The percentage of subjects with fibrosis 
improvement by at least 1 stage using NASH 
CRN score from Baseline to Month 12 is 
different between placebo and OCA. 
 
 
 
 
 
 
 
 
 
PK/PD analytical methods will be detailed in a 
separate modeling and simulations plan, and all 
results will be documented separate from the 
clinical study report. 
Approximately 540 subjects will be enrolled and 
randomized into the study in a 1:1:1 ratio to OCA 
10 mg, OCA 10 mg → 25 mg, or placebo arms.  
Randomized subjects will be stratified by the 
presence of type 2 diabetes at enrollment (yes or 
no).   
 
The mITT Population will include all ITT subjects 
except those who are not eligible to dose titrate 
due to safety or tolerability reasons.   
 
Primary and key secondary efficacy hypothesis 
testing will be based on the ITT population.  
Supportive analyses of the primary endpoint will 
be conducted using the mITT and PP population. 
The primary efficacy analysis will test the following 
hypotheses: 
• H01:  The percentage of subjects with fibrosis 
improvement by at least 1 stage and no increase in 
hepatocellular ballooning or lobular 
inflammation using the NASH CRN scoring 
system from Baseline to Month 12 is equal 
betweenplacebo and OCA 10 to 25 mg titration. 
• H11:  The percentage of subjects with fibrosis 
improvement by at least 1 stage and no worsening 
of NASH defined as no increase in hepatocellular 
ballooning or lobular inflammation, using the 
NASH CRN scoring system, from Baseline to 
Month 12 is different between placebo and OCA 10 
to 25 mg titration. 
• H02:  The percentage of subjects with fibrosis 
improvement by at least 1 stage and no 
worsening of NASH defined as no increase in 
hepatocellular ballooning or lobular 
Clarification 
 
 
 
Number of subjects have 
been increased to 
sufficiently power the study 
 
 
 
Clarification 
 
 
 
 
 
 
 
 
 
Clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The hypothesis testing of the primary and key 
secondary endpoint will be conducted in a 
sequential closed testing gate-keeping procedure.  
For the comparison of the primary and key 
secondary efficacy endpoints, a Cochran–
Mantel–Haenszel test stratified by the 
randomization strata (presence of type 2 diabetes 
at enrollment [yes/no] and cryptogenic cirrhosis 
[yes/no]) will be used.  
Additional secondary endpoints will be analyzed; 
however, statistical testing will be considered 
descriptive and exploratory only.   
 
 
 
 
 
 
 
Safety Analyses 
Safety evaluations will comprise treatment-
emergent AEs, adjudicated CV events, vital 
signs, electrocardiograms (ECGs), and clinical 
laboratory results. 
 
inflammation, using the NASH CRN score from 
Baseline to Month 12 is equal between placebo 
and OCA 10 mg. 
• H12:  The percentage of subjects with fibrosis 
improvement by at least 1 stage and no 
worsening of NASH defined as no increase in 
hepatocellular ballooning or lobular 
inflammation, using the NASH CRN score from 
Baseline to Month 12 is different between 
placebo and OCA 10 mg. 
 
The hypothesis testing of the key secondary 
endpoint will be conducted in a sequential closed 
testing gate-keeping procedure.  For the comparison 
of the primary and key secondary efficacy 
endpoints, a Cochran–Mantel–Haenszel (CMH) test 
stratified by the randomization strata (presence of 
type 2 diabetes at enrollment [yes/no] will be used.   
Analyses of the clinical outcomes composite 
endpoint and individual components of outcome 
events will evaluate the effect of OCA (10 mg 
and 25 mg) compared to placebo, as listed under 
the secondary objectives.  Only adjudicated 
events will be included in analyses.  Subjects 
with none of these events will be censored at the 
date of last contact.  For the analysis of time to 
first occurrence of adjudicated events, in 
addition to the CMH test statistics, a log rank 
test stratified by the randomization stratification 
factor will be used.  Kaplan-Meier estimates of 
the distribution of the time-to-event will be 
tabulated and graphed by treatment group. 
 
Safety Analyses 
Safety evaluations will comprise treatment-
emergent AEs, AEs of special interest including 
pruritus and hepatic safety, adjudicated 
cardiovascular events vital signs, 
 
 
 
 
 
 
 
 
 
 
Clarifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarification 
 
 
 
 
 
 


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Pharmacokinetic/Pharmacodynamic Analyses 
The change in each PD assessment (eg, C4, FGF-
19) over time will be incorporated into a 
maximum effect (Emax) model with OCA as an 
independent variable.   
 
Safety Analyses (OLE) 
Similar analyses to that which are described will 
also conducted for the OLE.   
 
Efficacy Analyses (OLE) 
Efficacy analyses conducted during the Double
Blind Phase will be repeated during the OLE.  
Separate summaries will be presented by the 
randomized treatment assignment in the double
blind phase.  For subjects with optional biopsy in 
OLE, histological changes will be assessed. 
electrocardiograms (ECGs), and clinical laboratory 
results. 
 
Pharmacokinetic/Pharmacodynamic Analyses 
The change in each PD assessment (eg, C4, FGF-
19) over time will be incorporated into a maximum 
effect (Emax) model with OCA dose level as an 
independent variable.   
These PK/PD analyses will be reported in a 
separate document outside of the clinical study 
report. 
 
Safety Analyses (OLE) 
Safety evaluations conducted during the Double-
Blind Phase will also be conducted for the OLE.   
 
Synopsis, Statistical 
Methods  
Sample Size 
Justification 
and  
Section 16.2, 
Determination of 
Sample Size 
A sample size of 180 subjects per group with an 
assumed 5% discontinuation rate will provide 
90% power to demonstrate a statistically 
significant treatment difference between OCA 
and placebo group based on Chi square test with 
2-sided type I error at 0.01 level, assuming a 
responder rate of 23% and 8% in the OCA and 
placebo groups, respectively, based on data from 
literature, observed effect size on fibrosis 
improvement in advanced fibrosis subjects in 
FLINT and practical consideration. 
A sample size of 180 subjects per group with an 
assumed 5% discontinuation rate will provide 90% 
power to demonstrate a statistically significant 
treatment difference between OCA 25 mg and 
placebo group based on Chi square test with 2-sided 
type I error at 0.01 level, assuming.  This assumes 
a responder rate of 23% and 8% in the OCA and 
placebo groups, respectively, based on data from 
literature, observed effect size on fibrosis 
improvement in advanced fibrosis subjects in the 
Farnesoid X receptor Ligand OCA in 
Nonalcoholic Steatohepatitis Treatment (FLINT) 
study and practical consideration. 
Editorial 
Section 5.1, Overview 
of Nonalcoholic 
Steatohepatitis and 
Obeticholic Acid  
For patients with NASH without diabetes, 
practice guidelines from the American 
Association for the Study of Liver Diseases 
recommend the use of vitamin E as first line 
therapy. 
For patients with NASH without diabetes, practice 
guidelines from the American Association for the 
Study of Liver Diseases recommend the use of 
vitamin E as first line therapy (Chalasani 2012). 
Clarification 


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Section 5.3, Clinical 
Experience with 
Obeticholic Acid 
OCA is under investigation for the treatment of 
multiple chronic liver diseases, including the 
treatment of NASH, primary biliary cirrhosis 
(PBC, also called primary biliary cholangitis 
[Beuers 2015a, Beuers 2015b, Beuers 2015c]), 
primary sclerosing cholangitis, biliary atresia, and 
other chronic liver diseases.  In May 2016, the 
United States (US) Food and Drug 
Administration (FDA) has granted accelerated 
approval for OCA (Ocaliva) for the treatment of 
PBC.  In December 2016, the European 
Medicines Agency’s Committee for Medicinal 
Products for Human Use (CHMP) approved 
conditional marketing authorization for Ocaliva 
for the treatment of PBC.  
 
The clinical development program for OCA in 
subjects with NAFLD or NASH includes data 
from the following 3 completed studies: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCA is under investigation for the treatment of 
multiple chronic liver diseases, including the 
treatment of NASH, primary biliary cholangitis 
(PBC, also called primary biliary cirrhosis) [Beuers 
2015a, Beuers 2015b, Beuers 2015c]), primary 
sclerosing cholangitis, biliary atresia, and other 
chronic liver diseases.  OCA was granted 
accelerated approval by the United States Food 
and Drug Administration (FDA) on 27 May 2016.  
Conditional approvals were obtained on 12 Dec 
2016 in the European Union (EU), and by Health 
Canada on 24 May 2017 under the trademark 
Ocaliva for the treatment of PBC in combination 
with ursodeoxycholic acid (UDCA) in adults with 
an inadequate response to UDCA, or as 
monotherapy in adults unable to tolerate UDCA. 
The clinical development program for OCA in 
subjects with NAFLD or NASH includes data from 
the following 4 completed studies: 
• Double-Blind Phase of Study 747-209: A Phase 
2, double-blind, randomized, placebo-controlled, 
multicenter study evaluating the effect of OCA, 
and the subsequent addition of statin therapy, on 
lipoprotein metabolism in subjects with NASH 
with fibrosis stage 1 to 4, but no evidence of 
hepatic decompensation.  
 
Study 747-209 enrolled subjects with histological 
evidence of definite or probable NASH 
confirmed by liver biopsy and a nonalcoholic 
fatty liver disease activity score (NAS) of 4 or 
greater, randomized in a 1:1:1:1 ratio to receive 
OCA 5 mg, OCA 10 mg, OCA 25 mg or placebo, 
orally once daily, for 16 weeks.  Randomization 
was stratified by LDL concentration (fasting 
serum low-density lipoprotein (LDL) cholesterol 
at Screening Visit 2;  ≤125 mg/dL or 
>125 mg/dL) and baseline fibrosis stage (stage 1, 
2 or stage 3, 4).  Statin-free subjects as well as 
Updated OCA approval 
information 
 
 
 
 
 
 
 
 
 
 
 
 
 
Updated information 
regarding OCA clinical 
development program 


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In addition, 2 studies evaluating OCA for the 
treatment of NASH are currently ongoing: 
• A Phase 2, double blind, randomized, placebo
controlled study (Study 747 209) evaluating the 
effect of OCA and atorvastatin treatment on 
lipoprotein metabolism in subjects with NASH 
statin-treated subjects (following a 4-week statin 
washout) were eligible for enrollment.  All 
subjects initiated treatment with atorvastatin at 
a dose of 10 mg once daily after 4 weeks of OCA 
treatment.  After 4 weeks of 10 mg atorvastatin 
treatment, dosing was increased to 20 mg once 
daily, and continued for an additional 4 weeks.  
After 4 weeks of treatment at 20 mg daily dose, 
atorvastatin dosing could be titrated up or down 
as clinically indicated.   
A total of 84 subjects were randomized into the 
study, with baseline cirrhosis status being pre 
cirrhotic in 62 (74%) subjects and cirrhotic in 22 
(26%) subjects.  Seventy-nine (94%) subjects 
completed the Double-Blind phase.  An increase 
in LDL cholesterol was observed following 
treatment with OCA and the addition of low-
dose atorvastatin (10 mg) reversed OCA-
associated changes in LDL cholesterol back to 
baseline levels and lower within 4 weeks. 
Three subjects discontinued due to AEs: 1 
subject on OCA 5 mg for Stage 4 breast cancer, 
and 2 subjects on OCA 25 mg for pruritus. 
 
In addition, the following studies evaluating OCA 
for the treatment of NASH are currently ongoing: 
• The open label extension portion of Study 
747-209. 
 


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Section 5.4.1, 
Rationale for Study 
Design 
The incidence of NASH is increasing and NASH 
is likely to be the leading cause of liver transplant 
by 2020, highlighting the need for development 
of effective therapies that may improve 
steatohepatitis and resulting fibrosis, potentially 
delaying liver transplant or death.  
Thus, Study 747 304 will evaluate efficacy and 
safety of OCA in subjects with NASH with 
cirrhosis (defined by a NASH Clinical Research 
Network [CRN] score of 4), with the exception of 
subjects with Child Pugh (CP) score ≥7.  
The incidence of NASH is increasing and NASH is 
likely to be the leading cause of liver transplant by 
2020, highlighting the need for development of 
effective therapies that may improve steatohepatitis 
and fibrosis, potentially delaying liver transplant or 
death.  
Thus, Study 747 304 will evaluate efficacy and 
safety of OCA in subjects with histological 
evidence of NASH with cirrhosis (defined by a 
NASH Clinical Research Network [CRN] score of 
4), with the exception of subjects with hepatic 
decompensation or Child Pugh (CP) score ≥7.  
Clarification 
Section 5.4.3, 
Rationale for 
Obeticholic Acid 
Doses and Duration 
Subjects will be randomized to receive OCA 
10 mg or placebo daily for the first 3 months then 
titrate to OCA 25 mg or placebo daily for the 
duration of the Double Blind Phase.   
This dose titration was selected based the known 
mechanism of FXR and on clinical experience in 
completed Phase 2 studies in subjects with 
NAFLD (747-203) and NASH (FLINT) as well 
as a clinical pharmacology study in subjects with 
hepatic impairment (Study 747-103). 
 
 
 
 
 
 
 
 
Guidelines for subjects who progress beyond CP 
Class A are provided in Section 7.5. 
In addition to placebo, two dosing regimens of 
OCA will be evaluated in this study: (1) Titration 
regimen (OCA 10 mg → 25 mg) in which OCA 
will be initiated at a dose of 10 mg once daily 
followed by uptitration to 25 mg once daily at 
Month 3; and (2) OCA 10 mg once daily for the 
entire duration of the study.  
This dose titration was selected based upon the 
known mechanism of FXR and on clinical 
experience in completed Phase 2 studies in subjects 
with NAFLD (747-203) and NASH (FLINT), as 
well as a clinical pharmacology study in subjects 
with hepatic impairment (Study 747-103). 
Study 747-209 evaluated a range of doses from 
5 mg to 25 mg in subjects with NASH and 
fibrosis, including subjects with compensated 
cirrhosis.  In this study, treatment of NASH 
subjects with compensated cirrhosis with up to 
25 mg OCA was found to be safe and well 
tolerated, and the AE profile of cirrhotic 
subjects was not different from that of 
precirrhotic subjects.  Guidelines for subjects who 
progress beyond CP Class A are provided in 
Section 7.4. 
Rationale for the changes in 
the study design is 
described. 


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Section 5.5, Summary 
of Known Potential 
Risks with 
Investigational 
Product 
 
 The rate of progression and risk of hepatic 
decompensation is variable and may be rapid in 
certain patients, necessitating closer surveillance 
of patients at risk.  Investigators should inform 
participating subjects of known and anticipated 
risks associated with OCA treatment and 
prompt them to communicate with the 
Investigators in the event of any adverse 
experiences. 
Post-Marketing Cases of Liver Injury in PBC 
Liver injury, liver decompensation, liver failure, 
and death have been reported in patients with 
moderate to severe hepatic impairment (Child-
Pugh B and C) when Ocaliva was dosed more 
frequently than recommended in labeling for 
such patients (up to 7 times the recommended 
dose).  In addition, serious liver adverse events 
have been reported in the post-marketing setting 
in OCA-treated patients without cirrhosis or 
with mild liver impairment, both early in 
treatment and after months of treatment.  
Signs and symptoms reported in patients 
experiencing liver-related adverse outcomes who 
received Ocaliva include:  increases in bilirubin 
and other liver enzymes, new or worsening 
pruritus, new or worsening fatigue, vague 
neuropsychiatric symptoms (such as dysphoria), 
abdominal pain, nausea, vomiting, diarrhea, 
dehydration, jaundice, and liver 
decompensation. 
Clinical Study Experience 
Liver-related events 
Systemic and hepatic concentrations of OCA 
increase significantly in patients with moderate 
to severe hepatic impairment.   In PBC clinical 
studies, a dose response relationship was 
observed for the occurrence of liver related 
adverse reactions with OCA, including jaundice, 
worsening ascites, and primary biliary 
 


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cholangitis flare with dosages of OCA 10 mg to 
50 mg once daily.  Most events occurred at a 
dose up to 5 fold higher (50 mg) than the 
maximum recommended marketed dose (10 mg).  
Clinically relevant increases in AST, ALT, or 
conjugated bilirubin (markers of liver injury) 
were rarely seen at the intended clinical doses of 
5 mg or 10 mg.  Elevated liver enzymes were 
observed in healthy subjects who were treated at 
doses ≥100 mg in Phase 1, multiple-dose studies; 
however, these elevations were only considered 
to be of clinical concern at the maximum dose of 
250 mg daily. Cases of hepatic decompensation 
cases have also occurred in PBC.  The majority 
of the cases were considered not related or 
unlikely related to investigational product by the 
Investigator.  In general, subjects who 
experienced hepatic decompensation either 
entered the study with more advanced disease, 
or for those studies where subjects started 
earlier in disease progression, events of hepatic 
decompensation generally occurred at least 
1 year after the initiation of treatment or on 
higher doses. 
Four cases of hepatic decompensation and 
potential drug induced liver injury (DILI) in the 
PBC program assessed as possibly related were 
examined by an independent hepatic 
adjudication committee.  Although the subjects 
experienced progression of liver dysfunction 
while on OCA treatment, the committee 
concluded the pattern was consistent with 
progression of underlying disease rather than a 
DILI event.      
Analyses of liver-related safety information from 
NASH subjects treated with OCA demonstrate 
an overall hepatic safety profile consistent with 
PBC.  There is no evidence to indicate a 
consistent, dose-dependent worsening of liver 


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biochemistries at doses up to 25 mg, including 
ALT, AST or bilirubin.  Modest increases in 
ALP levels have occurred following treatment 
with OCA, however levels were generally within 
upper limits of normal.  ALP elevations are 
generally not associated with a rise in GGT, 
suggesting that these changes are unlikely to be 
due to cholestatic liver injury.  
The incidence of liver-related adverse events in 
NASH clinical studies overall was low.  Events 
specifically reflective of hepatic decompensation 
in the NASH program was low with comparable 
incidence between OCA and placebo (2% OCA 
versus % placebo). 
Two cases of hepatic decompensation have been 
reported as SUSARs, 1 of which resulted in 
death.  In the ongoing Phase 3 clinical Study 
747-303, a NASH subject with no evidence of 
cirrhosis at baseline presented with acute liver 
injury, acute kidney injury, hyperbilirubinemia, 
and a generalized vesicular rash, which required 
hospitalization.  The Investigator assessed the 
events as severe, serious due to hospitalization, 
important medical events, and possibly related 
to the investigational product (remains blinded).  
In the ongoing Phase 2 open-label extension 
phase of Study 747-209, a NASH subject with a 
history of NASH cirrhosis with hepatic 
impairment and presumptive evidence of portal 
hypertension reported events of severe diarrhea, 
jaundice, and unintended weight loss (30 lbs in 
approximately 1 month) approximately 
5 months after initiating treatment with OCA 
25 mg; OCA was discontinued at that time.  The 
subject was subsequently hospitalized for acute 
renal failure and died due to renal failure and 
liver failure leading to cardiac arrest.  The 
Investigator assessed both the event of acute 
renal failure and the event of liver failure as fatal 


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in severity, serious, and unlikely related to 
investigational product. 
Pruritus 
Pruritus is an expected adverse event associated 
with OCA, particularly in subjects with 
cholestatic liver diseases such as PBC where 
pruritus is a common symptom of the disease.  In 
PBC clinical studies, the incidence of pruritus 
was 68% for OCA-treated subjects compared 
with 40% in placebo-treated subjects.  The 
majority of events have been reported as mild to 
moderate in severity and infrequently resulted in 
early discontinuation.  The majority of subject’s 
experiencing pruritus did not require an 
intervention for pruritus. The incidence and 
severity of pruritus have been shown to be dose 
dependent, but there is no evidence of 
association with stage or progression of 
underlying disease.  In NASH clinical trials, AEs 
of pruritus was reported less frequently with 
OCA treatment relative to PBC.  In the FLINT 
study, mild to moderate pruritus occurred in 
23% of OCA-treated subjects compared with 
6% of placebo-treated subjects and only 1 
subject discontinued therapy as a result of 
pruritus.    
Lipids 
In subjects with NASH (FLINT), compared to 
placebo, treatment with OCA was associated 
with statistically significant elevations in the 
mean total serum cholesterol and low-density 
lipoprotein (LDL) levels, and a decrease in the 
mean HDL, which remained within normal 
limits.  These changes developed within the first 
12-week time point after beginning of treatment, 
decreased over time after Week 12, and returned 
to baseline levels when OCA treatment was 
withdrawn.    


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Withdrawal of OCA treatment reversed the 
OCA-induced LDL increase in all groups, 
including subjects who were not on statins 
(Neuschwander-Tetri 2015a).  In Study 747-209, 
subjects with NASH and dyslipidemia received 
placebo or OCA 5mg, 10 mg, and 25 mg once 
daily, for up to 4 weeks.  Subjects then initiated 
concurrent treatment with 10 mg atorvastatin 
once daily titrated to 20 mg once daily based on 
tolerability.  At Week 4, subjects experienced 
approximately 20% to 25% increases in LDL-C 
particles across all OCA groups.  By Week 8, 
atorvastatin treatment effectively lowered 
LDL-C to below baseline levels across all OCA 
groups compared to patients not on a statin.     
Together, the small magnitude of OCA mediated 
cholesterol and LDL changes, coupled with their 
reversibility upon cessation of OCA treatment 
and/or responsiveness to statin-initiation, suggest 
that this risk can be managed by statins as 
needed. 
An independent data monitoring committee 
(DMC) has performed detailed reviews of 
several studies including the Phase 3, clinical 
outcomes study in PBC (747-302) and the Phase 
3, pivotal study in NASH with fibrosis (747-303).  
The DMC reviewed data (unmasked for PBC 
and unblinded by treatment group for NASH 
with a total of approximately 1000 subjects) in 
closed sessions, which excluded participation of 
the Sponsor.  Based on these reviews, the DMC 
recommended that both studies continue without 
modification providing further support for the 
lack of safety concern and positive benefit-risk 
profile of OCA. 
In summary, based on the robust efficacy of 
OCA observed in PBC and NASH clinical 
studies, including improvements in liver 
biochemistry, fibrosis, and key histological 


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features of NASH, as well as the overall safety 
profile of OCA (in >2300 healthy subjects and 
subjects with chronic liver diseases), the benefit-
risk profile is favorable.   
Section 5.6, 
Importance of 
Monitoring of Disease 
Progression 
This is a new section added to Version 3. 
NASH is a chronic, progressive liver disease; 
therefore, it is important that subjects with 
NASH are closely monitored to ensure early 
identification of potential disease progression to 
cirrhosis, decompensation and/or liver injury.  
The rate of progression and risk of 
decompensation is variable and may be rapid in 
certain patients necessitating closer surveillance 
of patients at risk.  Therefore, more extensive 
safety monitoring and appropriate dosing 
adjustments, interruptions, and discontinuations 
will be implemented to improve subject 
oversight and safety.  Investigators together with 
the Sponsor’s Medical Monitor or designee will 
consistently and frequently assess individual 
subjects to determine on an ongoing basis the 
totality of a subject’s clinical profile, which 
includes careful evaluation of signs and 
symptoms of potential hepatic injury and/or 
decompensation coupled with rules based 
laboratory monitoring. 
Subjects will be monitored for potential hepatic 
injury and/or progression to decompensation 
(Section 7.4).  Criteria for implementing dosing 
adjustments, interruptions, or discontinuations, 
and close monitoring procedures postdose-
adjustment are described in Section 7.5 and 
Section 7.6.  The more extensive monitoring is 
important given the elevated risk of 
decompensation and potential for higher hepatic 
exposure to OCA in this population. 
Additional safety procedure 
added to the protocol 


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Section 7.1.2,  
Table 1, Schedule of 
Study Procedures 
(Double-Blind Phase) 
The following study visit windows were changed:  
• 
Screening Visit 1: 8 Weeks prior to Day 1 
• 
Screening Visit 2:  4 Weeks prior to Day 1 ±2 
days 
• 
Day 1:  ±1 wk 
• 
Mth 12/EOT/EOS:  ±1 wk 
 
The following assessments were removed from 
Ver.3 
• 
LiverMultiScan 
• 
Microbiome/Metabolome Stool Sample 
Analysis (All US Subjects) 
• 
Blood Samples for Genetic Analysis 
 
 
The following timepoints were removed from 
Ver.3 
• 
Lipoprotein analysis: SV1, M1, M2, M3, 
M4, M5, and M9 
• 
Thyroid hormones: SV1 
• 
TE and MRE:  M3, and M9 
• 
Trough PK: M2, and M5 
The following study visit windows were changed:  
• 
Screening Visit 1:  ≤12 Weeks prior to Day 1 
• 
Screening Visit 2:  ≥4 after SV1 
• 
Day 1:  ≤12 Weeks after SV1 
• 
Mth 12/EOT/EOS:  -2 wk 
 
The following assessments were added to Ver. 3: 
• 
Waist and hip circumference:  All visits 
except at SV1 
• 
Vital signs: All visits except at SV2 
• 
Assess signs and symptoms of hepatic injury 
or decompensation: All visits except 
screening visits 
• 
Gallbladder assessment: at SV1, D1, M6, 
and M12 
• 
EGD Procedure: SV1 
• 
Review DILI management algorithm (liver 
biochemistry): All visits except SV1, SV2, 
and D1 
The following assessments were added to Ver. 3: 
• 
Liver biopsy (optional): ET 
• 
Pruritus VAS:  M3 
• 
Thyroid hormones: D1 
Clarification (study visits 
windows, vital assessments) 
 
Gallbladder assessment:  
Gathering additional data at 
Screening may be 
beneficial in identifying at 
risk populations (eg, to 
assist with the causality of 
potential gallbladder/ 
pancreatic complications)  
 
EGD procedure added for 
screening for varices 
 
LiverMultiScan, and 
Micobiome/Metabolome: 
These changes are based on 
the feasibility of conducting 
these procedure at study 
sites. 


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Section 7.1.2,  
Table 1, Schedule of 
Study Procedures, 
(Double-Blind Phase),  
FOOTNOTES 
a The 2 Screening Visits must occur at least 4 
weeks apart to confirm pretreatment serum 
chemistry levels, including ALT and AST. 
e Prior medications taken within 6 months of Day 
1 are to be recorded at Screening Visits 1 and 2, 
and Day 1 only.  For all other visits, only 
concomitant medications are to be recorded. 
f Body temperature, sitting heart rate, respiratory 
rate, and seated blood pressure after sitting 3 
minutes.  Height will be measured at Screening 
visit 1 only.  BMI and waist-to-hip ratio will be 
calculated via EDC from waist and hip 
circumference measurements. 
h AUDIT only at Screening Visit 1. 
j Hepatobiliary ultrasound for HCC screening at 
Screening is not required if data from a recent 
historic ultrasound (within 3 months of screening) 
are available. 
 
k If hepatobiliary ultrasound for HCC screening 
was not performed at Screening and the historic 
ultrasound is >3 months from Day 1, perform a 
hepatobiliary ultrasound. 
l Including assessment of ascites and hepatic 
encephalopathy.  
 
 
 
m On-study liver biopsies should be performed 
after the hepatobiliary ultrasound for HCC 
screening.  Liver biopsy procedure at Screening 
Visit 2 is not required for subjects who have had 
a biopsy ≤12 months prior to randomization (Day 
1) and can provide unstained slides. 
n Optional procedure.  If a biopsy was obtained 
within 12 months of Day 1, subjects do not need 
to undergo this procedure.  
a Screening Visit 2 must occur at least 4 weeks 
after Screening Visit 1 to confirm pretreatment 
serum chemistry levels, including ALT, AST, and 
bilirubin. 
e Prior medications taken within 12 months of Day 
1 are to be recorded at Screening Visits 1 and 2, 
and Day 1 only.  For all other visits, only 
concomitant medications are to be recorded. 
f Height will be measured at Screening Visit 1 only.  
The calculations for BMI and waist-to-hip ratio 
will be calculated performed via EDC:  BMI from 
weight and height measurements, and waist-to-
hip ratio from waist and hip circumference 
measurements. 
g Body temperature, sitting heart rate, 
respiratory rate, and seated blood pressure after 
sitting 3 minutes. 
h At Screening Visit 1, only AUDIT will be 
conducted.  At D1, M6, M12/EOT/EOS, and ET, 
all 3 assessments (AUDIT, smoking habit, and 
caffeine consumption) will be done. 
k Hepatobiliary ultrasound for HCC screening and 
gallbladder assessments at Screening are not 
required if data from a recent historic ultrasound 
(within 3 calendar months of Day 1) are available. 
l Ultrasound will be conducted to enhance HCC 
surveillance and for gallbladder assessment.  If 
ultrasound was not performed at Screening and the 
historic ultrasound is >3 months from Day 1, 
perform a hepatobiliary ultrasound. 
 
m Perform EGD procedure unless data from a 
recent EGD (within 6 months of Day 1) are 
available. Subjects with varices will not be 
enrolled in the study. 
n On-study liver biopsies should be performed after 
the hepatobiliary ultrasound for HCC screening.  
Liver biopsy procedure is not required for subjects 
Version 3 footnotes “a”, 
“e”, “g”, “h”, “n”, “o”, “r”, 
“s”, “t”) Clarifications.  
 
(Version 3 footnotes “k” & 
“l”) Gathering additional 
data at Screening may be 
beneficial in identifying at 
risk populations (eg, to 
assist with the causality of 
potential 
gallbladder/pancreatic 
complications) 
 
 
 
 
 
 
 
 
 
 
 
 
(Version 3 footnote “o”) 
Screening for varices, an 
exclusionary criterion. 
 
 
 
 
 
 
 
 


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o Health-related quality of life (EQ-5D-5L, 
CLDQ-NAFLD, WPAI, and SF 36), and 
standardized generic measure of health status for 
the assessment of health utilities (eg, 
hospitalization [reason, length of stay, major 
medical procedures], emergency room visits, 
outpatient physician visits, concomitant 
medications. 
r In the event either of the 2 ALT or AST 
assessments collected at Screening Visit 1 and 
Screening Visit 2 differ by ≥30%, a third sample 
will be collected at an unscheduled visit as a 
confirmatory sample to include in the mean 
result(s) that will be used to determine eligibility. 
s Other metabolic parameters include fasting 
plasma glucose, insulin, C-peptide, and HOMA-
IR. 
t Urine β-hCG pregnancy tests must be 
performed for females of childbearing potential 
before entry.  If positive, a confirmatory blood 
test must be performed.  If the blood test is also 
positive, the subject may not be enrolled in the 
study.   
u Sceening TE, LiverMultiScan, and MRE can be 
performed at either Screening Visit 1 or 
Screening Visit 2.  Baseline TE, LiverMultiScan, 
and MRE should be conducted prior to an on-
study liver biopsy.  Whichever modality/ies used 
at baseline must be collected consistently at each 
visit. 
w Serial PK blood samples will be obtained 0.5 
hour prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 
2.5, 3, 4, 5, and 6 hours postdose.   
x Subjects will be permitted to decline to provide 
a blood sample for the genetics study without 
affecting their involvement in the study.  Only 
who have had a biopsy ≤12 months prior to 
randomization (Day 1) and can provide unstained 
slides for central reading.  Liver biopsy at ET is 
an optional procedure. 
o Health-related quality of life (EQ-5D-5L, CLDQ-
NAFLD, and WPAI), and standardized generic 
measure of health status for the assessment of 
health utilities (eg, hospitalization [reason, length of 
stay, major medical procedures], emergency room 
visits, outpatient physician visits, concomitant 
medications). 
 
r In the event any of the 2 ALT, AST, or total 
bilirubin assessments collected at Screening Visit 1 
and Screening Visit 2 differ by ≥30% and either 
lab value is >ULN, a third sample will be collected 
at an unscheduled visit as a confirmatory sample. 
 
s Other metabolic parameters include fasting 
plasma glucose, insulin, C-peptide, HOMA-β, and 
HOMA-IR. 
t Urine β-hCG pregnancy tests must be performed 
for females of childbearing potential before entry.  
If positive, a confirmatory blood test must be 
performed.  If the blood test is also positive, the 
subject may not be enrolled in the study, and if 
already enrolled, must be discontinued 
immediately.   
u TE by Fibroscan® and MRE will be conducted 
at sites where device is available.  Baseline TE 
should be performed once at Screening Visit 1, 
Screening Visit 2, or Day 1 (prior to first study 
drug administration).  It is encouraged that TE 
is conducted prior to on-study liver biopsy(-ies). 
w Serial PK blood samples will be obtained at 0.5, 
0.75, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours postdose.  
 
 
(Version 3 footnote “p”) 
SF-36 procedure will not be 
conducted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Version 3 footnote “u”) 
LiverMultiScan will not be 
conducted. 
 


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RNA samples will be collected at Month 
12/EOS/EOT and ET. 
Section 7.1.2,  
Table 2, Schedule of 
Study Procedures 
(OLE Phase) 
 
 
 
The following study visit windows was changed:  
• 
Day 1 (Month 12 DB):  ±1 wk 
 
The following study visits were removed from 
Ver.3 
• 
Study Visits M15, M18, M21, and M24 
 
The following assessments were removed from 
Ver.3 
• 
LiverMultiScan and MRE 
• 
Serum markers of inflammation, apoptosis, 
and necrosis 
• 
PD blood samples 
• 
Trough PK blood samples 
• 
Serial PK blood samples 
• 
Blood samples for genetic analysis 
• 
Exploratory markers of disease severity 
 
The following timepoints were removed from 
Ver.3 
• 
Lipoprotein analysis: M1, M3, M4, AND M6 
 
Note:  Only those subjects who complete the 
Double-Blind Month 12 Visit and continue to 
receive investigational product are eligible to 
enroll into the OLE. 
The following study visit windows was changed:  
• 
Day 1 (Month 12 DB):  -2 wk 
 
 
 
 
The following assessments were added to Ver. 3: 
• 
Waist and hip circumference: All timepoints 
• 
Vital signs: All timepoints 
• 
Assess Signs and Symptoms of Hepatic 
Injury or Decompensation: All timepoints 
• 
EGD Procedure: D1 (M12 DB) 
• 
Review DILI management algorithm (liver 
biochemistry): All timepoints 
 
 
 
The following timepoints were added to Ver. 3: 
• 
Physical exam: M12/EOT,/EOS, and ET 
• 
12-lead electrocardiogram: M12/EOT,/EOS, 
and ET 
• 
AUDIT: ET 
• 
HCC Screening: ET 
• 
Liver biopsy: M12/EOT,/EOS, and ET 
• 
Urinalysis: M12/EOT,/EOS 
 
Clarification: 
• 
CP Score/Class (assessment of ascites and HE 
is required) 
Clarification 
 
 
 
 
 
 
OLE Phase has been 
decreased from 2 years to 
1 year 
 
 
Several assessments have 
been scaled back due to 
changed scope of the OLE 
Phase. 
 
 
 
 
 
 
Clarifications 


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Section 7.1.2,  
Table 2, Schedule of 
Study Procedures 
(OLE Phase), 
FOOTNOTES 
d Body temperature, sitting heart rate, respiratory 
rate, and seated blood pressure after sitting 3 
minutes.  Height will be measured at Screening 
only.  BMI and waist-to-hip ratio will be 
calculated via EDC from waist and hip 
circumference measurements. 
f Including assessment of ascites and hepatic 
encephalopathy. 
 
 
g Subjects randomized to placebo during the 
Double-Blind Phase will receive OCA 10 mg for 
3 months followed by OCA 25 mg in the OLE, 
unless there are safety concerns.  Subjects 
randomized to OCA during the Double-Blind 
Phase will continue the treatment they were 
assigned. 
 
 
 
h Optional procedure. 
 
 
 
j At the Month 1, 2, 4, and 5visit, investigational 
product dispensed/administered will be from the 
bottle issued at the previous visit. 
m Trough PK samples will be collected from all 
subjects at each specified Visit and must be 
completed prior to administration (predose) of 
investigational product. 
n Serial PK blood samples will be obtained 0.5 
hour prior to dosing and at 0.5, 0.75, 1, 1.5, 2, 
2.5, 3, 4, 5, and 6 hours post dose.  All 
assessments, except for the post dose collection 
of blood samples for subjects participating in the 
PK assessment, must be completed prior to 
d The calculations for BMI and waist-to-hip 
ratio will be performed via EDC:  BMI from 
weight and height measurements, and waist-to-
hip ratio from waist and hip circumference 
measurements.  (Note: Height will be measured 
at Screening Visit 1 only.) 
e Body temperature, sitting heart rate, respiratory 
rate, and seated blood pressure after sitting 3 
minutes. 
 
g Perform EGD procedure unless data from a 
recent EGD (within 6 months of OLE Day 1) are 
available. Subjects with varices will not continue 
in the OLE Phase. 
h Subjects randomized to placebo during the 
Double-Blind Phase will be re-randomize to OCA 
10 mg or OCA 10 mg → 25 mg arms on OLE 
Day 1; the placebo subjects in the OCA 10 mg → 
25 mg arm will receive OCA 10 mg for 3 months 
followed by OCA 25 mg in the OLE, unless there 
are safety concerns.  Subjects randomized to OCA 
(10 mg or 25 mg dose) during the Double-Blind 
Phase will continue the treatment they were 
assigned. 
i Biopsy at Month 12 DB/Day 1 OLE, must be 
completed prior to receiving investigational 
product on Day 1 of OLE.  At Month 12 of OLE 
and ET of OLE, the biopsy procedure is 
optional. 
k At the OLE Month 1, 2, 4, and 5 Visit, 
investigational product dispensed/administered will 
be from the bottle issued at the previous visit. 
Clarification 
 
 
 
 
 
 
 
 
 
Screening for varices (an 
exclusionary criterion) at 
the beginning of the OLE 
Phase. 
 
 
Clarification 
 
 
 
 
 
 
Clarification 
 
 
 
 
 
 
PK assessments have been 
removed from the OLE 
Phase 


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administration of investigational product.  
Subjects will be permitted to decline to provide a 
blood sample for the genetics study without 
affecting their involvement in the study.   
Section 7.3,  
Planned Dosing 
Regimen 
Subjects will be randomly assigned in a 1:1 ratio 
to receive placebo or OCA.   
Following assessments of liver chemistry and 
safety at Month 1 and Month 2, a dose titration to 
25 mg or matching placebo will be implemented 
at Month 3, unless there are safety and 
tolerability concerns identified by the 9.2medical 
monitor.   
Subjects will be randomly assigned in a 1:1:1 ratio 
to receive OCA 10 mg, OCA 10 mg → 25 mg, or 
placebo.   
For subjects in the OCA 10 mg → 25 mg group, 
a dose titration to 25 mg will be implemented at 
Month 3 after assessments of liver chemistry and 
safety at Month 1 and Month 2, unless there are 
safety and tolerability concerns identified by the 
Medical Monitor/or the Investigator.  Subjects 
randomized to the OCA 10 mg or placebo arms 
will continue the same dosing (dummy titration) 
(refer to Section 9.2). 
Rules for the titration arm 
have been clarified. 
Section 7.4, 
Monitoring and 
Management of 
Potential Hepatic 
Injury and/or Disease 
Progression 
Section 7.4, Management of Disease Progression 
 
A subject who progresses to CP Class B or C 
cirrhosis (CP score ≥7) will discontinue 
investigational product (Section 8.2.1.1), and the 
subject should be followed for the duration of the 
study.  Subjects should be encouraged to continue 
study visits, despite stopping investigational 
product, for continued collection of safety data 
but may withdraw consent at any time. 
Monitoring of disease progression using CP score 
and MELD will be continued throughout the 
study (Table 1).  In addition, subjects should be 
re assessed within a month for disease 
progression.  At a minimum, a physical exam, 
general biochemistry, serum electrolytes, and 
assessment of CP and MELD scores should be 
conducted.  Further monitoring outside of regular 
scheduled visits should be based on the 
Investigator’s assessment of the subject’s clinical 
status. 
Section 7.4, Monitoring and Management of 
Potential Hepatic Injury and/or Disease 
Progression 
To monitor for potential hepatic injury, disease 
progression and/or hepatic decompensation, 
Child-Pugh and MELD scores will be reviewed 
at each visit (Section 7.1.2).  In addition, adverse 
events, signs and symptoms of potential hepatic 
injury or decompensation, and laboratory values 
will also be reviewed at regular intervals as 
described in the following subsections (Section 
7.4.1 to Section 7.4.3).  Based on the assessments 
of signs and symptoms of hepatic injury and 
liver biochemistry, the investigational product 
will be interrupted or discontinued per criteria 
discussed in Section7.5, and close monitoring 
procedures will be implemented (refer to Section 
7.6). 
Additional safety procedure 
added to the protocol. 


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Section 7.4.1, Signs 
and Symptoms of 
Hepatic Injury or 
Decompensation 
 
Subjects will be evaluated at study visits for 
potential signs and symptoms of hepatic injury 
or decompensation: 
Signs and Symptoms of Hepatic Injury or 
Decompensation: 
• Specific signs and symptoms of liver 
impairment:  yellowing of the skin or the whites 
of eyes, pale-colored stools, urine color change 
from pale to deep amber [dark] (reflecting 
impaired bilirubin metabolism) 
• More general signs and symptoms of ascites 
and encephalopathy:  confusion, swelling of the 
legs or abdomen 
• Non-specific signs and symptoms of impaired 
health:  nausea, vomiting, abdominal pain, 
diarrhea, weight loss, fever and chills, worsening 
or new fatigue, weakness, loss of appetite 
• Significant intercurrent illnesses such as 
gastroenteritis may exacerbate hepatic injury or 
decompensation (eg, established severe 
abdominal pain, vomiting, and diarrhea for 
more than 4 days) and should be an indication 
for prompt investigational product interruption 
and complete subject evaluation 
Other Symptoms: 
• New or worsening pruritus 
• Worsening of renal function or likely 
dehydration 
Healthcare Provider (HCP) Interactions: 
• Visits to primary HCP or referral to any 
specialist for any new symptoms (other than 
ongoing care for stable comorbidities) 
• New medications or changes to current 
medications prescribed from HCP or any new 
over the counter medications or herbal 
supplements. 
• Laboratory procedures or assessments 
performed by an HCP  
Additional safety procedure 
added to the protocol. 


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Signs and symptoms for potential hepatic injury 
or decompensation should be followed by (1) 
evaluation of liver biochemistry for drug-
induced liver injury (DILI) (Section 7.4.2), (2) 
assessment for disease progression (Section 
7.4.3), (3) triggering of investigational product 
interruption or discontinuation per criteria 
(Section 7.5), (4) documentation in the AE eCRF 
or the SAE eCRFs (Section 15.1.4 and Section 
15.1.5), and (5) contact with the Medical 
Monitor. 


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Section 7.4.2, Drug-
Induced Liver Injury 
 
Liver biochemistry will be assessed at each visit 
to assess biochemical triggers that will prompt 
an immediate reevaluation of subjects.  Thus, 
these assessments will be performed at: 
• Each protocol-specified visit 
• Unscheduled visits for any safety follow-up as 
appropriate 
It is important that the laboratory assessments 
be completed as required and that the central 
laboratory be used for assessments whenever 
possible.  In the event that a subject cannot 
return to the clinic for a scheduled or 
unscheduled visit, or there is an event that 
triggers a need for an immediate assessment, the 
use of a local lab is permissible at the discretion 
of the Investigator. In these cases, the 
investigator will obtain the laboratory results 
and the laboratory normal ranges. 
The process for assessing criteria is presented in 
Figure 2, and the specific threshold(s) for each 
laboratory analyte to trigger mandatory repeat 
testing and potentially a complete subject 
evaluation (depending on the repeat result) are 
summarized in Table 3. 
 
(Figure 2) 
 
(Table 3) 
 
If any subject meets the triggering threshold 
limits for either conjugated bilirubin or 
creatinine, investigational product should be 
immediately interrupted (see Section 7.5 for 
dosing modifications).  
For the remaining liver biochemistry 
assessments, if a subject meets the upper 
threshold limits, the laboratory assessment 
should be repeated in 2 to 3 days (with the 
Additional safety procedure 
added to the protocol. 


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exception of ALP, which should be repeated in 
7 days).  If a repeat laboratory test cannot be 
performed within 2 to 3 days, the subject should 
be instructed to interrupt investigational 
product until repeat lab results have been 
reviewed.  
• If on repeat evaluation, values are normal or 
returned or trended back to prior values, no 
dosing modifications are required and the 
subject should continue to be monitored. 
• If on repeat evaluation, values remain above 
the specified threshold, investigational product 
should be interrupted (see Section 7.5 for dosing 
modifications).  In this case, a medical history 
and physical exam should be conducted and AE 
information (including signs and symptoms of 
liver injury as described in Section 7.4.1) 
collected.  The medical monitor should be 
promptly contacted upon awareness for 
consultation regarding management of the 
subject.  If symptoms persist or repeat testing 
shows persistent abnormality as described 
above, it is appropriate to initiate close 
observation to determine whether the 
abnormalities are improving or worsening.   
Subjects should, wherever possible, come back to 
the site.  It may be difficult for subjects who are 
distant from their study site to return to the site 
promptly.  Such subjects can have repeat (or any 
safety) laboratory tests performed at a local 
laboratory, but normal laboratory ranges and 
the results should be made available to the 
Investigator, and redacted copies provided to the 
Sponsor.  
It should be noted that it is difficult to recognize 
every potential marker of hepatic or renal 
deterioration.  There is no substitute for good 
medical judgment.  Investigators will be 
reminded to be cautious and mindful in their 


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evaluation of subjects’ symptoms, signs, and 
laboratory results.  However, for example, a 
single abnormal laboratory analyte result may 
be artefactual; accordingly, Investigators will be 
allowed to implement an alternate follow-up 
procedure if considered appropriate based on 
their medical judgement but only after 
documented agreement with the Sponsor’s 
medical monitor. 
Section 7.4.2, Drug-
Induced Liver Injury, 
Figure 2, DILI 
Management 
Algorithm for Study 
747-304 
 
Additional safety procedure 
added to the protocol. 


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Electrolytesc 
Sodium <130 
2-3 days 
NA = not applicable 
a Diagnosis of Gilbert’s Syndrome should be 
established during baseline. Conjugated 
bilirubin to be sole determinate in such subjects. 
b Does not apply in subjects on anti-coagulants 
c Sodium will be measured as an assessment of 
liver failure (hyponatremia). 
Section 7.4.3, 
Progression of Disease 
to Child-Pugh Class B 
or C 
 
Investigators will closely monitor subjects for 
potential progression of cirrhosis to CP Class B 
or C at every visit (or at unscheduled visits in the 
event of signs or symptoms of suspected hepatic 
injury or decompensation).  Assessment of CP 
Scores must be performed at every visit.  Refer 
to Section 7.4.3.1 for determination of CP Score.  
Investigational product discontinuation is 
required in subjects who progress to CP score of 
7 or higher. 
Additional safety procedure 
added to the protocol. 
 
 
 
 


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Section 7.4.3.1, Child-
Pugh Assessment 
 
Child-Pugh (CP) Score (Pugh 1973, Lucey 1997) 
is calculated and reported within the EDC 
system based on data entered into the eCRF by 
adding the scores from the 5 factors outlined in 
Table 4 and can range from 5-15.  The 
investigational product should be discontinued 
in subjects with CP score ≥7.  
Calculation of the CP Score includes 
Investigator assessments of ascites and hepatic 
encephalopathy, which may be assessed during 
the adverse event review at the scheduled visits, 
as well as total bilirubin, serum albumin, and 
prothrombin time, which will populate from the 
central laboratory.  The relationship of CP Score 
to disease progression is as follows: CP score 5-6 
= CP Class A; CP Score 7-9 = CP Class B; CP 
Score ≥10 = CP Class C. 
Table 4: Child-Pugh Scoring System 
Factor 
Units 
Points 
1 
2 
3 
Serum 
bilirubin 
μmol/L 
<35 
35-50 
>50 
mg/dL 
<2.0 
2.0-3.0 
>3.0 
Serum 
albumin 
g/L 
>35 
28-35 
<28 
g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin 
time 
Seconds 
prolonged 
0-3 
4-6 
>6 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites 
 
None 
Mild 
Moder
ate-
Severe 
Hepatic 
encephalopat
hya 
 
No 
Grade 
1 or 2 
Grade 
3 or 4 
INR = international normalized ratio 
Child-Pugh criteria: Pugh 1973, Lucey 1997. 
West Haven criteria: Vilstrup 2014.  
a Grade 0: normal consciousness, personality, 
neurological examination, electroencephalogram 
Additional safety procedure 
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 Grade 1: restless, sleep disturbed, 
irritable/agitated, tremor, impaired handwriting, 
5 cps waves 
 Grade 2: lethargic, time-disoriented, 
inappropriate, asterixis, ataxia, slow triphasic 
waves 
 Grade 3: somnolent, stuporous, place-
disoriented, hyperactive reflexes, rigidity, slower 
waves 
 Grade 4: unrousable coma, no 
personality/behavior, decerebrate, slow 2-3 cps 
delta activity 
Section 7.4.3.2, Model 
for End-Stage Liver 
Disease (MELD) 
Scoring 
 
MELD is a scoring system used to assess the 
severity of chronic liver disease.  An increasing 
MELD score is associated with increased 
severity of hepatic dysfunction and increased 
3-month mortality risk.  MELD scores will be 
calculated based on creatinine, bilirubin, INR, 
and sodium values as appropriate, collected at 
the same visit with modification by United 
Network for Organ Sharing.  If only 1 
component of MELD needs to be repeated, all 
other components should also be repeated.  INR 
will be calculated based on PT value by the 
central laboratory.  The MELD calculation 
adjusts for subject who have had 2 or more 
dialysis treatments within the prior week and 
will automatically assign a serum creatinine of 
4.0 mg/dL for these subjects. 
Additional safety procedure 
added to the protocol. 


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Section 7.4.4, Pruritus 
 
Pruritus is already being closely monitored but 
has not been shown to be a reliable predictor of 
hepatic injury.  However, Investigators should 
be vigilant in responding to subjects’ complaints 
of new or worsening pruritus symptoms with 
prompt follow-up.  Pruritus grading (as with all 
adverse events) should be performed in 
accordance with CTCAE Version 4.03 
(Appendix B). 
For subjects with Grade 3 pruritus per CTCAE 
Version 4.03 (Section 15.1.4.1), instruct the 
subject to discontinue investigational product 
(Table 5).  These subjects should continue to 
return for scheduled study visits for safety follow 
up; however, the subjects will not be 
rechallenged with investigational product.  
General guidance for the management of 
subjects experiencing significant pruritus 
(≤Grade 2) is provided in Table 5 and Section 
14.1.4.1. 
Safety procedures 






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not be rechallenged. 
Monitor closely for 
clinical outcomes 
according to 
protocol 
assessments. 
≥Grade 3 pruritusg 
Discontin
uef / 
No Rech
allenge 
Continue to return 
for scheduled study 
visits for safety 
follow up; however, 
the subject should 
not be rechallenged. 
Other AEs ≥Grade 
3 considered 
possibly, probably, 
or definitely related 
to IP 
Liver 
transplantation 
Bariatric Surgery 
Fully resolved = Return to baseline levels or 
return to within normal limits (WNL). IP = 
investigational product 
a If subject is unable to be evaluated promptly, 
investigational product must be immediately 
interrupted. 
b Requires complete documentation of complete 
resolution or normal/baseline based on 
laboratory parameters and symptoms. 
c The Investigator may rechallange at the same 
dose or reduced dosing frequency of the 
investigational product. 
d ALT, AST, ALP, total bilirubin, INR, GGT, 
albumin, platelets, and electrolytes (sodium). 
e Clinically evident complications of portal 
hypertension (eg, ascites, variceal hemorrhage, 
hepatic encephalopathy). 
f Subjects who permanently discontinue from 
investigational product are expected to continue 
in the study and should follow the regular visit 
schedule for the duration of the study.   
g Severity per CTCAE Version 4.03. 


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Section 7.6,  Close 
Observation 
 
If investigational product is interrupted or 
discontinued as described in Section 7.5, subjects 
should be closely monitored. If returning to the 
site for a scheduled visit is not feasible, use of a 
local lab may be permissible at the Investigator’s 
discretion.  Subjects who permanently 
discontinue from investigational product should 
continue regularly scheduled visits. 
At a minimum, the following assessments should 
be conducted at each study visit:   
• Physical exam and thorough review of subject 
reported signs and symptoms,  
• Liver biochemistry (including ALP, ALT, AST, 
GGT, total and conjugated bilirubin, creatinine, 
and albumin), prothrombin time (PT)/INR, 
serum electrolytes, and assessment of Child 
Pugh (only if the subject is at the study site) and 
MELD scores.  
In addition, a pharmacokinetic sample for 
assessment of OCA serum drug levels and its 
major metabolites should be obtained in any 
subject who develops an AE of hepatic injury or 
decompensation.  
For events of potential hepatic injury, the 
following additional monitoring procedures 
should be performed per FDA Guidance for 
Industry on Drug Induced Liver Injury.  These 
cases must to be discussed with the Sponsor’s 
medical monitor: 
• Repeating liver enzyme and serum bilirubin 
tests as described in Table 3.  Frequency of 
retesting can decrease to once a week or less if 
abnormalities stabilize or the study drug has 
been discontinued and the subject is 
asymptomatic, as clinically indicated.  
• Obtaining a more detailed history of symptoms 
and prior or concurrent diseases.  
Additional Safety 
Procedures 


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• Obtaining a history of concomitant drug use 
(including nonprescription medications and 
herbal and dietary supplement preparations), 
alcohol use, recreational drug use, and special 
diets is important. Concomitant drugs with 
potential hepatotoxicity should be recorded and 
discontinued unless alternative therapies are not 
available.  In the case of concomitant drugs 
potentially hepatotoxic, continued use of 
investigational product should be discussed with 
the Sponsor’s medical monitor.  The subject may 
be discontinued from investigational product, if 
clinically appropriate.  
• Obtaining a history of exposure to 
environmental chemical agents or herbal 
supplements which may be associated with liver 
toxicity.  
• Ruling out acute viral hepatitis types A, B, C, 
D (in those thought to have acute HBV 
infection), and E; autoimmune or alcoholic 
hepatitis; Wilson disease, hypoxic/ischemic 
hepatopathy; and biliary tract disease.  
• Obtaining additional tests to evaluate liver 
function, as appropriate (e.g., INR, direct 
bilirubin).  
• Seeking hepatology consultation, if the 
Investigator is not a hepatologist. 


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Section 8.2, Subject 
Withdrawal Criteria 
 
(Section 8.2 to 
Section 8.2.1.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The specific changes 
in text are as follows: 
 
 
 
 
 
 
 
 
 
Section 8.2 and its subsections were rearranged 
and updated in Version 3.  The headers in 
Version 2 were as follows: 
 
8.2. Subject Withdrawal Criteria 
8.2.1. Reasons for Mandatory Discontinuation of 
Investigational Product 
8.2.1.1. Progression to CP score ≥7 
8.2.1.2. Severe and Related Adverse Events 
8.2.1.3. Liver Transplantation 
8.2.1.4 Bariatric Surgery 
8.2.2 Reasons for Mandatory Interruption of 
Investigational Product 
8.2.2.1. Adverse Events ≥ Grade 4 in Severity 
and Not or Unlikely Related to Investigational 
Product 
8.2.2.2. Suspected Drug Induced Liver Injury 
8.2.3. Other Reasons for Discontinuation of 
Investigational Product or Study Termination 
8.2.3.1. Withdrawal of Consent to Continue in the 
Study 
8.2.3.2. Lost to Follow-Up 
8.2.3.3. Pregnancy 
 
The specific changes in text are as follows: 
 
8.2. Subject Withdrawal Criteria 
8.2.1. Reasons for Mandatory Discontinuation of 
Investigational Product 
8.2.1.1. Progression to CP score ≥7 
If a subject develops a CP score ≥7, liver related 
assessments used in CP score calculation should 
be confirmed within 48 to 72 hours and captured 
in the EDC.  If CP score is confirmed, a 
mandatory discontinuation of investigational 
product is required.  However, subjects should be 
Section 8.2 and its subsections were rearranged 
and updated in Version 3.  The headers in Version 3 
are as follows: 
 
8.2. Subject Withdrawal Criteria 
8.2.1. Other Reasons for Discontinuation of 
Investigational Product or Study Termination 
8.2.1.1. Withdrawal of Consent to Continue in the 
Study 
8.2.1.2. Lost to Follow-Up 
8.2.1.3. Pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
The specific changes in text are as follows: 
 
8.2. Subject Withdrawal Criteria 
Subjects can be discontinued from 
investigational product by the Investigator at 
any time for clinical safety concerns.  Subjects 
who are discontinued from investigational 
product are expected to continue in the study 
and should follow the regular visit schedule for 
the duration of the study phase (Double Blind or 
OLE).  Subjects who permanently discontinue 
from investigational product are expected to 
continue regular visit schedule for safety 
Clarifications 


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encouraged to continue study visits, despite 
stopping investigational product, for continued 
collection of safety data but may withdraw 
consent at any time. 
8.2.1.2. Severe and Related Adverse Events  
If a subject experiences an AE that is ≥Grade 3 in 
severity using the current version of the Common 
Terminology Criteria for Adverse Events 
(CTCAE) (Section 15.1.4) and is considered 
possibly, probably, or definitely related to 
investigational product, the investigational 
product must be discontinued.  However, subjects 
should be encouraged to continue study visits, 
despite stopping investigational product, for 
continued collection of safety data but may 
withdraw consent at any time. 
8.2.1.3. Liver Transplantation 
Subjects must discontinue investigational product 
after undergoing liver transplantation surgery.  
Subjects should be encouraged to continue study 
visits, despite stopping investigational product, 
for continued study data collection but may 
withdraw consent at any time. 
8.2.1.4. Bariatric Surgery 
Subjects must discontinue investigational product 
after undergoing bariatric surgery.  A biopsy 
should be obtained at the time of surgery.  
Subjects should be encouraged to continue study 
visits, despite stopping investigational product, 
for continued study data collection but may 
withdraw consent at any time. 
8.2.2. Reasons for Mandatory Interruption of 
Investigational Product 
8.2.2.1. Adverse Events ≥ Grade 4 in Severity 
and Not or Unlikely Related to Investigational 
Product 
If a subject experiences an AE categorized as ≥ 
Grade 4 in severity and not or unlikely related to 
assessments until stabilization of the clinical 
event has occurred leading to discontinuation 
(per discretion of the Investigator and upon 
discussion with the medical monitor). 
Refer to Section 7.4 and Section 7.5 for 
withdrawal criteria related to potential hepatic 
injury and/or decompensation; progression to 
cirrhosis with CP score ≥7; Grade 3 pruritus, 
AEs ≥Grade 3 in severity and possibly, probably, 
or definitely related to investigational product; 
AEs ≥Grade 4 in severity and NOT or unlikely 
related to investigational product; liver 
transplantation, bariatric surgery, and 
pregnancy.  Other reasons, including withdrawal 
of consent or lost to follow up, are described in 
Section 8.2.1 below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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investigational product, at least a mandatory 
interruption of investigational product is required. 
8.2.2.2. Suspected Drug Induced Liver Injury 
Cirrhotic patients have diminished liver reserve 
and lesser ability to recover, and these could 
make the consequences of a drug induced injury 
worse.  Their transaminase, especially ALT, 
levels may be normal or only slightly elevated, 
due to their lower hepatocellular reserve, even in 
advanced cases.  For this reason, relatively lower 
level of transaminase elevations can indicate 
severe drug induced liver injury and may require 
investigational product discontinuations. 
Subjects who discontinue investigational product 
are expected to be followed though to study 
closure (or at the discretion of the Sponsor) and 
should be encouraged to continue study visits 
despite stopping investigational product for 
continued study data collection but may withdraw 
consent at any time. 
Natural progression of the underlying condition 
and other causal factors such as a common bile 
duct stone or development of other concurrent 
liver disease should be considered before the 
investigational product is permanently 
discontinued.  Subjects who discontinue due to 
significant drug induced liver injury must be 
followed until the AE has resolved, stabilized, or 
is not of clinical concern. 
Investigational product must be interrupted in 
subjects if the following conditions develop:  
• Baseline values were <2x ULN, and ALT or 
AST increases to >5x baseline measurement 
(BLM). 
• Baseline values were ≥2x ULN but <5x ULN, 
and ALT or AST increases to >3x BLM. 
• Baseline values were ≥5x ULN, and ALT or 
AST increases to >2x BLM. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• ALT or AST increase >2x BLM AND the 
increase is accompanied by a concomitant total 
bilirubin increase to >2x BLM OR the INR 
concomitantly increases by >0.2. 
Investigational product will also be interrupted in 
presence of signs and symptom(s) such as rash, 
eosinophilia, nausea, vomiting, or right upper 
quadrant pain, anorexia and fatigue irrespective 
of the transaminase level, if the bilirubin is 
elevated above 2x BLM.  A potential drug
induced liver injury work up for competing 
etiologies must be performed, and a complete 
liver profile including prothrombin time 
(PT)/INR must be repeated within 48 72 hours.  
Study medication can be restarted only if an 
alternative etiology is definitively identified and 
liver tests have returned to baseline. 
Follow up procedures, including laboratory 
evaluations and physical examinations, must be 
performed after a maximum of 2 weeks of re
treatment and may be conducted at a local clinic 
if the subject is unable to return to the site. In this 
case, results as well as normal laboratory ranges, 
must be reported immediately to the site, and 
included in the case reports, so the Investigator 
can determine if the subject is to be allowed to 
continue treatment. 
 
8.2.3. Other Reasons for Discontinuation of 
Investigational Product or Study Termination 
- Consent may be modified to discontinue study 
visits but allow continued access to medical 
records to assess for suspected major adverse 
cardiovascular events (MACE), and liver-related 
clinical outcomes, and drug related hepatic injury 
events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.1. Other Reasons for Discontinuation of 
Investigational Product or Study Termination 
- Consent may be modified to discontinue study 
visits but allow continued access to medical records 
to assess for suspected major adverse 
cardiovascular events (MACE), and liver-related 
clinical outcomes 
 


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Section 8.2.2, 
Reinitiating 
Investigational 
Product After 
Interruption 
Prior to restarting investigational product after a 
prolonged interruption (ie, longer than 4 weeks), 
the subject must be reconsented.  New baseline 
procedures must be performed if the interval from 
the last visit was more than 3 months during the 
study.   
 
 Samples for genetic analyses (optional) 
• Noninvasive radiological liver fibrosis 
measurements (transient elastography [TE], 
LiverMultiScan, and magnetic resonance 
elastography [MRE]; conducted at sites where 
device is available).  Whichever modality/ies 
used at baseline must be collected consistently at 
each visit. 
Prior to restarting investigational product after a 
prolonged interruption (ie, longer than 1 month 
[+2 weeks]), the subject must be reconsented.  New 
baseline procedures must be performed if the 
interval from the last visit was more than 1 month 
(+2 weeks) during the study.  
 
• Perform hepatobiliary ultrasound for HCC 
screening unless data from a recent ultrasound 
(within 3 months) are available 
• Noninvasive radiological liver fibrosis 
measurement (transient elastography [TE]; 
conducted at sites where device is available). 
 
Section 7.5, Dosage 
Adjustment Criteria 
 
If during the study, a subject progresses to CP 
score ≥7 (CP Class B or C), the Investigator 
should discontinue investigational product.  In 
addition, subjects should be re-assessed monthly 
(or more frequently per Investigator discretion) 
for at least 3 months or until clinically stable.  
Additional safety procedure 
added to the protocol. 
Section 8.2, Subject 
Withdrawal Criteria 
 
The following text was moved from Section 7.4 of 
protocol version 2 to Section 8.2 of protocol 
version 3. 
Subjects can be discontinued from investigational 
product by the Investigator at any time for clinical 
safety concerns.  Subjects who are discontinued 
from investigational product are expected to 
continue in the study and should follow the regular 
visit schedule for the duration of the study phase 
(Double-Blind or OLE). 
Clarification 


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Section 9.1, 
Investigational 
Product Treatment 
Regimen 
Two treatment groups will be evaluated: 
• Placebo  
• OCA (10 mg and 25 mg) 
 
9.1.1. OLE Phase 
 
 
 
Three treatment groups will be evaluated: 
• Placebo  
• OCA (10 mg) 
• OCA (10 mg → 25 mg) 
 
The study will be blinded until the last subject 
completes the Double-Blind Phase and the 
database is locked. 
Clarifications 


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Section 9.2, 
Uptitration at 
Month 3. 
 
Section 9.2.1, Double-
Blind Phase  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.2, 9.2.1, and 9.2.2 were added to 
Version 3 
9.2. Uptitration at Month 3 
9.2.1. Double-Blind Phase 
Subjects randomized to the OCA 10 mg → 
25 mg arm in the Double-Blind Phase will 
receive OCA 10 mg for the first 3 months.  
Uptitration to 25 mg may occur at Month 3, 
following review of individual subject safety and 
tolerability data.   
Prior to the Month 3 study visit, the Medical 
Monitor will perform a review of consolidated 
safety data, including data from the Month 1 
and 2 study visits, as well as that from any 
unscheduled visit(s), for all study subjects.  Case 
review and discussion with the principal 
investigator will occur as needed.  A subject may 
proceed with uptitration to OCA 25 mg (or 
matching placebo), if no safety and/or 
tolerability concerns are evident in the clinical 
judgement of the reviewer(s).  The review will 
include but not be limited to the following: 
• Liver-related adverse events 
• Safety laboratories: chemistry panel including 
glucose, hematology panel, coagulation 
parameters; computed MELD score and Child-
Pugh score 
• Physical examination (development of 
clinically evident ascites or manifestations of 
hepatic encephalopathy) 
Additional considerations to determine the 
suitability to uptitrate will include an assessment 
of comorbid conditions, the subject’s overall 
adverse event profile, concomitant medications 
with a focus on potentially hepatotoxic 
concomitant medications, and/or any new 
treatment(s) for comorbid condition(s).  The 
uptitration review process is detailed in the 
study-specific Medical Management Plan. 
Clarification of dosing 
instructions for the titration 
arm 


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Section 9.2.2, OLE 
Phase 
If uptitration at Month 3 is not feasible due to 
special circumstances, the window for 
uptitration may be extended by up to one 
calendar month, after consultation and 
agreement with the Medical Monitor.  
Subjects randomized to the OCA 10 mg or 
placebo arms will undergo dummy titration to 
maintain study blind. 
In addition, dosing frequency post-titration may 
be temporarily decreased for tolerability 
reasons, following discussions with the Medical 
Monitor.  In addition, investigational product 
may be interrupted per safety criteria listed in 
Table 5 and Section 7.5.  The procedures for re 
initiating investigational product after prolonged 
interruption are provided in Section 8.2.2  
9.2.2. OLE Phase 
Subjects who were randomized to placebo in the 
Double-Blind Phase will be re-randomized to 
either OCA 10 mg or OCA 10 mg → 25 mg at 
entry into the OLE.  Uptitration to OCA 25 mg 
at Month 3 in the OLE will be conducted in the 
same manner applied in the Double-Blind Phase 
and described above.  Subjects randomized to 
OCA (10 mg or 25 mg dose) during the Double-
Blind Phase will continue the same dosing 
regimen. 
All dosing will be conducted in a dummy 
titration fashion in order to maintain the blind 
until all subjects complete the Double-Blind 
Phase and the database is locked. 


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Section 9.2, 
Concomitant 
Medications  
Relevant information about all concomitant 
medications taken before (ie, within 6 months of 
Day 1) and during the study must be recorded in 
the source documents and case report form, as 
well as any dose or dose regimen changes that 
occur during the study.   
To the extent possible, concomitant medications 
should be maintained at a stable dose throughout 
the study and at a minimum, from Day 1 through 
the end of double-blind treatment, unless the 
baseline therapy is no longer considered clinically 
appropriate by the Investigator or the subject’s 
primary care provider.   
Relevant information about all concomitant 
medications taken before (ie, within 12 months of 
Day 1) and during the study must be recorded in the 
source documents and case report form, as well as 
any dose or dose regimen changes that occur during 
the study.   
To the extent possible, concomitant medications 
should be maintained at a stable dose throughout 
the study and at a minimum, from Day 1 through 
the end of the Double-Blind Phase, unless the 
baseline therapy is no longer considered clinically 
appropriate by the Investigator or the subject’s 
primary care provider.   
The restrictions related to use of drugs 
historically associated with drug induced 
NAFLD are as follows: 
• Drugs with Potential NASH-modifying 
Properties 
Subjects should either not be taking any drugs 
with potential NASH-modifying properties 
(specifically, TZDs/glitazones or vitamin E) or be 
on a stable dose of these medications for 6 
months before Day 1.  Subjects providing 
historical biopsies to determine study eligibility 
should be on a stable dose of these medications 
for 12 months before Day 1 and these 
medications should not have been initiated after 
the historical liver biopsy was performed.  
Changes to these drugs with potential NASH-
modifying properties are not permitted for the 
duration of the Double-blind Phase unless the 
baseline therapy is no longer considered 
clinically appropriate by the Investigator/or the 
usual care provider. 
• Drugs with Potential NAFLD-inducing 
Properties  
Subjects chronically (≥12 months) using the 
following drugs, that are historically associated 
with NAFLD, will not be enrolled in the study: 
Restrictions related to use 
of drugs with potential 
NASH-modifying 
properties and drugs 
historically associated with 
drug induced NAFLD are 
clarified in this section. 


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amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, 
estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, 
valproic acid, and other known hepatotoxins 
(refer to exclusion criterion 28; Section 8.1.2). 
Section 9.3.1, Statins 
Use of statins (eg, simvastatin, atorvastatin) 
should be at a stable dose 1 month before Day 1.   
Use of statins (eg, simvastatin, atorvastatin) should 
be at a stable dose ≥30 days before Day 1.   
Clarification 
Section 9.5.1, 
Methods of Assigning 
Subjects to Treatment 
Groups 
9.4.1. Methods of Assigning Subjects to 
Treatment Groups 
This study will be conducted in a double-blind, 
placebo-controlled manner.  Enrolled subjects 
will be randomized in a 1:1 ratio to placebo or 
OCA based on a predefined randomization code 
(generated by Sponsor or designee) using an 
IWRS.  Subjects randomized to OCA will initiate 
investigational product of OCA 10 mg for 
3 months prior to uptitrating to OCA 25 mg.  
Uptitration will be based on safety and 
tolerability assessments completed at Month 1, 
Month9.2 2, and Month 3.  
Randomization of subjects will be stratified by 
the presence of type 2 diabetes at enrollment (yes 
or no) and cryptogenic cirrhosis (yes or no).   
All subjects who enroll into the OLE will receive 
OCA.  9.2Subjects randomized to placebo in the 
double-blind period will initiate investigational 
product of OCA 10 mg for the first 3 months of 
the OLE prior to uptitrating to OCA 25 mg.  
Uptitration will be based on safety and 
tolerability assessments completed at Month 1, 
Month 2, and Month 3.  Subjects will continue 
the same dosing regimen they received at the end 
of the Double-Blind Phase.   
Once all subjects have titrated to the 25 mg dose 
in the OLE, subjects may receive investigational 
product with an open label identifying the 
product as OCA 25 mg. 
9.5.1. Methods of Assigning Subjects to Treatment 
Groups 
This study will be conducted in a double-blind, 
placebo-controlled manner.  Enrolled subjects will 
be randomized in a 1:1:1 ratio to one of the three 
treatment arms: once daily dosing of OCA 
10 mg, OCA 10 mg → 25 mg (ie, OCA 10 mg 
with uptitration to OCA 25 mg at Month 3), or 
placebo.  Randomization will be done using an 
IWRS and will be based on a predefined 
randomization code generated by the Sponsor or 
designee.  Subjects randomized to OCA 10 mg → 
25 mg will initiate dosing at OCA 10 mg for 
3 months prior to uptitrating to OCA 25 mg.  
Uptitration will be based on safety and tolerability 
assessments completed prior to Month 3 
(Section 9.2). 
Randomization of subjects will be stratified by the 
presence of type 2 diabetes at enrollment (yes or 
no).   
All subjects who enroll into the OLE will receive 
OCA.  Subjects randomized to placebo in the 
Double-Blind Phase will be re-randomized to 
OCA 10 mg or OCA 10 mg → 25 mg arms, with 
uptitration at OLE Month 3 in the OCA 10 mg 
→ 25 mg arm (refer to Section 9.2). 
Clarification 


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Section 9.5.2, 
Blinding 
9.4.2. Blinding 
The subjects, Investigators, and study site staff 
will be blinded to the subject’s treatment 
allocation during the subject’s participation in the 
study. 
9.5.2. Blinding 
The subjects, Investigators, and study site staff will 
be blinded to the subject’s treatment regimen until 
all subject data have been collected from the 
study and the database is locked.  Using this 
approach, blinding of the trial will be 
maintained. 
Clarification 
Section 9.6.2, Subject 
Numbers 
9.5.2. Subject Numbers 
Subjects will be identified by a unique 6-digit 
number. The first 3 digits will represent the site 
number and the last 3 digits, the subject number. 
9.6.2. Subject Numbers 
Subjects are assigned using a unique 10-
character, 9-digit identifier (AAA BBBCCC), 
independent of the randomization number. The 
first 3 digits represent the last 3 digits of the 
protocol number, followed by a hyphen (AAA-). 
The next 3 digits represent the site number (BBB). 
The last 3 digits represent a unique screening 
number that is assigned in sequential order at 
each site starting with 001 (CCC). 
Clarification 
Section 9.8, Visit 
Procedures 
9.7. Visit Procedures 
Visits should be based on Day 1 (not on the prior 
visit) unless stated otherwise.  For example, 
Month 3 should ideally occur 3 calendar months 
(±1 week) following Day 1.  A month is defined 
as 4 weeks (ie, 28 days).   
Acceptable windows for PK sampling timepoints 
are in Table 5. 
9.8. Visit Procedures 
Visits should be based on Day 1 (not on the prior 
visit) unless stated otherwise.  If Day 1 occurs on 
January 1st, Month 3 should ideally occur on 
April 1st (±1 week).  This is the definition of a 
calendar month.   
Acceptable windows for PK sampling timepoints 
are in Table 7. 
Clarification 
Section 9.8.1, 
Subjects will also be required to provide consent 
prior to participating in any of the optional 
assessments, such as providing blood samples for 
genetic analysis or serial PK draws 
Subjects will also be required to provide consent 
prior to participating in any of the optional 
assessments, such as providing blood samples for 
serial PK draws. 
Genetic analysis 
assessments have been 
removed from the study. 


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Section 9.8.2, Fasting 
Requirement at Study 
Visits 
9.7.2. Fasting Requirement at Study Visits 
Starting on Day 1, all subjects must arrive to the 
study site in a fasted state (at least 8 hours before 
each visit).   
9.8.2. Fasting Requirement at Study Visits 
Starting with Screening Visit 2, all subjects must 
arrive to the study site in a fasted state (at least 
8 hours before each visit).  
If the subject reports having eaten within 
8 hours of the visit, the nonfasted state will be 
documented in the source and eCRF; however, 
scheduled assessments (blood collection) will still 
be performed during the visit, and these subjects 
will be reminded that fasting is required before 
all study visits. 
Correction made – fasting 
is also required at 
Screening Visit 2 


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Section 9.8.3.1, 
Screening Visit 1  
through 
Section 9.8.10, DB 
Month 12/EOT/EOS 
Changes across multiple sections from Section 
9.7.3.1 through 9.7.11 are indicated below by 
visit days: 
 
SV1, SV2, D1 
• Assess and record any pretreatment-emergent 
AEs (after the ICF has been signed) 
 
SV1, SV2 
• Record prior (if within 6 months of Day 1) and 
current concomitant medications 
 
 
 
 
SV1, D1, M6, M12 
• Perform hepatobiliary ultrasound for HCC 
screening unless data from a recent historic 
ultrasound (within 3 months of Screening) are 
available 
 
 
 
 
 
 
 
SV1, M1, M2, M3, M4, M5, M9 
 Lipoprotein analysis 
 
SV1, SV2, M1, M6, M12, and ET 
• Noninvasive radiological liver fibrosis 
measurements (TE, LiverMultiScan, and MRE; 
conducted at sites where device is available) 
Changes across multiple sections from Section 
9.8.31 through 9.8.10 are indicated below by visit 
days: 
 
SV1, SV2, D1 
• Assess and record any pretreatment AEs (after the 
ICF has been signed) 
 
SV1, SV2 
• Record prior (if within 12 months of Day 1) and 
current concomitant medications 
 
SV2 through M12, and ET 
• Measure circumference of waist and hips 
 
SV1, D1, M6, M12 
• Perform hepatobiliary ultrasound for HCC 
screening and gallbladder assessment unless data 
from a recent historic ultrasound (within 3 months 
of Day 1) are available 
(M1) 
• If a hepatobiliary ultrasound for HCC 
screening and gallbladder assessment was 
not performed at Screening and the historic 
ultrasound is >3 months from Day 1, perform 
a hepatobiliary ultrasound 
(M6, M12) 
Perform hepatobiliary ultrasound for HCC 
screening and gallbladder assessment 
 
 
SV1, SV2, M1, M6, M12, and ET 
• Noninvasive radiological liver fibrosis 
measurements (TE; conducted at sites where device 
is available) 
 
 
 
 
 
Editorial 
 
 
 
 
 
 
 
Clarification 
 
 
 
Gathering additional data at 
Screening may be 
beneficial in identifying at 
risk populations (eg, to 
assist with the causality of 
potential 
gallbladder/pancreatic 
complications. 
 
 
 
 
 
 
 
 
LiverMultiScan assessment 
has been removed from the 


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Whichever modality/ies used at baseline must be 
collected consistently at each visit. 
 
SV1 through M12, and ET 
- CP Score/Class 
 
 
 
 
 
D1, M1, M3, M6, M12, and ET 
• Obtain stool sample (collected at home) for 
microbiome/metabolome analysis (US subjects 
only) 
 
D1, M12, and ET 
 Genetic analyses (optional) 
 
M1, M4, and M12 
• If subject consented to participate in serial PK 
assessment, the following procedures will be 
conducted 
- 0.5 hour to dosing:  collect predose blood 
sample 
 
 
SV1 through M12, and ET 
- CP Score/Class (assessment of ascites and 
hepatic encephalopathy is required) 
 
M1 through M12, and ET 
• Assess signs and symptoms of hepatic injury or 
decompensation 
- DILI management algorithm (liver 
biochemistry) 
 
 
 
 
 
 
M1, M4, and M12 
• If subject consented to participate in serial PK 
assessment, the following procedures will be 
conducted 
study due to feasibility 
issues 
 
 
Clarification 
 
 
 
Additional safety 
procedures 
 
 
 
Microbiome/metabolome 
analyses have been 
removed from the study 
 
 
 
 
Clarification 
 


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Section 9.8.3.1, 
Screening Visit 1 
9.7.3.1. Screening Visit 1 
The Screening Visit assessments must be 
performed within ≤8 weeks prior to Day 1 to 
determine whether the subject meets all the 
inclusion criteria and none of the exclusion 
criteria.  Subjects who do not fulfill all eligibility 
criteria will not be enrolled in the study. 
For rescreening, all Screening procedures should 
be repeated and a new 3 digit screening number 
assigned.  Subjects should be reconsented, as 
appropriate, at this time. 
• Record weight and BMI 
• Determine alcohol consumption (Alcohol Use 
Disorders Identification Test [AUDIT] 
questionnaire) 
 
 
 
 
 
 
For subjects without a recent liver biopsy with 
unstained slides, a second Screening Visit 
(Screening Visit 2, [Section 9.7.3.2]) must be 
performed within the 8-week screening window 
before Day 1 (assuming all other Screening 
assessments indicate a likelihood that the subject 
will qualify based on biopsy).   
 
Note:  Noninvasive radiological measurements 
may be completed any time after Screening Visit 
1 through Day 1 but should be conducted prior to 
an on- study liver biopsy. 
 
 Thyroid hormones 
9.8.3.1. Screening Visit 1 
The Screening Visit assessments must be performed 
within ≤12 weeks prior to Day 1 to determine 
whether the subject meets all the inclusion criteria 
and none of the exclusion criteria.  Subjects who do 
not fulfill all eligibility criteria will not be enrolled 
in the study. 
When rescreening, all Screening procedures should 
be repeated and a new screening number assigned.  
Subjects should be reconsented, as appropriate, at 
this time. 
• Measure height.  Record weight and BMI 
• Determine alcohol consumption (Alcohol Use 
Disorders Identification Test [AUDIT] 
questionnaire), smoking habits, and caffeine 
consumption 
• Perform EGD procedure unless data from a 
recent EGD (within 6 months of Day 1) are 
available. Subjects with varices will not be 
enrolled in the study. 
 
For subjects without a recent liver biopsy with 
unstained slides, or adequate tissue block, an 
on-study liver biopsy must be performed within 
the 12-week screening window before Day 1 
(assuming all other Screening assessments indicate 
a likelihood that the subject will qualify based on 
biopsy).   
 
Note:  Noninvasive radiological measurements may 
be completed any time during Screening Visit 1 
through Day 1 but should be conducted prior to an 
on- study liver biopsy, if one is necessary, and 
before initiation of investigational product on 
Day 1. 
Screening period has been 
extended. 
 
 
 
 
 
 
 
 
 
Clarifications 
 
 
 
Subjects will be screened 
for the presence of varices 
at Screening 
 
 
 
Clarification 
 
 
 
 
 
 
Clarification 


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Section 9.8.3.2, 
Screening Visit 2 
9.7.3.2. Screening Visit 2 
Screening Visit 2 procedures must be performed 
within ≤4 weeks ±2 days prior to Day 1 and are 
as follows: 
9.8.3.2. Screening Visit 2 
Screening Visit 2 procedures must be performed 
≥4 weeks after Screening Visit 1 and are as 
follows: 
• For subjects without a recent liver biopsy with 
unstained slides or adequate tissue block 
(≤12 months prior to Day 1), collect liver biopsy 
sample.  (Procedure may be performed within 
the 12 week screening window, and assuming all 
other Screening assessments indicate a likelihood 
that the subject will qualify based on biopsy). 
Clarification 
Section 9.8.4, Day 1 
Procedures 
9.7.4. Day 1 Procedures (Randomization) 
• Assessment of baseline pruritus 
9.8.4. Day1 Procedures (Randomization) 
• Assessment of baseline pruritus (via medical 
history evaluation) 
- Thyroid hormones 
Clarification 
Section 9.8.5, DB 
Month 1 Procedures 
9.7.5. Month 1 Procedures 
- Metabolic parameters (excluding HbA1c) 
9.8.5. DB Month 1 Procedures 
- Metabolic parameters 
Refer to Table 1 for 
changes in assessments 
Section 9.8.6, DB 
Month 2 and Month 5 
Procedures 
9.7.6. Month 2 Procedures 
9.7.9. Month 5 Procedures 
9.8.6. DB Month 2 and Month 5 Procedures 
Editorial 
Section 9.8.7, DB 
Month 3 and Month 9 
Procedures 
9.7.7. Month 3 and Month 9 Procedures 
9.8.7. DB Month 3 and Month 9 Procedures 
• Health-related quality of life questionnaires 
and health status for the assessment of health 
utilities (Month 3 only) 
• Pruritus VAS (Month 3 only) 
- Metabolic parameters (including HbA1c) 
- Markers of inflammation, apoptosis, and 
necrosis (Month 3 only) 
- Trough PK assessment (all subjects) (Month 3 
only) 
- PD assessments (all subjects) (Month 3 only) 
- Noninvasive panel of liver fibrosis (ELF, 
FibroMax, and Fibrometer) (Month 3 only) 
Refer to Table 1 for 
changes in assessments 


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Section 9.8.8, DB 
Month 4 Procedures 
9.7.8. Month 4 Procedures 
• Health related quality of life questionnaires and 
health status for the assessment of health utilities 
- Metabolic parameters (excluding HbA1c) 
9.8.8. DB Month 4 Procedures 
• Pruritus VAS 
- Metabolic parameters 
Refer to Table 1 for 
changes in assessments 
Section 9.8.9, DB 
Month 6 Procedures 
9.7.10. Month 6 Procedures 
9.8.9. DB Month 6 Procedures 
Editorial 
Section 9.8.10, DB 
Month 12/EOT/EOS 
9.7.11. Month 12/EOT/EOS 
• Health-related quality of life questionnaires and 
health status for the assessment of health utilities 
• Liver biopsy 
9.8.10. DB Month 12/EOT/EOS 
 
• Liver biopsy (must be completed prior to dosing 
with investigational product at Day 1 OLE) 
 
 
Clarification 
Section 9.7.10.1,
 Additional 
Procedures at Month 
12/OLE Day 1 . . . 
Section 9.7.11.1 
 
 
 
 
 
• Record the visit in IWRS, and dispense open
label investigational product 
- To take the first dose of open label 
investigational product the next day 
Section 9.8.10.1 
• Review OLE ICF and obtain signatures before 
performing any OLE-related procedures 
• Perform EGD procedure unless data from a 
recent EGD (within 6 months of OLE Day 1) are 
available. Subjects varices will not continue in 
the OLE Phase. 
• Record the visit in IWRS, and dispense 
investigational product 
- To take the first dose of investigational product 
the next day 
Clarification 


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Section 9.8.11, OLE 
Month 1 
through 
Section 9.8.14, OLE 
Month 12 
The following OLE study days have been 
eliminated: M15, M18, M21, and M24. 
 
 
The following assessments have been removed 
from the protocol: 
• Serum markers of inflammation, apoptosis, and 
necrosis  all timepoints 
• Exploratory biomarkers of disease severity  all 
timepoints 
• PD blood samples  all timepoints 
• Trough PK blood samples  all timepoints 
• Serial PK blood samples  all timepoints 
• Lipoprotein analysis  M3, M4, and M9 
• LiverMultiScan  all timepoints where 
scheduled in Version 2 
 
Note: With the elimination of M24 study day, the 
OLE EOT/EOS study day is now M12. Thus, all 
EOS procedures scheduled at M24 in Version 2 will 
now be performed at M12 in Version 3. 
 
Assessments added to the OLE study days include 
the following: 
• Waist and hip circumference – all timepoints 
• EGD procedure – OLE Day 1, M6, M12, ET 
• Review DILI management algorithm – all 
timepoints 
 
The changes in assessments 
in OLE reflect change in 
the OLE study period from 
2 years to 1 year, and 
change in scope of 
assessments during OLE 
(Refer to Table 2 for 
changes in assessments) 
 
EGD and review of DILI 
management algorithm are 
safety procedures added to 
the protocol.  
Section 9.7.16, Early 
Termination 
Procedures 
• Health-related quality of life questionnaires (eg, 
patient reported outcomes) and health status for 
the assessment of health utilities (eg, healthcare 
resource use). 
• Pruritus VAS. 
• Health-related quality of life questionnaires (eg, 
patient reported outcomes) and health status for the 
assessment of health utilities (eg, healthcare 
resource use) (Double-Blind Phase only) 
• Pruritus VAS (Double-Blind Phase only). 
Clarification 
Section 10.4, 
Investigational 
Product 
Administration 
Refer to Section 9.1. 
Refer to Section 9.1 and Section 9.2. 
Clarification 
Section 12.1, Liver 
Biopsies 
Given that historical biopsies are to be obtained 
no more than 12 months before Day 1, slides 
should be sent for central reading at least 4 weeks 
before the end of the 6-month window to ensure 
that the results are available in time for Day 1. 
Given that historical biopsies are to be obtained no 
more than 12 months before Day 1, slides should be 
sent for central reading at least 4 weeks before the 
end of the 12-month window to ensure that the 
results are available in time for Day 1. 
Correction 
Section 12.1.1, Central 
Reading of Liver 
Histology 
Histological presence of NASH with a fibrosis 
score of 4 based on the NASH CRN scoring 
system or cryptogenic cirrhosis with metabolic 
factors assumed to be due to NASH must be 
confirmed for study eligibility. 
Histological presence of NASH with a fibrosis 
score of 4 based on the NASH CRN scoring system 
must be confirmed for study eligibility. 
Cryptogenic cirrhosis is no 
longer considered as the 
inclusion criteria in this 
protocol 


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Section 12.2, Child-
Pugh Assessment 
The CP score is used to assess the prognosis of 
chronic liver disease, particularly cirrhosis (Pugh 
1973, Lucey 1997).  The score uses 5 clinical 
measures of liver disease (total bilirubin, serum 
albumin, PT, ascites, and hepatic 
encephalopathy), each scored 1 3, with 3 
indicating most severe.  Chronic liver disease is 
classified into CP Class A to Class C as indicated 
in Table 4.  CP score will be calculated according 
to the frequency listed in Table 1 (Double-Blind 
Phase) and Table 2 (OLE Phase). 
Table 4: Child Pugh Scoring System 
Factor 
Points 
1 
2 
3 
Bilirubin (mg/dl) 
<2 
2 3 
>3 
Albumin (g/dl) 
>3.5 
3.5-2.8 
<2.8 
Prothrombin time 
(seconds 
prolonged)  
or INR 
0-3 
4-6 
>6 
<1.7 
1.7-2.3 
>2.3 
Ascites 
None 
Mild 
Moderate
Severe 
Hepatic 
Encephalopathy 
None 
Grade 1 
or 2 
Grade 3 
or 4 
INR = international normalized ratio 
The CP score is calculated by adding the scores 
for the 5 factors and can range from 5 15.  CP 
class is either A (a score of 5 6), B (7 9), or C (10 
or above).  Decompensation indicates cirrhosis 
with a CP score of 7 or more (Class B).  This 
level has been the accepted criterion for listing 
for liver transplantation (Pugh 1973, Lucey 
1997). 
CP score will be calculated as described in 
Section 7.4.3.1 and according to the frequency 
listed in Table 1 (Double-Blind Phase) and Table 2 
(OLE Phase). 
The information in this 
section is redundant with 
Section 7.4.3.1. 


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Section 12.3, MELD 
Score 
The MELD scoring system is used to assess the 
severity of chronic liver disease.  The MELD 
score is useful in assessing patients with 
significant decompensation7.4.3.2 and the MELD 
score is now used by the United Network for 
Organ Sharing in the US and Eurotransplants to 
manage the organ allocation for liver 
transplantation.  The threshold for placement on 
an organ transplantation queue varies between 
regions across the globe, but a score of 15 results 
in a place on the transplant waiting list in the US.   
An increasing MELD score is associated with 
increased severity of hepatic dysfunction and 
increased 3 month mortality risk.  MELD scores 
will be calculated based on creatinine, bilirubin, 
INR, and sodium values as appropriate, collected 
at the same visit with modification by United 
Network for Organ Sharing.  If only 1 component 
of MELD needs to be repeated, all other 
components should also be repeated. INR will be 
calculated based on PT value by the central 
laboratory.   
MELD score will be calculated according to the 
frequency listed in Table 1 (Double-Blind Phase) 
and Table 2 (OLE Phase). 
MELD score will be calculated as described in 
Section 7.4.3.2 and according to the frequency 
listed in Table 1 (Double-Blind Phase) and Table 2 
(OLE Phase). 
The information in this 
section is redundant with 
Section 7.4.3.2. 


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Section 12.5, Patient-
Reported Outcomes 
and Healthcare 
Resource Use 
• Short Form Health Survey (SF 36):  The SF 36 
is a 36 item, self report measure designed to 
assess the quality of life in patients (Ware 2000). 
 
These may require transcription to the eCRF by 
study site staff. 
Healthcare resource use will be collected from 
eCRFs including number, reason for and duration 
of hospitalizations and emergency room visits, 
number of outpatient physician visits (patient 
reported), and use of concomitant medications.  
The purpose is to evaluate the effects of OCA 
compared to placebo on patient reported 
outcomes and healthcare resources. 
  
The patient reported 
outcome instrument SF-36 
will not be used to evaluate 
health-related quality of life 
in this study.  
 
 
Deleted since this level of 
details is not necessary in a 
protocol. 
Section 12.6.3,  
 
At investigational sites where the device is 
available, TE using the Fibroscan instrument 
(Echosens, Paris, France), LiverMultiScan 
technology (Perspectum Diagnostics, Oxford, 
United Kingdom), or MRE, to assess liver 
fibrosis will be conducted by staff who are 
trained in the use and data interpretation of the 
device.  Assessments will be performed 
according to the schedule presented in Table 1 
(Double-Blind Phase) and Table 2 (OLE Phase). 
Whichever modality/ies used at baseline must be 
collected consistently at each visit. 
At investigational sites where the device is 
available, TE using the Fibroscan instrument 
(Echosens, Paris, France), to assess liver fibrosis 
will be conducted by staff who are trained in the use 
and data interpretation of the device.  Assessments 
will be performed according to the schedule 
presented in Table 1 during the Double-Blind 
Phase only.  MRE will be assessed only in 
subjects who had a baseline MRE already 
performed. 
LiverMultiScan and MRE 
assessments have been 
removed from the protocol. 
Section 12.7, Efficacy 
Laboratory 
Assessments 
 
(Section 15.2.7) 
Homeostatic model assessment  insulin 
resistance (HOMA-IR) values will be calculated 
based on glucose and insulin concentrations.   
 
The following text was moved from Section 15.2.7 
to Section 12.7 
HOMA-β and HOMA-IR values will be 
calculated based on glucose and insulin 
concentrations.   
Laboratory analyte results may be used to 
calculate various cardiovascular risk and 
fibrosis measurement scores. 
HOMA-β has been added to 
the protocol. 


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Section 13.1, 
Pharmacokinetic 
Blood Sampling 
An assessment of steady-state exposures (on an 
aggregate level) will be performed by an internal 
Intercept clinical pharmacologist/ 
pharmacometrician who is discrete from the study 
team. 
Subjects participating in serial PK assessments 
will provide blood samples for measurement of 
OCA and its conjugates (glyco-OCA and tauro-
OCA) 0.5 hour prior to administration of 
investigational product (predose).  Subjects will 
then receive a dose of investigational product 
with approximately 240 mL of water. 
 
 
 
 
During the OLE Phase: 
• Subjects who agree to participate in the Serial 
PK assessments will have samples obtained at 
Month 1, Month 4, and Month 24 OLE. 
• Trough PK samples will be obtained from all 
subjects prior to dose administration on Months 
1, 2, 3, 4, 5, 6, 12, 18, 24 OLE, and ET. 
An assessment of steady-state exposures (on an 
aggregate level) will be performed by an internal 
Intercept clinical pharmacologist/ 
pharmacometrician or designee who is discrete 
from the study team. 
Subjects participating in serial PK assessments will 
provide blood samples for measurement of OCA 
and its conjugates (glyco-OCA and tauro-OCA). 
 
Subjects should be reminded to fast for at least 
8 hours prior to the PK assessment; although 
water is allowed during the fasting period.  If the 
subject reports having eaten within the fasting 
period, this will be documented in the source and 
the eCRF; however, the PK assessment will still 
be conducted. 
Subjects will then receive a dose of 
investigational product with approximately 
240 mL of water.   
Clarifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK assessments during the 
OLE Phase have been 
removed 
Section 13.3, 
Bioanalysis 
 
The following text was moved from Section 15.2.7 
to Section 13.3 
Total OCA will be calculated based on OCA, 
tauro-OCA, and glyco OCA concentrations. 
Editorial 


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Section 14.3, 
Microbiome/ 
Metabolome Analysis 
14.3. Microbiome/Metabolome Analysis 
Stool specimens collected for 
microbiome/metabolome analyses will be 
collected from all subjects at US sites.  
Specimens will undergo microbiota 16S 
ribosomal RNA gene analysis, genome testing, 
fecal metabolomics, fecal bile acid analysis, and 
other appropriate assays to determine if and how 
OCA influences the composition and activity of 
the resident microbiota in the gastrointestinal 
tract.  Subjects will be provided kits and 
instructions for collection of stool specimens at 
home, as appropriate. 
Microbiome/metabolome analyses will be 
assessed in subjects according to the schedule 
presented in Table 1 (Double Blind Phase). 
This section has been deleted from Version 3 
 
Microbiome/metabolome 
assessments have been 
removed from the study. 
Section 14.3.1, 
Exploratory 
Biomarkers of Disease 
Severity 
Clarifications 
Section 15.1.1.1, 
Adverse Event 
 
Subjects should be instructed to contact the site 
promptly upon awareness if they develop signs 
and symptoms of potential hepatic 
decompensation such as:  pale-colored stools, 
urine color from pale to deep amber [dark], 
nausea, vomiting, abdominal pain, diarrhea, 
weight loss, fever and chills, fatigue, weakness, 
loss of appetite, confusion, swelling of the legs or 
abdomen, yellowing of the skin or whites of eyes, 
and bruising easily. 
Additional safety procedure 
added to the protocol. 


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Section 15.1.3, 
Relationship to Study 
Procedures 
Table 7: Relationship of Adverse Events Study 
Procedures 
Table 7: Relationship of Adverse Events to Liver 
Biopsy and Other Study Procedures 
Clarification 
Section 15.1.4.1, 
Severity of Pruritus 
(as an Adverse Event) 
Per Section 8.2.1.2, subjects with pruritus ≥Grade 
3 in severity and possibly, probably, or definitely 
related to investigational product must 
discontinue investigational product but are 
encouraged to continue study visits 
Per Section 8.2.1.2, subjects with pruritus ≥Grade 3 
in severity (per CTCAE) and possibly, probably, or 
definitely related to investigational product must 
discontinue investigational product but are 
encouraged to continue study visits 
Clarification 
Section 15.1.5.1, 
Reporting of Adverse 
Events 
 
 
Redacted medical record source documentation 
will be requested for all SAEs and emergency 
room visits. 
In addition, the Investigator should contact the 
study Medical Monitor upon awareness when 
any signs or symptoms of hepatic 
decompensation are observed in any subject. 
Redacted medical record source documentation will 
be requested for all SAEs. 
Additional safety procedure 
added to the protocol. 
Section 15.1.7, 
Additional 
Investigator 
Responsibilities for 
SAEs 
The Investigator should comply with requests by 
the Medical Monitor or other Sponsor personnel 
to record the SAE on the subject’s AE EDC.   
The Investigator should comply with requests by 
the Medical Monitor or other Sponsor personnel to 
record the SAE on the subject’s AE eCRF.   
Editorial 
Section 15.1.9, 
Notification of Post-
Study SAEs 
If an Investigator becomes aware of an SAE that 
may be attributable to the investigational product 
at any time after the end of the study, the Sponsor 
should be notified immediately (ie, within 24 
hours) by following the instructions provided in 
Section . 
 
Clarification 
Section 15.1.10, 
Follow-Up of AEs and 
SAEs 
All subjects showing possible drug-induced liver 
injury should be followed until all abnormalities 
return to normal or to the baseline state. 
All subjects showing possible drug-induced liver 
injury or disease progression should be followed 
until all abnormalities return to normal or to the 
baseline state. 
If a subject is suspected to have acute 
pancreatitis or develops signs and symptoms 
consistent with acute pancreatitis, amylase and 
lipase levels should be monitored for 3 months 
after the onset of symptoms per standard of care.  
The Investigator should contact the Medical 
Monitor upon awareness.  Results should be 
recorded promptly in the eCRF. 
Additional safety procedure 
added to the protocol. 


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Section 15.1.11, 
Pregnancy and 
Follow-Up 
Thereafter, the subject and infant must be 
followed as considered appropriate by the 
Investigator and the Sponsor. 
Thereafter, the subject and infant must be followed 
as considered appropriate by the Investigator and 
any new updates should be sent to the Sponsor. 
Clarification 
Section 15.2.1, 
Medical History/ 
Demographics 
Baseline pruritus by severity will be obtained on 
Day 1.  
Baseline pruritus by severity will be obtained on 
Day 1 using the Pruritus VAS questionnaire. 
Clarification 


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Section 15.2.7, 
Laboratory 
Assessments 
The following text was moved from Section 15.2.7 
to Section 13.3 or 14.4.2 
All exploratory biomarkers of disease 
severity and blood samples collected will be 
stored for up to 1 year after the end of the 
study and destroyed if not analyzed. 
Homeostatic model assessment – insulin 
resistance (HOMA-IR) values will be 
calculated based on glucose and insulin 
concentrations.   
Total OCA will be calculated based on 
OCA, tauro-OCA, and glyco OCA 
concentrations.   
Laboratory analyte results may be used to 
calculate various cardiovascular risk and 
fibrosis measurement scores. 
Table 12 
In Table 10, the OLE Phase was deleted from the 
following laboratory assessments: lipoprotein 
analysis, markers of inflammation, apoptosis, 
necrosis, PD assessment, PK analytes (Trough 
PK), Exploratory biomarkers of disease severity, 
and PK analytes. 
Laboratory Assessment 
(Phase) 
Scores and Analytesa 
Metabolic parameters 
(Double-Blind and OLE) 
Fasting plasma glucose, insulin, 
C-peptide, HbA1c, and HOMA-
IR 
Microbiome/Metabolom
e Analysis (Double 
Blind only) 
Microbiota 16S ribosomal RNA 
gene analysis, genome testing, 
fecal metabolomics, fecal bile 
acid analysis, and other 
appropriate assays to determine 
if and how OCA influences the 
composition and activity of the 
resident microbiota in the 
gastrointestinal tract  
Genetics analysis 
(Double Blind and OLE) 
DNA and RNA analysis for 
nucleotide polymorphisms that 
may be involved in NASH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 12 
 
Laboratory Assessment 
(Phase) 
Scores and Analytesa 
Metabolic parameters 
(Double-Blind and OLE) 
Fasting plasma glucose, insulin, 
C-peptide, HbA1c, HOMA-β, 
and HOMA-IR 
Cardiovascular risk 
scores 
FRS, Reynolds score, and 
SCORE 
PK analytes (Serial PK; 
Double-Blind) 
OCA, tauro-OCA and glyco-
OCA and possible other 
conjugates or metabolites not yet 
identified 
This text is moved to other 
sections of Version 3 for 
clarity 
Section 15.2.8, 
Pruritus Assessment 
15.2.8.   Health Related Quality of Life 
15.2.8.   Pruritus Assessment 
Editorial change 


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Section 16.5.2, 
Clinical Outcomes 
 
Analyses of the clinical outcomes composite 
endpoint and individual components of outcome 
events will evaluate the effect of OCA (10 mg 
and 25 mg) compared to placebo.  
Only adjudicated events will be included in 
analyses.  Subjects with none of these events will 
be censored at the date of last contact.  
Clarifications 
Section 16.11, Safety 
Analyses 
Safety evaluations will comprise treatment-
emergent AEs, adjudicated CV events, vital 
signs, electrocardiograms (ECGs), pruritus VAS, 
and clinical laboratory results. 
Safety evaluations will comprise treatment-
emergent AEs, AEs of special interest including 
pruritus and hepatic safety, adjudicated CV 
events, vital signs, electrocardiograms (ECGs), 
pruritus VAS, and clinical laboratory results. 
Clarification 


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Section 16.5.1 Other 
Histology Endpoints 
o Ishak scoring criteria from Baseline to Month 
12  
- Improvement to Stage 4  
o Laennec staging system from Baseline to 
Month 12 
- Improvement to Stage 3  
 
• Percentage of subjects with no worsening of 
fibrosis using the following criteria: 
o Ishak (if baseline Ishak stage <6) 
o Laennec staging system (if baseline Laennec 
stage <4C) 
• Percentage of subjects with progression of 
fibrosis using the following criteria: 
o Ishak (if baseline Ishak stage <6) 
o Laennec staging system (if baseline Laennec 
stage <4C) 
• Percentage of subjects with improvement in 
each component of NAS (steatosis, lobular 
inflammation, and hepatocellular ballooning) 
• Changes in NAS  
• Changes in SAF score 
 
 
 
 
Responder endpoints will be analyzed using a 
CMH test stratified by the randomization strata 
(presence of type 2 diabetes at enrollment 
[yes/no] and cryptogenic cirrhosis [yes/no].  The 
change in NAS, SAF, and PCA will be analyzed 
using an ANCOVA model at each visit with 
change from baseline as the dependent variable 
including treatment group and randomization 
o Ishak scoring criteria from Baseline to Month 12  
- Improvement to Stage 4 or lower 
o Laennec staging system from Baseline to Month 
12 
- Improvement to Stage 3 or lower 
 
• Percentage of subjects with no worsening 
(includes improvement) of fibrosis using the 
following criteria: 
o Ishak scoring criteria (if baseline Ishak stage <6) 
from Baseline to Month 12 
o Laennec staging system (if baseline Laennec stage 
<4C) from Baseline to Month 12 
• Percentage of subjects with progression of fibrosis 
using the following criteria: 
o Ishak scoring criteria (if baseline Ishak stage <6) 
from Baseline to Month 12 
o Laennec staging system (if baseline Laennec stage 
<4C) from Baseline to Month 12 
• Change in morphometric assessment of 
quantitative collagen from Baseline to Month 12 
(assessed as PCA) 
• Percentage of subjects with improvement in each 
component of NAS (steatosis, lobular inflammation, 
and hepatocellular ballooning) from Baseline to 
Month 12 
• Changes in NAS from Baseline to Month 12 
• Changes in SAF score from Baseline to Month 
12 
Responder endpoints will be analyzed using a CMH 
test stratified by the randomization strata (presence 
of type 2 diabetes at enrollment [yes/no] and 
cryptogenic cirrhosis [yes/no].  The change in NAS, 
SAF, and PCA will be analyzed using an analysis 
of covariance (ANCOVA) model at each visit with 
change from baseline as the dependent variable 
including treatment group and randomization 
Clarification 


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stratification factor as fixed effects and baseline 
as a covariate.  
stratification factor as fixed effects and baseline as a 
covariate.  
Section 16.5.2, 
Clinical Outcomes 
• MELD score ≥15 (if MELD ≤12 at Baseline) 
• Liver transplant (if MELD <15 at Baseline) 
The percentage of subjects who reported any 
adjudicated events will be analyzed using a CMH 
test stratified by the randomization strata 
(presence of type 2 diabetes at enrollment 
[yes/no] and cryptogenic cirrhosis [yes/no]).  
• MELD score ≥15 
• Liver transplant  
The percentage of subjects who reported any 
adjudicated events will be analyzed using a CMH 
test stratified by the randomization strata (presence 
of type 2 diabetes at enrollment [yes/no]. 
The outcomes have been 
updated per study 
objectives and exclusion of 
subjects with MELD 
score >12. 
Section 16.5.4, 
Metabolic Parameters 
Metabolic parameters include fasting glucose, 
fasting insulin, C-peptide, HbA1c, and HOMA 
IR.   
Metabolic parameters include fasting glucose, 
fasting insulin, C-peptide, HbA1c, HOMA-β, and 
HOMA IR.   
HOMA-β assessment added 
to the study 
Section 16.5.6, 
Health-Related 
Quality of . . . 
Health-Related Quality of Life endpoints derived 
from the following patient-reported outcomes 
will be summarized by treatment group:  CLDQ-
NAFLD, EQ-5D-5L, WPAI, and the SF 36.   
 
The following statement was deleted from 
Sections 16.5.6, 16.5.6.1, 16.5.6.2, and 16.5.7:  
Further details regarding analyses will be 
specified in the SAP.    
Health-Related Quality of Life endpoints derived 
from the following patient-reported outcomes will 
be summarized by treatment group:  CLDQ-
NAFLD, EQ-5D-5L, and WPAI.   
SF-36 will not be used to 
evaluate health-related 
quality of life in this study. 
 
 
 
Clarification 
Section 16.5.6.2, 
Noninvasive 
Radiological 
Assessment of Liver 
Fibrosis 
16.5.7.3. Noninvasive Radiological Assessment 
of Liver Fibrosis 
Noninvasive radiological assessments of liver 
fibrosis include TE using the Fibroscan TE 
device, liver magnetic resonance imaging (using 
LiverMultiScan), and liver MRE. 
16.5.6.2. Noninvasive Radiological Assessment of 
Liver Fibrosis 
Noninvasive radiological assessments of liver 
fibrosis include TE using the Fibroscan TE device. 
LiverMultiScan and MRE 
assessments have been 
removed from the study. 
Section 16.8, PK/PD 
Analysis 
 
Results from these analyses will be reported 
separate from the clinical study report. 
Clarifications 
Section 16.10, 
Examination of 
Subgroups 
and 
Section 16.11.3 
Further details regarding subgroups analyses will 
be specified in the SAP. 
 
Clarification 


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Section 16.11, Safety 
Analyses 
Safety evaluations will comprise treatment-
emergent AEs, adjudicated CV events, vital 
signs, electrocardiograms (ECGs), and clinical 
laboratory results. 
Safety evaluations will comprise treatment-
emergent AEs, adjudicated CV events, vital signs, 
electrocardiograms (ECGs), pruritus VAS, and 
clinical laboratory results. 
Clarification 
Section 16.11.1, 
Adverse Events 
 
Adverse events of special interest, to be specified 
in the SAP, will be summarized for each 
treatment group. 
Clarification 
Section 16.12.1, 
Safety Analyses 
(OLE) 
Similar analyses to those are described above will 
be conducted for the OLE.   
Safety evaluations conducted during the Double-
Blind Phase will also be conducted for the OLE.   
Editorial 
Section 16.12.2, 
Efficacy Analyses 
(OLE) 
16.12.2. Efficacy Analyses (OLE) 
Efficacy analyses conducted during the Double
Blind Phase will be repeated during the OLE.  
Separate summaries will be presented by the 
randomized treatment assignment in the double 
blind phase.  For subjects with optional biopsy in 
OLE, histological changes will be assessed. 
This section has been deleted in Version 3. 
Any efficacy analyses 
during OLE is not specified 
in the protocl due to scaled-
back assessments during the 
OLE Phase. Further details 
may be included in SAP. 
Section 16.13, Data 
Monitoring 
Committee 
An independent data monitoring committee 
(DMC) that includes hepatologists, 
pharmaceutical physicians, 
epidemiology/cardiology expert(s), and 
statistician(s) 
The DMC will meet approximately quarterly at 
scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review PK, safety 
and efficacy data as well as the adjudication 
assessments from the 3 adjudication committees 
listed in Section 16.14.   
An independent data monitoring committee (DMC) 
will include hepatologists, pharmaceutical 
physicians, epidemiology/cardiology expert(s), 
DILI expert(s), and statistician(s) 
The DMC will meet approximately quarterly at 
scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review PK, safety and 
efficacy data as well as the adjudication 
assessments from the 2 adjudication committees 
listed in Section 16.14.   
Clarifications 


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Section 22, List of 
References 
Ware JE. SF 36 Health Survey Update. Spine. 
2000 25 (24: 3130 3139. 
Younossi Z, Younossi I, Huong T, et al. 
Development and Validation of Disease-Specific 
Health Related Quality (HRQL) Instrument for 
Patients with Non-alcholic Fatty Liver Disease 
(NAFLD) and Non-alchoholic Steatohepatitis 
(NASH):  The CLDQ-NAFLD. Hepatology. 2016 
64 (1), 118A. 
 
Younossi ZM, Younossi I, Pham, HT, et al. 
Development and Validation of Disease-Specific 
Health Related Quality (HRQL) Instrument for 
Patients with Non-alcholic Fatty Liver Disease 
(NAFLD) and Non-alchoholic Steatohepatitis 
(NASH):  The CLDQ-NAFLD. Hepatology. 2016 
64 (1), 118A. 
Vilstrup H, Amodio P, Bajaj J, et al. Hepatic 
encephalopathy in chronic liver disease: 2014 
Practice Guideline by the American Association 
for the Study of Liver Diseases and the 
European Association for the Study of the Liver. 
Hepatology. 2014;60(2):715-35. 
Editorial changes 


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APPENDIX D. SUMMARY OF CHANGES:  PROTOCOL VERSION 1.0 TO PROTOCOL VERSION 2.0 
(DATED:  17 MAY 2017) 
Rationale and Summary of Changes 
The following revisions were made to Protocol Version 1.0.  Each revision also includes a reason or justification for the change.  The 
text deleted from Protocol Version 1.0 is crossed out and revised text in Version 2.0 is indicated in bold font in the table below.  Minor 
changes including typos or editorial revisions are not listed individually in the summary table below. 
Section 
Original Text (Version 1.0) 
Revised Text (Version 2.0) 
Key Change 
Reasons/Justification for 
Change 
Study 
Personnel 
Contact 
Information 
b 
 
 MD 
 Drug Safety  
Intercept Pharmaceuticals, Inc. (Intercept) 
Organization change 
Study 
Personnel 
Contact 
Information 
Clinical Operations and Project Management 
Contact: 
 Clinical Operat
Intercept 
Telephone: 
Mobile: 
Fax: 
Email: 
Deletion 
Organization change 
Synopsis 
Approximately 75 to 100 investigational sites, globally. • 
Approximately 150 investigational sites, 
globally. 
Additional number of sites 
added to ensure enrollment 
feasibility. 
Synopsis 
  Primary 
Objectives 
• 
Histological improvement in fibrosis by assessing the 
percentage of subjects with improvement in fibrosis by 
at least 1 stage using Ishak scoring criteria from 
Baseline to Month 12 
• 
Histological improvement in fibrosis by 
assessing the percentage of subjects with 
improvement in fibrosis by at least 1 stage 
using the Nonalcoholic Steatohepatitis 
NASH CRN criteria were 
developed specifically for 
the NAFLD population 
(histological assessment in 
patients with fibrosis and 


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(NASH) Clinical Research Network 
(CRN) scoring system from Baseline to 
Month 12 
 
cirrhosis secondary to 
NASH) 
Synopsis 
  Secondary 
Objectives 
Section 6.2 
Secondary 
Objectives 
Key Secondary Objectives: 
To evaluate the effects of OCA treatment compared with 
placebo on: 
Histological improvement in fibrosis by assessing the 
percentage of subjects with improvement in fibrosis by 
at least 1 stage using Nonalcoholic Steatohepatitis 
(NASH) Clinical Research Network (CRN) scoring 
system from Baseline to Month 12 
Secondary Objectives: 
To evaluate the effects of OCA treatment 
compared with placebo on: 
• 
Histological improvement in fibrosis by 
assessing the percentage of subjects with 
improvement in fibrosis by at least 2 stages 
using Ishak scoring criteria from Baseline 
to Month 12 
 
Morphometric assessment 
moved to exploratory 
endpoint because it is not a 
validated assessment and 
the magnitude of change 
that may be clinically 
meaningful is not well-
established. Therefore, this 
endpoint has been moved 
from a key secondary 
endpoint to further down in 
the hierarchy.   
Instead, improvement 
assessed using the modified 
Ishak score (adapted to 
NASH) will be moved up 
as the key secondary 
endpoint.  To ensure that a 
clinically significant 
magnitude of change is 
assessed, this endpoint will 
evaluate an improvement 
by 2 points or more. 
Synopsis 
  Secondary 
Objective 
Section 6.2 
Secondary 
Objectives 
• 
All-cause mortality and liver-related clinical outcomes 
as measured by the time to first occurrence of any of 
the following adjudicated events (clinical outcomes 
composite endpoint):  
• 
Time to occurrence of liver related death 
• 
Occurrence of all-cause mortality and liver-
related clinical outcomes of the following 
adjudicated events (clinical outcomes 
composite endpoint):  
• 
Occurrence of individual components of 
outcome events  
 
Clarification of analysis of 
adjudicated clinical 
outcomes, including both 
time-to-event analysis and 
incidence. 


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Synopsis 
  Additional 
Secondary 
Objectives 
Section  
6.3 Additional 
Secondary 
Objectives  
Synopsis 
  Additional Secondary Objectives Section  
6.3 Additional Secondary Objectives 
Deletion 
Key secondary and 
additional objectives were 
combined under Secondary 
Objectives 
Synopsis 
  Secondary 
Objectives 
Section 6.2   
Secondary 
Objectives 
Insertion 
This endpoint was moved 
from key secondary to an 
additional secondary 
objective. 
Synopsis 
  Secondary 
Objectives 
Section 6.2 
Secondary 
Objectives 
To evaluate the effects of OCA treatment compared with 
placebo on: 
• 
Histological changes in fibrosis including 
improvement, no worsening, and progression from 
Baseline to Month 12 using the following criteria, as 
appropriate:  
 
Ishak scoring criteria 
 
NASH CRN criteria 
Laennec staging system 
To evaluate the effects of OCA treatment 
compared with placebo on: 
• 
Histological changes in fibrosis including 
improvement, no worsening, and 
progression from Baseline to Month 12 
using the following criteria, as appropriate:  
− 
NASH CRN scoring system 
− 
Ishak scoring criteria 
− 
Laennec staging system 
Primary and secondary 
objectives were reordered, 
which affected the order of 
the additional secondary 
objectives. 
Synopsis 
Secondary 
Objectives  
Section 6.2 
Secondary 
Objectives 
• 
Liver histology by morphometric assessment of percent 
fat at Month 12 
 
Deletion 
This assessment is 
considered unnecessary for 
the study. 


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Synopsis  
  Methodology 
Section 7.1 
Overall Study 
Design 
This Phase 3, double-blind, randomized, placebo-
controlled, multicenter international study will evaluate the 
efficacy and safety of OCA in subjects with a biopsy-
confirmed diagnosis of cirrhosis (Ishak fibrosis score ≥5 
[incomplete, probable, or definitive cirrhosis]) due to 
NASH (or cryptogenic cirrhosis with evidence of metabolic 
syndrome) determined by central reading of liver histology.  
Subjects with hepatic decompensation or CP Class B or 
Class C cirrhosis are excluded.  All histology assessments 
will be performed centrally.   
Double-Blind Phase (12 Months):  Subjects will be 
screened for a period of up to 8 weeks before entering the 
study.  Subjects who meet the entry requirements will be 
randomized in a 1:1 ratio to receive placebo or OCA 25 mg 
daily in conjunction with local standard of care.  
Randomized subjects will be stratified by the presence of 
type 2 diabetes at enrollment (yes or no) and by Ishak 
fibrosis stage (Ishak fibrosis 5 or 6). 
Investigational product (ie, OCA or placebo) will be taken 
orally, with water, once daily.  Safety and laboratory 
assessments will be evaluated at clinical visits at Day 1, 
Month 1, and once every 3 months following the initiation 
of treatment (Day 1) through Month 12.   
Open-Label Extension (up to 24 Months):  Subjects who 
complete the Double-Blind Month 12 Visit are eligible to 
enroll into the OLE for the evaluation of safety.  All 
subjects will receive OCA upon entry into the OLE.  
Subjects will continue the same dosing regimen they 
received at the end of the Double-Blind Phase.   
This Phase 3, double-blind, randomized, 
placebo-controlled, multicenter international 
study will evaluate the efficacy and safety of 
OCA in subjects with a biopsy-confirmed 
diagnosis of cirrhosis (based on fibrosis score 
of 4 using NASH CRN scoring system) due to 
NASH determined by central reading of liver 
histology.  Up to approximately 30% of total 
enrolled subjects may have a diagnosis of 
cryptogenic cirrhosis and presence of 
metabolic risk factors.  Subjects with hepatic 
decompensation or CP Class B or Class C 
cirrhosis are excluded.  Subjects who progress 
to CP Class B or Class C during the study 
will discontinue investigational product, but 
should be encouraged to continue study visits.   
Double-Blind Phase (12 Months):  Subjects will 
be screened for a period of up to 8 weeks before 
entering the study.  Subjects who meet the entry 
requirements will be randomized in a 1:1 ratio to 
receive placebo or OCA daily in conjunction 
with local standard of care.  Subjects will 
receive OCA 10 mg for the first 3 months.  At 
Month 3, all subjects will titrate to OCA 
25 mg once daily unless there are safety 
concerns.   
Randomized subjects will be stratified by the 
presence of type 2 diabetes at enrollment (yes or 
no) and cryptogenic cirrhosis (yes or no).  
Investigational product (ie, OCA or placebo) 
will be taken orally, with water, once daily.  
Efficacy, safety and laboratory assessments will 
be evaluated at clinical visits at Day 1, monthly 
for the initial 6 months (Month 1 through 
Month 6 Visits), Month 9, and Month 12.   
 
Up to 30% of subjects with 
cryptogenic cirrhosis will 
be included in the study as 
a significant proportion of 
patients with cirrhosis due 
to NASH may lose their 
characteristic histologic 
features of NASH and may 
present as cryptogenic 
cirrhosis based on 
histopathology.   However, 
it is not known whether 
these patients will have a 
different response 
compared to those with 
clear histologic features of 
NASH, no more than 30% 
of subjects with cryptogenic 
cirrhosis will be included.    
Subjects who progress to 
Child Pugh Class B or C 
will be discontinued from 
the study as they may 
exhibit moderate to severe 
hepatic impairment, and are 
likely to result in increased 
serum concentrations of 
OCA. Since optimal dosing 
for NASH subjects with 
hepatic impairment has not 
yet been determined, these 
subjects will discontinue IP.  
The 10 mg dose titration at 
Month 3 provides adequate 
time to lower endogenous 




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prior to Day 1 will have a biopsy at 
Screening Visit 2.   
b During the double-blind period, all subjects 
will titrate to OCA 25 mg (or matching 
placebo) at Month 3 unless safety concerns 
dictate otherwise.  A blinded review of 
Month 1 and Month 2 safety data, 
including liver biochemistry and adverse 
events by the medical monitor will be 
conducted prior to a subject’s Month 3 
visit. 
c All subjects who enroll into the OLE will 
receive OCA.  Subjects randomized to 
placebo in the Double-Blind Phase will 
initiate investigational product of OCA 
10 mg for the first 3 months of the OLE 
prior to uptitrating to OCA 25 mg.  
Uptitration will be based on safety and 
tolerability assessments completed at 
Month 1, Month 2, and Month 3 of the 
OLE.  Subjects randomized to OCA will 
continue the same dosing regimen they 
received at the end of the Double-Blind 
Phase.   
d The study will remain blinded until all 
subjects complete the double-blind Phase.  
To maintain blinding, all placebo, OCA 
10 mg, and OCA 25 mg tablets and bottles 
will be identical.  Once all subjects have 
titrated to the 25 mg dose in the OLE, 
subjects may receive investigational 
product with an open-label identifying the 
product as OCA 25 mg. 
 


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Synopsis  
  Inclusion 
Criteria 
Section 8.1.1 
Subject 
Inclusion 
Criteria 
2.Subjects with confirmed diagnosis of NASH with an 
Ishak fibrosis score ≥5 determined by central reading 
of a liver biopsy obtained no more than 6 months 
before Day 1, OR 
Subjects with cryptogenic cirrhosis assumed to be due 
to NASH as determined by central reading of a liver 
biopsy obtained no more than 6 months before Day 1 
with metabolic syndrome accompanied by any of the 
following risk factors:  
− 
Obesity (body mass index ≥30 kg/m2) 
− 
Type 2 diabetes diagnosed per 2013 American 
Diabetes Association criteria (hemoglobin A1c 
≥6.5%, fasting plasma glucose ≥126 mg/dL, 2-
hour plasma glucose ≥200 mg/dL during oral 
glucose tolerance test, or random plasma glucose 
≥200 mg/dL) 
− 
Abdominal obesity (waist circumference >102 cm 
[>40 in] for men and >88 cm [>35 in] for women) 
− 
Dyslipidemia (triglyceridemia ≥150 mg/dL and 
low high-density lipoprotein [<40 mg/dL in men 
and <50 mg/dL in women])  
 
Prehypertension or hypertension (blood pressure 
≥130/≥85 mmHg)  
2. Subjects with confirmed diagnosis of 
NASH with a fibrosis score of 4 based on 
NASH CRN scoring system determined by 
central reading of a liver biopsy obtained no 
more than 12 months before Day 1, OR 
Subjects with cryptogenic cirrhosis assumed 
to be due to NASH as determined by central 
reading of a liver biopsy obtained no more 
than 12 months before Day 1 accompanied 
by TWO of the following risk factors 
− 
Obesity (body mass index ≥30 kg/m2) 
− 
Type 2 diabetes diagnosed per 2013 
American Diabetes Association criteria 
(hemoglobin A1c ≥6.5%, fasting 
plasma glucose ≥126 mg/dL, 2-hour 
plasma glucose ≥200 mg/dL during oral 
glucose tolerance test, or random 
plasma glucose ≥200 mg/dL) or on any 
prescription glucose-lowering agent 
for Type 2 diabetes 
− 
Abdominal obesity (waist 
circumference >102 cm [>40 in] for 
men and >88 cm [>35 in] for women) 
with no evidence of ascites by 
imaging unless obvious on physical 
exam  
− 
Dyslipidemia (triglyceridemia 
≥150 mg/dL and low high-density 
lipoprotein [<40 mg/dL in men and 
<50 mg/dL in women]) or using a 
prescription lipid-lowering 
medication due to dyslipidemia 
 
Updated with NASH CRN 
criteria because these are 
considered more 
appropriate for the study 
population and the primary 
endpoint is based on NASH 
CRN criteria. 
The window of historic 
biopsy changed from 
6 months to 12 months 
before Day 1 because the 
NASH CRN fibrosis score 
of a cirrhotic patient is 
unlikely to improve to a 
lower fibrosis score within 
12 months, if all other entry 
criteria are met. 
The number of qualifying 
criteria for identifying 
cryptogenic cirrhosis 
subjects was increased to 
ensure the etiology of 
cryptogenic cirrhosis is 
NASH. 
Prehypertension or 
hypertension is not 
considered as part of 
qualifying criteria for 
defining cryptogenic 
cirrhosis by the FDA and 
therefore was removed.  


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Synopsis  
  Exclusion 
Criteria 
Section 8.1.2 
Subject 
Exclusion 
Criteria 
Criteria with exclusionary laboratory values are to be based 
on the most recent laboratory result available prior to 
randomization.  Subjects who satisfy any of the following 
exclusion criteria will be ineligible for enrollment: 
1. Current or past history of hepatic decompensation 
such as ascites (identified on physical exam), variceal 
bleeding, spontaneous bacterial peritonitis, hepatic 
encephalopathy (Grade I or greater based on West 
Haven classification), or hepatorenal/hepatopulmonary 
syndromes 
4. Aspartate transaminase >7× upper limit of normal 
(ULN) 
5. Alanine aminotransferase >7× ULN 
7.Platelet count ≤75,000/mm3 at Screening 
11. Creatine phosphokinase >5× ULN 
28. Previous exposure to OCA 
Criteria with exclusionary laboratory values are 
to be based on the most recent laboratory result 
available prior to randomization.  Subjects who 
satisfy any of the following exclusion criteria 
will be ineligible for enrollment: 
1. Current or past history of hepatic 
decompensation such as clinically 
significant ascites (requiring medical 
intervention), variceal bleeding, 
spontaneous bacterial peritonitis, hepatic 
encephalopathy (Grade I or greater based on 
West Haven classification), or 
hepatorenal/hepatopulmonary syndromes 
4. Aspartate transaminase ≥5× upper limit 
of normal (ULN) 
5. Alanine aminotransferase ≥5× ULN 
7. Platelet count ≤100000/mm3 at Screening 
11. Creatine phosphokinase >3× ULN 
28. Previous exposure to OCA within 
12 months 
The threshold of the 
exclusion criteria for AST 
and ALT were lowered to 
≥5x ULN to exclude 
subjects with significantly 
high aminotransaminases at 
study entry. 
The exclusion criterion for 
platelet counts was 
modified to ≤100000/mm3 
to further ensure subjects 
enrolled in the study are 
well compensated. 
 The exclusion criterion for 
creatine phosphokinase was 
revised to >3x ULN 
because CPK >3x ULN is 
consider too high. 
Due to limited 
hepatocellular reserve, 
cirrhotic patients might 
have advanced liver failure 
with relatively less 
elevated, even normal 
transaminase levels. For 
this reason, ALT and AST 
exclusion criteria were 
modified to exclude 
subjects with significant 
worsening of ALT and 
AST. 
Synopsis  
  Liver 
Histology and 
Central Reading of Liver Histology:  All biopsy 
assessments will be performed centrally, including 
assessments of biopsies to determine study eligibility.  
Central Reading of Liver Histology:  All biopsy 
assessments will be performed centrally, 
including assessments of biopsies to determine 
Order of the assessments 
was changed.  
 


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Event 
Adjudication 
and Data 
Monitoring 
Committee 
Oversight: 
 
Histological presence of NASH with an Ishak fibrosis score 
≥5 or cryptogenic cirrhosis assumed to be due to NASH 
must be confirmed for study eligibility.  For each biopsy, 
fibrosis will be graded in accordance with Ishak scoring 
system (Ishak 1995).  In addition to the primary scoring of 
Ishak, biopsy samples will also be scored based on the 
NASH CRN criteria (Kleiner 2005), Laennec staging 
(Wang 2015), and SAF scoring (Bedossa 2014), and for 
quantitative collagen and percent fat. 
 
study eligibility.  Histological presence of 
NASH with a fibrosis score of 4 based on 
NASH CRN scoring system or cryptogenic 
cirrhosis with metabolic factors assumed to be 
due to NASH must be confirmed for study 
eligibility.  For each biopsy, fibrosis will be 
graded in accordance with NASH CRN scoring 
system (Kleiner 2005).  In addition to the 
primary scoring using NASH CRN scoring 
system, biopsy samples will also be scored 
based on the modified Ishak scoring criteria 
(Ishak 1995), Laennec staging (Wang 2015), 
and SAF scoring (Bedossa 2014), and for 
quantitative collagen. 
 
 
Synopsis  
  Liver 
Histology and 
Event 
Adjudication 
and Data 
Monitoring 
Committee 
Oversight: 
DMC Oversight:  An independent DMC will review all 
safety and efficacy data resulting from the study at periodic 
intervals.   
DMC Oversight:  An independent DMC will 
review all safety and efficacy data resulting 
from the study at periodic intervals.  In 
addition, PK exposure data will be available, 
if needed.   
PK data will be available to 
the DMC for additional 
safety monitoring purposes. 
Synopsis 
  Investigational 
Product, 
Dosage and 
Mode of 
Administration 
OCA tablet, 25 mg, once daily, oral administration 
OCA tablet, 10 mg or 25 mg, once daily, oral 
administration 
Added to allow dose 
titration 
Synopsis  
  Criteria for 
Evaluation 
Histological improvement of fibrosis using Ishak  
Endpoint:  Improvement in fibrosis by at least 1 stage using 
Ishak scoring criteria from Baseline to Month 12 
Histological improvement of fibrosis using 
NASH CRN scoring system 
Updated with NASH CRN 
criteria because the primary 
endpoint using the NASH 


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Section 11 
Overview of 
Assessments  
Endpoint:  Improvement in fibrosis by at least 
1 stage using NASH CRN scoring system from 
Baseline to Month 12 
CRN criteria are considered 
more appropriate for this 
population. 
Synopsis  
  Criteria for 
Evaluation 
Section 11 
Overview of 
Assessments 
Liver histology by morphometric assessment of quantitative 
collagen 
Histological improvement in fibrosis using NASH CRN 
Endpoint:  Improvement in fibrosis by at least 1 stage using 
NASH CRN scoring system from Baseline to Month 12 
Clinical outcomes 
Endpoint:  Time to first occurrence of any of the following 
adjudicated events:   
Liver related death 
Endpoint:  Time to occurrence of liver related death 
Liver histology by morphometric assessment of 
quantitative collagen 
Histological improvement in fibrosis using 
Ishak scoring criteria 
Endpoint:  Improvement in fibrosis by at least 
2 stages using the NASH CRN Ishak scoring 
criteria from Baseline to Month 12 
Clinical outcomes 
Endpoint:  Occurrence of any of the following 
adjudicated events:   
Individual components of outcome events 
Endpoint:  Occurrence of individual 
components of outcome events 
Morphometric assessment 
moved to exploratory 
endpoint because it is not a 
validated assessment and 
the magnitude of change 
that may be clinically 
meaningful is not well-
established. Therefore, this 
endpoint has been moved 
from a key secondary 
endpoint to further down in 
the hierarchy.   
Instead, improvement 
assessed using the modified 
Ishak score (adapted to 
NASH) will be moved up 
as the key secondary 
endpoint.  To ensure that a 
clinically significant 
magnitude of change is 
assessed, this endpoint will 
evaluate an improvement 
by 2 points or more. 
Synopsis  
  Criteria for 
Evaluation 
Section 11 
Overview of 
Assessments 
Additional Secondary Objectives 
Histological change in fibrosis (improvement, no 
worsening, and progression, as appropriate) 
Endpoint:   
Change in Ishak scoring criteria from Baseline to Month 12 
Change in NASH CRN criteria from Baseline to Month 12 
 
Secondary Objectives 
Histological change in fibrosis (improvement, 
no worsening, and progression, as appropriate) 
Endpoint:   
Change in NASH CRN scoring system from 
Baseline to Month 12 
Change in Ishak scoring criteria from Baseline 
to Month 12 
Order modified. 
 


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  Criteria for 
Evaluation 
Section 11 
Overview of 
Assessments 
Key Secondary Objectives 
Liver histology by morphometric assessment of quantitative 
collagen 
Endpoint: 
Secondary Objectives 
Liver histology by morphometric assessment of 
quantitative collagen 
Endpoint: 
Specified instruction will be 
provided in the histology 
manual. 
Synopsis  
Enrollment and 
Randomization 
A total of approximately 360 subjects will be enrolled and 
randomized into the study in a 1:1 ratio to placebo or OCA 
25 mg.  Randomized subjects will be stratified by the 
presence of type 2 diabetes at enrollment (yes or no) and 
fibrosis (Ishak fibrosis score 5 or 6). 
A total of approximately 360 subjects will be 
enrolled and randomized into the study in a 1:1 
ratio to placebo or OCA.  Randomized subjects 
will be stratified by the presence of type 2 
diabetes at enrollment (yes or no) and 
cryptogenic cirrhosis (yes or no). 
Randomized subjects will 
be stratified by the presence 
of cryptogenic cirrhosis to 
balance the number of 
subjects with cryptogenic 
cirrhosis between the two 
treatment arms (placebo vs. 
OCA). 
Synopsis  
  Analysis 
Populations 
Section 16.1 
Analysis 
Populations 
Insertion 
Modified Intent-to-Treat (mITT) Population 
The mITT Population will include all ITT 
subjects who dose titrate at Month 3 per 
protocol.  Treatment assignment will be 
based on the randomized treatment. 
Additional analysis 
population added due to 
dose-titration design.  
Synopsis  
  Analysis 
Populations 
Section 16.1 
Analysis 
Populations 
• 
The Per Protocol (PP) Population will include all 
ITT subjects who do not have any major protocol 
violations that potentially affect the efficacy 
conclusions.  Treatment assignment will be based 
on the randomized treatment.   
• 
The Per Protocol (PP) Population will 
include all mITT subjects who do not 
have any major protocol violations that 
potentially affect the efficacy 
conclusions.  Treatment assignment 
will be based on the randomized 
treatment.   
Clarification of PP 
Population due to addition 
of mITT population. 
Synopsis 
  Efficacy 
Analyses 
Primary and key secondary efficacy hypothesis testing will 
be based on the ITT population.  Exploratory analyses of 
Primary and key secondary efficacy hypothesis 
testing will be based on the ITT population.  
Exploratory analyses of the primary endpoint 
Modification due to 
addition of mITT 
population, modification of 
primary and key secondary 


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the primary endpoint will be conducted using PP 
population. 
The primary efficacy analysis will test the following 
hypotheses: 
• 
H0:  The percentage of subjects with fibrosis 
improvement by at least 1 stage using Ishak score from 
Baseline to Month 12 is equal between placebo and 
OCA 25 mg. 
• 
H1:  The percentage of subjects with fibrosis 
improvement by at least 1 stage using Ishak score from 
Baseline to Month 12 is different between placebo and 
OCA 25 mg. 
The type I error for the primary efficacy analysis will be 
controlled at 0.05.  For the comparison of the primary 
efficacy endpoint, a Cochran–Mantel–Haenszel test 
stratified by the randomization strata (presence of type 2 
diabetes at enrollment [yes/no] and baseline fibrosis stage 
[Ishak 5 or 6]) will be used.  Missing values will be 
considered a nonresponse.   
Exploratory analyses of the primary endpoint will be 
conducted using PP population. 
Key secondary efficacy endpoints are: 
• 
Percentage of subjects with fibrosis improvement by at 
least 2 stages using Ishak scoring criteria from Baseline 
to Month 12 
The hypothesis testing of key secondary endpoints will be 
conducted in a sequential closed testing gate keeping 
procedure, provided the primary efficacy comparison is 
will be conducted using the mITT and PP 
populations. 
The primary efficacy analysis will test the 
following hypotheses: 
• 
H0:  The percentage of subjects with fibrosis 
improvement by at least 1 stage using 
NASH CRN score from Baseline to Month 
12 is equal between placebo and OCA. 
• 
H1:  The percentage of subjects with fibrosis 
improvement by at least 1 stage using 
NASH CRN score from Baseline to Month 
12 is different between placebo and OCA. 
Key secondary efficacy endpoint is: 
• 
Percentage of subjects with fibrosis 
improvement by at least 2 stages using 
Ishak scoring criteria from Baseline to 
Month 12 
The type I error for the primary efficacy analysis 
will be controlled at 0.01.  The hypothesis 
testing of primary and key secondary 
endpoints will be conducted in a sequential 
closed testing gate-keeping procedure.   
For the comparison of the primary and key 
secondary efficacy endpoints, a Cochran–
Mantel–Haenszel test stratified by the 
randomization strata (presence of type 2 diabetes 
at enrollment [yes/no] and cryptogenic 
cirrhosis [yes or no]) will be used.  Missing 
values will be considered a nonresponse.   
Additional secondary endpoints will be 
analyzed; however, statistical testing will be 
considered descriptive and exploratory only.   
efficacy endpoints and 
randomization stratification 
factors. 
 
Modified type 1 error based 
on discussions with 
regulatory authorities. 


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statistically significant in favor of OCA.  This procedure 
controls the study wise type I error and is described below. 
First, placebo and OCA 25 mg will be compared with 
respect to the primary efficacy endpoint at Month 12.  If the 
comparison of primary efficacy endpoint achieves statistical 
significance at the 2 sided 0.05 level in favor of OCA, then 
Placebo and OCA 25 mg will be compared with respect to 
improvement in liver histology by morphometric 
assessment of quantitative collagen (assessed as PCA) at 
Month 12.  If the comparison achieves statistical 
significance at the 2 sided 0.05 level in favor of OCA, then 
Placebo and OCA 25 mg will be compared with respect to 
the percentage of subjects with fibrosis improvement by at 
least 1 stage using NASH CRN criteria from Baseline to 
Month 12, at 2 sided 0.05 level.   
If at any step defined above, the comparison is not 
statistically significant at the 2 sided 0.05 level, then the 
remaining comparisons in the stated hierarchy will be 
considered descriptive and exploratory. 
Additional secondary endpoints will be analyzed; however, 
statistical testing will be considered descriptive and 
exploratory only.  Additional secondary analyses will be 
conducted using PP population.   
 
Synopsis  
  Safety 
Analysis 
 
Safety data, including treatment-emergent AEs, vital signs, 
electrocardiograms (ECGs), and clinical laboratory results 
will compare OCA 25 mg and placebo at Month 12. 
Safety evaluations will comprise treatment-
emergent AEs, adjudicated CV events, vital 
signs, electrocardiograms (ECGs), and clinical 
laboratory results. 
Modified to include both 
double-blind and open label 
study periods. 
Synopsis  
  Sample Size 
Justification 
A sample size of 180 subjects per group with an assumed 
10% discontinuation rate will provide 80% power to 
demonstrate a statistically significant treatment difference 
between OCA and placebo group based on Chi-square test 
with 2-sided type I error at 0.05 level, assuming a responder 
rate of 43% and 28% in the OCA and placebo groups, 
A sample size of 180 subjects per group with an 
assumed 5% discontinuation rate will provide 
90% power to demonstrate a statistically 
significant treatment difference between OCA 
and placebo group based on Chi-square test with 
2-sided type I error at 0.01 level, assuming a 
Modified statistical 
assumptions due to 
emerging natural history 
data on NASH with 
cirrhosis and regulatory 
feedback. 


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Section 16.2 
Determination 
of Sample Size 
respectively, based on data from literature and practical 
consideration. 
responder rate of 23% and 8% in the OCA and 
placebo groups, respectively, based on data from 
literature, observed effect size on fibrosis 
improvement in advanced fibrosis subjects in 
FLINT, and practical consideration 
Section 5.4.1 
Rationale for 
Study Design 
Thus, Study 747-304 will evaluate efficacy and safety of 
OCA in subjects with NASH with cirrhosis (defined by a 
Ishak score ≥5), with the exception of subjects with 
Child-Pugh (CP) score ≥7.  The efficacy of OCA in this 
study will be evaluated based on histological improvement 
in fibrosis 
Thus, Study 747-304 will evaluate efficacy and 
safety of OCA in subjects with NASH with 
cirrhosis (defined by a NASH Clinical 
Research Network [CRN] score of 4), with the 
exception of subjects with Child-Pugh 
(CP) score ≥7.  The efficacy of OCA in this 
study will be evaluated based on histological 
improvement in fibrosis.   
Updated with NASH CRN 
criteria because these are 
considered more 
appropriate for the study 
population and the primary 
endpoint is based on NASH 
CRN criteria  
Section 5.4.2 
Rationale for 
Placebo Control 
Group 
The use of a randomized placebo control group added to 
established standard of care provides the best scientific 
evidence of efficacy and safety.   
The use of a randomized placebo control group 
added to established standard of care, including 
lifestyle modification counseling, provides the 
best scientific evidence of efficacy and safety.   
Added clarification. 
Section 5.4.3 
Rationale for 
Obeticholic 
Acid Dose and 
Duration 
Subjects will be randomized to receive OCA 25 mg or 
placebo daily during the Double-Blind Phase.   
This dose was selected based clinical experience in 
completed Phase 2 studies in subjects with NAFLD 
(747-203) and NASH (FLINT) as well as a clinical 
pharmacology study in subjects with hepatic impairment 
(Study 747-103). 
 
Subjects will be randomized to receive OCA 
10 mg or placebo daily for the first 3 months 
then titrate to OCA 25 mg or placebo daily 
for the duration of the Double-Blind Phase.   
This dose titration was selected based on the 
known mechanism of FXR and clinical 
experience in completed Phase 2 studies in 
subjects with NAFLD (747-203) and NASH 
(FLINT) as well as a clinical pharmacology 
study in subjects with hepatic impairment (Study 
747-103). 
FXR is a nuclear receptor that senses bile 
acids and regulates their intracellular levels 
in hepatocytes.  FXR activation leads to the 
reduction of intracellular bile acid levels by 
increasing the export of bile acids out of cells, 
Updated dose rationale to 
incorporate 10 mg dose. 
Incorporated FXR 
activation as key rationale 
for selection of titration 
dose regimen. 


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thereby decreasing bile acid uptake and bile 
acid synthesis.  After 12 weeks of dosing 
OCA, FXR activation has been shown to 
reduce systemic bile acid levels while 
maintaining relatively low OCA levels in the 
total bile acid pool (<2%).  
Section 5.4.3 
Rationale for 
Obeticholic 
Acid Dose and 
Duration 
The dedicated hepatic impairment study (747-103) using 
OCA 10 mg has shown only 10% increase in the systemic 
concentrations of total OCA in subjects with CP Class A 
compared to healthy subjects.  Because a linear relationship 
from doses of OCA 5 mg up to OCA 100 mg has been 
demonstrated (Studies 747 102, 747 103, 747 105, 747
112, and 747 115), it is expected that similar systemic 
exposures of OCA 25 mg will be observed in subjects with 
CP Class A compared to noncirrhotic subjects. 
Therefore, the OCA 25 mg dose is considered appropriate 
for evaluation of safety and efficacy of OCA in all eligible 
subjects at study entry.  Guidelines for subjects who 
progress beyond CP Class A are provided in Section 7.5. 
Study duration was determined based on findings in prior 
NASH studies ranging from 6 months to 72 weeks 
The dedicated hepatic impairment study 
(747-103) using OCA 10 mg has shown only 
10% increase in the systemic concentrations of 
total OCA in subjects with CP Class A 
compared to that of healthy subjects.   
Therefore, the dose of OCA 10 mg will be 
administered for 3 months to support the 
lowering of bile acid levels in CP Class A 
subjects.  After 3 months, titration of OCA 
25 mg administration is introduced to provide 
clinically proven beneficial doses.  Guidelines 
for subjects who progress beyond CP Class A 
are provided in Section 7.6. 
The duration of the 12-week titration is based 
upon results seen in the prior PBC program 
which effectively demonstrated titration for 
biologically altering the FXR signaling 
pathways thus inducing bile acid levels.  
Overall study duration was determined based on 
findings in prior NASH studies ranging from 
6 months to 72 weeks.   
To incorporate the titration 
dose justification based 
upon FXR MOA and prior 
study experience. 
Section 5.5 
Summary of 
Known 
Potential Risks 
with 
An increase in liver enzymes and hepatic AEs, including 
jaundice, were observed in subjects with liver disease at 
OCA doses between 10 mg and 50 mg and in healthy 
subjects who were treated at doses ≥100 mg in Phase 1, 
multiple dose studies. 
Consistent with the dose-limiting hepatic 
toxicities observed in the non-clinical studies, 
dose-related but reversible and asymptomatic 
increases in ALT and AST were observed in 
healthy volunteers treated with multiple 
Safety language updated 


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Investigational 
Product 
doses of OCA starting at the 100 mg dose 
(Study 747-102).   
In patients with chronic liver disease such as 
PBC, hepatobiliary findings including 
increased transaminases and bilirubin and 
signs or symptoms of hepatic decompensation 
such as development of jaundice were 
observed.  In addition, cholecystitis, including 
acute cholecystitis, was reported in 
association with treatment with OCA. 
Section 6.1 
Primary 
Objective 
• 
Histological improvement in fibrosis by assessing the 
percentage of subjects with improvement in fibrosis by 
at least 1 stage using Ishak scoring criteria from 
Baseline to Month 12 
• 
Histological improvement in fibrosis by 
assessing the percentage of subjects with 
improvement in fibrosis by at least 1 stage 
using the NASH CRN scoring system from 
Baseline to Month 12 
Updated with NASH CRN 
criteria because the primary 
endpoint using the NASH 
CRN criteria is considered 
more appropriate for this 
population. 
Section 7.1.2 
Schedule of 
Study 
Procedures:  
Double-Blind 
Phase 
Table 1 
Insertion  
Mth 2, Mth 4, Mth 5 procedures 
Additional study visits for 
safety monitoring. 
Section 7.1.2 
Schedule of 
Study 
Procedures:  
Double-Blind 
Phase 
Table 1 
Insertion 
 
Change in intervals for assessment of HbA1c  
Microbiome/Metabalome Stool Sample 
Analysis (All US Subjects) assessments at Day 
1, Month 1, Month 3, Month 6, Month 12, ET 
ELF at Month 3, Month 9 
TE, Liver Multiscan, and MRE et Month 3, 
Month 9 
 
Metabolic Parameter:  HbA1c.  Assessments 
at Screening Visit 1, Day 1, Months 3, 6, 9 
and 12. 
 
Examination of microbiota 
and their metabolites in a 
well-defined NASH 
population, as proposed in 
this study, could provide 
additional insight into 
NASH 
pathogenicity.  Since OCA 
has been shown to impact 
dysbiosis in animal models, 


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Other Metabolic Parameters split into separate 
row. 
 
its effect in NASH subjects 
will be evaluated via 
examination of fecal gut 
microbiome, fecal 
metabolomes, and fecal bile 
acid composition. 
Section 7.1.2 
Schedule of 
Study 
Procedures:  
Double-Blind 
Phase 
Table 1 
a Not required for subjects who have had a biopsy ≤6 months 
prior to randomization (Day 1) and can provide unstained 
slides. 
 
a The 2 Screening Visits must occur at least 4 
weeks apart to confirm pretreatment serum 
chemistry levels, including ALT and AST. 
 
Footnotes updated to align 
with updated text and 
procedures.   
Section 7.1.2 
Schedule of 
Study 
Procedures:  
Double-Blind 
Phase 
Table 1 
m On-study liver biopsies should be performed after the 
hepatobiliary ultrasound for HCC screening.  
n Optional procedure.  If a biopsy was obtained within 6 months, 
subjects do not need to undergo this procedure 
q At the Month 1 and Month 12/EOT/EOS visit, investigational 
product administered will be from the bottle dispensed at the 
previous visit. 
 
m On-study liver biopsies should be performed after 
the hepatobiliary ultrasound for HCC screening.  
Liver biopsy procedure at Screening Visit 2 is 
not required for subjects who have had a biopsy 
≤12 months prior to randomization (Day 1) and 
can provide unstained slides. 
n Optional procedure.  If a biopsy was obtained 
within 12 months, subjects do not need to undergo 
this procedure.  
q At the Month 1, 2, 4, 5, and Month 12/EOT/EOS 
visit, investigational product administered will be 
from the bottle dispensed at the previous visit. 
s Other metabolic parameters include fasting 
plasma glucose, insulin, C-peptide, and HOMA-
IR.  
Footnotes updated to align 
with updated text and 
procedures.   
Section 7.1.2 
Schedule of 
Study 
Procedures:  
Double-Blind 
Phase 
Table 1 
Insertion 
r In the event either of the 2 ALT/AST 
assessments collected at Screening Visit 1 and 
Screening Visit 2 differ by ≥30%, a third 
sample will be collected at an unscheduled 
visit as a confirmatory sample to include in 
the mean result(s) that will be used to 
determine eligibility. 
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 
recover, and may progress 
into end stage liver failure 
relatively faster. As 
mentioned above this may 


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result in increased serum 
concentrations of IP and 
since optimal dosing for 
subjects with hepatic 
impairment has not yet 
been determined, these 
subjects will require study 
drug discontinuations. 
Additional safety and 
tolerability considerations 
including dose titration is 
required in this vulnerable 
population with decreased 
hepatic reserve. 
Section 7.1.2 
Schedule of 
Study 
Procedures:  
OLE Phase 
Table 2 
Insertion  
Change in intervals for assessment of HbA1c 
Mth 2, Mth, 3, Mth 4, Mth 5 procedures 
 
Metabolic Parameter:  HbA1c.  Assessments 
at Day 1, Months 3, 6, 9, 12, 15, 18, 21, 
24/EOT/EOS, and ET. 
 
Other Metabolic Parameters split into separate 
row. 
 
 
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 
recover, and may progress 
into end stage liver failure 
relatively faster. As 
mentioned above this may 
result in increased serum 
concentrations of IP and 
since optimal dosing for 
subjects with hepatic 
impairment has not yet 
been determined, these 
subjects will require study 
drug discontinuations. 
Additional safety and 
tolerability considerations 
including dose titration is 
required in this vulnerable 
population with decreased 
hepatic reserve. 


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Section 7.1.2 
Schedule of 
Study 
Procedures:  
OLE Phase 
Table 2 
g  Subjects randomized to placebo during the Double-
Blind Phase will receive OCA 25 mg in the OLE.  
Subjects randomized to OCA during the Double-Blind 
Phase will continue the treatment they were assigned. 
j At the Month 1 and/or Month 24/EOT/EOS visit, 
investigational product dispensed/administered will be from the 
bottle issued at the previous visit. 
g Subjects randomized to placebo during the 
Double-Blind Phase will receive OCA 10 mg 
for 3 months followed by OCA 25 mg in the 
OLE, unless there are safety concerns.  
Subjects randomized to OCA during the Double-
Blind Phase will continue the treatment they 
were assigned. 
j At the Month 1, 2, 4, 5, and/or Month 24/EOT/EOS 
visit, investigational product 
dispensed/administered will be from the bottle 
issued at the previous visit. 
Titration schedule followed 
in the double-blind phase, 
continued in the open-label 
phase of the study. 
Clarification on dispensing 
of investigational product. 
7.3 Treatment 
Assignment 
Planned 
Dosing 
Regimen 
Subjects will be randomly assigned in a 1:1 ratio to receive 
placebo or OCA 25 mg. 
 
Subjects will be randomly assigned in a 1:1 ratio 
to receive placebo or OCA. 
Following assessments of liver chemistry and 
safety at Month 1 and Month 2, a dose 
titration to 25 mg or matching placebo will be 
implemented at Month 3, unless there are 
safety and tolerability concerns.   
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 
recover, and may progress 
into end stage liver failure 
relatively faster. As 
mentioned above this may 
result in increased serum 
concentrations of IP and 
since optimal dosing for 
subjects with hepatic 
impairment has not yet 
been determined, these 
subjects will require study 
drug discontinuations. 
Additional safety and 
tolerability considerations 
including dose titration is 
required in this vulnerable 
population with decreased 
hepatic reserve. 
7.4 
Management of 
For a subject who reaches a CP score ≥7 (CP Class B or C), 
an adjustment to the dose frequency will be implemented 
A subject who progresses to CP Class B or C 
cirrhosis (CP score ≥7) will discontinue 
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 


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Disease 
Progression 
(see Section 7.5) and serial PK samples will be collected 
(see Section 13.1).  Monitoring of disease progression using 
CP score and MELD will be continued throughout the study 
(Schedule of Study Procedures Table 1).   
investigational product (Section), and the 
subject should be followed for the duration of 
the study.  
Subjects should be encouraged to continue 
study visits, despite stopping investigational 
product, for continued collection of safety 
data but may withdraw consent at any time. 
 Monitoring of disease progression using CP 
score and MELD will be continued throughout 
the study (Schedule of Study Procedures Table 
1).  In addition, subjects should be re-assessed 
within a month for disease progression.  At a 
minimum, a physical exam, general 
biochemistry, serum electrolytes, and 
assessment of CP and MELD scores should 
be conducted.  Further monitoring outside of 
regular scheduled visits should be based on 
the Investigator’s assessment of the subject’s 
clinical status. 
recover, and may progress 
into end stage liver failure 
relatively faster. As 
mentioned above this may 
result in increased serum 
concentrations of IP and 
since optimal dosing for 
subjects with hepatic 
impairment has not yet 
been determined, liver 
disease progression defined 
by CP score will require 
study drug discontinuations. 
Section 7.5 
Dosage 
Adjustment  
. 
Deletion  
CP language was modified 
Section 7.5 
Dosage 
Adjustment 
Dosages for investigational product should be maintained 
constant during the study.  However, dose frequency may 
be modified for the management of pruritus or other safety 
findings as described in Section 15.1.5.1. 
If during the study, a subject progresses to CP score ≥7 (CP 
Class B or C), the Investigator should reduce the dose 
frequency of the randomized investigational product to 
every other day administration.  In addition, subjects 
With an exception of the planned dose 
titration at Month 3, dosages for 
investigational product should be maintained 
constant during the study.  However, dose 
frequency may be modified for the management 
of pruritus or other safety findings as described 
in Section 15.1.4.1. 
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 
recover, and may progress 
into end stage liver failure 
relatively faster. Additional 
safety and tolerability 
considerations including 
dose reduction may be 


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should be re assessed within a month for disease 
progression.  At a minimum, a physical exam, liver 
biochemistry, prothrombin time (PT)/INR, serum 
electrolytes, and assessment of CP and MELD scores 
should be conducted.  Further monitoring outside of regular 
scheduled visits should be based on the investigator’s 
assessment of the subject’s clinical status 
In the event of tolerability issues such as 
pruritus, the dosing frequency may be 
decreased at the discretion of the 
Investigator.  
If at any point, safety concerns are noted 
based on review of liver biochemistry and 
adverse events, down titration to 10 mg daily 
may be considered in consultation with the 
medical monitor. 
required in this population 
with decreased hepatic 
reserve. 
Section 8.1 
Subject 
Population 
This study will be conducted at approximately 75 to 100 
international study sites with experience in treating patients 
with compensated cirrhosis due to NASH 
This study will be conducted at approximately 
150 international study sites with experience in 
treating patients with compensated cirrhosis due 
to NASH 
Additional sites will be 
utilized to ensure 
enrollment of subjects.  
Section 8.2.1.1 
Progression to 
CP score ≥7 
Insertion 
If a subject develops a CP score ≥7, 
liver-related assessments used in CP score 
calculation should be confirmed within 48 to 
72 hours and captured in the EDC.  If CP 
score is confirmed, a mandatory 
discontinuation of investigational product is 
required.  However, subjects should be 
encouraged to continue study visits, despite 
stopping investigational product, for 
continued collection of safety data but may 
withdraw consent at any time. 
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 
recover, and may progress 
into end stage liver failure 
relatively faster. As 
mentioned above this may 
result in increased serum 
concentrations of IP and 
since optimal dosing for 
subjects with hepatic 
impairment has not yet 
been determined, liver 
disease progression defined 
by CP score will require 
study drug discontinuations. 
Following FDA guidance, 
discontinuation criteria 
were updated for subjects 


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who progress to CP score 
≥7 
Section 8.2.1.2 
Severe Drug 
Induced Liver 
Injury 
Subjects who develop severe drug induced liver injury, 
which is considered to be causally related to the 
investigational product, should be discontinued from 
investigational product and should not be rechallenged.  
Using the investigator’s clinical judgement, laboratory 
measures may be repeated for clinical confirmation.  
Subjects who discontinue investigational product are 
expected to be followed though to study closure (or at the 
discretion of the Sponsor). 
Severe drug induced liver injury is described in detail in 
Appendix B.  Natural progression of the underlying 
condition and other causal factors such as a common bile 
duct stone or development of other concurrent liver disease 
should be considered before the investigational product is 
permanently discontinued.  Subjects who discontinue due to 
significant drug induced liver injury must be followed until 
the AE has resolved, stabilized, or is not of clinical concern. 
Severe drug induced liver injury that is not considered 
related to investigational product must be discussed with 
the Sponsor before investigational product is reinitiated.  
Follow up procedures for subjects resuming treatment, 
including laboratory evaluations and physical examinations, 
must be performed after a maximum of 2 weeks of 
retreatment and may be conducted at a local clinic if the 
subject is unable to return to the site.  Results must be 
reported immediately to the site so the Investigator can 
determine if the subject is to be allowed to continue 
treatment.  Subjects should be encouraged to continue study 
visits despite stopping investigational product for continued 
study data collection but may withdraw consent at any time. 
Deletion 
Language on drug-induced 
liver injury was combined 
and streamlined in 
Section 8.2.2.2. 


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Section 8.2.2.2 
Suspected Mild 
or Moderate 
Drug-Induced 
Liver Injury 
Because transient fluctuations of ALT or AST are common, 
and progression to severe drug induced liver injury or acute 
liver failure is uncommon, automatic discontinuation of 
investigational product with an elevation of ALT or AST 
that is >3x ULN/baseline/nadir or total bilirubin >2x 
ULN/baseline/nadir, as described in Appendix B, may be 
unnecessary.  If a subject develops signs of a mild or 
moderate event of drug induced liver injury, regardless of 
causality, investigational product should be interrupted until 
the event has resolved or returned to baseline but the 
subject should continue with the study visit schedule.  
The subject may restart treatment after resolution of the 
event or return to baseline.  Follow-up procedures, 
including laboratory evaluations and physical examinations, 
must be performed after a maximum of 2 weeks of 
re-treatment and may be conducted at a local clinic if the 
subject is unable to return to the site. 
Results must be reported immediately to the site so the 
Investigator can determine if the subject will be allowed to 
continue treatment. 
 
Cirrhotic patients have diminished liver 
reserve and lesser ability to recover, and 
these could make the consequences of a 
drug-induced injury worse.  Their 
transaminase, especially ALT, levels may be 
normal or only slightly elevated, due to their 
lower hepatocellular reserve, even in 
advanced cases.  For this reason, relatively 
lower level of transaminase elevations can 
indicate severe drug-induced liver injury and 
may require investigational product 
discontinuations.  Subjects who discontinue 
investigational product are expected to be 
followed though to study closure (or at the 
discretion of the Sponsor) and should be 
encouraged to continue study visits despite 
stopping investigational product for 
continued study data collection but may 
withdraw consent at any time. 
Natural progression of the underlying 
condition and other causal factors such as a 
common bile duct stone or development of 
other concurrent liver disease should be 
considered before the investigational product 
is permanently discontinued.  Subjects who 
discontinue due to significant drug-induced 
liver injury must be followed until the AE has 
resolved, stabilized, or is not of clinical 
concern. 
• 
Investigational product must be 
interrupted in subjects if the following 
conditions develop: Baseline values were 
<2x ULN, and ALT or AST increases to 
>5x baseline measurement (BLM). 
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 
recover, and may progress 
into end stage liver failure 
relatively faster. As 
mentioned above this may 
result in increased serum 
concentrations of IP and 
since optimal dosing for 
subjects with hepatic 
impairment has not yet 
been determined, liver 
disease progression defined 
by CP score will require 
study drug discontinuations. 


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• 
Baseline values were ≥2x ULN but <5x 
ULN, and ALT or AST increases to >3x 
BLM 
• 
Baseline values were ≥5x ULN, and ALT 
or AST increases to >2x BLM 
• 
ALT or AST increase >2x BLM AND the 
increase is accompanied by a 
concomitant total bilirubin increase to 
>2x BLM OR the INR concomitantly 
increases by >0.2. 
Investigational product will also be 
interrupted in presence of signs and 
symptom(s) such as rash, eosinophilia, 
nausea, vomiting, or right upper quadrant 
pain, anorexia and fatigue irrespective of the 
transaminase level, if the bilirubin is elevated 
above 2x BLM.  A potential drug-induced 
liver injury work-up for competing etiologies 
must be performed, and a complete liver 
profile including prothrombin time (PT)/INR 
must be repeated within 48-72 hours.  Study 
medication can be restarted only if an 
alternative etiology is definitively identified 
and liver tests have returned to baseline. 
Follow-up procedures, including laboratory 
evaluations and physical examinations, must be 
performed after a maximum of 2 weeks of 
retreatment and may be conducted at a local 
clinic if the subject is unable to return to the site.  
In this case, results as well as normal 
laboratory ranges, must be reported 
immediately to the site, and included in the 
case reports, so the Investigator can determine 


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if the subject is to be allowed to continue 
treatment. 
Section 9.1 
Investigational 
Product 
Treatment 
Regimen 
Two treatment groups will be evaluated: 
• 
Placebo  
• 
OCA 25 mg 
Each dose will be made up of 1 tablet (ie, one placebo 
tablet or one OCA 25 mg tablet). 
Two treatment groups will be evaluated: 
• 
Placebo  
• 
OCA (10 mg and 25 mg) 
Each dose will be made up of 1 tablet. 
Inclusion of 10 mg dose 
due to study design 
changes. 
Section 9.1.1 
OLE Phase 
Investigational product during the OLE Phase will be 
provided as open label OCA tablets at strength of 25 mg. 
 
Investigational product during the OLE Phase 
will be provided as open-label OCA tablets. 
Placebo subjects will be 
receiving 3 months of OCA 
10 mg before uptitrating to 
OCA 25 mg.  
Section 9.4.1 
Methods of 
Assigning 
Subjects to 
Treatment 
Groups 
This study will be conducted in a double-blind, placebo-
controlled manner.  Enrolled subjects will be randomized in 
a 1:1 ratio to placebo or OCA 25 mg based on a predefined 
randomization code (generated by Sponsor or designee) 
using an IWRS. Randomization of subjects will be stratified 
by the presence of type 2 diabetes at enrollment (yes or no) 
and Ishak cirrhosis score 5 or 6.  
All subjects who enroll into the OLE will receive OCA 25 
mg.   
 
This study will be conducted in a double-blind, 
placebo-controlled manner.  Enrolled subjects 
will be randomized in a 1:1 ratio to placebo or 
OCA based on a predefined randomization code 
(generated by Sponsor or designee) using an 
IWRS. 
Subjects randomized to OCA will initiate 
investigational product of OCA 10 mg for 
3 months prior to uptitrating to OCA 25 mg.  
Uptitration will be based on safety and 
tolerability assessments completed at Month 
1, Month 2, and Month 3. Randomization of 
subjects will be stratified by the presence of type 
2 diabetes at enrollment (yes or no) and 
cryptogenic cirrhosis (yes or no).  All subjects 
who enroll into the OLE will receive OCA. 
All subjects who enroll into the OLE will 
receive OCA.  Subjects randomized to placebo 
in the double blind period will initiate 
investigational product of OCA 10 mg for the 
Inclusion of 10 mg dose 
due to study design 
changes. 


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first 3 months of the OLE prior to uptitrating 
to OCA 25 mg.  Uptitration will be based on 
safety and tolerability assessments completed 
at Month 1, Month 2, and Month 3.  Subjects 
will continue the same dosing regimen they 
received at the end of the Double-Blind Phase.   
Section 9.4.1 
Methods of 
Assigning 
Subjects to 
Treatment 
Groups 
Insertion 
To maintain blinding after subjects complete 
the Double-Blind Phase and enter the OLE, 
all placebo, OCA 10 mg, and OCA 25 mg 
tablets and bottles will be identical.  Once all 
subjects have titrated to the OCA 25 mg dose 
in the OLE, subjects may receive 
investigational product with an open label 
identifying the product as OCA 25 mg. 
Information on how 
blinding will be maintained 
as subjects enter the OLE. 
Section 9.7.3 
Screening Visit 
Procedures 
Insertion 
Two Screening Visit assessments must be 
performed to determine whether the subject 
meets all the inclusion criteria and none of 
the exclusion criteria.  Subjects who do not 
fulfill all eligibility criteria will not be 
enrolled in the study.  Subjects may be 
rescreened after 2 months have elapsed from 
the date of their most recent screening visit 
procedure; however, all Screening 
procedures (including obtaining informed 
consent) should be repeated and a new 
three-digit Screening number assigned. 
The 2 Screening visits must occur at least 4 
weeks apart to confirm pretreatment serum 
chemistry levels, including ALT and AST.   
• 
Screening Visit 1 will occur 8 weeks 
prior to Day 1;  
• 
Screening Visit 2 will occur 4 weeks ± 
2 days prior to Day 1, depending on 
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 
recover, and may progress 
into end stage liver failure 
relatively faster. As 
mentioned above this may 
result in increased serum 
concentrations of IP and 
since optimal dosing for 
subjects with hepatic 
impairment has not yet 
been determined, these 
subjects will require study 
drug discontinuations. 
Additional study visits will 
allow a closer safety 
monitoring to detect disease 
progression signals. 


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the date that the first serum 
chemistry sample was collected.   
If either the 2 ALT or 2 AST assessments 
collected at Screening Visit 1 and Screening 
Visit 2 differ by ≥30%, a third sample must 
be collected at an unscheduled visit as a 
confirmatory sample to include in the mean 
result(s) that will be used to determine 
eligibility. 
Section 9.7.3.1 
Screening 
Visit 1 
The Screening Visit assessments must be performed within 
≤8 weeks prior to Day 1 to determine whether the subject 
meets all the inclusion criteria and none of the exclusion 
criteria 
• 
Assess availability of liver biopsy samples 
obtained ≤6 months prior to Day 1, for which 
unstained slides can be prepared and submitted for 
central review 
• 
Instruct the subject to fast overnight (at least 
8 hours) before the next visit (water is 
permitted).  Fasting is not required before 
Screening Visit 2.  
The Screening Visit assessments must be 
performed within ≤8 weeks prior to Day 1 to 
determine whether the subject meets all the 
inclusion criteria and none of the exclusion 
criteria 
• 
Assess availability of liver biopsy 
samples obtained ≤12 months prior to 
Day 1, for which unstained slides can 
be prepared and submitted for central 
review 
• 
Instruct the subject to fast 
overnight (at least 8 hours) before 
the next visit (water is permitted).  
Fasting is required before 
Screening Visit 2.  
To allow for AST and ALT 
assessments to be 
conducted twice. 
Section 9.7.3.2 
Screening 
Visit 2 
Screening Visit 2 procedures for all subjects without a 
recent liver biopsy with unstained slides must be performed 
within ≤8 weeks prior to Day 1 and are as follows: 
Screening Visit 2 procedures must be performed 
within ≤4 weeks ± 2 days prior to Day 1 and are 
as follows: 
Updated to require all 
subjects to follow updated 
screening procedures.  
Section 9.7.3.2 
Screening 
Visit 2 
Insertion 
• 
Verify that the subject has fasted for at 
least 8 hours 
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 
recover, and may progress 
into end stage liver failure 


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− 
Record fasting status in the source and 
eCRF 
• 
If the subject reports having eaten within 
8 hours, document accordingly in the 
source and eCRF and remind the subject 
that fasting is required before all study 
visits 
• 
Medical History 
• 
Obtain urine sample for urinalysis 
• 
Obtain blood samples for: 
o 
Serum chemistry, hematology, 
and coagulation 
• 
Calculations will be performed by the 
Sponsor or designee for: 
o 
MELD Score 
o 
CP Score/Class 
• 
Perform a urine-based beta human 
chorionic gonadotropin (β-hCG) 
pregnancy test for females of 
childbearing potential 
relatively faster. As 
mentioned above this may 
result in increased serum 
concentrations of IP and 
since optimal dosing for 
subjects with hepatic 
impairment has not yet 
been determined, these 
subjects will require study 
drug discontinuations.  
Section 9.7.4 
Day 1 
Procedures 
9.7.5 Month 1 
Procedures 
9.7.7 Month 3 
and Month 9 
Procedures 
Insertion 
• 
Obtain stool sample (collected at home) 
for microbiome/metabolome analysis (US 
subjects only) 
Examination of microbiota 
and their metabolites in a 
well-defined NASH 
population, as proposed in 
this study, could provide 
additional insight into 
NASH pathogenicity and 
may also potentially serve 
as a non-invasive marker of 
fibrosis. Since OCA has 


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9.7.7 Month 6 
Procedures 
9.7.11 Month 
12/EOT/EOS 
Procedures 
9.7.13 Early 
Termination 
Procedures 
been shown to normalize 
dysbiosis in animal models, 
its effect in NASH subjects 
will be evaluated via 
examination of fecal gut 
microbiome, fecal 
metabolomics, and fecal 
bile acid composition. 
Section 9.7.6 
Month 2 
Procedures 
Section 9.7.8 
Month 4 
Procedures 
Section 9.7.9 
Month 5 
Procedures 
Insertion 
Section 9.7.6 Month 2 Procedures  
Section 9.7.8 Month 4 Procedures 
Section 9.7.9 Month 5 Procedures 
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 
recover, and may progress 
into end stage liver failure 
relatively faster. As 
mentioned above this may 
result in increased serum 
concentrations of IP and 
since optimal dosing for 
subjects with hepatic 
impairment has not yet 
been determined, these 
subjects will require study 
drug discontinuations. 
Additional study visits will 
allow a closer safety 
monitoring to detect disease 
progression signals. 
Section 9.7.7 
Month 3 and 
Month 9 
Procedures 
Insertion 
• 
Month 3:  Obtain stool sample (collected 
at home) for microbiome/metabolome 
analysis (US subjects only) 
• 
Noninvasive panel of liver fibrosis (ELF, 
FibroMax, and FibroMeter) 
Examination of microbiota 
and their metabolites in 
biopsy-confirmed cirrhotic 
subjects, as proposed in this 
study, could provide 
additional insight into 
NASH pathogenicity and 


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• 
Month 3: Noninvasive radiological liver 
fibrosis measurements (TE, 
LiverMultiScan, and MRE; conducted at 
sites where device is available) if not 
conducted during Screening.  Whichever 
modality/ies used at baseline must be 
collected consistently at each visit. 
may also potentially serve 
as a non-invasive marker of 
fibrosis. Since OCA has 
been shown to impact 
dysbiosis in animal models, 
its effect in cirrhotic 
subjects will be evaluated 
via examination of fecal gut 
microbiome, fecal 
metabolomics, and fecal 
bile acid composition  
Section 9.7.13. 
Month 2, 3, 5, 
9, 15, and 21 
OLE 
Section 9.7.13. Month 3, 9, 15, and 21 OLE 
• 
Calculations will be performed by the Sponsor 
or designee for: 
− 
Noninvasive panel of liver fibrosis (ELF, 
FibroMax, and FibroMeter) 
 
Section 9.7.13. Month 2, 3, 5, 9, 15, and 21 OLE 
 
− 
Month 2, 5:  Trough PK (All Subjects) 
− 
Month 2, 5: PD Blood Samples (All 
Subjects) 
• 
Calculations will be performed by 
the Sponsor or designee for: 
− 
Month 3 OLE:  Noninvasive 
panel of liver fibrosis (ELF, 
FibroMax, and FibroMeter) 
 
Cirrhotic patients have 
diminished hepatocellular 
function, lesser ability to 
recover, and may progress 
into end stage liver failure 
relatively faster. As 
mentioned above this may 
result in increased serum 
concentrations of IP and 
since optimal dosing for 
subjects with hepatic 
impairment has not yet 
been determined, these 
subjects will require study 
drug discontinuations. 
Additional study visits will 
allow a closer safety 
monitoring to detect disease 
progression signals. 
Section 9.7.14. 
Month 4 OLE 
Insertion  
Section 9.7.14. Month 4 OLE 
Additional study visits will 
allow a closer safety 
monitoring to detect disease 
progression signals. 


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Section 10.1 
Investigational 
Product 
Investigational Product will be supplied as white, round, 
film-coated tablets containing, OCA 25 mg, or placebo.   
Investigational Product will be supplied as 
white, round, film-coated tablets containing 
OCA 10 mg, OCA 25 mg, or placebo.   
Inclusion of 10 mg dose 
due to study design 
changes. 
Section 12.1. 
Liver Biopsy  
Given that historical biopsies are to be obtained no more 
than 6 months before Day 1 … 
Given that historical biopsies are to be obtained 
no more than 12 months before Day 1 … 
The window of historic 
biopsy changed from 6 
months to 12 months before 
Day 1 because the NASH 
CRN fibrosis score of a 
cirrhotic patient is unlikely 
to improve to a lower 
fibrosis score within 
12 months, if all other entry 
criteria are met. 
 
Section 12.1. 
Liver Biopsy 
Biopsies should be at least 2 cm in length.   
Deletion 
Specifics will be provided 
in the manual. 
Section 12.1.1 
Central 
Reading of 
Liver Histology 
Histological presence of NASH with an Ishak fibrosis score 
≥5 or cryptogenic cirrhosis assumed to be due to NASH 
must be confirmed for study eligibility.  For each biopsy, 
fibrosis will be graded in accordance with Ishak scoring 
system (Table 3) (Ishak 1995).   
Table 11: 
Ishak Scoring System for Determining 
Eligibility and Primary Histological 
Endpoint Assessment 
Modified Staging:  Architectural Changes, 
Fibrosis, and Cirrhosis 
Change 
Score 
No fibrosis  
0 
Histological presence of NASH with a fibrosis 
score of 4 based on the NASH CRN or 
cryptogenic cirrhosis with metabolic factors 
assumed to be due to NASH must be confirmed 
for study eligibility.  For each biopsy, fibrosis 
will be graded in accordance with the NASH 
CRN scoring system (Table 3) (Kleiner 2005). 
Table 3: 
NASH CRN Scoring System 
for Determining Eligibility 
and Primary Histological 
Endpoint Assessment 
NAFLD Activity Score (NAS) 
Parameter 
Scoring Criteria 
Steatosis 
0 = <5%  
Updated with NASH CRN 
criteria because these are 
considered more 
appropriate for the study 
population and the primary 
endpoint is based on NASH 
CRN criteria. 
 


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Fibrous expansion of some 
portal areas, with or without 
short fibrous septa 
1 
Fibrous expansion of most 
portal areas, with or without 
short fibrous septa 
2 
Fibrous expansion of most 
portal areas with occasional 
portal to portal bridging 
3 
Fibrous expansion of portal 
areas with marked bridging 
(portal to portal as well as 
portal to central  
4 
Marked bridging (portal to 
portal and/or portal to 
central) with occasional 
nodules (incomplete 
cirrhosis) 
5 
Cirrhosis, probably or 
definite 
6 
Adapted from Ishak 1995.  
In addition to the primary scoring of Ishak, biopsy samples 
will also be scored based on the NASH CRN criteria 
(Kleiner 2005), Laennec staging (Wang 2015), and SAF 
scoring (Bedossa 2014), and for quantitative collagen and 
percent fat. 
1 = 5% - 33% 
2 = >33% - 66%  
3 = >66%  
Lobular 
Inflammatio
n 
0 = No Foci 
1 = <2 Foci per 200 × field  
2 = 2-4 Foci per 200 × field   
3 = > 4 Foci per 200 × field  
Ballooning 
0 = None  
1 = Few balloon cells  
2 = Many cells / prominent 
ballooning  
 
In addition to the primary scoring of NASH 
CRN, biopsy samples will also be scored based 
on the modified Ishak criteria (Ishak 1995), 
Laennec staging (Wang 2015), and SAF scoring 
(Bedossa 2014), and for quantitative collagen. 
 
Section 12.1.1 
Central 
Reading of 
Liver Histology 
In addition to the primary scoring of Ishak, biopsy samples 
will also be scored based on the NASH CRN criteria 
(Kleiner 2005), Laennec staging (Wang 2015), and SAF 
In addition to the primary scoring using NASH 
CRN, biopsy samples will also be scored based 
on the Ishak criteria (Ishak 1995), Laennec 
NASH CRN used here 
because considered more 
appropriate for the study 
population and the primary 


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scoring (Bedossa 2014), and for quantitative collagen and 
percent fat. 
 
staging (Wang 2015), and SAF scoring 
(Bedossa 2014), and for quantitative collagen. 
 
endpoint is based on NASH 
CRN criteria. 
Section 13.1 
Pharmacokineti
c Blood 
Sampling 
Subjects may opt to provide blood samples for serial PK 
assessments.  Trough PK blood samples will be obtained 
from all subjects. 
Subjects may opt to provide blood samples for 
serial PK assessments.  Serial blood samples 
will be used to characterize the PK at steady-
state for a cohort of subjects at both OCA 10 
mg and (when titrated) 25 mg doses. An 
assessment of steady-state exposures (on an 
aggregate level) will be performed by an 
internal Intercept clinical pharmacologist/ 
pharmacometrician who is discrete from the 
study team.  These results may be made 
available to the DMC as appropriate (see 
Section 16.13).   
To best assess exposure and 
safety data across the 
duration of the trial, an 
unblinded 
pharmacometrician outside 
of the study team will 
analyze data and provide 
results to the DMC. 
Section 13.1 
Pharmacokineti
c Blood 
Sampling 
No other food or drink (water is permitted) will be allowed 
until after the 6-hour sample collection. 
 
No other food or drink (water is permitted) will 
be allowed until after the 6-hour sample 
collection. 
Trough PK blood samples will be obtained 
from all subjects.   
Because trough PK samples 
must be taken from subjects 
who have fasted, a 
clarifying statement for 
collection of PK samples 
after the 6-hour fast was 
added. 
Section 13.1 
Pharmacokineti
c Blood 
Sampling 
During the Double-Blind Phase: 
• 
Serial PK samples will be obtained at Month 1 and 
Month 12 from subjects who agree to participate in 
the assessment. 
• 
Trough samples will be obtained from all subjects 
prior to dose administration from all subjects at 
Months 1, 3, 6, 9, 12, and ET. 
During the OLE Phase: 
During the Double-Blind Phase: 
• 
Serial PK samples will be obtained at 
Month 1, Month 4, and Month 12 from 
subjects who agree to participate in the 
assessment. 
• 
Trough samples will be obtained from 
all subjects prior to dose administration 
from all subjects at Months 1, 2, 3, 4, 5, 
6, 9, 12, and ET. 
Because the titration 
schedule necessitates the 
need for steady state PK 
data at both 10 and 25 mg 
doses, an additional 
assessment at Month 4 was 
added. 
Because of the added visit 
days to the schedule, 
additional PK samples will 


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• 
Subjects who agree to participate in the Serial 
PK assessments will have samples obtained at 
Month 1 OLE and Month 24 OLE. 
• 
Trough PK samples will be obtained from all 
subjects prior to dose administration on 
Months 1, 6, 12, 18, 24 OLE, and ET. 
 
During the OLE Phase: 
• 
Subjects who agree to participate 
in the Serial PK assessments will 
have samples obtained at Month 1, 
Month 4, and Month 24 OLE. 
• 
Trough PK samples will be 
obtained from all subjects prior to 
dose administration on Months 1, 
2, 3, 4, 5, 6, 12, 18, 24 OLE, and 
ET. 
be collected to measure 
drug exposure. 
To align serial PK sampling 
from the double-blind phase 
with the OLE Phase, an 
additional 4 month 
assessment was added. 
Section 14.3 
Microbiome/M
etabolome 
Analysis 
Insertion 
Stool specimens collected for 
microbiome/metabolome analyses will be 
collected from all subjects at US sites.  
Specimens will undergo microbiota 16S 
ribosomal RNA gene analysis, genome 
testing, fecal metabolomics, fecal bile acid 
analysis, and other appropriate assays to 
determine if and how OCA influences the 
composition and activity of the resident 
microbiota in the gastrointestinal tract.  
Subjects will be provided kits and 
instructions for collection of stool specimens 
at home, as appropriate. 
Microbiome/metabolome analyses will be 
assessed in subjects according to the schedule 
presented in Schedule of Study Procedures 
Table 1 (Double-Blind Phase). 
Examination of microbiota 
and their metabolites in 
biopsy-confirmed cirrhotic 
subjects, as proposed in this 
study, could provide 
additional insight into 
NASH pathogenicity and 
may also potentially serve 
as a non-invasive marker of 
fibrosis. Since OCA has 
been shown to impact 
dysbiosis in animal models, 
its effect in cirrhotic 
subjects will be evaluated 
via examination of fecal gut 
microbiome, fecal 
metabolomics, and fecal 
bile acid composition. 
Section 14.4.2 
Exploratory 
Biomarkers 
Added language to allow 
for additional biomarkers 
not yet identified. 


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Section 15.1.3 
Relationship to 
Study 
Procedures 
Table 7 
A reaction that follows a reasonable temporal sequence 
from the liver biopsy; that follows a known or expected 
response pattern to the liver biopsy. 
A reaction that follows a reasonable temporal 
sequence from the required procedure (eg, 
liver biopsy); that follows a known or expected 
response pattern to the required study 
procedure. 
Updated to indicate that this 
applies to any study 
procedure.  
Section 15.1.4.1 
Severity of 
Pruritus (as an 
Adverse Event) 
For subjects with mild or moderate pruritus, consider dose 
frequency adjustment (OLE only), dosing frequency and/or 
temporary dosing interruption 
 
Less frequent dosing of investigational 
product (eg, on alternate days) may be tried, 
after which subjects may return to their 
original daily dose as soon as tolerated.   
 
Language updated to match 
safety language in other 
protocols. 
Section 15.1.9 
Notification of 
Post-Study 
SAEs 
Insertion 
All SAEs that occur within 30 days following 
discontinuation from the study, whether or 
not they are related to the investigational 
product, must be reported to the Sponsor 
within 24 hours by following the instructions 
provided in Section 15.1.5. 
If an Investigator becomes aware of an SAE 
that may be attributable to the investigational 
product at any time after the end of the study, 
the Sponsor should be notified immediately 
(ie, within 24 hours) by following the 
instructions provided in Section 15.1.5. 
Updated safety reporting 
including with additional 
instructions. 
Section 15.2.7 
Laboratory 
Assessments  
CHI3L1 and P3NP 
CHI3L1, P3NP, and emerging biomarkers for 
NASH diagnosis and/or pathophysiology 
Additional biomarkers for 
NASH will be assessed 


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  Table 10 
Section 15.2.7 
Laboratory 
Assessments  
  Table 10 
Microbiome/Metabolome Analysis (Double-Blind only) 
Microbiota 16S ribosomal RNA gene analysis, 
genome testing, fecal metabolomics, fecal bile 
acid analysis, and other appropriate assays to 
determine if and how OCA influences the 
composition and activity of the resident 
microbiota in the gastrointestinal tract  
Microbiome will be 
assessed in this population 
Section 16.3 
Primary 
Efficacy 
Analysis 
The primary efficacy analysis will be conducted using the 
ITT population and test the following hypotheses: 
• 
H0:  The percentage of subjects with fibrosis 
improvement by at least 1 stage using Ishak 
score from Baseline to Month 12 is equal 
between placebo and OCA 25 mg. 
• 
H1:  The percentage of subjects with fibrosis 
improvement by at least 1 stage using Ishak 
score from Baseline to Month 12 is different 
between placebo and OCA 25 mg. 
The type I error for primary efficacy analysis will be 
controlled at 0.05.   
For the comparison of the primary efficacy endpoint, a 
Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization strata (presence of type 2 diabetes at 
enrollment [yes/no] and baseline fibrosis stage [Ishak 5 or 
6]) will be used.  Missing values will be considered a 
nonresponse.   
Exploratory analyses of the primary endpoint will be 
conducted using PP population. 
The primary efficacy analysis will be conducted 
using the ITT population and test the following 
hypotheses: 
• 
H0:  The percentage of subjects 
with fibrosis improvement by at 
least 1 stage using NASH CRN 
score from Baseline to Month 12 is 
equal between placebo and OCA. 
• 
H1:  The percentage of subjects 
with fibrosis improvement by at 
least 1 stage using NASH CRN 
score from Baseline to Month 12 is 
different between placebo and 
OCA. 
The type I error for primary efficacy analysis 
will be controlled at 0.01.   
For the comparison of the primary efficacy 
endpoint, a Cochran-Mantel-Haenszel (CMH) 
test stratified by the randomization strata 
(presence of type 2 diabetes at enrollment 
[yes/no] and cryptogenic cirrhosis [yes/no]) 
will be used.  Missing values will be considered 
a nonresponse.   
Modification due to 
addition of mITT 
population, modification of 
primary and key secondary 
efficacy endpoints and 
randomization stratification 
factors. 
 
Modified type 1 error based 
on discussions with 
regulatory authorities. 


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Exploratory analyses of the primary endpoint 
will be conducted using the mITT and PP 
populations. 
Section 16.4 
Key Secondary 
Efficacy 
Analyses 
Key secondary efficacy endpoints are: 
• 
Percentage of subjects with fibrosis 
improvement by at least 1 stage using NASH 
CRN criteria from Baseline to Month 12 
be conducted in a sequential closed testing gate-
keeping procedure, provided the primary efficacy 
comparison is statistically significant in favor of OCA.  
If the primary efficacy comparison is not statistically 
significant, then the comparison of key secondary 
efficacy endpoints will be considered descriptive and 
exploratory.  This procedure controls the study wise 
type I error and is described below. 
First, placebo and OCA 25 mg will be compared with 
respect to the primary efficacy endpoint at Month 12.  
If the comparison of primary efficacy endpoint 
Key secondary efficacy endpoint is: 
• 
Percentage of subjects with fibrosis 
improvement by at least 2 stages using 
Ishak scoring criteria from Baseline to 
Month 12 
The percentage of subjects with fibrosis 
improvement by at least 2 stages using 
Ishak scoring criteria will be analyzed 
similarly to the primary endpoint. 
The hypothesis testing of the key secondary 
endpoint will be conducted in a sequential 
closed testing gate-keeping procedure, 
provided the primary efficacy comparison is 
statistically significant in favor of OCA.  If 
the primary efficacy comparison is not 
statistically significant, then the comparison 
of key secondary efficacy endpoint will be 
considered descriptive and exploratory.   
 
Modified key secondary 
efficacy endpoint. 


Pr ot oc ol 7 4 7 -3 0 4  
Versi o n 6 . 0:  0 6 Mar 2 0 2 0  
 
Pa ge 2 8 1  
 
C o nfi de ntial a n d Pr o prietar y  
Secti o n  
Ori gi n al Te xt ( Versi o n 1. 0)  
Re vise d Te xt ( Versi o n 2. 0)  
Ke y C h a n ge  
Re as o ns/ J ustific ati o n f or 
C h a n ge  
ac hie ves statistical si g nifica nce at t he 2 si de d 0. 0 5 
le vel i n fa v or of O C A, t he n 
Plac e b o a n d O C A 2 5 m g will be c o m pare d wit h res pect 
t o i m pr o ve me nt i n li ver hist ol o g y b y m or p h o metric 
assess me nt of q ua ntitati ve c olla ge n (assesse d as 
) 
at M o nt h 1 2.  If t he c o m paris o n ac hie ves statistical 
si g nifica nce at t he 2 si de d 0. 0 5 le vel i n fa v or of O C A, 
t he n 
Place b o a n d O C A 2 5 m g will be c o m pare d wit h 
res pect t o t he perce nta ge of s u bjects wit h fi br osis 
i m pr o ve me nt of at least 1 sta ge usi n g N A S H C R N 
criteria fr o m Baseli ne t o M o nt h 1 2 at t he 2 si de d 
0. 0 5 le vel.   
If at a n y ste p defi ne d a b o ve, t he c o m paris o n is n ot 
statisticall y si g nifica nt at t he 2 si de d 0. 0 5 le vel, t he n 
t he re mai ni n g c o m paris o ns i n t he state d hierarc h y will 
be c o nsi dere d descri pti ve a n d e x pl orat or y.    
Secti o n 1 6. 5 
A d diti o nal 
Sec o n dar y 
Efficac y 
A nal yses  
A d diti o nal efficac y a nal yses will be c o n d ucte d usi n g P P 
p o p ulati o n.  
A d diti o nal efficac y a nal yses will be c o n d ucte d 
usi n g mI T T a n d  P P p o p ulati o ns  
A d diti o n of mI T T 
p o p ulati o n.  
Secti o n 1 6. 5. 1  
Ot her Hist ol o g y 
E n d p oi nts  
•  
Perce nta ge of s u bjects wit h c ha n ges i n fi br osis usi n g 
t he f oll o wi n g criteria:  
o  
Is ha k sc ori n g criteria fr o m Baseli ne t o M o nt h 1 2  
 
At least 2 sta ge i m pr o ve me nt  
o  
N A S H C R N  criteria fr o m Baseli ne t o M o nt h 1 2  
 
At least 2 sta ge i m pr o ve me nt  
 
•  
Perce nta ge of s u bjects wit h c ha n ges i n 
fi br osis usi n g t he f oll o wi n g criteria:  
o  
N A S H C R N  sc ori n g s yste m fr o m 
Baseli ne t o M o nt h 1 2  
 
At least 2 sta ge i m pr o ve me nt  
o  
Is h a k sc ori n g criteria fr o m Baseli ne t o 
M o nt h 1 2  
 
At least 1  sta ge i m pr o ve me nt 
C ha n ge d or deri n g of 
fi br osis sc ori n g s yste m d ue 
t o m o dificati o n i n pri mar y 
a n d sec o n dar y efficac y 
e n d p oi nts. 
D


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Section 
Original Text (Version 1.0) 
Revised Text (Version 2.0) 
Key Change 
Reasons/Justification for 
Change 
 
Improvement to Stage 4 
Section 16.5.1  
Other Histology 
Endpoints 
Insertion 
Moved from key secondary 
endpoint to other histology 
endpoints. 
Section 16.5.1  
Other Histology 
Endpoints 
Responder endpoints will be analyzed using a CMH test 
stratified by the randomization strata (presence of type 2 
diabetes at enrollment [yes/no] and baseline fibrosis stage 
[Ishak 5 or 6].  The change in NAS and SAF score will be 
analyzed using an ANCOVA model at each visit with 
change from baseline as the dependent variable including 
treatment group and randomization stratification factor as 
fixed effects and baseline as a covariate.  In addition, 
changes in NAS and SAF score will be summarized by each 
category.  
Overall shift and frequency tables will be presented for 
NAS score, NAS components, SAF score, and fibrosis 
scores (according to Ishak, NASH CRN, and Laennec 
criteria). 
Responder endpoints will be analyzed using a 
CMH test stratified by the randomization strata 
(presence of type 2 diabetes at enrollment 
[yes/no] and cryptogenic cirrhosis [yes/no].  
The change in NAS, SAF score, and PCA will 
be analyzed using an ANCOVA model at each 
visit with change from baseline as the dependent 
variable including treatment group and 
randomization stratification factors as fixed 
effects and baseline as a covariate.  In addition, 
changes in NAS and SAF score will be 
summarized by each category.  
Overall shift and frequency tables will be 
presented for NAS score, NAS components, 
SAF score, and fibrosis scores (according to 
NASH CRN, Ishak, and Laennec criteria). 
Clarification due to 
modification in primary 
efficacy endpoint. 
Section 16.5.2 
Clinical 
Outcomes 
Treatment groups will be compared on time to first 
occurrence of any of the following adjudicated events:   
 
Treatment groups will be compared on the 
percentage of subjects who reported any of 
the following adjudicated events, as well as the 
time to first occurrence:   
Clarification of analysis 
Section 16.5.2 
Clinical 
Outcomes 
A log rank test stratified by the randomization stratification 
factor will be used.   
In addition, treatment groups will be compared on liver-
related death. 
For the analysis of time to first occurrence of 
adjudicated events, a log rank test stratified by 
the randomization stratification factor will be 
used.   
Clarification of analysis. 


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Section 
Original Text (Version 1.0) 
Revised Text (Version 2.0) 
Key Change 
Reasons/Justification for 
Change 
In addition, treatment groups will be compared 
on each component of the outcome events. 
Section 16.5.2 
Clinical 
Outcomes 
Insertion 
The percentage of subjects who reported any 
adjudicated events will be analyzed using a 
CMH test stratified by the randomization 
strata (presence of type 2 diabetes at 
enrollment [yes/no] and cryptogenic cirrhosis 
[yes/no]).  Percentage of subjects who 
reported each component of the outcome 
events will also be analyzed separately in a 
similar manner.    
Clarification of analysis. 
Section 16.9.4 
Incidence 
Endpoints 
Insertion 
For the analyses of the percentage of subjects 
who reported any of the adjudicated clinical 
outcome events or adjudicated cardiovascular 
events, all subjects, regardless of whether one 
has reported any adjudicated events will be 
included in the denominator, and only 
subjects with adjudicated events will 
contribute to the numerator.  This represents 
the proportion of subjects experiencing 
events to number of subjects at risk. 
Sensitivity analyses may consider all events 
regardless of adjudication.  Events with 
discrepant adjudication will be analyzed 
using both results. 
Clarification of endpoint. 
Section 16.11 
Safety Analyses 
Safety data, including AEs and clinical laboratory 
observations, will be summarized by treatment group using 
the Safety Population  
Safety evaluations will comprise treatment-
emergent AEs, adjudicated CV events, vital 
signs, electrocardiograms (ECGs), and 
clinical laboratory results. 
Safety data will be summarized by treatment 
group using the Safety Population. 
Updated to align with the 
synopsis. 


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Section 
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Revised Text (Version 2.0) 
Key Change 
Reasons/Justification for 
Change 
Section 16.13 
Insertion 
The DMC will review the safety data, which 
will include AE data as well as lab values.  PK 
results will be made available to the DMC as 
appropriate.   
The DMC will meet approximately quarterly at 
scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review PK, safety 
and efficacy data as well as the adjudication 
assessments from the 3 adjudication committees 
listed in Section 16.14.   
To further provide clarity 
for the DMC review of data 
including safety and PK. 
Appendix B 
Guidance for 
Elevated Liver 
Biochemistry 
Values 
Deletion 
 
Drug-induced liver injury 
criteria were modified in 
Section 8.2.2.2.  This 
appendix was redundant. 

SAP_001.pdf: 
Intercept J 
OBETICHOLIC ACID (OCA) 
747-304
A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study 
to Evaluate the Efficacy and Safety of Obeticholic Acid in Subjects with 
Compensated Cirrhosis due to Nonalcoholic Steatohepatitis 
Statistical Analysis Plan 
Author: 
Min Mo, Associate Director of Biostatistics 
Protocol Version and Date: 
Version 7: 16 June 2021 
Analysis Plan Version: 
Version 3.0 
Analysis Plan Date: 
15 September 2022 
CONFIDENTIAL 
The info1mation contained herein is the property of Intercept Phannaceuticals, Inc. and may not be reproduced, 
published, or disclosed to others without written authorization of Intercept Phrumaceuticals, Inc. 
ClinicalTrials.gov Identifier: NCT03439254 


SPONSOR'S APPROVAL OF THE STATISTICAL ANALYSIS PLAN 
Intercept 7 47-304 SAP v3 15Sep2022 7 47-304 Statistical Analysis Plan v3 15Sep2022 (16.1.9) 
(Published, v1 .0) 
W -CLIN-017745 
Product: INT-747 Document Type: Clinical> Statistics> Statistical Analysis Plan 
Regulatory 
Clinical 
Approve 
Task: Approve-no signature 
page 
9/15/2022 2:41 PM EDT 
Approve 
Task: Approve-no signature 
page 
9/15/2022 1 :41 PM EDT 
Approve 
Task: Approve-no signature 
page 
9/15/2022 1 :38 PM EDT 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
SCOPE ..........................................................................................................................9 
2. 
STUDY OBJECTIVES ..............................................................................................10 
2.1. 
Primary Objectives Assessed at the End of the DB Phase .........................................10 
2.2. 
Secondary Objectives Assessed at the End of the DB Phase .....................................10 
2.3. 
 
2.4. 
PK/PD Objectives Assessed at the End of the DB Phase ...........................................12 
2.5. 
Safety Objectives Assessed at the End of the DB Phase ............................................12 
2.6. 
Primary Objective Assessed at the End of the OLE Phase .........................................13 
2.7. 
3. 
SUMMARY OF STUDY DESIGN ............................................................................14 
3.1. 
Overall Study Design ..................................................................................................14 
3.2. 
Study Design Diagram ................................................................................................16 
3.3. 
Randomization Methodology .....................................................................................16 
3.4. 
Sample Size Determination ........................................................................................17 
3.5. 
Biopsy Reads ..............................................................................................................17 
4. 
ANALYSIS POPULATIONS AND APPROACHES TO ANALYSIS ....................18 
4.1. 
Intent-to-Treat Population ..........................................................................................18 
4.2. 
Modified Intent-to-Treat Population ...........................................................................18 
4.3. 
Per Protocol Population ..............................................................................................18 
4.4. 
Safety Population ........................................................................................................18 
4.5. 
PK Population .............................................................................................................18 
5. 
GENERAL CONSIDERATIONS ..............................................................................19 
5.1. 
Baseline Definitions ....................................................................................................19 
5.2. 
Analysis Windows ......................................................................................................19 
6. 
SUPPORTING STUDY INFORMATION ................................................................20 
6.1. 
Subject Disposition .....................................................................................................20 
6.2. 
Demographics and Baseline Disease Characteristics .................................................22 
6.3. 
Baseline Cirrhosis/NASH Disease Characteristics .....................................................23 
6.4. 
Medical History ..........................................................................................................23 
6.5. 
Pretreatment, Prior and New Concomitant Medication ..............................................24 


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6.6. 
Medical and Surgical Procedures ...............................................................................25 
6.7. 
Protocol Deviations ....................................................................................................25 
7. 
EFFICACY ANALYSES ASSESSED AT THE END OF THE DB PHASE ...........25 
7.1. 
Primary Efficacy Endpoint .........................................................................................25 
7.1.1. 
Estimand .....................................................................................................................25 
7.1.2. 
Hypotheses Testing .....................................................................................................26 
7.1.3. 
Analyses of Primary Endpoint ....................................................................................27 
7.1.4. 
Handling Missing Data and Early Discontinuation ....................................................27 
7.1.4.1. 
Non-responder Imputation ..........................................................................................27 
7.1.4.2. 
Multiple Imputation (MI) ...........................................................................................27 
7.1.4.3. 
Tipping Point Analysis ...............................................................................................28 
7.2. 
Secondary Efficacy Endpoints ....................................................................................28 
7.2.1. 
Change from Baseline to Month 18 in Liver Stiffness as Measured by 
Fibroscan® TE Device ................................................................................................28 
7.2.2. 
Change from Baseline to Month 18 in FIB-4 .............................................................29 
7.2.3. 
Change from Baseline to Month 18 in ELF (Enhanced Liver Fibrosis) .....................29 
7.3. 
Other Secondary Efficacy Endpoints ..........................................................................29 
7.3.1. 
Percentage of Subjects with Resolution of NASH .....................................................29 
7.3.2. 
Percentage of Subjects with Improvement of Fibrosis by at Least 2 Stages ..............30 
7.3.3. 
Clinical Outcome Composite Endpoint ......................................................................30 
7.5. 
Interim Analyses .........................................................................................................33 
7.6. 
Statistical Analysis Methods/Issues ............................................................................33 
7.6.1. 
General Statistical Methods ........................................................................................33 
7.6.2. 
Supportive Analyses ...................................................................................................34 
7.6.2.1. 
Analyses on mITT and PP Population ........................................................................34 
7.6.2.2. 
Alternative Definition of No Worsening of NASH ....................................................34 
7.6.3. 
Multiple Imputation Analysis .....................................................................................34 
7.6.4. 
Sensitivity Analyses ....................................................................................................35 
7.6.4.1. 
Subjects who do not have on-treatment post baseline biopsies ..................................35 
7.6.4.2. 
Subjects who have post-baseline biopsies at Month 12 or Month 18 .........................35 


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7.6.4.3. 
Biopsy read at baseline ...............................................................................................35 
7.6.4.4. 
Multivariate analysis ...................................................................................................35 
7.6.5. 
Multiple Comparisons/Multiplicity ............................................................................36 
7.6.6. 
Efficacy Subgroups .....................................................................................................37 
7.6.7. 
COVID-19 ..................................................................................................................38 
8. 
EFFICACY ANALYSES IN OLE .............................................................................38 
9. 
SAFETY ANALYSES IN DB AND OLE .................................................................38 
9.1. 
Extent of Exposure .....................................................................................................40 
9.2. 
Adverse Events ...........................................................................................................40 
9.3. 
Adverse Events of Special Interest .............................................................................42 
9.3.1. 
Pruritus ........................................................................................................................43 
9.3.2. 
Hepatic Adverse Events ..............................................................................................44 
9.3.3. 
Cardiovascular Adverse Events ..................................................................................44 
9.3.4. 
Dyslipidemia ...............................................................................................................44 
9.3.5. 
Gallbladder Disease and Related Complications ........................................................44 
9.3.6. 
Pancreatitis ..................................................................................................................44 
9.3.7. 
Renal Injury ................................................................................................................45 
9.3.8. 
Urolithiases .................................................................................................................45 
9.3.9. 
Hyperglycemia/New Onset Diabetes Mellitus ...........................................................45 
9.4. 
Cardiovascular Risk ....................................................................................................45 
9.4.1. 
Adjudicated Cardiovascular Events ............................................................................45 
9.4.2. 
Markers of Cardiovascular Safety ..............................................................................45 
9.4.3. 
Serum Chemistry Lipids .............................................................................................45 
9.5. 
Adjudicated Acute Kidney Injury (AKI) Events ........................................................45 
9.6. 
Adjudicated Hepatic Injury (DILI) Events .................................................................46 
9.7. 
Clinical Laboratory Evaluations .................................................................................46 
9.7.1. 
Serum Chemistry, Hematology, and Coagulation ......................................................46 
9.7.2. 
Hepatic Biochemical Analysis ....................................................................................46 
9.7.3. 
Lipoprotein Evaluations ..............................................................................................47 
9.7.4. 
Urine Chemistry and Urinalysis .................................................................................47 
9.7.5. 
Renal Function Evaluations ........................................................................................48 
9.8. 
Pregnancies .................................................................................................................48 


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9.9. 
Vital Signs ..................................................................................................................48 
9.10. 
Electrocardiograms .....................................................................................................48 
9.11. 
Safety Subgroups ........................................................................................................48 
10. 
PK/PD ANALYSES IN DB PHASE ..........................................................................49 
11. 
CHANGE FROM PROTOCOL PLANNED ANALYSIS .........................................49 
APPENDIX A. CHILD-PUGH SCORING SYSTEM ...............................................................50 
APPENDIX B. SAMPLE SAS CODE FOR MULTIPLE IMPUTATION ................................51 
APPENDIX C. 
LIST OF LAB TESTS USE MEAN OF PRE-DOSE VALUES AS 
BASELINE ........................................................................................................53 
 
LIST OF TABLES 
Table 1: 
Analysis Window ........................................................................................................20 
Table 2: 
Primary Efficacy Estimand .........................................................................................26 
Table 3: 
Clinical Outcome Component Endpoints ...................................................................31 
 
 
LIST OF FIGURES 
 
Figure 1: 
Study Design Schematic .............................................................................................16 
Figure 2: 
Multiple Comparisons Chart .......................................................................................36 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
AIM-NASH 
AI-based histologic Measurement of NASH  
ANCOVA 
analysis of covariance 
ApoA-1 
apolipoprotein A-1 
ApoB 
apolipoprotein B 
ApoE 
apolipoprotein E 
AUDIT 
Alcohol Use Disorders Identification Test 
BAS 
bile acid sequestrants 
BMI 
body mass index 
C4 
7α-hydroxy-4-cholesten-3-one 
CAC 
Cardiovascular Adjudication Committee 
CI 
confidence interval 
CLDQ 
Chronic Liver Disease Questionnaire 
CMH 
Cochran-Mantel-Haenszel 
CRN 
Clinical Research Network 
CS 
clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
CP 
Child-Pugh 
DB 
Double blind 
DILI 
drug-induced liver injury 
ECG 
electrocardiogram 
EGD 
esophagogastroduodenoscopy 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELF 
Enhanced Liver Fibrosis 
EOS 
end of study 
EOT 
end of treatment 


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Abbreviation or Specialist Term 
Explanation 
ET 
early termination 
FDA 
Food and Drug Administration 
FIB-4 
Fibrosis-4 
FLINT 
Farnesoid X receptor Ligand OCA in Nonalcoholic Steatohepatitis Treatment 
glyco-OCA 
glycine conjugate of obeticholic acid 
HbA1c 
hemoglobin A1c  
HCC 
hepatocellular carcinoma 
HDL 
high-density lipoprotein 
HE 
hepatic encephalopathy 
INR 
international normalized ratio  
ITT 
Intent-to-Treat 
IWRS 
interactive web response system 
KM 
Kaplan-Meier 
LDL 
low-density lipoprotein 
LS 
least-squares 
MACE 
major adverse cardiovascular events 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model for end-stage liver disease 
mITT 
modified intent-to-treat 
MNAR 
missing not at random 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
nonalcoholic fatty liver disease activity score 
NASH 
nonalcoholic steatohepatitis 
NCS 
not clinically significant 


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Abbreviation or Specialist Term 
Explanation 
OCA 
obeticholic acid 
OLE 
open-label extension 
PBC 
primary biliary cholangitis 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTcF 
QT interval corrected by the Fridericia’s formula 
RTSM 
Randomization and trial supply management 
SAP 
statistical analysis plan 
SCORE 
systemic coronary risk evaluation 
SMQ 
Standardized MedDRA Query 
TE 
transient elastography 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
VLDL 
very low-density lipoprotein 
VAS 
visual analog scale 


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1. 
SCOPE 
This statistical analysis plan (SAP) provides a detailed description of the strategy, rationale, and 
statistical techniques to be used to meet the objectives of Study 747-304, which includes a 
double-blind (DB) phase and an open-label extension (OLE) phase.  The SAP provides 
additional details on the statistical analyses that were described in the protocol.  The SAP will be 
finalized and signed off prior to database lock and study unblinding for the analysis of the DB 
phase.  Any deviations from the methods specified in this SAP will be documented in the clinical 
study report (CSR).  If additional analyses are required to supplement the planned analyses 
described in this SAP, they will be identified as post-hoc.  
The following is a summary of key changes from Version 1 to Version 2: 
• Reorganization and ranking of secondary and exploratory objectives. Notable changes are 
the inclusion of non-invasive liver fibrosis endpoints (previously considered exploratory) 
as secondary endpoints. 
• 
Ishak scoring 
system and 
   
• Modified section on estimand for primary efficacy (Section 7.1.1) by clarifying definition 
of the intercurrent event and confirming the treatment policy strategy will be applied.  
• Included section for handling of missing data, added details for multiple imputation 
(i.e. covariates to be included in the model and sample code with seed), and as 
recommended by FDA added tipping point analysis as a sensitivity analysis to assess the 
impact of missing data on the primary efficacy endpoint. 
• The sensitivity analysis for subjects missing biopsies due to COVID-19 (Section 7.6.7 in 
Version 1.0) was removed. We take the FDA’s recommendation of assuming missingness 
at random. The multiple imputation methodology will cover these scenarios.  
Additional changes and clarifications from Version 2 to Version 3 include: 
• Secondary clinical outcomes composite endpoint has been expanded to include 
gastroesophageal varices confirmed by endoscopy (not adjudicated). This has been added 
to the End of the DB and OLE phases. The presence or absence of varices and the date of 
occurrence is captured in the eCRF as objective evidence and therefore adjudication is 
not necessary.  
• Day 1 was removed from MMRM change from baseline, since Day 1 is baseline 
• Added clarifying note for the derivation of Resolution of NASH objective for End of DB 
phase 
• Analysis for subjects with improvement in fibrosis by 3 stages will no longer be analyzed 
by histology and AIM-NASH.   


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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objectives Assessed at the End of the DB Phase 
The primary objective is to evaluate the effects of OCA treatment compared with placebo on: 
• Histological improvement in fibrosis by assessing the percentage of subjects with 
improvement in fibrosis by at least 1 stage with no worsening of nonalcoholic 
steatohepatitis (NASH) defined as no increase in hepatocellular ballooning or lobular 
inflammation, using the NASH Clinical Research Network (CRN) scoring system, 
from Baseline to the end of the Double-Blind Phase 
2.2. 
Secondary Objectives Assessed at the End of the DB Phase  
The secondary objectives are to evaluate the effects of OCA treatment compared with placebo on: 
• Noninvasive assessments of liver disease assessed by serum markers and imaging 
tests. These include the following:  
o Assessment of liver stiffness by transient elastography (FibroScan)  
o Calculated laboratory-based score of fibrosis-4 (FIB-4) 
o Blood-based marker of liver fibrosis (enhanced liver fibrosis [ELF]) 
• Resolution of NASH defined as overall histopathological interpretation of 1) “no fatty 
liver disease” or 2) “fatty liver disease (simple or isolated steatosis) without 
steatohepatitis” AND a nonalcoholic fatty liver disease (NAFLD) activity score 
(NAS) of 0 for ballooning and 0-1 for inflammation, using the NASH CRN scoring 
system, from Baseline to the end of the Double-Blind Phase 
Note: This analysis will be derived based on NAFLD activity score (NAS) of 0 for 
ballooning and 0-1 for inflammation, using the NASH CRN scoring system, from 
Baseline to the end of the Double-Blind Phase. 
• Histological improvement in fibrosis by 2 stages regardless of changes in NAS using 
the NASH CRN scoring system, from baseline to the end of the Double-Blind Phase  
• Occurrence of all-cause mortality and liver-related clinical outcomes for the 
following events (clinical outcomes composite endpoint):  
Adjudicated 
− Death (all cause) 
− Liver transplant 
− Model for End-Stage Liver Disease (MELD) score ≥15 
− Worsening of Child-Pugh (CP) score (by at least 2 points) 
− Hospitalization (as defined by a stay of ≥24 hours) for: 
o Variceal bleed 
o Hepatic encephalopathy (as defined by a West Haven score of ≥2) 


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o Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
− Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or 
paracentesis) 
− Hepatocellular carcinoma (HCC) as confirmed by 2 complementary imaging 
modalities unless already confirmed by biopsy 
Not Adjudicated 
− New onset of gastroesophageal varices as confirmed by endoscopy. The 
occurrence of this event will be used as collected in 
Esophagogastroduodenoscopy eCRF page. 


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2.5. 
Safety Objectives Assessed at the End of the DB Phase  
• To evaluate the safety and tolerability of OCA treatment compared to placebo  
− The effect of OCA treatment compared to placebo on the following AEs of 
special interest (including cardiovascular adverse events, pruritus, renal injury, 
urolithiasis, gallbladder disease and related complications, pancreatitis, hepatic 
adverse events, dyslipidemia, and hyperglycemia/ new-onset diabetes mellitus) 


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• The effect of OCA treatment compared to placebo on the following additional 
measures and markers: 
− Markers of cardiovascular safety 
− Incidence of adjudicated CV events include core MACE (cardiovascular death, 
non-fatal MI, non-fatal stroke) and expanded MACE (all causes of death, heart 
failure (hospitalization and urgent visit), unstable angina (requiring 
hospitalization), revascularization procedures (coronary or peripheral vascular 
intervention), transient ischemic attack, arrhythmias, other events related to 
adverse cardiovascular events). 
− Incidence of adjudicated acute kidney injury events (AKI) 
− Incidence of adjudicated hepatic safety (drug-induced liver injury, DILI) events 
2.6. 
Primary Objective Assessed at the End of the OLE Phase  
• To evaluate and summarize the longer-term safety and tolerability of OCA treatment  
• To evaluate the effect of OCA on the following noninvasive assessments of liver 
disease assessed by serum markers and imaging tests:  
− Liver stiffness by transient elastography (FibroScan)  
− Calculated laboratory-based scores of fibrosis-4 (FIB-4) 
− Blood-based markers of liver fibrosis (enhanced liver fibrosis [ELF]) 
• Noninvasive assessments of liver disease assessed by serum markers and imaging tests 
• To summarize the effects of OCA treatment on the occurrence of all-cause mortality 
and liver-related clinical outcomes for the following events (clinical outcomes 
composite endpoint):  
Adjudicated 
− Death (all cause)  
− Liver transplant  
− MELD score ≥15  
− Worsening of CP score (by at least 2 points)  
− Hospitalization (as defined by a stay of ≥24 hours) for:  
o Variceal bleed  
o Hepatic encephalopathy (as defined by a West Haven score of ≥2)  
o Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)  
− Ascites secondary to cirrhosis and requiring medical intervention (e.g., diuretics 
or paracentesis)  
− HCC as confirmed by 2 complementary imaging modalities or biopsy 


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Not Adjudicated 
− New onset of gastroesophageal varices as confirmed by endoscopy.  The 
occurrence of this event will be used as collected in 
Esophagogastroduodenoscopy eCRF page. 
 
  
  
 
 
 
  
 
  
• Disease progression as assessed by MELD score 
3. 
SUMMARY OF STUDY DESIGN 
3.1. 
Overall Study Design 
This Phase 3, DB, randomized, placebo-controlled, multicenter international study will evaluate 
the efficacy and safety of OCA in subjects with a biopsy-confirmed diagnosis of cirrhosis (based 
on a fibrosis score of 4 using the NASH CRN scoring system) due to NASH (determined by 
central reading of liver histology at the time of enrollment in the study).  Subjects with hepatic 
decompensation or CP Class B or Class C cirrhosis are excluded.  Subjects who progress to CP 
Class B or Class C during the study will discontinue investigational product but are expected to 
be followed through to study closure (or at the discretion of the Sponsor). 
During the study, several protocol amendments and revisions were made.  The following are the 
major changes: 
• Protocol Version 3 (05 Dec 2017) added the OCA10 mg arm without titration in 
response to FDA concern about safety of OCA in the PBC program and exposure to 
25 mg daily in subjects with cirrhosis. The sample size was increased from 360 to 540. 
• Protocol Version 5 (19 Jul 2019) extended the DB phase from 12 months to 
18 months, increased the sample size from 540 to 900.
 Uptitration criteria were modified. 
• Protocol Version 7 (16 Aug 2020) allowed a 3-month maximum extension of IP if the 
liver biopsy could not be obtained at M18 due to COVID restrictions.  Once obtained, 
the liver biopsy would still be recorded in the M18 CRFs. 
DB Phase (18 Months):   
Subjects will be screened for a period of up to 12 weeks before entering the study.  Subjects who 
meet the entry requirements will be randomized in a 1:1:1 ratio to one of the three treatment 
arms:  once daily dosing of OCA 10 mg, OCA 10 mg→ 25 mg (ie, OCA 10 mg with uptitration 
to OCA 25 mg at Month 3), or placebo, in conjunction with local standard of care.  Uptitration 
will be determined based on the laboratory criteria and safety and tolerability assessments 
completed prior to Month 3.  If uptitration at Month 3 is not feasible, the window for uptitration 


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may be extended by up to one calendar month, after consultation and agreement with the 
Medical Monitor.  The uptitration review process is detailed in the study-specific Medical 
Management Plan. 
Randomized subjects will be stratified by the presence of type 2 diabetes at enrollment (yes or 
no).  Investigational product (ie, OCA or placebo) will be taken orally, with water, once daily.  
Efficacy, safety, and laboratory assessments will be evaluated at clinical visits on Day 1, 
monthly for the initial 6 months (Month 1 through Month 6 Visits), Month 9, Month 12, 
Month 15, and Month 18. 
OLE (up to 12 Months): 
Subjects who complete the DB Month 12 (prior to version 5) or Month 18 Visit (and continue to 
receive investigational product) are eligible to enroll into the OLE.  Subjects with endoscopic 
evidence of varices at the end of treatment visit for the double-blind period are not eligible to 
participate in the OLE Phase.  All subjects will receive OCA upon entry into the OLE.  Subjects 
randomized to placebo in the DB phase will be re-randomized to either OCA 10 mg or OCA 
10 mg→ 25 mg titration (ie, OCA 10 mg for the first 3 months of the OLE prior to uptitrating to 
OCA 25 mg at OLE Month 3). Uptitration will be determined based on the same criteria and 
assessments as employed in the DB phase. Subjects randomized to OCA (10 mg or OCA 
10 mg→ 25 mg titration dose) during the DB phase will continue the same dosing regimen they 
received at the end of the DB-Phase; however, they will undergo dummy titration to maintain 
study blind until all subjects complete the DB phase and the database is locked. 
Details of study procedures and assessments are described in the protocol.  
 
 


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3.2. 
Study Design Diagram 
Figure 1: 
Study Design Schematic 
 
CRN = clinical research network; NASH = nonalcoholic steatohepatitis; OCA = obeticholic acid; OLE = open-label 
extension; QD = once daily. 
a Subjects who meet the entry requirements will be randomized in a 1:1:1 ratio to one of the three treatment arms:  
once daily dosing of OCA 10 mg, OCA 10 mg → 25 mg (i.e., OCA 10 mg with uptitration to OCA 25 mg at 
Month 3), or placebo, in conjunction with the standard of care 
b All subjects will receive OCA upon entry into the OLE:  Subjects who received placebo during the Double-Blind 
Phase will be re randomized 1:1 to either OCA 10 mg or OCA 10 mg → 25 mg (i.e., OCA 10 mg with uptitration 
to OCA 25 mg at OLE Month 3).  Subjects who received OCA during the Double-Blind Phase will continue the 
same dosing regimen they received at the end of the Double-Blind Phase. 
c During the OLE period, subjects will return for site visits at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
Note: 
• 
Subjects with cirrhosis (based on a NASH CRN fibrosis score 4) due to NASH (determined by central 
reading of liver histology) will be enrolled in the study.  Subjects with hepatic decompensation or CP Class 
B or CP Class C cirrhosis are excluded.   
• 
Two screening visit assessments will be performed.  Screening Visit 1 will occur no more than 12 weeks 
prior to Day 1, and Screening Visit 2 will occur at least 4 weeks after Screening Visit 1.   
• 
Randomized subjects will be stratified by the presence of type 2 diabetes at enrollment (yes or no). 
• 
The study will remain blinded until all subjects complete the Double-Blind Phase, and the database is 
locked.  To maintain blinding, all investigational product (placebo and OCA) tablets and bottles will be 
identical. 
3.3. 
Randomization Methodology 
This study will be conducted in a double-blind, placebo-controlled manner in DB phase.  
Enrolled subjects will be randomized in a 1:1:1 ratio to one of the three treatment arms:  once 
daily dosing of OCA 10 mg, OCA 10 mg → 25 mg (ie, OCA 10 mg with uptitration to OCA 
25 mg at Month 3), or placebo. Randomization will be done using an RTSM and will be based 
on a predefined randomization code generated by the Sponsor or designee. Subjects randomized 
to OCA 10 mg → 25 mg will initiate dosing at OCA 10 mg for 3 months prior to up titrating to 
OCA 25 mg. Uptitration will be determined based on the laboratory criteria and safety and 
tolerability assessments completed prior to Month 3. 
Randomization of subjects will be stratified by the presence of type 2 diabetes at enrollment (yes 
or no).   
1:1:1 
Randomizatiorf 
NASHwilh 
Cirrhosis (NASH 
CRN Fibrosis 
seore 4) 
'----' .. 
Screening Day 1 
(S12weeks) • 
Biopsy 
Double~bl11ld 
Placebo QD 
3 Months 
6 Months 
9 MonlllS 
Standard of Care 
OLE 
(up to 1 year) 
OCAo.c 
12Monl.hs 
15Months 
18Monlhs 
30 Months 
• 
Biopsy 
• 
Optional 
Biopsy 


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All subjects who enroll into the OLE will receive OCA.  Subjects randomized to placebo in the 
DB phase will be re-randomized to OCA 10 mg or OCA 10 mg → 25 mg arms, with uptitration 
at OLE Month 3 in the OCA 10 mg → 25 mg arm. 
The RTSM will also serve as the investigational product inventory and management system.  
The Investigator or designee will be required to register the subject in the RTSM and may be 
prompted to provide patient data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned and investigational product (OCA or 
placebo) dispensing information will be provided (eg, bottle numbers allocated) while 
maintaining the study blind.   
3.4. 
Sample Size Determination 
During the study, the following protocol amendments and revisions were made that affected 
sample size.  The sample size was increased from 360 to 900 as follows: 
• Protocol Version 3 (05 Dec 2017) added OCA10 mg arm without titration.  Sample size 
was increased from 360 to 540. 
• Protocol Version 5 (19 Jul 2019) extended DB phase from 12 months to 18 months, 
increased the sample size from 540 to 900. 
A sample size of 300 subjects per group provides at least 90% power to detect a statistically 
significant treatment difference of 10% between OCA 10 mg → 25 mg titration treatment and 
placebo groups based on a Chi-square test with 2-sided type I error at 0.05 level, assuming a 
responder rate of 10% in the placebo group.  As there was no previous study performed using the 
same endpoint in this disease, the assumption was determined based on data from literature, and 
results from the FLINT study and Month 18 Interim Analysis from Study 747-303. 
3.5. 
Biopsy Reads 
Eligibility Read for Screening Visits:  During Screening Visits 1 or 2, biopsy data may be 
collected either from historical unstained slides or from a new procedure if suitable historical 
slides are unavailable.  These are assessed for adequacy and if the subject meets other study 
eligibility criteria, the slides are sent to a central reader to determine whether the subject meets 
the inclusion/exclusion criteria with respect to liver histopathology.  The screening biopsy was 
evaluated for fibrosis stage with presence of NASH or not but does not include NAS scores.  The 
SAP refers to the biopsy read for study eligibility as the “Eligibility Read.”  
Consensus Read for Screening Visits:  All slides from screening visits will be re-read by a panel 
of expert pathologists using a consensus read methodology.  Based on communications with the 
FDA, an updated independent consensus approach for evaluating biopsies was developed using a 
panel composed of 3 pathologists with experience in NASH histopathology.  Slides from all 
subjects collected during the study will be read using whole slide images (WSIs) employing the 
independent consensus read approach.  The details of the consensus reading process can be 
found in the Central Histology Manual. 
Both fibrosis stage and NAS scores will be available from the Consensus Read. The SAP refers 
to this biopsy data as the “Consensus Read” for Screening Visits.   


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Post-Baseline Read for M12/M18/EOT/EOS Visits:  A biopsy is required for all subjects at 
Month 12 or Month 18, or for subjects who discontinue treatment or terminate the study earlier 
during the DB phase.  At Month 18/Month 12 or early termination, biopsy slides will be read in a 
blinded fashion. The SAP refers to this as the “Post-Baseline Read”. 
Ishak Criteria: in addition to primary endpoint analysis using the NASH CRN scoring system, 
biopsy samples will also be scored based on modified Ishak criteria (Ishak 1995) for fibrosis.  
The Ishak system scores fibrosis using seven categories (0–6), with a score of 5 representing 
incomplete cirrhosis and 6 representing established cirrhosis. 
4. 
ANALYSIS POPULATIONS AND APPROACHES TO ANALYSIS 
4.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population will include all randomized subjects and will represent the 
primary efficacy analyses population.  Treatment assignment will be based on the randomized 
treatment.   
4.2. 
Modified Intent-to-Treat Population 
The Modified ITT Population (mITT) will include all ITT subjects except those who are not 
eligible to dose titrate due to safety or tolerability reasons.  Treatment assignment will be based 
on the randomized treatment.  
4.3. 
Per Protocol Population 
The Per Protocol (PP) Population will include all mITT subjects who do not have any major 
protocol violations that potentially affect the efficacy conclusions.  Treatment assignment will be 
based on the randomized treatment.  
4.4. 
Safety Population 
The Safety Population will include all randomized subjects who receive at least 1 dose of 
investigational product (OCA or placebo).  The Safety Population will be the primary population 
used for safety analyses.  Treatment assignment will be based on the actual treatment received. 
Once subjects are exposed to OCA 25 mg, they will be included in the OCA 25 mg group, even 
if they get down titrated to 10 mg at some later timepoint. 
4.5. 
PK Population 
The PK Population will consist of all subjects who receive OCA, have at least one confirmed 
analyzable sample, and have no major protocol deviations that may potentially affect the PK 
analysis.  The final determination of subjects included in the PK Population and the samples 
included in the analysis will be determined based on a review of data before database lock.  The 
PK population will be the population used for OCA PK and PK/PD (ie, exposure-response) 


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analyses.  For the exposure-response analyses, the placebo group from the ITT population will 
also be included as the reference group representing the absence of drug exposure. 
5. 
GENERAL CONSIDERATIONS 
Individual subject data obtained from electronic case report forms (eCRFs), central laboratories, 
other vendors (eg, eRT), and any derived data will be presented in data listings by subject.  Due 
to COVID-19, some of laboratory assessments are from local laboratories.  The local laboratory 
results will not be summarized, these will be listed in the lab listings, used for safety monitoring. 
All summaries will be based on observed values.  All data listings that contain an evaluation date 
will contain a relative study day.  Pre-treatment and on-treatment study days are numbered 
relative to the day of the first dose of investigational product which is designated as Day 1.  The 
preceding day is Day -1, the day before that is Day -2, etc.   
All descriptive statistical analyses will be performed using SAS statistical software Version 9.4 
or higher unless otherwise noted.  Medical history and AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA version 23.0).  Concomitant medications will be 
coded using World Health Organization (WHO) Drug Dictionary (WHODrug Global B3). 
5.1. 
Baseline Definitions 
In general, baseline is defined as the last value collected prior to the first administration of the 
investigational product (IP).  
The following lipid parameters and markers of glucose metabolism will be based on the last 
fasted evaluation prior to the first administration of IP as Baseline: C-peptide, Insulin, 
Cholesterol, Glucose, HDL Cholesterol, LDL Cholesterol, Triglycerides, LDL Cholesterol, and 
Glucose.  
For selected lab tests (Appendix C), Baseline is defined as the mean of all available evaluations 
prior to first administration of IP. 
5.2. 
Analysis Windows 
For DB phase, analysis windows will be applied on selective assessments. For OLE phase, no 
visit windows will be applied. Analysis for OLE phase will be done by scheduled visits. 
Analysis windows will be defined around the target date of the visit as planned in the protocol.  
Day 1 is the first day of receiving investigational product (OCA or placebo).   
Each timepoint window will have the target date as the center and the lower bound is the 
midpoint between the target date of this window and the preceding one.  The upper bound is the 
midpoint between the target date of the current window and the following one.  If more than one 
assessment is collected within a window, then the assessment closest to the target date will be 
selected.  If more than one assessment has the same distance from the target date, then the latest 
assessment will be used, where “latest” will be based on sorting by date, time, record 
number/sequence number.  Table 1 shows the analysis windows of each timepoint.  
For post baseline biopsy assessments, there is no analysis window defined.  The biopsy at the 
end of the DB phase (End of DB Phase) will include subjects who had a biopsy at Month 12, and 
subjects who had a biopsy at Month 18.  


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Table 1: 
Analysis Window 
 
 
Coagulation, 
MELD Score, FIB-
4, 
 
ELF, 
  
Cardiovas-
cular Risk 
Scores and 
ECG 
Anthropometric 
measures, Liver 
Stiffness 
DB Phase 
Target Study Day and Window  
Screening 
 
 
 
 
 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Day 1 
Month 1 
30 (2, 61) 
30 (2, 61) 
 
 
 
Month 3 
91 (62, 137) 
 
91 (62, 137) 
 
 
Month 6 
183 (138, 228) 
183 (138, 228) 
183 (138, 228) 
 
183 (138, 228) 
Month 9 
274 (229, 320) 
 
 
 
 
Month 12 
365 (321, 411) 
365 (321, 411) 
365 (321, 411) 
365 (321, 
411) 
365 (321, 411) 
Month 15 
457 (412, 502) 
 
 
 
 
Month 18 
548 (503, before 
OLE) 
548 (503, 
before OLE) 
548 (503, 
before OLE) 
548 (503, 
before OLE) 
548 (503, before 
OLE) 
End of DB Phase 
Latest post-baseline 
before OLE 
Latest post-
baseline before 
OLE 
 
Latest post-
baseline 
before OLE 
Latest post-
baseline before 
OLE 
6. 
SUPPORTING STUDY INFORMATION 
6.1. 
Subject Disposition 
Subject disposition will be tabulated by treatment group and all treatment group combined and 
will include the number of subjects: 
DB Phase 
• Screened 
• Reason for screen failure 
• Randomized 
• Randomized but not treated 
• Uptitrated (dummy or actual) at Month 3/Month 4 during DB phase 
• Down titrated (dummy or actual) during DB phase 
• Biopsy Collected 
o Performed biopsy at Month 12 but not early termination of investigational 
product 


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o Performed biopsy at Month 18 but not early termination of investigational 
product 
o Early termination of investigational product and performed biopsy at early 
investigational product termination date 
o Early termination of investigational product and performed biopsy at Month 12  
 Off IP prior biopsy >90 days 
o Early termination of investigational product and performed biopsy at Month 18  
 Off investigational product prior biopsy >90 days 
o Early termination of DB phase and performed biopsy at early termination date 
(optional biopsy) 
• Biopsy Not Collected  
o Early terminated investigational product and no biopsy collected 
o Early terminated DB phase and no biopsy collected 
o Completed investigational product and no biopsy collected 
• Primary reasons for investigational product discontinuation 
• Contacted for Follow-up if Discontinued Investigational Product 
• Study Discontinuation prior to end of DB phase 
• Primary Reason for DB phase discontinuation 
OLE 
• Subjects entered OLE phase  
• Uptitrated (dummy or actual) at Month 3/Month 4 of OLE phase  
• Down titrated (dummy or actual) during OLE phase  
• Completed OLE  
o Performed biopsy at the end of OLE 
o No biopsy 
• Investigational product discontinuation prior to end of OLE 
o Performed biopsy at early termination visit 
o Performed biopsy at the end of OLE 
o No biopsy 
• Primary reasons for investigational product discontinuation 
• Contacted for follow-up if discontinued investigational product 
• Study discontinuation prior to end of OLE phase 
• Primary reason for OLE phase discontinuation 


Statistical A nal ysis Pla n  v 3 . 0 
1 5 Se p 2 0 2 2  
Pr ot oc ol 7 4 7 -3 0 4  
Pa ge 2 2  
 
C o nfi de ntial a n d Pr o prietar y  
Dis p ositi o n s u m maries will be prese nte d f or eac h a nal ysis p o p ulati o n a n d will be ta b ulate d b y 
treat me nt gr o u p a n d o verall.   
S u bject e nr oll me nt b y st u d y site will be ta b ulate d b y treat me nt gr o u p a n d o verall. 
A b y- s u bject data listi n g of st u d y c o m pleti o n i nf or mati o n i ncl u di n g t he reas o n f or pre mat ure 
st u d y wit h dra wal, if a p plica ble, will be prese nte d. 
6. 2.  
De m o gr a p hics a n d B aseli ne Dise ase C h ar acteristics  
De m o gra p hic varia bles will i ncl u de t he f oll o wi n g:  
•  A ge at t he ti me of i nf or me d c o nse nt a n d gr o u p ( < 6 5 years, ≥6 5 years, ≥7 5 years)  
•  Ge n der 
•  Race  
•  Et h nicit y  
•  Ge o gra p hic re gi o n: N ort h A merica, E ur o pe, a n d Rest of W orl d ( R O W ) 
Ot her baseli ne c haracteristics will i ncl u de t he f oll o wi n g:  
•  He pat ocell ular ball o o ni n g sc ore 
•  L o b ular I nfla m mati o n  sc ore 
•  Steat osis  sc ore 
•  N o nalc o h olic fatt y li ver disease acti vit y sc ore ( N A S; < 6, ≥6)  
•  Wei g ht ( k g)  
•  Hei g ht (c m)  
•  B o d y mass i n de x ( B MI; k g/ m 2): Cate g orical ( < 3 0 k g/ m 2, ≥3 0 k g/ m2 - 3 5 k g/ m2, 
≥3 5  k g/ m2) 
•  Dia betes stat us at e nr oll me nt  ( Yes/N o)  
•  
•  
•  L o w de nsit y li p o pr otei n ( L D L; m g/ d L) ( ≥1 0 0 m g/ d L, ≥1 9 0 m g/ d L) 
•  Tri gl yceri des ( m g/ d L) ( ≥1 5 0 m g/ d L)  
•  Hi g h de nsit y li p o pr otei n ( H D L; m g/ d L) ( < 4 0 m g/ d L [ me n] or < 5 0 m g/ d L [ w o me n])  
•  Hist or y of c h olec ystect o m y ( Yes/ N o)  
•  Baseli ne Alc o h ol C o ns u m pti o n as assesse d b y Alc o h ol Use Dis or ders I de ntificati o n 
Test ( A U DI T) Q uesti o n naire ( A U DI T Sc ore ≤7, > 7)  
•  Baseli ne S m o ki n g Stat us ( Yes/ N o)  
 
:  FI B - 4,  
, E L F, a n d 
 
P


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• Baseline MELD Score 
• Baseline Child-Pugh Score 
Liver biochemistries, and eGFR results will be summarized as continuous variables and as 
frequencies for categorizations. 
• eGFR (chronic kidney disease epidemiology collaboration [CKD-EPI] calculation) 
and groups (G1/Normal, G2, G3) 
• 
• 
• 
Demographics and Baseline characteristics will be summarized and presented by treatment group 
and overall, for each analysis population.   
For continuous measures, number of subjects, mean, SD, median, Q1, Q3, minimum, and 
maximum will be presented.  For categorical measures, number and percentage of subjects will 
be presented.  No inferential statistical comparisons will be performed.   
All demographic and Baseline characteristic data will be presented in by-subject data listings. 
6.3. 
Baseline Cirrhosis/NASH Disease Characteristics 
Baseline Cirrhosis/NASH disease characteristics will be summarized using data collected from 
the Diagnosis of Cirrhosis/NASH eCRF.  Variables include the following: 
• Age at diagnosis of cirrhosis/NASH 
• Duration of diagnosis of cirrhosis/NASH in years at time of informed consent 
Baseline Cirrhosis/NASH disease characteristics will be summarized and presented by treatment 
group and overall, for each analysis population.  For these continuous measures, the number of 
subjects, mean, SD, median, Q1, Q3, minimum, and maximum will be presented.  No inferential 
statistical comparisons will be performed. 
Baseline Cirrhosis/NASH disease characteristics will be presented in by-subject data listings. 
6.4. 
Medical History 
Verbatim terms will be mapped to Preferred Term (PT) and System Organ Class (SOC) using 
Medical Dictionary for Regulatory Activities (MedDRA) version 23.0. 
Medical history will be summarized by SOC, PT, and treatment group using the Safety 
Population.  Summaries will be ordered by descending order of incidence of SOC and PT within 
each system organ class.   
Lastly, separate summaries will be provided by SOC and PT for the number and percentage of 
subjects with medical history in the following categories: 
• Cardiovascular 
• Pruritus 


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• Hepatic adverse events 
• Dyslipidemia 
• Gallbladder disease and related complications 
• Pancreatitis 
• Renal injury 
• Urolithiases 
• Hyperglycemia/New Onset Diabetes mellitus 
Medical history, including statin use history, will be presented in a by-subject data listing. 
6.5. 
Pretreatment, Prior and New Concomitant Medication 
Verbatim terms on eCRFs will be mapped to Anatomical Therapeutic Chemical (ATC) class and 
Preferred Name using the WHO Drug Dictionary version WHODrug-Global-B3. 
Pretreatment concomitant medications are those medications with start and stop prior to the 
initial dose of investigational product.  
Prior concomitant medications are those medication started prior to and continued after the initial 
dose of investigational product. The following prior concomitant medication will be presented in 
a separate table: 
− Anticoagulants/antiplatelets 
− Antidiabetic medications 
− GLP-1 Agonists (indication for T2DM or weight loss), includes semaglutide, 
liraglutide, dulaglutide, bydurean, lixisenatide, exenatide 
− Bile acid sequestrants (BAS), also known as BABA-Bile acid binding agents 
− Lipid lowering medications 
− Statins only 
− Methotrexate  
− Vitamin E 
New concomitant medications are those medications that were started after the initial dose of 
investigational product. 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 initial dose of investigational product, then it will be counted as a new 
concomitant medication. 
Pretreatment, prior, and new concomitant medications will be summarized separately for each 
treatment group by WHO ATC level 2, WHO ATC level 4, and preferred name using the Safety 
Population. These summaries will present the number and percentage of subjects using each 
medication. Subjects may have more than one medication per ATC level and preferred name. At 
each level of subject summarization, a subject is counted once if he/she reported one or more 


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medications at that level. Each summary will be ordered by descending order of incidence of 
ATC level and preferred name within each ATC level. A listing will also be provided.  
6.6. 
Medical and Surgical Procedures 
Medical and surgical procedures will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 23.0. Frequency summaries will be provided by SOC, and PT. 
Prior procedures are defined as those started before the first dose of IP (whether or not ended 
before the first dose of IP). A concomitant procedure is defined as non-study procedure started 
during the phase, or non-study procedure started before the phase and ended or remained 
ongoing during the phase.  
6.7. 
Protocol Deviations 
Eligibility deviations specified in the protocol and any other deviation identified during the 
course of the study that impact analysis of the primary endpoint will be considered a major 
deviation and subjects meeting any of these deviations will not be included in the PP Population. 
Major deviations that exclude a subject from inclusion in the PP population will be determined 
prior to unblinding.  
Specifically, Inclusion Criteria #2 will be based on Eligibility Read for Screening Visits. 
Subjects will NOT be considered as a protocol deviation if Consensus Read for the Screening 
Visit is not a fibrosis score of 4. All major protocol deviations will be summarized and listed by 
treatment group. 
7. 
EFFICACY ANALYSES ASSESSED AT THE END OF THE DB 
PHASE 
7.1. 
Primary Efficacy Endpoint  
7.1.1. 
Estimand 
The following table identifies the elements of the intercurrent events and strategies to address for 
the primary efficacy endpoint. 


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Table 2: 
Primary Efficacy Estimand 
Estimand 
Target study 
population 
Adult subjects with compensated cirrhosis due to nonalcoholic steatohepatitis  
Primary analysis 
population 
Intent to treat (ITT) 
Endpoint (variable) 
Improvement in fibrosis by at least 1 stage with no worsening of NASH (No 
worsening of NASH is defined as no increase in hepatocellular ballooning or 
lobular inflammation using NASH CRN scoring system) from Baseline to the 
end of the DB phase. Biopsy scores are based on the “Consensus Read” at both 
baseline and post-baseline. 
Summary measure 
Percentage of subjects with fibrosis improvement by at least 1 stage and no 
worsening of NASH from Baseline to the end of the DB phase, including all 
biopsies collected after treatment discontinuation. 
Analysis  
Comparison between placebo vs OCA 10 mg → 25 mg, then placebo vs OCA 
10 mg will be performed using a CMH test stratified by the randomization 
strata (type 2 diabetes at enrollment [yes/no]). 
Intercurrent events/ 
Strategies to address 
Discontinuous treatment due to 
AE/Death 
Treatment policy: For subjects with 
early discontinuation due to AE or 
death, the last available post-
baseline biopsy will be used. 
Shorter treatment exposure: (1) subjects 
who discontinue IP prior to termination 
of the study and continue to follow the 
regular visit schedule through to study 
closure (2) subjects who restart IP after 
a prolonged interruption (ie, longer than 
1 month [+2 weeks])  
Treatment policy:  Treatment effect 
regardless of intercurrent event.   
 
7.1.2. 
Hypotheses Testing 
The primary efficacy hypothesis of OCA 10 mg → 25 mg titration based on fibrosis 
improvement without worsening of NASH: 
• Null: The percentage of subjects with fibrosis improvement by at least 1 stage and no 
worsening of NASH, the latter defined as no increase in hepatocellular ballooning or 
lobular inflammation using NASH CRN scoring system, from Baseline to the end of 
the DB phase, is equal between placebo and OCA 10 mg → 25 mg titration. 
• Alternative: The percentage of subjects with fibrosis improvement by at least 1 stage 
and no worsening of NASH, the latter defined as no increase in hepatocellular 
ballooning or lobular inflammation using NASH CRN scoring system, from Baseline 
to the end of the DB phase, is different between placebo and OCA 10 mg → 25 mg 
titration.  


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Note: OCA 10 mg → 25 mg titration includes all subjects randomized to the OCA 10 mg → 
25 mg arm regardless of whether they were up-titrated or not.   
The primary efficacy hypothesis of OCA 10 mg without titration based on fibrosis improvement 
without worsening of NASH: 
• Null: The percentage of subjects with fibrosis improvement by at least 1 stage and no 
worsening of NASH, the latter defined as no increase in hepatocellular ballooning or 
lobular inflammation using NASH CRN scoring system, from Baseline to the end of 
the DB phase, is equal between placebo and OCA 10 mg. 
• Alternative: The percentage of subjects with fibrosis improvement by at least 1 stage 
and no worsening of NASH, the latter defined as no increase in hepatocellular 
ballooning or lobular inflammation using NASH CRN scoring system, from Baseline 
to the end of the DB phase, is different between placebo and OCA 10 mg.  
7.1.3. 
Analyses of Primary Endpoint 
A Cochran-Mantel-Haenszel (CMH) test will be performed and stratified by the randomization 
strata (type 2 diabetes at enrollment [yes/no]). The difference in response rate and associated 
95% CI, and p-values will be reported. The response ratio may be additionally presented.  
Type I error for the primary efficacy analysis will be controlled at the 0.05 level, adjusting for 
multiplicity as described in Section 7.6.5.  
7.1.4. 
Handling Missing Data and Early Discontinuation 
7.1.4.1. 
Non-responder Imputation 
For the primary analyses, any subject who discontinued treatment due to an AE or died and who 
does not have an evaluable post-baseline biopsy assessment will be considered a non-responder. 
That is, for the percentage of responders, the subject will be included in the denominator and will 
not contribute to the numerator.  
7.1.4.2. 
Multiple Imputation (MI) 
Multiple imputation (MI) will be performed to handle other missing data in the primary analysis. 
If a subject who does not have post-baseline biopsy assessment and who also discontinued 
treatment early due to an AE or death, the non-responder imputation will be applied first. Then, 
for all other missing data scenarios, multiple imputation (MI) methods will be used assuming it is 
missing at random (MAR). 
1000 imputed data sets will be drawn separately for each randomized group, replacing missing 
outcome values with simulated values using predictive mean matching from a set of imputation 
models containing all potential prognostic baseline covariates as well as efficacy endpoints. The 
weighted average method will be fitted to each of the 1000 imputed data sets and the results will 
be combined using Rubin’s rules (Rubin, 1987).  
Sample SAS codes are provided in Appendix B. 


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7.1.4.3. 
Tipping Point Analysis 
A tipping point analysis will be performed to examine the impact of missing data under missing 
not at random (MNAR) assumption. The tipping point analysis will only be performed for the 
primary efficacy endpoints when the MI analysis result is statistically significant. 
Except for subjects who discontinued due to an AE or died, whose missing data is imputed as 
non-responder, missing data is first replaced using the MI procedure described in the main 
analysis. The imputed post-baseline values in the imputed datasets are then subsequently shifted 
toward a null hypothesis, until the significance of model estimates is overturned. The plausibility 
of the magnitude in the shift parameter required to overturn the significance is then interpreted 
from a clinical perspective. 
The tipping points that alter the statistical conclusion will be provided. 
7.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Change from baseline to Month 18 in liver stiffness measurement (LSM) as measured 
by vibration controlled transient elastography (FibroScan®), absolute (kPa) and 
percent change 
• Change from baseline to Month 18 in FIB-4 (Fibrosis-4) 
• Change from baseline to Month 18 in ELF (Enhanced Liver Fibrosis) 
If the null hypothesis concerning the primary efficacy endpoint is statistically significant, 
statistical tests for the secondary endpoints will be performed using a hierarchical strategy. The 
sequential closed testing gate-keeping procedure is described in Section 7.6.5. Lower level 
endpoints will be tested only if upper level endpoints are statistically significant at the pre-
specified alpha level.  OCA 10 mg vs PBO will be tested only if the corresponding comparison 
for OCA 10-25 mg vs PBO is statistically significant. 
7.2.1. 
Change from Baseline to Month 18 in Liver Stiffness as Measured by Fibroscan® 
TE Device 
Noninvasive radiological methods to assess liver stiffness will be conducted at selected study 
sites where the respective devices are available. These assessments are taken by vibration 
controlled transient elastography (TE) method using FibroScan®. 
The hypotheses for the OCA 10 mg → 25 mg titration group are: 
• Null:  The change from baseline to Month 18 in liver stiffness median is equal 
between the placebo and OCA 10 mg → 25 mg titration arms. 
• Alternative:  the change from baseline to Month 18 in liver stiffness median is 
different between the placebo and OCA 10 mg → 25 mg titration arms. 
The hypotheses for the OCA 10 mg group are: 
• Null:  The change from baseline to Month 18 in liver stiffness median is equal 
between the placebo and OCA 10 mg arms. 
• Alternative:  the change from baseline to Month 18 in liver stiffness median is 
different between the placebo and OCA 10 mg arms. 


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A Mixed model repeated measures (MMRM) analysis will be used to track the trajectory over 
time in the change from baseline to Month 18 in liver stiffness median. The model will include 
terms for randomized treatment group, visits (Month 6, Month 12, and Month 18), stratification 
factor, randomized treatment group by visit interaction and baseline score as covariates. Subject 
will be included as a random effect and an unstructured covariance matrix can be used assuming 
convergence can be attained. The principal comparison is at Month 18. The corresponding least 
square means (lsmeans), the associated standard errors, the difference in lsmeans the associated 
95%CI, and p-values will be presented. 
7.2.2. 
Change from Baseline to Month 18 in FIB-4 
FIB-4 is a noninvasive assessment of liver disease assessed by a combination of age, ALT and 
platelet results. FIB-4 will be analyzed using the similar MMRM model as described in 
Section 7.2.1 at visits Month 1, Month 3, Month 6, Month 12, Month 15, and Month 18. 
7.2.3. 
Change from Baseline to Month 18 in ELF (Enhanced Liver Fibrosis) 
ELF is a noninvasive panel of circulating fibrosis markers calculated from serum biomarkers. 
ELF will be analyzed using the similar MMRM model as described in Section 7.2.1 at visits 
Month 3, Month 6, Month 12, and Month 18. 
7.3. 
Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints by assessments are as follows: 
• Resolution of NASH defined as overall histopathological interpretation of 1) “no fatty 
liver disease” or 2) “fatty liver disease (simple or isolated steatosis) without 
steatohepatitis” AND a nonalcoholic fatty liver disease (NAFLD) activity score 
(NAS) of 0 for ballooning and 0-1 for inflammation, using the NASH CRN scoring 
system, from Baseline to the end of the Double-Blind Phase (see Section 7.3.1 for 
derivation clarification).Histological improvement in fibrosis by 2 stages regardless 
of changes in NAS using the NASH CRN scoring system, from baseline to the end of 
the Double-Blind Phase 
• Clinical outcome composite endpoint regarding occurrence of all-cause mortality and 
liver-related outcomes.  
The analyses for these secondary efficacy endpoints will be supportive and interpreted 
descriptively. No adjustments for multiplicity will be made. Both 95% CIs and nominal 
p-values will be provided.  
7.3.1. 
Percentage of Subjects with Resolution of NASH  
Resolution of NASH is defined as no fatty liver disease or fatty liver disease (simple or isolated 
steatosis) without steatohepatitis AND a NAS of 0 for ballooning and 0-1 for inflammation, 
using the NASH CRN scoring system, from Baseline to the end of the DB phase. 
This endpoint will be derived based on NAFLD activity score (NAS) of 0 for ballooning and 0-1 
for inflammation, using the NASH CRN scoring system, from Baseline to the end of the DB 
Phase. 


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Percentage of subjects with NASH resolution at Month 12/Month 18 will be analyzed in the 
same manner to the primary analysis of the primary endpoint described in Section 7.1.3 and 
Section 7.1.4.1. The CMH test will be performed and non-responder imputation will be used. 
7.3.2. 
Percentage of Subjects with Improvement of Fibrosis by at Least 2 Stages 
The percentage of subjects with improvement in fibrosis by at least 2 stages regardless of 
changes in NAS using the NASH CRN scoring system, from baseline to the end of the DB 
phase, will be analyzed in the same manner to the primary analysis of the primary endpoint 
described in Section 7.1.3 and Section 7.1.4.1. The CMH test will be performed and non-
responder imputation will be used. 
7.3.3. 
Clinical Outcome Composite Endpoint 
Table 3 lists the clinical outcome composite endpoint, as well as the individual components of 
the composite endpoint.  Only adjudicated events will be included in analyses.  The time to first 
occurrence of the clinical outcome composite component and each? individual component 
endpoints will evaluate the effect of OCA (10 mg and 10 mg → 25 mg titration) compared to 
placebo for the ITT Population.  
For the analysis of time to event, a log rank test stratified by the randomization stratification 
factor will be used.  All summaries of incidence will include the associated exact binomial 
95% CI.  The hazard ratio and its 95% CI will be determined based on a Cox regression model 
stratified by randomization strata to estimate the magnitude of effect. Subjects who do not 
experience an event will be censored at the date of last contact.  The detail is provided in 
Section 7.6.1. 
In addition, the treatment groups will be compared by the percentage of subjects who reported 
these adjudicated events. 


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Table 3: 
Clinical Outcome Component Endpoints 
Clinical Outcomes Composite Endpoint  
Occurrence of all-cause mortality and liver-related clinical outcomes for the following events:  
Adjudicated 
− Death (all cause) 
− Liver transplant 
− MELD score ≥15 
− Worsening of CP score (by at least 2 points) 
− Hospitalization (as defined by a stay of ≥24 hours) for: 
o Variceal bleed 
o Hepatic encephalopathy (as defined by a West Haven score of ≥2) 
o Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis) 
− Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or 
paracentesis) 
− HCC (as confirmed by 2 complementary imaging modalities or biopsy 
Not Adjudicated  
− New onset of gastroesophageal varices as confirmed by endoscopy. The occurrence of 
this event will be used as collected in Esophagogastroduodenoscopy eCRF page 
 
7.4. 
Exploratory Efficacy Endpoints 


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7.4.2. 
Exploratory Efficacy Endpoints by Other Assessments 
Table 5 describes the assessments by serum markers, imaging tests, health utilities, and other 
scoring systems. Descriptive summaries will be provided by treatment group and visit. 


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7.5. 
Interim Analyses 
This study has no plan for an interim Analyses. 
7.6. 
Statistical Analysis Methods/Issues 
7.6.1. 
General Statistical Methods 
For categorical variables, summary tabulations of the number and percentage of subjects within 
each category (with a category for missing data) of the parameter will be presented.  Percentage 
calculations will be based on analysis population unless otherwise specified.   
In response analysis [yes/no] of histological endpoints, the comparison between treatment groups 
will be performed using a CMH test stratified by the randomization strata (type 2 diabetes at 
enrollment [yes/no]).   
For continuous variables, the number of subjects, mean, standard deviation (SD), standard error 
of the mean (SEM), median, 25th and 75th quartiles, minimum, and maximum values will be 
presented.   
Longitudinal summaries of continuous variables will present absolute values, change, and 
percentage change from baseline at each post-baseline visit. 
For continuous endpoints satisfying normality assumptions, change from baseline over time will 
be analyzed using MMRM, with treatment, baseline, visit, visit by treatment interaction and 


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stratification factors to be included in the model.  An unstructured covariance model will be 
used.  If the computational algorithm fails to converge, an appropriate covariance structure will 
be selected.  Estimates of least-square (LS) means, standard errors will be presented by treatment 
group.  Unless indicated otherwise 95% CIs will be provided for efficacy endpoints by treatment 
group.  
Time-to-event data will be summarized using Kaplan-Meier (KM) methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% CIs, as well as the percentage of 
censored observations.  KM estimates will be plotted as a “survival curve” for each treatment 
group, with the number at risk identified.  In addition, time-to-event data will be summarized 
with descriptive statistics for those subjects with an event.  Subjects without any documentation 
of events will be censored at the date of last contact if they do not participate in OLE, otherwise, 
they will be censored at the date of last contact or the date of randomization into OLE, whichever 
occurs first. 
7.6.2. 
Supportive Analyses 
7.6.2.1. 
Analyses on mITT and PP Population 
The primary and key secondary endpoint analyses will be conducted in the following populations 
defined in Section 4, in addition to ITT: 
• mITT population 
• Per-protocol population 
7.6.2.2. 
Alternative Definition of No Worsening of NASH 
In the protocol, the definition of “no worsening of NASH” was defined as no increase in 
hepatocellular ballooning or lobular inflammation using the NASH CRN scoring system.  A 
supportive analysis will be conducted based on the modified definition of no worsening of 
NASH as follows: 
• Improvement in fibrosis by at least 1 stage with no worsening of NASH defined as no 
increase in steatosis, hepatocellular ballooning or lobular inflammation using NASH 
CRN scoring system, from Baseline to the end of the DB phase  
7.6.3. 
Multiple Imputation Analysis 
As discussed in Section 7.1, a multiple imputation method will be performed to estimate the 
expected treatment effect on the ITT population for the primary endpoint. To further assess the 
impact on these missing biopsy data, an additional sensitivity analysis will be conducted which 
will impute all missing primary endpoint using the same method, regardless of discontinuation 
reasons. 
MAR assumption states that the missing data mechanism is independent of the missing 
observations conditional on the observed data.  If missing outcome values are deemed to be 
MAR, and to avoid loss of efficiency, missing outcome values will be imputed 
using below multiple imputation steps.  
1000 imputed data sets will be drawn separately for each randomized group, replacing missing 
outcome values with simulated values using predictive mean matching from a set of imputation 
models containing all potential prognostic baseline covariates as well as efficacy endpoints. 


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The weighted average method will be fitted to each of the 1000 imputed data sets and the results 
will be combined using Rubin’s rules (Rubin, 1987). 
Sample SAS codes are provided in Appendix B. 


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7.6.5. 
Multiple Comparisons/Multiplicity 
The multiple testing procedure (MTP) based on gatekeeping procedure to control the family-wise 
type I error rate at 5% will be used in this study.  The primary efficacy endpoint will be tested 
first at an alpha of 5% for the comparison between OCA 10 mg → 25 mg titration arm versus 
Placebo.  If the primary hypothesis between OCA 10 mg → 25 mg titration versus placebo is 
rejected, the comparison between OCA 10 mg versus Placebo will be tested at an alpha of 0.05; 
otherwise, testing of the primary efficacy endpoint at the 10 mg dose will be considered 
descriptive and nominal.  If the primary null hypothesis for both treatment arms are rejected, the 
gate keeping procedure will continue and test the hypotheses on the two secondary endpoints, 
respectively, at the same level, ie, change from baseline in liver stiffness, and change from 
baseline in Fib-4 will be tested at the same level between OCA 10 mg → 25 mg titration versus 
placebo. 
The following chart (Figure 2) describes the step by step: 
Figure 2: 
Multiple Comparisons Chart 
 
CFB = change from baseline, ELF = enhanced liver fibrosis. 
* Alpha level will be either 0.05 or 0.025, depending on the testing results from higher rank. 
 
Multiple testing will follow a hierarchical order: the lower level will be tested only if the upper 
level is statistically significant at a pre-specified alpha level. OCA 10 mg vs PBO will be tested 
only if corresponding comparison for OCA 10-25 mg vs PBO is statistically significant. Nominal 
p-values will be reported for other secondary endpoints.   
Primary Endpoint: Fibrosis 
wo worse NASH 
OCA I0-25 mg vs PBO 
Alpha=0.05 
Primary Endpiont: Fibrosis 
wo worse NASH 
OCA 10 mg vs PBO 
Alpha=0.05 
/ 
\ 
CFB in Liver Stiffness 
OCA 10-25 mg vs PBO 
Alpha=0.025 
CFB in Liver Stiffness 
OCA 10 mg vs PBO 
Alpha=0.025 
\ 
-----------
CFB in Fib4 
OCA 10-25 mg vs PBO 
Alpha=0.025 
CFB in ELF 
CFB in Fib4 
OCA 10 mg vs PBO 
Alpha=0.025 
/ 
OCA 10-25 mg vs PBO 
Alpha=0.05 or 0.025* 
I 
CFB in ELF 
OCA 10 mg vs PBO 
Alpha=0.05 or 0.025* 


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7.6.6. 
Efficacy Subgroups 
Subgroup analyses will be performed only if there are enough subjects in each group 
(eg, >5 subjects per category). 
1. Subgroup analyses for the primary endpoint using ITT and limited to summary statistics 
with no reporting of p-values will be presented for the following factors:  
a. Baseline diabetes status at enrollment:  Yes, No 
b. BMI (<30 kg/m2, ≥30 kg/m2 and <35 kg/m2, ≥35 kg/m2) 
c. Age categories:  <65, ≥65 years, ≥75 years 
d. Gender:  Male, Female 
e. Race:  White, Non-White (Black or African American, Asian, Native Hawaiian or 
Other Pacific Islander, American Indian or Alaska Native) 
f. Geographic Region:  North America, Europe, and the Rest of the World (ROW) 
g. 
h. 
i. 
j. 
k. 
2. The change from baseline in the following parameters will be analyzed by response to the 
primary endpoint and treatment group.  These summaries will be based on subjects with a 
post-baseline biopsy.  
b. Lipids:  LDL, HDL, VLDL and total cholesterol   
  
• FIB-4, 
, ELF, and 
  
 
   
e. PD biomarkers of FXR activation including: C4, FGF-19, plasma bile acids 
3. In the OCA 10 mg → 25 mg titration arm, there are subjects who either do not meet 
criteria for uptitration OR do not undergo uptitration for safety reason based on PI 
discretion.  Two subgroup analyses will be performed: 
a. Comparison of Placebo and OCA 10 mg treatment group by adding those subjects 
who remained on OCA 10 mg but were randomized to the OCA 10 mg → 25 mg 
group.  
b. Comparison of Placebo and OCA 10 mg → 25 mg treatment group by excluding 
those subjects who remained at 10 mg in the OCA 10 mg → 25 mg group. 


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7.6.7. 
COVID-19 
Due to the limitations caused by the COVID-19 pandemic, subjects who have been unable to 
complete the liver biopsy procedure at the Month 18 Visit, investigational product may be 
extended beyond the Month 18 Visit for a maximum of 3 additional months of the DB phase.  
All post-baseline biopsies obtained by the end of DB phase will be included in ITT population.  
Due to the COVID-19, subjects who cannot have lab assessments performed at a central 
laboratory may have lab assessments performed at a local laboratory.  The local lab results may 
be used if central lab assessment is not available.  
To evaluate whether COVID-19 impacts on the study safety assessments, frequencies of selected 
adverse events summaries for the safety population will be split into 2 periods: pre-COVID-19 
(occurring on or before 30 Jan 2020) and post-COVID-19 (occurring after 30 Jan 2020).  The 
data for both periods will be presented side-by-side by treatment group.  A summary of AEs will 
be provided. 
8. 
EFFICACY ANALYSES IN OLE 
A subset of efficacy assessments conducted in the DB phase will be repeated in the OLE Phase. 
Descriptive summaries will be provided by treatment group and scheduled visit. 
Treatment groups will be defined as follows: 
• Placebo / OCA 10 mg 
• Placebo / OCA 10 mg → 25 mg titration  
• OCA 10 mg / 10 mg 
• OCA 10 mg → 25 mg titration / 10 mg → 25 mg titration 
9. 
SAFETY ANALYSES IN DB AND OLE 
DB Phase: 
Safety summaries will be conducted using the safety population by treatment groups, subgroups, 
and total OCA (both OCA 10 mg and OCA 10 mg → 25 mg combined) during the DB phase.  
If a subject is randomized to placebo and subsequently receives OCA, each safety assessment 
will be attributed to the administered OCA dose.  
Treatment groups and subgroups will be defined as follows: 
• Placebo 
• OCA 10 mg 
• OCA 10 mg → 25 mg:  Subjects receiving this treatment will be further categorized 
into the following treatment subgroups: 
− Remained on 10 mg:  These comprise subjects who do not titrate to the OCA 
25 mg dose level, either because of ineligibility per protocol or any other reason.  
Such subjects should have received only OCA 10 mg for the entire duration of 
their participation in the DB phase. 


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− Titrated to 25 mg:  These comprise subjects who receive OCA 25 mg at any time 
after the titration eligibility assessment is made, even if they subsequently down 
titrated for any reason. 
− OCA 10-25 mg Combined 
• Total OCA:  both OCA 10 mg and OCA 10 mg → 25 mg combined 
No inferential comparison of safety endpoints will be performed, unless otherwise specified.   
Selected safety summaries will be prepared including all subjects in the ITT Efficacy Population. 
Analyses based on the DB baseline will be performed using the actual treatment received in the 
DB phase.   
OLE: 
Adverse events and concomitant medications will be summarized cumulatively in OLE. i.e.    
For exposure-adjusted incidence of adverse events, the summary will be based on the duration of 
active treatment. 
For quantitative parameters including, but not limited to, vital signs, ECG, and clinical 
laboratory results, changes from the DB baseline will be presented by OLE nominal visits.  
Change from OLE baseline value may be additionally considered if deemed appropriate. 
Treatment groups and subgroups will be defined as follows: 
• Placebo / OCA 10 mg 
• Placebo / OCA 10 mg → 25 mg titration: Subjects receiving this treatment will be 
further categorized into the following treatment subgroups: 
− Remained on 10 mg:  These comprise subjects who do not titrate to the 25 mg 
dose level, either because of ineligibility per protocol or any other reason.  Such 
subjects should have received only OCA 10 mg for the entire duration of their 
participation in the OLE phase. 
− Titrated to 25 mg:  These comprise subjects who receive 25 mg at any time after 
the titration eligibility assessment is made, even if they subsequently down 
titrated for any reason. 
− OCA 10-25 mg Combined 
• OCA 10 mg  
• OCA 10 mg → 25 mg titration:  Subjects receiving the same treatment as they 
received in DB phase: 
− Remained on 10 mg during DB phase: Subjects should have received only OCA 
10 mg for the entire duration of their participation in the OLE phase. 
− Titrated to 25 mg during DB phase: Subjects should have received only OCA 
25 mg for the entire duration of their participation in the OLE phase. 
− OCA 10-25 mg Combined during DB phase 


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9.1. 
Extent of Exposure 
The exposure analysis will be presented separated for DB and OLE.   
For DB phase, the extent of exposure will be summarized both continuously using descriptive 
statistics and categorically (n and % for ≤1 month, >1 and ≤3 months, >3 and ≤6 months, >6 and 
≤9 months, >9 and ≤12 months, >12 and ≤18 months). 
Extent of exposure (days) to investigational product 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, interruption, and/or missed doses} 
The duration of each incidence of temporary investigational product discontinuation will be 
calculated as follows: 
• Duration of temporary discontinuation, interruption, and/or missed doses of 
investigational product = (Date of restart of investigational product – Date of temporary 
discontinuation, interruption, and/or missed doses of investigational product) + 1. 
The total duration of temporary investigational product discontinuation is the sum duration of 
temporary discontinuation, interruption, and/or missed doses of investigational product over each 
incidence of discontinuation / interruption. 
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. 
A summary of subjects who had an at least one temporary investigational product interruption, 
discontinuation, and/or missed doses during the study will be provided in terms of frequency 
count (n) and percentages (%) and mean duration of the interruptions/missed doses.  This 
summary will be presented by reason of interruption as specified in the eCRF.   
Subject’s overall compliance (%) with investigational product will be calculated as follows: 
• Compliance = duration of Exposure/(duration of Exposure + missed doses) *100  
where drug holidays are not included in this calculation since compliance reflects subjects’ 
adherence to the taking IP as required.  
Subject compliance with investigational product will be summarized by treatment group using 
descriptive statistics.  For discontinued subjects, the expected tablets to be consumed will be 
calculated based on the time of discontinuation.  
All exposure data will be presented in a by-subject data listing. 
9.2. 
Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
fully completes her/his participation in the study.  AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA, version 23.0).  AEs are graded for severity (ie, 
intensity) using the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03). 
All AE summaries will be restricted to TEAEs.  TEAEs are defined as any AEs that newly 
appear, increase in frequency, or worsen in severity after 1 dose of investigational product during 


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the DB phase.  If it cannot be determined whether the AE is treatment emergent due to a partial 
onset date, then it will be counted as such.  Verbatim terms on eCRFs will be mapped to 
preferred terms (PT) and system organ classes (SOC) using MedDRA version 23.0. Each AE 
summary will be displayed by treatment group.  Summaries that are displayed by SOC and PT 
will be ordered defined by descending order of incidence (OCA 10 mg → 25 mg titration, 
followed by OCA 10 mg, followed by placebo, detail in Section 9) of SOC and PT within each 
system organ class.  Summaries of the following types will be presented: 
• Overall summary of TEAEs. 
• Subject incidence of TEAEs and the total number of entries by SOC and PT. 
• Subject incidence of TEAEs and the total number of entries by PT in descending order. 
• Subject incidence of serious TEAEs and the total number of entries by SOC and PT. 
• Subject incidence of TEAEs leading to investigational product withdrawal by SOC and PT. 
• Subject incidence of TEAEs by SOC, PT, and highest severity (common terminology 
criteria for adverse events [CTCAE] grade).  
Notes: At each level of subject summarization, a subject is classified according to the 
highest severity if the subject reported 1 or more events.  AEs with missing severity 
(CTCAE grade) will be considered grade 3 (severe) for this summary. 
• Subject incidence and total number of entries of CTCAE grade 3 or higher TEAEs by 
SOC and PT.  
Notes:  At each level of subject summarization, a subject is classified according to the 
highest severity if the subject reported 1 or more events. AEs with missing severity 
(CTCAE grade) will be considered grade 3 (severe) for this summary. 
• Subject incidence and total number of entries of related TEAEs by SOC and PT.  
Notes:  At each level of subject summarization, a subject is classified according to the 
closest relationship to investigational product if the subject reported 1 or more events. 
TEAEs with a missing relationship will be considered related for this summary. 
• Subject incidence and total number of entries of related CTCAE grade 3 or higher TEAEs 
by SOC and PT.  
Notes:  At each level of subject summarization, a subject is classified according to the 
highest severity if the subject reported 1 or more events.  AEs with missing severity 
(CTCAE grade) will be considered grade 3 (severe) for this summary.  TEAEs with a 
missing relationship will be considered related for this summary. 
• Subject incidence of TEAEs occurring by SOC and PT with frequency at least 5% within 
any treatment group. 
• Subject incidence of TEAEs by SOC, PT, and closest relationship to liver biopsy 
(Related/Not Related).  


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Notes:  At each level of subject summarization, a subject is classified according to the 
closest relationship to biopsy if the subject reported 1 or more events.  AEs with a 
missing relationship will be considered related for this summary. 
• Subject incidence of TEAEs leading to death and the total number of entries by SOC and 
PT. 
• Overall Summary of TEAEs Over Time 
• Exposure-adjusted incidence of TEAEs leading to death 
• Exposure-adjusted incidence of serious TEAEs  
• Exposure-adjusted incidence of TEAEs leading to investigational product withdrawal  
The following listings will be presented by treatment group and subject: 
• All TEAEs 
• Serious TEAEs  
Notes: This is a subset of the TEAEs where serious is marked as “Yes”. 
• CTCAE Grade 3 or higher TEAEs  
Notes: This is a subset of TEAEs where severity is marked as CTCAE grade 3, 4, or 5) 
• Study Drug Related TEAEs  
Notes: This is a subset of the TEAEs where relationship to study drug marked as 
“Definite,” “Probable,” or “Possible”. 
• Liver Biopsy-related TEAEs  
Notes:  This is a subset of the TEAEs where relationship to liver biopsy marked as 
“Definite”, “Probable”, or “Possible”. 
• TEAEs leading to Study Drug Withdrawal  
• TEAEs leading to study discontinuation 
• TEAEs leading to Death  
Notes:  This is a subset of the TEAEs where outcome is indicated as “Fatal” or the 
CTCAE grade is 5. 
9.3. 
Adverse Events of Special Interest 
Adverse Events of Special Interest (AESI) are defined using SMQs and/or custom MedDRA 
version 23.0 for 747-304.  The following adverse events of special interest (AESIs) will be 
evaluated and summarized for Safety populations.  
• Pruritus 
• Hepatic adverse events 
• Cardiovascular adverse events (CV is addressed in detail in Section 9.4) 
• Dyslipidemia 


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• Gallbladder disease and related complications 
• Pancreatitis 
• Renal injury 
• Urolithiases 
• Hyperglycemia /new onset diabetes mellitus 
Each subcategory of interest will be defined using standardized MedDRA queries (SMQs) and/or 
custom MedDRA queries, as specified in the subsequent sections. 
AESI analyses will include all the following: 
• Incidence of treatment-emergent AESIs by PT 
• Incidence of treatment-emergent AESIs by PT and severity 
• Incidence of serious treatment-emergent AESIs by PT 
• Incidence of treatment-emergent AESIs leading to IP withdrawal by PT 
• Incidence of related treatment-emergent AESIs by PT 
• Incidence of treatment-emergent AESIs leading to death by PT 
• Exposure-adjusted incidence of treatment-emergent AESIs by PT 
• Exposure-adjusted incidence of serious treatment-emergent AESIs by PT 
• Exposure-adjusted incidence of treatment-emergent AESIs by baseline diabetes status 
• Exposure-adjusted incidence of severe (Grade 3+) AESIs by PT 
• KM statistics for time to first onset of treatment-emergent AESI 
• KM statistics for time to onset of first severe (Grade 3+) or serious treatment-emergent 
AESI 
• Percentage of subject-days with treatment-emergent AESIs per subject exposure year 
(SEY), by severity 
All summaries noted above will include crude incidence rates for each level of summation.  For 
overall incidence summary of each AESI, analyses will be performed separately for the AESI 
collected on-treatment only and during study.  Exposure-adjusted incidence rate difference (with 
corresponding 95% CIs) will be calculated for the number of subjects with any event by 
subcategory of interest (not for each PT).   
Additional special analyses for each AESI may be provided if deemed necessary. 
9.3.1. 
Pruritus 
Treatment-emergent pruritus, defined as any preferred term within the pruritus Not Elsewhere 
Classified (NEC) high level term (HLT) or including “prur,” will be summarized separately by 
the MedDRA SOC, treatment group, and PT as a subset of all TEAEs.  Additional summaries of 
overall pruritus TEAEs will be provided.  These summaries will be generated for the Safety 
Population. 


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An analysis of treatment-emergent pruritus event days per patient years on study will be 
performed.  The days at each severity grade, including the total days of event, the total patient 
years on study, and the event days per patient year on study at each severity grade, including the 
total, will be summarized.  Each individual patient year on study will be derived as the last 
known date during the study minus the first dose date plus 1 divided by 365.25 days/year.  
In addition, an analysis of treatment-emergent pruritus events by preferred term and severity over 
time will be performed. 
• Two listings of all treatment-emergent pruritus events will be provided: the standard AE 
listing, and an additional listing which will include the concomitant medication(s) used to 
treat the pruritus, adjustments to investigational product dosing frequency or amount, 
mandatory investigational product interruption, and/or holiday.  The time between each 
event and it’s preceding one will be presented per subject. 
9.3.2. 
Hepatic Adverse Events 
Hepatic adverse events are defined as events included in the Hepatic Disorders SMQ, excluding 
the following sub-SMQs:  
- 
alcohol related 
- 
congenital, familial, neonatal, and genetic disorders of the liver 
- 
liver infections 
- 
pregnancy-related hepatic disorders 
9.3.3. 
Cardiovascular Adverse Events 
Cardiovascular adverse events are defined as:  
- 
Embolic and thrombotic events broad SMQ 
- 
Ischemic heart disease broad SMQ 
- 
Central nervous system vascular disorders narrow SMQ 
9.3.4. 
Dyslipidemia 
Dyslipidemia is defined as events included in the dyslipidemia SMQ.  
9.3.5. 
Gallbladder Disease and Related Complications 
Gallbladder disease and related complications adverse events are defined as: 
- 
Gallbladder related disorders narrow SMQ 
- 
Gallstone related disorders narrow SMQ 
- 
Additional Preferred terms of Biliary abscess, Biliary sepsis, Biliary tract infection, 
Gallbladder abscess, Gallbladder empyema, Bile duct necrosis, Bile duct obstruction, 
Bile duct stenosis, Biliary colic, Cholangitis, Cholangitis acute, Cholangitis chronic, 
Cholecystocholangitis, or Perforation bile duct 
9.3.6. 
Pancreatitis 
Pancreatitis is defined as acute pancreatitis narrow SMQ. 


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9.3.7. 
Renal Injury 
Renal injury is broadly defined as:  
- 
Acute Renal Failure SMQ 
- 
Chronic Kidney Disease SMQ 
- 
Proteinuria SMQ 
- 
Renovascular disorders broad SMQ 
- 
Tubulointerstitial disease broad SMQ 
9.3.8. 
Urolithiases 
Urolithiases are defined as high-level group term Urolithiases (under the SOC Renal and Urinary 
Disorders). 
9.3.9. 
Hyperglycemia/New Onset Diabetes Mellitus 
Hyperglycemia/new onset diabetes mellitus are defined as hyperglycemia/new onset diabetes 
mellitus narrow SMQ.   
9.4. 
Cardiovascular Risk 
Summaries of adjudicated cardiovascular events include core MACE (cardiovascular death, non-
fatal MI, non-fatal stroke) and expanded MACE will be performed as follows, in addition to the 
AESI analysis in Section 9.3.3. 
9.4.1. 
Adjudicated Cardiovascular Events 
Summaries of adjudicated cardiovascular events including major adverse cardiovascular events 
(MACE) will include the overall summary of cardiovascular TEAEs, incidence of TEAEs, 
incidence of serious TEAEs, annualized adjudicated CV event rate, and a time-to-event analysis 
as described below.  All summaries of incidence will include the associated exact binomial 95% 
confidence interval (CI).  Summaries will be carried out for the Safety population. 
9.4.2. 
Markers of Cardiovascular Safety 
Framingham Risk Score (FRS) will be summarized by treatment group using descriptive 
statistics of the results at baseline and at each post-baseline visit.  The change and percentage 
change from baseline values will be summarized.  All summaries will be based on observed 
values.  A shift table from baseline FRS to each post-baseline visit will also be provided. 
9.4.3. 
Serum Chemistry Lipids 
Lipoproteins (LDL, HDL, VLDL, and triglycerides, ApoB, ApoA-1, ApoE, Lp[a]), total 
cholesterol, triglycerides, and PCSK9 results by treatment group using descriptive statistics at 
baseline and at each on-study evaluation presented.  Laboratory values, change, and percentage 
change from baseline will also be summarized.   
9.5. 
Adjudicated Acute Kidney Injury (AKI) Events 
Summaries of adjudicated acute kidney injury events will include the overall summary of AKI 
TEAEs, incidence of AKI TEAEs, incidence of serious AKI TEAEs, annualized adjudicated 
AKI event rate, and a time-to-event analysis.  All summaries of incidence will include the 


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associated exact binomial 95% confidence interval (CI).  Summaries will be carried out for the 
Safety population. 
9.6. 
Adjudicated Hepatic Injury (DILI) Events 
Summaries of adjudicated hepatic injury events will include the overall summary of hepatic 
injury TEAEs, incidence of hepatic injury TEAEs, incidence of serious hepatic injury TEAEs, 
annualized adjudicated hepatic injury event rate, and a time-to-event analysis.  All summaries of 
incidence will include the associated exact binomial 95% confidence interval (CI).  Summaries 
will be carried out for the Safety population. 
Potential DILI Triggers:  Potential cases of drug induced liver injury (DILI) are identified via a 
set of biochemical, adverse event (SMQ based) and study visit questionnaire triggers.  These 
cases then undergo clinical review by the Hepatic Safety Adjudication Committee (HSAC) of all 
available data for each identified subject to determine liver injury status (including causality and 
severity).  As part of a comprehensive DILI analysis, the HSAC will apply these criteria to all 
subjects in 747-304. 
Summary tables for identified cases will present frequencies of triggers by treatment group as 
well as highest causality and severity association. 
9.7. 
Clinical Laboratory Evaluations 
Laboratory parameters will be summarized in both conventional units and the standard 
international (SI) system of units.  The submitted datasets will also include results from local lab 
evaluations.  
All clinical laboratory data will be presented in by-subject data listings.  The following analyses 
will be done for the Safety population. 
9.7.1. 
Serum Chemistry, Hematology, and Coagulation 
Quantitative serum chemistry (including calculated eGFR), hematology, and coagulation results 
by treatment group using descriptive statistics at baseline and at each on-study evaluation will be 
presented.  Laboratory values, change, and percentage change from baseline, will also be 
summarized.  Baseline is defined as the mean of all available evaluations prior to treatment.   
Shifts in CTCAE toxicity grade of laboratory tests from baseline to worst value (scheduled or 
unscheduled), last value (scheduled or unscheduled), and at each scheduled post-baseline visit 
will be provided.  The toxicity grades are in the CTCAE version 4.03.  
Summaries will present the number and percentage of subjects with shifts in laboratory toxicity 
grade by treatment group. 
9.7.2. 
Hepatic Biochemical Analysis 
Summary statistics will be presented by visit, including change from baseline and percent change 
from baseline.  


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While portal hypertension is defined by hepatic venous pressure gradient, there are non-invasive 
surrogate markers that can rule-out clinically significant portal hypertension (CSPH) as well as 
identify the potential for increased risk of portal hypertension.   
• A shift summary for platelet (PLT) count by baseline category: 100,000 -
150,000/mm3, 150,000 -200,000/mm3 and >200,000/mm3 that are improved, stable, 
or worsened (worse post-baseline value) at month 6, 12, and 18 visits will be 
presented.  
• In addition, a composite result of baseline FibroScan (FS) and PLT count (to rule-out 
the presence of CSPH), will be defined as follows: 
o Composite Result = “Yes” if FS<=15kPa and PLT>=150,000/mm3 – No evidence 
of CSPH 
o Otherwise, composite result = “No” 
o A shift summary for a composite result improved (N->Y), stable (Y->Y and 
N->N), worsened (Y->N) from baseline to month 6, 12, and 18 visits will also be 
presented. 
Evaluation of drug-induced serious hepatotoxicity (eDISH) will be conducted to visually 
compare maximum 
values at any post-baseline visit.  For subjects with 
baseline 
above ULN, eDISH plots will also be generated based on 
multiples of elevations above the baseline (BL) value (2×BL and 3×BL for ALT, and 2×BL for 
total bilirubin).  
Similar eDISH analysis as described above will be performed for 
 Plots 
based on multiples of elevations above the baseline value will use 
 
The summary table as well as visual plots will be based on central lab data. 
In addition, eDISH using maximum post-baseline 
will be repeated with 
central and local lab data.  
9.7.3. 
Lipoprotein Evaluations 
Serum chemistry-based assessments are the standard safety tool for monitoring subjects’ serum 
lipids.  Additional lipoprotein samples, separate from the serum chemistry samples, will be 
obtained, and assayed in addition to the serum chemistry panel lipid assay. 
The lipoprotein analyte values, change from baseline, and percentage change from baseline will 
be summarized by treatment group for the lipoprotein analytes.  Baseline is defined as the last 
fasting assessment before treatment.  This analysis will use only samples that have a confirmed 
fasting of approximately 8 hours or more before their visit.  
Only descriptive statistics will be provided.  
9.7.4. 
Urine Chemistry and Urinalysis 
Quantitative urine chemistry and urinalysis results by treatment group and by baseline body 
weight will be summarized using descriptive statistics at baseline and at each on-study 


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evaluation.  The lab results and percentage change from baseline will also be summarized.  
Baseline is defined as the mean of all available evaluations prior to treatment.   
9.7.5. 
Renal Function Evaluations 
Summary statistics for absolute values, change from baseline, and percent change from baseline 
to each on-study evaluation visit, as well as worst and last postbaseline values, will be presented 
for eGFR and serum creatinine.  The summary will also be repeated for baseline CKD stage.  
Annualized change in eGFR (mL/min/1.73 m2/yr) will be summarized descriptively.  The 
proportion of subjects that experience rapid eGFR decline (defined as >4 mL/min/1.73 m2/yr) 
will be presented.  
In addition, shifts from baseline to each on-study evaluation will be presented for eGFR, based 
on the standard eGFR categories. 
9.8. 
Pregnancies 
If any subject gets pregnant during the study, a by-subject data listing will be provided including 
all data on the Pregnancy eCRF. 
9.9. 
Vital Signs  
The results, change from baseline, and percentage change from baseline to each on-study 
evaluation visit will be summarized for systolic blood pressure, diastolic blood pressure, sitting 
heart rate, respiratory rate, body weight, waist circumference and BMI.   
All vital sign data will be presented in by-subject data listings. 
9.10. 
Electrocardiograms 
Summary statistics for the values, change from baseline, and percent change from baseline to 
each on-study evaluation visit will be presented for RR interval, PR interval, QRS duration, QT 
interval, QTcF interval.  A summary of abnormal ECG results that are identified by centrally 
analyzed ECG results by ERT will be provided. 
A categorical summary of abnormal QTcF values will be presented by treatment group.  The 
number of subjects with values of >450 msec, >480 msec, and >500 msec will be presented, and 
the number of subjects with change from baseline values of >30 msec and >60 msec will also be 
presented.   
All electrocardiogram (ECG) results will be presented in by-subject data listings. 
9.11. 
Safety Subgroups 
Subgroup analyses for safety selected endpoints including overall TEAE, serious TEAEs, overall 
treatment-emerging AESI, and serious treatment-emerging AESI may be presented for the Safety 
Population and may include the following factors: 


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a. Baseline diabetes status at enrollment:  Yes, No   
b. Age categories:  <65, ≥65 years, ≥75 years 
c. Baseline in BMI (<30 kg/m2, ≥30 kg/m2 and <35 kg/m2, ≥35 kg/m2) 
d. Baseline Framingham (FRS) risk score:  ≤10, >10 - ≤20, >20  
e. Baseline eGFR 
10. 
PK/PD ANALYSES IN DB PHASE 
Details of PK analyses will be specified in a separate Clinical Pharmacology Analysis Plan 
(CPAP).  
11. 
CHANGE FROM PROTOCOL PLANNED ANALYSIS 
The following changes were made after the protocol 7 version was finalized: 
1. Protocol Stat section 17.4 (page 139), secondary efficacy analyses will be conducted 
using ITT populations.   
2. Impact: the secondary endpoints are in multiple testing and will be based in ITT 
population.   Other mITT or PP population may be analyzed but they are sensitivity 
analysis.   
3. Inclusion of other exploratory histological endpoints as measured by Ishak scoring 
system and AI-based histologic Measurement of NASH (AIM NASH).   
4. The adverse events of special interest defined in the protocol are modified to align with 
the other NASH studies.  
Original text 
Adverse events of special interest include cardiovascular, pruritus, renal, urinary tracts stones 
including nephrolithiasis, gallbladder/gallstones-related pancreatitis, hepatic, dyslipidemia and 
hyperglycemia/new-onset diabetes mellitus AEs.  
Change made to 
Adverse events of special interest include pruritus, hepatic adverse events, cardiovascular 
adverse events, dyslipidemia, gallbladder disease and related complications, pancreatitis, renal 
injury, urolithiases, hyperglycemia/new onset diabetes mellitus. 
Additional changes made were in response to FDA’s information request from 18 Jan 2022. 
Other notable change is the inclusion of liver non-invasive procedures to the secondary 
endpoints. Summary of key updates can be found in Section 1. 


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APPENDIX A. CHILD-PUGH SCORING SYSTEM 
 
Factor 
Units 
Points 
1 
2 
3 
Serum total bilirubin 
μmol/L 
<34 
34-50 
>50 
mg/dL 
<2.0 
2.0-3.0 
>3.0 
Serum albumin 
g/L 
>35 
28-35 
<28 
g/dL 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
Seconds prolonged 
0-3 
4-6 
>6 
INR 
<1.7 
1.7-2.3 
>2.3 
Ascites 
 
None 
Mild 
Moderate-
Severe 
Hepatic encephalopathya 
 
None 
Grade 1 or 2 
Grade 3 or 4 
INR = international normalized ratio 
Child-Pugh criteria:  Pugh 1973, Lucey 1997. 
West Haven criteria:  Vilstrup 2014.  
a Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram 
 Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves 
 Grade 2:  lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
 Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
 Grade 4:  unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity  
 
 


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APPENDIX C. LIST OF LAB TESTS USE MEAN OF PRE-DOSE 
VALUES AS BASELINE 
ActiTest Score 
Ery. Mean Corpuscular Volume 
Activated Partial Thromboplastin Time 
Erythrocytes 
Alanine Aminotransferase 
Ferritin 
Albumin 
Free Fatty Acid 
Albumin 
Haptoglobin 
Albumin/Creatinine 
Hematocrit 
Alkaline Phosphatase 
Hemoglobin 
Alkaline Phosphatase Serum or Plasma 
Hemoglobin 
Alk-Phosphatase Other Calc (ARUP) 
Ketones 
Alpha-2 Macroglobulin 
Leukocyte Esterase 
Apolipoprotein A1 
Leukocytes 
Apolipoprotein B 
Liver Specific Alkaline Phosphatase 
Apolipoprotein E 
Lymphocytes 
AshTest Score 
Lymphocytes/Leukocytes 
Aspartate Aminotransferase 
Magnesium 
Basophils 
Monocytes 
Basophils/Leukocytes 
Monocytes/Leukocytes 
Bicarbonate 
Neutrophils 
Bilirubin 
Neutrophils/Leukocytes 
Bilirubin 
Nitrite 
Blood Urea Nitrogen 
pH 
Bone Specific Alkaline Phosphatase 
Phosphate 
C Reactive Protein 
Platelets 
Calcium 
Potassium 
Chloride 
Protein 
CK-18 (M30) 
Protein 
CK-18 (M65) 
Prothrombin Intl. Normalized Ratio 
Creatine Kinase 
Prothrombin Time 
Creatinine 
PT Ratio 
Creatinine 
Sodium 
Direct Bilirubin 
Specific Gravity 
Eosinophils 
Thyrotropin 
Eosinophils/Leukocytes 
Thyroxine, Free 
Ery. Mean Corpuscular Hemoglobin 
TIMP-1 for ELF Score 
Ery. Mean Corpuscular HGB 
Concentration 
Triiodothyronine, Free