Clinical trial NCT02548351
Conditions: Non Alcoholic Steatohepatitis (NASH)
Keywords: Non Alcoholic Steatohepatitis, fatty liver disease, NASH
Sponsor: Intercept Pharmaceuticals
Start date: 2015-09-22; Completion date: 2023-09-15
Enrollment: 2477 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the effect of Obeticholic Acid treatment compared to placebo on 1) histological improvement and 2) liver-related clinical outcomes in patients with non-cirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis.

Detailed description:

Arms: arm 1: 10 mg Obeticholic Acid daily for the remainder of the study arm 2: 25 mg Obeticholic Acid daily for the remainder of the study arm 3: One tablet daily for the remainder of the study
Interventions: intervention 1: Obeticholic Acid intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Intercept 
Clinical Study Protocol 7 4 7-303 
OBETICHOLIC ACID (OCA) 
A Phase 3, Double-Blind, Randomized, Long-Term, Placebo-Controlled, 
Multicenter Study Evaluating the Safety and Efficacy of Obeticholic Acid in 
Subjects with Nonalcoholic Steatohepatitis 
The REGENERATE Study 
RandomizEd Qlobal Phase 3 Study to ,Evaluate the Impact on NASH with 
FibRosis of Obeticholic Acid TreatmEnt 
-
-
-
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Version 11.0: 04 May 2021 
EudraCT Number: 2015-002560-16 
Sponsor 
Intercept Pharmaceuticals, Inc. 
9520 Towne Centre Drive, Suite 200 
San Diego, CA 92121 
USA 
TEL: +l 858 652 6800 
FAX: + 1 858 558 5961 
CONFIDENTIAL 
The infonuation contained herein is the property of Intercept Phannaceuticals, Inc. and may not be reproduced, 
published, or disclosed to others without written authorization of Intercept Phannaceuticals, Inc. 
NCT Number: NCT02548351
This NCT number has been applied to the document for purposes of posting on Clinicaltrials.gov


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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 747-303.  Having fully considered all the information available, 
I agree that it is ethically justifiable to give OCA to selected subjects according to this protocol. 
I understand that all information concerning OCA supplied to me by the Sponsor, Intercept 
Pharmaceuticals, Inc., and/or its agents in connection with this study and not previously 
published is confidential information.  This includes the IB, clinical study protocol, case report 
forms, 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 747-303 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 
Medical Monitor 
Investigators are encouraged to call the PRA Medical Support Center phone number for the 
United States and Canada at +1 866 326 5053 or for Europe/Asia/Pacific at +44 179 2525 608, 
or send an email to the NASH medical monitor email at REGENERATE@prahs.com with safety 
questions as these lines of contact are monitored 24 hours a day.  The following individual 
medical monitors may also be contacted through the NASH medical monitor hotline and email 
address. 
Primary Contact: 
PRA Health Sciences Medical Monitor Team 
, MD 
, MD 
, MD (Lead) 
 
 
Secondary Contact: 
, MD 
, Medical Monitoring, Clinical Development 
Intercept Pharmaceuticals, Inc. 
Email: 
Telephone: -


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2.
SYNOPSIS
Name of Sponsor/Company: 
Intercept Pharmaceuticals, Inc. 
Name of Investigational Product: 
Obeticholic Acid 
Name of Active Ingredient: 
Obeticholic acid (OCA); 6α-ethyl-chenodeoxycholic acid (6-ECDCA); INT-747 
Title of Study: 
A Phase 3, Double-Blind, Randomized, Long-Term, Placebo-Controlled, Multicenter Study Evaluating the Safety 
and Efficacy of Obeticholic Acid in Subjects with Nonalcoholic Steatohepatitis 
Study Center(s): 
Up to 400 investigational sites, globally 
Studied Period: 
The study is event driven and total duration will be determined 
by the time required to accrue approximately 291 adjudicated 
events for the clinical outcomes composite endpoint, in the OCA 
25 mg and placebo groups combined, for subjects with fibrosis 
stage 2 and stage 3, estimated to take approximately 10 years. 
Phase of Development: 
Phase 3 
Objectives: 
Primary Objective Assessed at the Month 18 Interim Analysis: 
•
To evaluate the effect of OCA compared to placebo on histological improvement in nonalcoholic
steatohepatitis (NASH) by assessing the following primary endpoints using NASH Clinical Research
Network (CRN) scoring criteria:
−
Improvement in fibrosis by at least 1 stage with no worsening of NASH, OR
−
Resolution of NASH with no worsening of fibrosis
Secondary Objectives Assessed at the Month 18 Interim Analysis: 
•
To evaluate the effect of OCA compared to placebo on histological improvement in NASH by assessing the
following using NASH CRN scoring criteria:
−
Improvement of fibrosis by at least 1 stage AND/OR resolution of NASH, without worsening of either
−
No worsening of fibrosis AND no worsening of NASH
−
Improvement in each key histological feature of NASH by at least 1 point (steatosis, lobular
inflammation, and hepatocellular ballooning)
−
Improvement of fibrosis by at least 2 stages
−
Improvement in nonalcoholic fatty liver disease activity score (NAS) by at least 2 points with no
worsening of fibrosis
−
Improvement of fibrosis and resolution of NASH as a composite endpoint and as defined by both
endpoints being met in the same subject
−
Resolution of fibrosis
−
Histological progression to cirrhosis
•
To evaluate the effect of OCA compared to placebo on liver biochemistry and markers of liver function


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Primary Objective Assessed at End of Study (EOS): 
•
To evaluate the effect of OCA compared to placebo on 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):
−
Death (all cause)
−
Model of end stage liver disease (MELD) score ≥15
−
Liver transplant
−
Hospitalization (as defined by a stay of ≥24 hours) for onset of:
•
Variceal bleed
•
Hepatic encephalopathy (as defined by a West Haven score of ≥2)
•
Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
−
Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or paracentesis)
−
Progression to cirrhosis
Secondary Objectives Assessed at EOS: 
•
To evaluate the effect of OCA compared to placebo on histological improvement in NASH by assessing the
following endpoints using NASH CRN scoring criteria:
−
Improvement in fibrosis by at least 1 stage with no worsening of NASH
−
NASH resolution with no worsening of fibrosis
−
Improvement of fibrosis by at least 1 stage AND/OR resolution of NASH, without worsening of either


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−
No worsening of fibrosis AND no worsening of NASH
−
Improvement in each key histological feature of NASH by at least 1 point (steatosis, lobular
inflammation, and hepatocellular ballooning)
−
Improvement of fibrosis by at least 2 stages
−
Improvement in NAS by at least 2 points with no worsening of fibrosis
−
Improvement of fibrosis and resolution of NASH as a composite endpoint and as defined by both
endpoints being met in the same subject
−
Resolution of fibrosis
•
To evaluate the effect of OCA compared to placebo on liver biochemistry and markers of liver function
Safety Objectives Assessed at EOS 
•
To evaluate the effect of OCA compared to placebo on:
−
Incidence of adjudicated cardiovascular events
−
Incidence of adjudicated acute kidney injury (AKI)
−
Incidence of adjudicated events of hepatic injury
−
Long-term safety and tolerability (TEAEs, ECGs, vital signs, clinical laboratory assessments)
•
To evaluate the correlation between histology and noninvasive scores of liver fibrosis with clinical outcomes
at the end of the study
Methodology: 
Study Design 
This Phase 3, double-blind, randomized, long-term, placebo-controlled, multicenter international study will 
evaluate the effect of OCA on histological improvements in NASH, all-cause mortality, and liver-related clinical 
outcomes.  The study will enroll approximately 2370 subjects with NASH.  The population will comprise 
approximately 2085 subjects with biopsy-confirmed, noncirrhotic NASH and evidence of stage 2 or stage 3 liver 
fibrosis, including approximately 60% with fibrosis stage 3 and approximately 40% with fibrosis stage 2; and an 
additional cohort of approximately 285 subjects with stage 1 fibrosis with at least 1 accompanying comorbidity to 
gather information on the safety of OCA and progression of liver disease in this population.   
A planned Interim Analysis is to be performed when a minimum of 750 randomized subjects (the first sequential) 
with fibrosis stage 2 or stage 3 would have reached their actual/planned Month 18.  For the purpose of 
determining the timing of the Month 18 Interim Analysis, subjects that discontinue before their Month 18 visit 
are considered to have reached their Month 18 Visit and will be part of the Month 18 Interim Analysis cohort.  
The cutoff for the Month 18 Interim Analysis cohort database lock will be defined in the SAP.  The study will be 
continued in a blinded fashion, and subjects will be followed for clinical outcomes to confirm clinical benefit.  
Final analysis will evaluate the effect of OCA on mortality and liver-related clinical outcomes and long-term 
safety of OCA after the accrual of approximately 291 adjudicated clinical outcomes composite events combined 
in the OCA 25 mg and placebo groups for subjects with fibrosis stage 2 or stage 3 (projected to take 


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approximately IO years in total). Subjects are expected to have a minimum follow-up time of approximately 
4years. 
Subjects will be screened for a period of up to 12 weeks before entering the study. Approximately 23 70 subjects 
with NASH who meet all eligibility criteria will be randomized to receive OCA IO mg, OCA 25 mg, or matching 
placebo in a I: l: I ratio for the duration of the study, in conjunction with local standard of care. Randomization 
of subjects with fibrosis stage 2 or stage 3 will be stratified by presence of type 2 diabetes at enrollment (yes/no) 
and use of thiazolidinediones (TZDs )/glitazones or vitamin E at baseline (yes/no). Biopsy-confomed NASH will 
be detennined by central reading of liver histology at Screening, and all subsequent histology assessments will be 
performed centrally in a blinded fashion. 
Investigation.al product (ie, OCA or placebo) will be taken orally, with water, once daily. Subject safety and 
laboratory assessments will be evaluated at clinical visits occuning after the first month and once every 3 months 
following the initiation of treatment (Day 1) through Month 18. Following the Month 18 visit. clinic visits will 
occur every 6 months for the remaining duration of the study. 
With the exception of liver transplant, if a subject experiences a suspected or confirmed clinical outcomes event, 
he or she should continue the regular visit schedule and continue taking i.nvestigational product as long as the 
subject has not met any of the crite1ia for discontinuation outlined in the protocol. Subjects who discontinue 
investigational product are expected to be followed through to study closure (or at the discretion of the Sponsor). 
Additional strategies to encourage continued subject paiticipation in the study will be outlined in a Subject 
Retention Plan. 
I 1:1:1 Randomization 
Screening 
;;12 Weeks 
EOS = end of study 
II 
0 1 
3 
(Day 1) 
6 
Standard of Care 
Placebo 
Months 
9 
12 
15 
18 
t 
Interim Analysis 1 
at Month 18 
750 subjects} 
Semi-annual 1,1sits 
I 
48 
EOS 
t 
Final Analysis 
After 291 Events" 
.A. Biopsy (Subjects without a liver biopsy performed within 6 months before Day I will have a biopsy at the 
second Screening Visit). 
• Nmnber of adjudicated events accrued in placebo and OCA 25 mg groups combined.
Concomitant Medications: 
Concomitant medications will be used at the discretion of the usual care provider ( or Investigator if also the us11al 
care provider). Relevant info1mation 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 repmt fonn, 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. between Day 1 and Month 18, unless the 
baseline therapy is no longer considered clinically appropriate by the Investigator. In general, Investigators will 
be encouraged to follow guidelines for care based upon local and institutional practice patterns and any relevant 
published practice guidelines. 
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Exceptions to this general requirement are noted below. 
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•
Subjects providing historical biopsies to determine study eligibility should either not be taking any drugs
with potential NASH-modifying properties (specifically, TZDs/glitazones or vitamin E) or should be on a
stable dose of these medications for 6 months before Day I through Month 18. Changes to these drugs with
potential NASH-modifying prope1ties are not pennitted for the first 18 months of the study. Ideally, subjects
should generally remain on baseline TZDs/glitazones or vitarnin E from Month 18 through the end of the
study, unless the baseline therapy is no longer considered clinically appropriate by the Investigator.
•
Given the prevalence of dyslipidemia in subjects with NASH and the potential increase in total and
low-density lipoprotein cholesterol (LDLc) following treatment with OCA, it is recommended that
Investigators proactively monitor and manage lipid levels via appropriate medicinal interventions
(eg, statins). Recent guidelines stress the imp01tance of evaluating atherosclerotic cardiovascular disease
(ASCVD) risk in all patients to help guide decisions in recommending therapies and reducing LDLc to
reduce the risk and prevent onset or recwrence of ASCVD.
Prospective Surveillance: 
- screening will include a hepatobiliary ultrasound an=ha-fetoprotein assessment according to the
:dule presented in Table 1. For subjects who de, elop- during the study, llllscreening assessments for
study visits after onset of 
are not required.
Liver Histology, Event Adjudication, and Data Monitm·ing Committee Oversight: 
Central Reading of Liver Histology: All biopsy assessments will be pe1formed centrally, including assessments 
of biopsies to determine study eligibility and unscheduled biopsies. To determine eligibility at emollment 
a central pathologist must confum histological presence of NASH and a minimum NAS of 4 with a score of at 
least I in each component ofNAS. For each biopsy, key features of NASH and fibrosis sta • 
will be !?;faded in 
accordance with the NASH CRN criteria for scorin . 
einer 2005 . 
Event Adjudication: All potential liver-related clinical outcomes and potential events of hepatic injury, AKI, 
major adverse cardiovascular events (MACE), 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 (CAC): 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 including
clinical events and histological findings of potential disease progression to cilThosis
•
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 il1clude experts with relevant adjudication experience; they will not be 
ilwolved in the study as Investigators, Data Monitoring Committee (DMC) members, or consultants. 
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Specific details of the events that will be adjudicated by the CAC, Hepatic Outcomes Committee, HSAC, and 
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 outside of a protocol amendment. 
DMC Oversight:  An independent DMC will review all safety and efficacy data resulting from the study at 
periodic intervals.  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 are expected to have considerable experience with clinical study conduct 
and DMCs before joining the DMC. 
Number of Subjects (Planned): 
The study will enroll approximately 2370 subjects with NASH.  The population will comprise approximately 
2085 subjects with biopsy-confirmed, noncirrhotic NASH and evidence of stage 2 or stage 3 liver fibrosis, 
including approximately 60% with fibrosis stage 3 and approximately 40% with fibrosis stage 2; and an 
additional cohort of approximately 285 subjects with stage 1 fibrosis with at least 1 accompanying comorbidity to 
gather information on the safety of OCA and progression of liver disease in this population.  At selected 
investigational sites, approximately 300 subjects will have the option to provide blood samples for measurement 
of OCA PK concentrations.  At selected centers where the devices are available, subjects may participate in 
.  At study sites in the United States, subjects will have the 
option to provide stool samples for microbiome/metabolome analysis only if they provided baseline (Day 1) 
samples.   
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria 
1.
Histologic evidence of NASH upon central read of a liver biopsy obtained no more than 6 months before
Day 1 defined by presence of all 3 key histological features of NASH with a score of at least 1 for each
and a combined score of 4 or greater out of a possible 8 points according to NASH CRN criteria.
2.
Histologic evidence of fibrosis stage 2 (perisinusoidal and portal/periportal) or stage 3 (bridging fibrosis)
as defined by the NASH CRN scoring of fibrosis, or
Histologic evidence of fibrosis stage 1a or stage 1b (mild or moderate, zone 3 perisinusoidal) as defined
by the NASH CRN scoring of fibrosis if accompanied by ≥1 of the following risk factors:
−
Obesity (BMI ≥30 kg/m2)
−
Type 2 diabetes diagnosed per 2013 American Diabetes Association criteria (hemoglobin A1c
[HbA1c] ≥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)
−
ALT >1.5× upper limit of normal (ULN).
3.
For subjects with a historical biopsy, is either not taking or is on stable doses of TZDs/glitazones or
vitamin E for 6 months before Day 1.
4.
Stable body weight (ie, not varying by >10% for at least 3 months) before Day 1.
5.
Age ≥18 years.
6.
Female subjects of childbearing potential must use ≥1 effective method of contraception during the study
and until 30 days following the last dose of investigational product.  Effective methods of contraception
are considered to be those listed below:
−
Barrier method, ie, condom (male or female) with spermicide or diaphragm with spermicide
−
Intrauterine device
−
Vasectomy (partner)
−
Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection)
−
Abstinence (defined as refraining from heterosexual intercourse).
7.
Must provide written informed consent and agree to comply with the study protocol.


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Exclusion Criteria 
Criteria with exclusionary laboratory values are to be based on the most recent laboratory result available prior to 
randomization. 
1.
Current or history of significant alcohol consumption for a period of more than 3 consecutive months
within 1 year before Screening (significant alcohol consumption is defined as more than 2 units/day for
females and more than 4 units/day for males, on average).
2.
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).
3.
HbA1c >9.5% within 60 days before Day 1.
4.
Evidence of other forms of known 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’s 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 
 
−
History of liver transplant, current placement on a liver transplant list, or MELD score >12.
5.
Histological presence of cirrhosis.  
6.
Total bilirubin >1.5 mg/dL (subjects with Gilbert’s syndrome may be enrolled despite a total bilirubin
level >1.5 mg/dL if their conjugated bilirubin is <1.5× ULN).
7.
Conjugated bilirubin ≥1.5 x ULN.
8.
AST or ALT ≥10× ULN, international normalized ratio (INR) ≥1.4, or serum creatinine ≥1.5 mg/dL.
9.
Creatine phosphokinase >5x ULN.
10. Platelet count <100 000/mm3.
11. LDL ≥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.
12. Inability to safely undergo a liver biopsy.
13. History of biliary diversion.
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14. Known positivity for human immunodeficiency virus infection.
15. Subjects with recent history (within 1 year of Day 1) of significant atherosclerotic cardiovascular disease
(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 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 atherosclerotic
cardiovascular disease and placement of cardiac pacemaker or defibrillator for reasons other
than atherosclerotic cardiovascular disease (eg, for treatment of atrial fibrillation subsequent to
nodal ablation) is not exclusionary.
16. Other medical conditions that may diminish life expectancy to <2 years, including known cancers
(except carcinomas in situ or other stable, relatively benign carcinomas).
17. Known substance abuse in the year before Screening.
18. Pregnancy, planned pregnancy, potential for pregnancy (ie, unwillingness to use effective birth control
during the study), or current or planned breast feeding.
19. Participated in a clinical research study with any investigational product being evaluated for the
treatment of diabetes, weight loss, or NASH in the 6 months before Day 1.
20. Received any investigational product not being evaluated for the treatment of diabetes, weight loss, or
NASH 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.
21. Previous exposure to OCA.
22. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant
with the study, is uncertain.
23. History of known or suspected clinically significant hypersensitivity to OCA or any of its components.
24. Any other condition that, in the opinion of the Investigator, would impede compliance or hinder
completion of the study.
25. Acute cholecystitis or acute biliary obstruction.
26. BMI >45 kg/m2 with at least 1 of the following comorbidities:
−
Hypertension with a blood pressure ≥140/90 mmHg if <60 years, ≥150/90 mmHg if ≥60 years,
or on antihypertensive medication
−
Hyperlipidemia defined as LDL cholesterol ≥160 mg/dL, total cholesterol ≥200 mg/dL, or on
lipid lowering medication
−
Type 2 diabetes per 2013 American Diabetes Association criteria.
Investigational Product, Dosage, and Mode of Administration: 
OCA tablet, 10 mg, oral administration 
OCA tablet, 25 mg, oral administration 


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Reference Therapy, Dosage, and Mode of Administration: 
Placebo tablet, matched in size and appearance to OCA tablets, oral administration 
Study Duration: 
The overall study duration is event driven and will be detennined by the time required to achieve approximately 
291 adjudicated events for the clinical outcomes composite endpoint in the OCA 25 mg and placebo groups 
combined for subjects with fibrosis stage 2 and stage 3, estin1ated to take approxin1ately 10 yeru·s. 
Intel'im Analysis Criteria for Evaluation: 
Interim Analyses Variables 
Assessments 
Primarv Objective Assessed at the Month 18 Interim Analvsis (All Snbiects) 
Improvement in fibrosis with no 
worsening of NASH 
Resolution of NASH with no 
worsening of fibrosis 
A reduction in fibrosis stage of at least 1 with no increase in hepatocellular 
ballooning, lobular inflammation or steatosis from baseline based on liver biopsy 
using NASH CRN criteria 
NASH resolution defined as the overall histopathologic inte1pretation 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 with no 
increase in fibrosis stage from baseline based on liver biopsy using NASH CRN
criteria 
Secondarv Objectives A<Jsessed at the Month 18 Interim Analvsis (All Sobjeds) 
Improvement of fibrosis by at least 
1 stage AND/OR resolution of 
ASH_, without worsening of either 
o worsening of fibrosis AND no
worsening of NASH 
Improvement in each key 
histological feature of NASH 
Improvement of fibrosis by at least 
2 stages 
Improvement in AS by at least 
2 points ,vith no worsening of 
fibrosis 
Improvement of fibrosis and 
resolution of NASH as a composite 
endpoint and as defined by both 
endpoints being met in the same 
subject 
Resolution of fibrosis 
Histological progression to 
ci11·hosis 
Liver biochemistry and markers of 
liver fonction 
Confidential and Proprietary 
A reduction in fibrnsis stage of at least 1 with no increase in hepatocellular 
ballooning, lobular inflammation or steatosis from baseline based on live-r biopsy 
using NASH CRN criteria AND/OR NASH resolution defined as the overall 
histopathologic inte1pretatio11 of 1) "no fatty liver disease·• or 2) "fatty liver disease 
(simple or isolated steatosis) without steatohepatitis'' AND a NAS of O for 
ballooning and 0-1 for inflammation with no increase in fibrosis stage from 
baseline based on liver biopsy using NASH CRN criteria 
No increase from baseline in fibrosis stage AND no increase in hepatocellular 
ballooning, lobular inflammation or steatosis based on liver biopsy using ASH 
CRN criteria 
A reduction in score of at least 1 from baseline for steatosis, lobular inflammation, 
or hepatocellular ballooning based on liver biopsy using ASH CRN criteria 
A reduction from baseline in fibrosis of at least 2 stages at Month 18 based on liver 
biopsy using NASH CRN criteria 
A reduction in NAS by at least 2 points with no increase in fibrosis stage from 
baseline base.cl on liver biopsy using NASH CRN crite1i.a 
A reduction from baseline in fibrosis stage of at least 1 and resolution of ASH as 
defined above 
A fibrosis stage of O based on liver biopsy using ASH CRN criteria 
A fibrosis stage of 4 based on liver biopsy using ASH CRN criteria 
ALT, AST, GOT, ALP, total and direct bilirubin, albumin INR, and platelets 


Protocol 747-303 
Adjudicated cardiovascular events 
for cardiovascular outcomes 
assesSlllent 
Safety and tolerability 
EOS Ciiteria for Evaluation: 
End of Study Analyses Val'iables 
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Cardiovascular events including core MACE (cardiovascular death, nonfatal 
myocardial infarction. nonfatal stroke), expanded MACE (unstable angina 
requiring hospitalization, transient ischemic attack, peripheral or c-0ronaiy 
revascularization procedures, hospitalization for congestive heart failure). Other 
events potentially related to adverse cardiovascular outcomes as defined in 
Appendix. E and included in the CAC charter will be sent to the CAC for 
adjudication. 
TEAEs, ECGs, vital signs. clinical laborat01y assessments (including lipid profile 
changes) 
Assessments 
Priman Objective Assessed at EOS (All Subjects) 
Clinical outcomes composite 
endpoint 
Confidential and Proprieta1y 
Time to first occurrence of any of the following adjudicated events: death (all 
cause); MELD score 2:15; liver transplant; hospitalization (as defined by a stay of 
ɳ24 hours) for onset of variceal bleed, hepatic encephalopathy (as defined by a 
West Haven score ofɴ2), or spontaneous bacterial peritonitis (con.fumed by 
diagnostic aracentesis : ascites secon 
to cirrhosis and re uirin medical 


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intervention (eg, diuretics or paracentesis); or progression to cinhosis 
Secondan Objective Assessed at EOS (All Subjects) 
Improvement in fibrosis with no 
worsening of ASH 
Resolution of ASH 'with no 
worsening of fibrosis 
Improvement of fibrosis by at least 
I stage AND/OR resolution of 
ASH, without worsening of either 
o worsening of fibrosis AND no
worsening of ASH 
Improvement of fibrosis by at least 
2 stages 
Improvement in each key 
histological feature of NASH 
Improvement in AS by at least 
2 points "\vith no worsening of 
fibrosis 
Improvement of fibrosis and 
resolution of ASH as a composite 
endpoint and as defined as both 
endpoints being met in the sat11e 
subject 
Resolution of fibrosis 
Liver biochemistry and markers of 
liver function 
Confidential and Prop1ietary 
A reduction from baseline in fibrosis of at least 1 stage and no increase in 
hepatocellular ballooning, lobular inflammation or steatosis based on liver biopsy 
using NASH CRN criteria 
NASH resolution defined as the overall histopathologic inte1pretation of 1) "no 
fatty liver disease·• or 2) "fatty liver disease (simple or isolated steatosis) without
steafohepatitis" AND a NAS of0 for ballooning and 0-1 for inflammation with no 
increase in fibrosis stage from baseline based on liver biopsy using NASH CRN 
criteria 
A reduction in fibrosis stage of at least 1 with no increase in hepalocellular 
ballooning, lobular inflammation or steatosis from baseline based on liver biopsy 
using NASH CRN criteria AND/OR NASH resolution defined as the overall 
histopathologic inte1pretation of 1) "no fatty liver disease" or 2) "fatty liver disease 
(sin1ple or isolated steatosi) without steatohepatitis" AND a NAS of0 for 
ballooning and 0-1 for inflammation 'with no increase in fibrosis stage from 
baseline based on liver biopsy using NASH CRN criteria 
No increase from baseline in fibrosis stage AND no increase in hepatocellular 
ballooning, lobular inflaimnation or steatosis based on liver biopsy using ASH 
CRN criteria 
A reduction from baseline in fibrosis of at least 2 stages based on liver biopsy 
using NASH CRN criteria 
A reduction in score of at least 1 from baseline for steatosis, lobular inflannnation, 
or hepatocellular ballooning based on liver biopsy using NASH CRN criteria 
A reduction in NAS by at least 2 points with no increase in fibrosis stage. from 
baseline based on liver biopsy using NASH CRN criteria 
A reduction from baseline in fibrosis stage of at least I using NASH CRN c1ite1ia 
and resolution of NASH as defined above. 
A fibrosis stage of 0 based on liver biopsy using NASH CRN criteria 
ALT, AST. GGT, ALP, total and direct bilimbin, albumin, INR, ai1d platelets 


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Pa e 16 
Safetv Objectives Assessed at EOS (All Subjects) 
Adjudicated cardiovascular events
for cardiovascular outcorn.es
assessn1ent
Adjudicated events of hepatic
lllJIDY
Cardiovascular events including core MACE (cardiovascular death, nonfatal
rn.yocardial infarction, nonfatal stroke) and expanded MACE (m1stable angina
requiring hospitalization, transient ischemic attack, peripheral or coronary 
revascularization procedures hospitalization for congestive heait failure and
an-hythmias). Any hospitalization (2:24 hours) where a cause has not been
identified by the Investigator will be treated as a cardiovascular event and sent for
adjudication. Other events potentially related to adverse cardiovascular outcomes 
as defined in Appendix E in the protocol and included in the CAC charter v.rill be
sent to the CAC for adjudication
Incidence of adjudicated events of hepatic injmy
Adjudicated events of acute kidney 
Incidence of adjudicated events of acute kidney injury
llljllfY
Long-teru1 safety and tolerability 
TEAEs, ECGs, vital signs, clinical laborat01y assessments (including lipid profile
changes) 
ALP = alkaline phosphatase; ALT = alanine aminotransferase:
aminotransferase;
-d' d' at:ion Committee; 
EOS = end of stu y;
events; MELD = model of en stage
-
AFLD = nonalcoholic fa
treatment-emergent adverse event; 
Statistical Methods: 
Enrnllment and Randomization 
Subjects will be randomized in a I: 1: I ratio to placebo, OCA 10 mg, or OCA 25 mg. The study will enroll 
approxilllately 2370 subjects with NASH. The population will comprise approxilllately 2085 subjects with 
biopsy-confumed, noncin·hotic NASH and evidence of stage 2 or stage 3 liver fibrosis, including approximately 
60% with fibrosis stage 3 and approxilllately 40% with fibrosis stage 2; and an additional coh01t of 
approximately 285 subjects with stage I fibrosis with at least 1 accompanying comorbidity to gather inf01mation 
on the safety of OCA and progression of liver disease in this population. 
Randomization of subjects with fibrosis stage 2 or stage 3 will be stratified by presence of type 2 diabetes at 
enrollment (yes/no) and use of TZDs/glitazones or vitamin E at baseline (yes/no). 
P1imary Analysis Populations (For· End-of-Study Analysis) 
Intent-to-Treat (ITT) Population: 
The ITr Population will include all randomized subjects with fibrosis stage 2 or stage 3 who receive at least 
1 dose of investigational product (OCA or placebo). The ITT Population will be the primaiy population used for 
efficacy analyses. Treatment assigmnent will be based on the randomized treatment. 
Full Analysis Population: 
The Full Analysis Population will include all randomized subjects, all fibrosis stages. who receive at least 1 dose 
of investigational product (OCA or placebo). Treatment assignment will be based on the randomized treatment. 
Per-Protocol (PP) Population: 
The 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. 
Confidential and Proprietary 


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Safety Population: 
The Safety Population will include all randomized subjects, all fibrosis stages, 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. 
PK Population: 
The PK Population will include all OCA subjects who have at least 1 confirmed fasted analyzable sample.  
Subjects must have been fasting for approximately 8 hours before the visit and must not have any major protocol 
deviations that potentially affect exposure levels.  The PK Population will be used for OCA PK and PK/PD 
analyses. 
Additional information regarding the data cutoff date for the Month 18 Interim Analysis population will be 
defined in the SAP.  
Analyses 
Efficacy Analyses: 
All efficacy hypothesis testing will be based on the ITT population including only fibrosis stage 2 and 
stage 3 subjects.  Supportive analyses will be conducted using PP population and all fibrosis stages (Full Analysis 
Population).  
The 2-sided alpha allocated to all testing in this single study will be 0.05.  The histological endpoints will be 
tested at the Month 18 Interim Analysis with alpha level of 0.02.  The primary clinical outcomes endpoint will be 
tested with a minimum alpha level of 0.03 and this may be augmented by recycled alpha from the Month 18 
interim analysis.   
For the Month 18 Interim Analysis, multiplicity adjustment will be implemented to control the type 1 error. 
Details will be provided in the SAP. 
Primary Efficacy Analysis at the Month 18 Interim Analysis: 
The primary efficacy analysis for fibrosis improvement at Month 18 will test the following hypotheses using the 
ITT population (the ITT population for the Month 18 Interim Analysis is not the same as that for the overall study 
and is defined in the SAP): 
•
H01:  The percentage of subjects with fibrosis improvement by at least 1 stage with no worsening of NASH is
equal between placebo and OCA 25 mg.
•
H11:  The percentage of subjects with fibrosis improvement by at least 1 stage with no worsening of NASH is
different between placebo and OCA 25 mg.
The primary efficacy analysis for the resolution of NASH will test the following hypotheses: 
•
H02:  The percentage of subjects with resolution of NASH and no worsening of fibrosis is equal between
placebo and OCA 10 mg.
•
H12:  The percentage of subjects with resolution of NASH and no worsening of fibrosis is different between
placebo and OCA 10 mg.
The primary efficacy analyses at the Month 18 Interim Analysis will compare placebo and OCA using a 
Cochran–Mantel–Haenszel test stratified by the randomization strata (presence of type 2 diabetes at enrollment 
[yes/no] and use of TZDs/glitazones or vitamin E at baseline [yes/no]).  Subjects with missing histology results at 
Month 18, will be considered non-responders.  Post-baseline biopsies at early termination visit (prior to Month 
18) will be included in the analysis regardless of the timing of the biopsy.
Secondary Efficacy Analyses at the Month 18 Interim Analysis:
Histology Analysis 
Secondary efficacy endpoints at the Month 18 Interim Analysis are: 
•
Improvement of fibrosis by at least 1 stage AND/OR resolution of NASH, without worsening of either
•
No worsening of fibrosis AND no worsening of NASH


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•
Percentage of subjects with improvement in each key histological feature of NASH by at least 1 point
(steatosis, lobular inflammation, and hepatocellular ballooning).
•
Percentage of subjects with improvement of fibrosis by at least 2 stages
•
Percentage of subjects with improvement in NAS by at least 2 points with no worsening of fibrosis
•
Improvement of fibrosis and resolution of NASH as a composite endpoint and as defined by both endpoints
being met in the same subject
•
Resolution of fibrosis
•
Histological progression to cirrhosis
Primary Efficacy Analysis at EOS: 
The primary efficacy endpoint at the end of the study will evaluate the effect of OCA (10 mg and 25 mg) 
compared to placebo on the clinical outcomes composite endpoint including all-cause mortality and liver-related 
clinical outcomes, as listed under the objectives for EOS section above.  Only adjudicated events will be included 
in analyses.     
The hypothesis test for the clinical outcomes composite endpoint is: 
•
H0:  The time to first occurrence of any of the adjudicated events including all-cause mortality and
liver-related clinical outcomes is equal between placebo and OCA.
•
H1:  The time to first occurrence of any of the adjudicated events including all-cause mortality and
liver-related clinical outcomes is different between placebo and OCA.
The hypothesis testing for this primary efficacy endpoint at EOS will be conducted with control of Type 1 error 
(OCA 25 mg, then 10 mg).  
Placebo and each OCA dose will be compared separately using a log rank test stratified by the randomization 
stratification factor.  The primary efficacy analyses at EOS will compare placebo and OCA, using a 
Cochran-Mantel-Haenszel (CMH) test stratified by the randomization strata (type 2 diabetes at enrollment 
[yes/no] and use of TZDs/glitazones or vitamin E at baseline [yes/no]).  The hazard ratio and 95% confidence 
interval will be determined based on a Cox regression model stratified by randomization strata to estimate the 
magnitude of the effect.   
Secondary Efficacy Analyses at EOS: 
Histology Analysis 
•
Improvement in fibrosis by 1 stage or more, with no worsening of hepatocellular ballooning, no worsening of
lobular inflammation, and no worsening of steatosis
•
NASH resolution with no worsening of fibrosis
•
Improvement of fibrosis by at least 1 stage AND/OR resolution of NASH, without worsening of either
•
No worsening of fibrosis AND no worsening of NASH
•
Percentage of subjects with improvement in each key histological feature of NASH by at least 1 point
(steatosis, lobular inflammation, and hepatocellular ballooning).
•
Percentage of subjects with improvement of fibrosis by at least 2 stages
•
Percentage of subjects with improvement in NAS by at least 2 points with no worsening of fibrosis
•
Improvement of fibrosis and resolution of NASH as a composite endpoint and as defined by both endpoints
being met in the same subject
•
Resolution of fibrosis
Interim Analyses of Clinical Outcomes Post Month 18 Interim Analysis:
There will be 2 planned interim analyses to be conducted using group sequential approach in accordance to the 
SAP and DMC Charter at the accumulation of 50% and 80% of the total planned 291 adjudicated clinical 


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outcome events.  The primary efficacy endpoint for these planned interim analyses will be the clinical outcomes 
composite endpoint.  
If either of these 2 interim analyses is significant, then all analyses described in Section 16.4 will be carried out. 
Safety Analyses: 
Safety data, including TEAEs, adjudicated cardiovascular outcomes including MACE, vital signs, ECGs, and 
clinical laboratory results will compare OCA (10 mg and 25 mg) and placebo at the Month 18 Interim Analysis 
and at EOS.  


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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF
FIGURES
TABLE OF CONTENTS 
1.
TITLE PAGE ................................................................................................................1 
2.
SYNOPSIS ...................................................................................................................5 
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............20 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................28 
5.
INTRODUCTION ......................................................................................................32 
5.1. 
Overview of Nonalcoholic Steatohepatitis and Obeticholic Acid ..............................32 
5.2. 
Nonclinical Experience with Obeticholic Acid ..........................................................33 
5.3. 
Clinical Experience with Obeticholic Acid ................................................................34 
5.4. 
Rationale for Study Design .........................................................................................35 
5.4.1. 
Rationale for Placebo Control Group .........................................................................36 
5.4.2. 
Rationale for OCA Dose .............................................................................................36 
5.5. 
Summary of Known Potential Risks with Investigational Product ............................36 
5.6. 
Importance of Monitoring of Disease Progression .....................................................38 
6.
STUDY OBJECTIVES AND PURPOSE ..................................................................38 
6.1. 
Primary Objective Assessed at Month 18 Interim Analysis .......................................38 
6.2. 
Secondary Objectives Assessed at Month 18 Interim Analysis .................................38 
6.4. 
Primary Objective Assessed at End of Study .............................................................40 
6.5. 
Secondary Objectives Assessed at End of Study ........................................................40 
6.7. 
Safety Objectives Assessed at End of Study ..............................................................41 
7.
INVESTIGATIONAL PLAN .....................................................................................41 
7.1. 
Overall Study Design ..................................................................................................41 
7.1.1. 
Study Design Diagram ................................................................................................43 
7.1.2. 
Schedule of Study Procedures ....................................................................................44 
7.1.3. 
Study Duration ............................................................................................................50 
7.2. 
Number of Subjects ....................................................................................................50 
7.3. 
Treatment Assignment ................................................................................................50 
7.4. 
Monitoring and Management of Potential Hepatic Injury and/or 
Decompensation .........................................................................................................50 


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7.4.1. 
Drug-Induced Liver Injury .........................................................................................51 
7.4.2. 
Progression of Disease to Cirrhosis ............................................................................57 
7.4.2.1. 
Child-Pugh Assessment ..............................................................................................58 
7.4.2.2. 
Model for End-Stage Liver Disease (MELD) Scoring ...............................................59 
7.4.3. 
Close Observation .......................................................................................................60 
7.4.4. 
Pruritus ........................................................................................................................61 
7.5. 
Medical Management of Subjects with Symptomatic Cholelithiasis and/or 
Cholecystitis or Pancreatitis .......................................................................................61 
7.5.1. 
Symptomatic Cholelithiasis and/or Cholecystitis .......................................................61 
7.5.2. 
Pancreatitis ..................................................................................................................62 
7.6. 
Monitoring for Renal Impairment and Nephrolithiasis ..............................................62 
7.6.1. 
Renal Impairment .......................................................................................................62 
7.6.2. 
Nephrolithiasis ............................................................................................................64 
7.7. 
Investigational Product Adjustment, Interruption, and Discontinuation 
Criteria ........................................................................................................................65 
7.8. 
Criteria for Study Termination ...................................................................................67 
7.9. 
Subject Retention ........................................................................................................68 
8.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................68 
8.1. 
Subject Population ......................................................................................................68 
8.1.1. 
Subject Inclusion Criteria ...........................................................................................68 
8.1.2. 
Subject Exclusion Criteria ..........................................................................................69 
8.2. 
Subject Withdrawal Criteria .......................................................................................71 
8.2.1. 
Other Reasons for Discontinuation of Investigational Product ..................................72 
8.2.2. 
Withdrawal of Consent and Requirements to Re-Enter the Study .............................73 
8.2.3. 
Lost to Follow-up .......................................................................................................73 
8.2.4. 
Subject Discontinuation Notification .........................................................................73 
9.
TREATMENT OF SUBJECTS ..................................................................................73 
9.1. 
Investigational Product Treatment Regimen ..............................................................73 
9.2. 
Lifestyle Modification Counseling .............................................................................74 
9.3. 
Standard of Care and Concomitant Medications ........................................................74 
9.3.1. 
Bile Acid Sequestrants ................................................................................................75 
9.3.2. 
Other Concomitant Medications .................................................................................75 
9.3.3. 
Standard of Care:  Management of Dyslipidemia ......................................................75 


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9.3.4. 
Standard of Care:  Management of Hyperglycemia ...................................................76 
9.4. 
Treatment Compliance ................................................................................................77 
9.5. 
Randomization and Blinding ......................................................................................77 
9.5.1. 
Emergency Unblinding Procedures ............................................................................78 
9.6. 
Assignment of Site and Subject Numbers ..................................................................78 
9.6.1. 
Site Numbers ..............................................................................................................78 
9.6.2. 
Subject Numbers .........................................................................................................79 
9.7. 
Restrictions .................................................................................................................79 
9.8. 
Highly Effective Contraception ..................................................................................79 
9.9. 
Visit Procedures ..........................................................................................................79 
9.9.1. 
Visit Windows ............................................................................................................79 
9.9.2. 
Informed Consent Procedures .....................................................................................80 
9.9.3. 
Screening Visit Procedures (≤12 weeks before Day 1) ..............................................81 
9.9.4. 
Day 1 Procedures (Randomization) ............................................................................82 
9.9.5. 
Month 1, 3, 9, and 15 Procedures ...............................................................................84 
9.9.6. 
Month 6 and Month 12 Procedures ............................................................................86 
9.9.7. 
Month 18 Procedures ..................................................................................................88 
9.9.8. 
Semi-Annual Visit Procedures ...................................................................................90 
9.9.8.1. 
Semi-Annual Procedures (Months 24, 30, 36, 42, 48, 54, 60, 66, 72, 78 and 
every 6 months until the EOS) ....................................................................................90 
9.9.8.2. 
Month 48 Visit Procedures .........................................................................................92 
9.9.8.3. 
Additional Annual Procedures (Months 30, 42, 54, 66, 78 and every 12 
Months until the EOS) ................................................................................................94 
9.9.9. 
End of Study and/or End of Treatment Procedures for Subjects that 
Withdraw from Investigational Product or Withdraw Consent ..................................94 
9.9.10. 
Unscheduled Safety Visit ...........................................................................................97 
10.
STUDY MANAGEMENT DURING COVID-19 ......................................................98 
10.1. 
Alternative Approaches for Study Conduct Due to COVID-19 .................................98 
11.
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT ...........100 
11.1. 
Investigational Product .............................................................................................100 
11.2. 
Investigational Product Packaging and Labeling .....................................................100 
11.3. 
Investigational Product Storage ................................................................................100 
11.4. 
Investigational Product Administration ....................................................................100 


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11.5. 
Investigational Product Accountability and Disposal ...............................................100 
12.
OVERVIEW OF ASSESSMENTS ..........................................................................101 
13.
ASSESSMENTS OF EFFICACY ............................................................................104 
13.1. 
Liver Biopsies ...........................................................................................................104 
13.1.1. 
Central Reading of Liver Histology .........................................................................105 
13.2. 
Prospective Surveillance ...........................................................................................106 
13.4. 
Efficacy Laboratory Assessments .............................................................................106 
13.7. 
Assessments for the Various Subsets of Subjects .....................................................107 
13.7.2. 
Microbiome/Metabolome Analysis ..........................................................................108 
13.8. 
Blood Samples for Future Analysis ..........................................................................108 
14.
CLINICAL PHARMACOLOGY ASSESSMENTS ................................................108 
14.1. 
Pharmacokinetics ......................................................................................................108 
14.1.1. 
Serial PK Assessment ...............................................................................................109 
14.1.2. 
Subjects Who Develop Cirrhosis and Child-Pugh Class A ......................................109 
14.1.2.1. 
Subjects Who Interrupt or Discontinue Investigational Product due to 
Cirrhosis or Hepatic Injury .......................................................................................109 
15.
ASSESSMENTS OF SAFETY ................................................................................110 
15.1. 
Adverse Events and Serious Adverse Events ...........................................................110 
15.1.1. 
Definition of Adverse Events ...................................................................................110 
15.1.1.1. 
Adverse Event ...........................................................................................................110 
15.1.1.2. 
Treatment-Emergent Adverse Event ........................................................................110 
15.1.1.3. 
Serious Adverse Event ..............................................................................................110 
15.1.2. 
Suspected Unexpected Serious Adverse Reaction ...................................................111 
15.1.3. 
Relationship to Investigational Product ....................................................................111 
15.1.4. 
Relationship to Liver Biopsy ....................................................................................112 
15.1.5. 
Recording Adverse Event Severity ...........................................................................112 
15.1.5.1. 
Severity of Pruritus (as an AE) .................................................................................113 
15.1.6. 
Reporting of Adverse Events and Serious Adverse Events ......................................114 
15.1.6.1. 
Reporting of Adverse Events ....................................................................................114 
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15.1.6.2. 
Reporting of Serious Adverse Events .......................................................................114 
15.1.7. 
Potential Liver-Related Clinical Outcome Events ....................................................115 
15.1.8. 
Additional Investigator Responsibilities for SAEs ...................................................116 
15.1.9. 
Notification of Post-Treatment SAEs for Subjects Who Continue in the 
Study .........................................................................................................................116 
15.1.10. 
Notification of Post-Study SAEs ..............................................................................116 
15.1.11. 
Follow-Up of AEs and SAEs ....................................................................................116 
15.1.12. 
Pregnancy and Follow-Up ........................................................................................117 
15.2. 
Other Safety Parameters ...........................................................................................118 
15.2.1. 
Medical History/Demographics ................................................................................118 
15.2.2. 
Physical Examination ...............................................................................................118 
15.2.3. 
Vital Signs ................................................................................................................118 
15.2.4. 
Electrocardiogram .....................................................................................................118 
15.2.5. 
Alcohol Consumption, Smoking Habits, and Caffeine Consumption ......................118 
15.2.6. 
Laboratory Assessments ...........................................................................................118 
16.
STATISTICS ............................................................................................................120 
16.1. 
Primary Analysis Populations (For End-of-Study Analysis) ....................................121 
16.2. 
Determination of Sample Size ..................................................................................121 
16.3. 
Efficacy Analysis at Month 18 Interim Analysis .....................................................123 
16.3.1. 
Primary Efficacy Analysis ........................................................................................123 
16.3.2. 
Secondary Efficacy Analyses ...................................................................................124 
16.3.2.1. 
Histology Analysis ....................................................................................................124 
16.3.2.2. 
Liver Biochemistry and Liver Function ...................................................................124 


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16.4. 
Efficacy Analyses at End of Study ...........................................................................127 
16.4.1. 
Primary Efficacy Analysis ........................................................................................127 
16.4.2. 
Secondary Efficacy Analyses ...................................................................................128 
16.4.2.1. 
Histology Analysis ....................................................................................................128 
16.4.2.2. 
Liver Biochemistry and Liver Function ...................................................................128 
16.5. 
Interim Analyses Post Month 18 Interim Analysis ...................................................129 
16.6. 
Handling of Missing Data .........................................................................................129 
16.6.1. 
Time to Event Endpoints ..........................................................................................130 
16.6.2. 
Quantitative Endpoints .............................................................................................130 
16.6.3. 
Responder Endpoints ................................................................................................130 
16.7. 
Multiple Comparisons/Multiplicity ..........................................................................130 
16.7.1. 
Multiplicity Adjustment for the Month 18 Interim Analysis ....................................130 
16.7.2. 
Multiplicity Adjustment for Interim (Post Month 18 Interim Analysis) and 
EOS Analyses ...........................................................................................................130 
16.8. 
Examination of Subgroups .......................................................................................131 
16.9. 
Safety Analysis .........................................................................................................131 
16.9.1. 
Adverse Events .........................................................................................................131 
16.9.2. 
Hepatic and Renal Safety Adjudication ....................................................................131 
16.9.3. 
Cardiovascular Event Adjudication ..........................................................................131 
16.9.4. 
Cardiovascular Risk Assessments ............................................................................133 
16.9.5. 
Clinical Laboratory Evaluations ...............................................................................133 
16.9.6. 
Lipoprotein Evaluations ............................................................................................133 
16.9.7. 
Additional Safety Analysis .......................................................................................133 
16.9.7.1. 
Vital Signs ................................................................................................................133 
16.9.7.2. 
Electrocardiograms ...................................................................................................134 
16.10. 
Data Monitoring Committee .....................................................................................134 
16.11. 
Adjudication Committees .........................................................................................135 
17.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .......................................136 
17.1. 
Study Monitoring ......................................................................................................136 
17.2. 
Audits and Inspections ..............................................................................................136 
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17.3. 
Documentation Associated with Interim Data ..........................................................137 
18.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................137 
19.
ETHICS ....................................................................................................................137 
19.1. 
Ethics Review ...........................................................................................................137 
19.2. 
Ethical Conduct of the Study ....................................................................................138 
19.3. 
Written Informed Consent ........................................................................................138 
19.4. 
Subject Confidentiality and Data Protection ............................................................138 
20.
INVESTIGATOR OBLIGATIONS .........................................................................139 
20.1. 
AE Reporting ............................................................................................................139 
20.2. 
Protocol Deviations ..................................................................................................139 
20.3. 
Regulatory Documentation .......................................................................................139 
20.4. 
Ethics Review (IRB or IEC) .....................................................................................139 
20.5. 
Archiving and Record Retention ..............................................................................140 
21.
PUBLICATION POLICY ........................................................................................140 
22.
REFERENCES .........................................................................................................142 
APPENDIX A. MANAGEMENT OF CHANGES IN CHOLESTEROL ................................146 
APPENDIX B. MANAGEMENT OF HYPERGLYCEMIA ...................................................149 
APPENDIX C. 
EDUCATION AND ASSESSMENT OF SIGNS/SYMPTOMS OF 
INTERCURRENT ILLNESS AND/OR POTENTIAL ADVERSE 
EVENTS AT EACH STUDY VISIT ..............................................................150 
APPENDIX D. COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ........153 
APPENDIX E. STANDARDIZED DEFINITIONS FOR CARDIOVASCULAR 
ENDPOINT EVENTS .....................................................................................234 
APPENDIX F. SUMMARY OF CHANGES: PROTOCOL 747-303 VERSION 11.0 
(DATED 04 MAY 2021) ................................................................................254 


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LIST OF TABLES 
Table 1: 
Schedule of Study Procedures ....................................................................................44 
Table 2: 
Liver Laboratory Criteria for Monitoring for Potential Hepatic Injury ......................54 
Table 3: 
Child-Pugh Scoring System ........................................................................................59 
Table 4: 
Criteria for Dose Adjustment, Interruption, Discontinuation and Rechallenge .........66 
Table 5: 
Visit Windows and/or Intervals ..................................................................................80 
Table 6: 
Early Discontinuation Scenarios .................................................................................95 
Table 7: 
NASH CRN Scoring System for Determining Eligibility and Primary 
Histological Endpoint Assessment ...........................................................................105 
Table 8: 
Relationship of Adverse Events to Investigational Product .....................................112 
Table 9: 
Relationship of Adverse Events to Liver Biopsy .....................................................112 
Table 10: Severity of Adverse Events ......................................................................................113 
Table 11: Severity of Pruritus ...................................................................................................113 
Table 12: List of Laboratory Analytes to be Tested .................................................................119 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................43 
Figure 2: 
Potential DILI Management Algorithm for Study 747-303 .......................................53 
Figure 3: 
Algorithm for Determining Progression to Cirrhosis .................................................58 
Figure 4: 
Algorithm for Monitoring Subjects for Potential Renal Impairment .........................63 
Figure 5: 
Therapeutic Targets for LDLc Based on Subject ASCVD Risk ................................76 
Figure A1: LDL Management Flow Chart ..................................................................................148 
Figure B2: Glucose-Lowering Medication in Type 2 Diabetes: Overall Approach ...................149 


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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and specialist terms are used in this protocol. 
Abbreviation or Specialist Term 
Explanation 
A1AT 
alpha-1-antitrypsin 
ADA 
American Diabetes Association 
AE 
adverse event 
AFP 
alpha-fetoprotein 
AKI 
acute kidney injury 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AUDIT 
Alcohol Use Disorders Identification Test 
 
BAS 
bile acid sequestrants 
β-hCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
BNP 
B-type natriuretic peptide
BUN 
blood urea nitrogen 
CI 
confidence interval 
CMH 
Cochran–Mantel–Haenszel 
CP 
Child-Pugh 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRN 
Clinical Research Network 
CS 
clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
1111 
•• 


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Abbreviation or Specialist Term 
Explanation 
DAP 
data access plan 
DILI 
drug-induced liver injury 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
EASD 
European Association of the Study of Diabetes 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EDC 
electronic data capture 
EGD
esophagogastroduodenoscopy 
EOS 
end of study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
 
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 
h 
hours 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen 
HCP 
healthcare provider 
HCV 
hepatitis C virus 
HDLc 
high-density lipoprotein cholesterol 
HSAC 
Hepatic Safety Adjudication Committee 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
• 
--
- - - - -
--


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Abbreviation or Specialist Term 
Explanation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IIEF-15 
International Index of Erectile Function 
IL-6 
interleukin-6 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISF 
Investigator site file 
ITT 
Intent-to-Treat 
IWRS 
interactive web response system 
IWQoL-Lite 
Impact of Weight on Quality of Life-Lite 
KM 
Kaplan-Meier 
LDLc 
low-density lipoprotein cholesterol 
LP(a) 
lipoprotein(a) 
LS 
least-square 
LTF 
lost to follow-up 
MACE 
major adverse cardiovascular events 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
model of end stage liver disease 
MW 
molecular weight 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
nonalcoholic fatty liver disease activity score 
NASH 
nonalcoholic steatohepatitis 
NCS 
not clinically significant 
NFS 
nonalcoholic fatty liver disease fibrosis score 
OCA 
obeticholic acid 
PAI-1 
plasminogen activator inhibitor-1 
PBC
primary biliary cirrhosis or primary biliary cholangitis 
-• 
-
• 


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Abbreviation or Specialist Term 
Explanation 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PLIN2 
perilipin 2 
PNPLA3 
patatin-like phospholipase domain-containing protein, 3 
PP 
per protocol 
PSC 
primary sclerosing cholangitis 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTcF 
QT interval corrected by the Fridericia’s formula 
RNA 
ribonucleic acid 
RR 
time between 2 consecutive R waves 
SAE
serious adverse event 
SAMM50 
sorting and assembly machinery component 50 homolog 
SAP
statistical analysis plan 
SAR
suspected adverse reaction 
SUSAR 
suspected unexpected serious adverse reaction 
T3 
triiodothyronine 
T4 
thyroxine 
TE 
transient elastography 
TM6SF2 
transmembrane 6 superfamily 2 
TNF-α 
tumor necrosis factor- α 
TSH 
thyroid stimulating hormone 
TZD 
thiazolidinedione 
ULN 
upper limit of normal 
VAS 
visual analogue scales 
wks 
Weeks 
• 
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5.
INTRODUCTION
5.1. 
Overview of Nonalcoholic Steatohepatitis and Obeticholic Acid 
Nonalcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the 
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 histological diseases, which progresses 
from simple steatosis to nonalcoholic steatohepatitis (NASH).  Up to one-third of these 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, 
 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).  Patients with 
NASH develop progressive fibrosis over a period of 4 to 6 years (Pagadala 2012) and 21% to 
26% of these patients develop cirrhosis in 8.2 years (Loomba 2013).  Between 38% and 45% of 
patients with NASH who have progressed to cirrhosis develop liver failure in 7 years to 10 years, 
and 2% to 5% of this population will develop 
per year 
(World Gastroenterology Organisation 2012).  Accumulating evidence suggests that patients 
with NASH can progress to 
, even in absence of apparent cirrhosis (Ertle 2011, 
Williams 2013).   
Despite the seriousness of the disease, especially when advanced fibrosis/cirrhosis is present, 
there are currently no approved pharmacologic treatments.  The current 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), although 
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.  
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).  CDCA is the natural ligand 
for FXR, which is a nuclear receptor expressed at high levels in the liver, intestine, kidney, and 
adrenal glands.  In the liver, FXR is expressed in hepatocytes, Kupffer cells, and endothelial 
cells, and at a low level in hepatic stellate cells.  Nuclear receptors constitute a family of 
ligand-activated transcription factors that can either activate or repress a variety of target genes. 
OCA’s potent FXR agonist effects make it an attractive novel therapeutic agent for NASH due to 
its multiple FXR-mediated actions, including prevention and reversal of liver fibrosis, anti-
inflammatory effects in liver and vasculature, and hepatocyte protection against bile acid-
induced cytotoxicity (Adorini 2012, Mudaliar 2013).  Thus, there is strong rationale to advance 
OCA for the treatment of NASH. 
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5.2. 
Nonclinical Experience with Obeticholic Acid 
Nonclinical studies have shown several potentially beneficial properties of FXR agonism in 
NASH, including: 
Effects of OCA on 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 (Mudaliar 2013, 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 addition, OCA and other FXR agonists are anti-atherogenic and cardioprotective in
animal models (Miyazaki-Anzai 2010, Hartman 2009).
Anti-inflammatory and anti-fibrotic effects of OCA: 
•
OCA exerts direct effects on serum-starved LX2 cells (an immortalized hepatic
stellate cell line) to reduce the expression of key fibrotic genes (collagen I, alpha-1
smooth muscle actin, transforming growth factor β-1 and matrix metalloproteinases)
(Albanis 2005).
•
In primary and cultured hepatocytes treated with pro-inflammatory mediators, OCA
exerted direct effects to inhibit pro-inflammatory gene expression (eg, tumor necrosis
factor-α [TNF- α], cyclooxygenase-2, and inducible nitric oxide synthase)
(Wang 2008).
•
FXR activation (with WAY-362450) reduced inflammatory cell infiltration and
hepatic fibrosis in a mouse model of NASH (Zhang 2009).
•
OCA improves portal hypertension in cirrhosis models (Mookerjee 2015).
•
OCA inhibits gastrointestinal inflammation and preserves intestinal barrier function
in models of inflammatory bowel diseases (Gadaleta 2011).
In summary, there is strong rationale to advance OCA for the treatment of NASH based on its 
FXR-mediated hepatoprotective properties and results indicating that OCA improves glycemia 
by increasing peripheral glucose uptake, enhances glucose-stimulated insulin secretion, and 
inhibits hepatic lipid synthesis and content while inducing lipid uptake by adipocytes.  


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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), primary sclerosing cholangitis (PSC), 
biliary atresia, and other chronic liver diseases.  Ocaliva has received marketing authorization in 
the United States, Europe, and Canada 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.  Please see the approved, region-specific 
labeling for more information including its specific marketing requirements. 
The clinical development program for OCA in subjects with NAFLD or NASH includes data 
from the following 3 studies, as well as 1 ongoing study with no data available yet: 
•
Study 747-203:  A proof-of-concept, Phase 2 study in subjects with type 2 diabetes
and 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.
•
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, placebo-controlled study investigating the effect of OCA
and atorvastatin treatment on lipoprotein metabolism in subjects with 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 pruritus general) 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 subjects from Study 747-203 
withdrew from the study due to pruritus.   
The FLINT study demonstrated that OCA was superior to placebo in improving not only the key 
histologic features important in the underlying pathophysiology of the disease (inflammation, 
ballooning, and steatosis), but notably that OCA was superior to placebo in improving fibrosis, a 
strong predictor of liver-related death.  OCA treatment was also associated with improvement in 
markers of hepatocellular injury and some cardiometabolic features, including weight and 
systolic blood pressure.  Salutary effects on weight and blood pressure are important 
considerations since patients with NASH present with higher cardiovascular risk given the 
comorbidities of obesity and diabetes.  On average, low-density lipoprotein (LDL) cholesterol 
demonstrated a modest but significant increase in 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 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.  


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The general adverse event (AE) profile was similar across both 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).  The number of pruritus-associated 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 LDL 
metabolism in subjects with NASH to better understand the lipid profile changes observed in the 
FLINT study.  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 10 mg atorvastatin 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 low-
density lipoprotein cholesterol (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. 
5.4. 
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 has become one of the leading 
causes of liver transplant (Wong 2020, Younossi 2020), highlighting the need for development 
of effective therapies that can improve steatohepatitis and resulting fibrosis, potentially delaying 
liver transplant or death.  In the FLINT study, OCA demonstrated statistically significant 
improvements over placebo in all individual features of steatohepatitis as well as fibrosis 
(Neuschwander-Tetri 2015) and merits further evaluation in a larger study.   
Given the slow natural history of progression for NASH, assessing clinical endpoints is a 
long-term endeavor.  Hence, Study 747-303 is designed to initially assess efficacy based on a 
surrogate endpoint to support a regulatory filing, and subsequently confirm the ability of OCA to 
confer clinical benefit over placebo.   
Enriching the population for Study 747-303 with a mix of subjects with more advanced and 
aggressive disease states serves to enroll subjects with the greatest unmet need and at highest risk 


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of disease progression, and increases the likelihood of accruing outcomes to confirm clinical 
benefit in a reasonable time frame. 
5.4.1. 
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 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.  Notably, accounting for the standard of care effect is critical 
when designing an outcome-based study conducted globally when there are regional differences 
in the treatment of subjects with NASH. 
5.4.2. 
Rationale for OCA Dose 
The dose of 25 mg was chosen based on prior studies in subjects with NAFLD and NASH 
(Study 747-203 and FLINT).  In Study 747-203, 64 subjects with type 2 diabetes and NAFLD 
were treated with placebo, OCA 25 mg or OCA 50 mg for 6 weeks.  Both doses were similarly 
efficacious.  Only mild constipation was seen more frequently in the 50 mg OCA group (24%) 
than the 25 mg OCA and placebo groups (0% each) in this 6-week, proof-of-concept study. 
The subsequent, Phase 2 randomized, double-blind FLINT study evaluated OCA 25 mg and 
placebo in subjects with NASH over 72 weeks.  While OCA was well-tolerated overall, there 
was an increased incidence of mostly mild or moderate pruritus in OCA-treated subjects 
compared to placebo-treated subjects.  Pruritus was also the most common AE associated with 
OCA in PBC studies, and has been shown to be dose related, warranting 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 the proposed NASH study in addition to the 25 mg dose. 
5.5. 
Summary of Known Potential Risks with Investigational Product 
The primary AE shown to be related to OCA is pruritus.  Pruritus has also been observed in 
clinical studies with OCA in other indications, as well as in healthy subjects, with the highest 
frequency observed in subjects with PBC.  The incidence and severity of pruritus have been 
shown to be dose dependent, but there is no evidence of association with stage or progression of 
underlying disease. 
The rate of progression and risk of decompensation is variable and may be rapid in certain 
patients, necessitating closer surveillance of patients at risk.  Recent safety findings in NASH 
clinical trials include 9 cases of hepatic decompensation 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 an SAE of variceal bleed, hepatic encephalopathy, 
or spontaneous bacterial peritonitis.  The fatal case was reported in a subject with cirrhosis and 
hepatic impairment at baseline; the subject was in the OCA 25 mg treatment group.   


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Key liver-related findings: 
•
eDISH analyses show no evidence of hepatic injury with OCA compared to placebo.
•
In PBC, hepatic AEs evaluated by Standardized MedDRA criteria showed a rate of
hepatic AEs higher in OCA-treated subjects compared with those treated with
placebo.  In NASH clinical trials, the incidence of hepatic TEAEs was similar
between OCA and placebo groups.  Serious hepatic TEAEs, however, occurred more
frequently with OCA 25 mg, as compared to OCA 10 mg and placebo
•
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 Classification.  While 1.5- and 1.7-fold increases in liver
concentrations of OCA are predicted for subjects with Child-Pugh Class B and C,
respectively, liver concentrations of OCA in subjects with Child-Pugh A are predicted
to be similar to those of healthy control subjects (1.1-fold increase).  In a hepatic
impairment study in NASH subjects with compensated 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).
•
Serious liver-related adverse reactions have been reported in postmarketing in PBC
patients with decompensated cirrhosis or Child-Pugh Class B or C hepatic
impairment when Ocaliva was dosed more frequently than the recommended starting
dosage of 5 mg once weekly.
OCA-related changes in serum lipids (decrease in high-density lipoprotein cholesterol [HDLc] 
and increase in LDLc) have been observed in healthy volunteers, in subjects with PBC and 
NASH, and in subjects with other underlying conditions.  However, the pattern and magnitude, 
as well as the clinical significance of these changes, are not well understood and clearly depend 
on a subject’s underlying condition and other comorbidities.  Although increases in LDLc have 
generally been considered to be associated with increased cardiovascular risk, it is not possible to 
draw conclusions regarding the cardiovascular effect of OCA-related changes in lipid profile 
given the concurrent positive effects of OCA on other metabolic factors such as a decrease in 
hs-CRP (in PBC studies), and relative improvement of triglyceride and very low-density 
lipoprotein (VLDL) cholesterol levels.  In order to better assess cardiovascular risk, longer 
treatment periods and larger numbers of subjects are necessary and are being studied further.   
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 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. 
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). 


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Following a request from the FDA, an ad hoc DMC review was held and the DMC 
recommended that: 
•
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. 
Refer to the IB 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; 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 subjects necessitating closer surveillance of subjects 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 will consistently and frequently assess individual 
subjects to determine on an ongoing basis the totality of a subject’s clinical profile, which 
includes careful evaluation of signs and symptoms of potential hepatic injury and/or 
decompensation coupled with rules-based laboratory monitoring. 
Subjects will be monitored for potential hepatic injury and/or decompensation and progression to 
cirrhosis (Section 7.4).  Criteria for implementing dosing adjustments, interruptions, or 
discontinuations, and close monitoring procedures postdose-adjustment are described in 
Section 7.4.3 and Section 7.7.  The more extensive monitoring is important given the elevated 
risk of decompensation and potential for higher hepatic exposure to OCA in this population. 
6.
STUDY OBJECTIVES AND PURPOSE
6.1. 
Primary Objective Assessed at Month 18 Interim Analysis 
•
To evaluate the effect of OCA compared to placebo on histological improvement in
NASH by assessing the following primary endpoints using NASH CRN scoring
criteria:
−
Improvement in fibrosis by at least 1 stage with no worsening of NASH, OR
−
Resolution of NASH with no worsening of fibrosis
6.2. 
Secondary Objectives Assessed at Month 18 Interim Analysis 
•
To evaluate the effect of OCA compared to placebo on histological improvement in
NASH by assessing the following using NASH CRN scoring criteria:


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−
Improvement of fibrosis by at least 1 stage AND/OR resolution of NASH,
without worsening of either
−
No worsening of fibrosis AND no worsening of NASH
−
Improvement in each key histological feature of NASH by at least 1 point
(steatosis, lobular inflammation, and hepatocellular ballooning)
−
Improvement of fibrosis by at least 2 stages
−
Improvement in NAFLD activity score (NAS) by at least 2 points with no
worsening of fibrosis
−
Improvement of fibrosis and resolution of NASH as a composite endpoint and as
defined by both endpoints being met in the same subject
−
Resolution of fibrosis
−
Histological progression to cirrhosis
•
To evaluate the effect of OCA compared to placebo on liver biochemistry and
markers of liver function


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−
Incidence of adjudicated cardiovascular events
−
Safety and tolerability (TEAEs, ECGs, vital signs, clinical laboratory
assessments)
6.4. 
Primary Objective Assessed at End of Study 
•
To evaluate the effect of OCA compared to placebo on 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):
−
Death (all cause)
−
Model of end stage liver disease (MELD) score ≥15
−
Liver transplant
−
Hospitalization (as defined by a stay of ≥24 hours) for onset of:
•
Variceal bleed
•
Hepatic encephalopathy (as defined by a West Haven score of ≥2)
•
Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
−
Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or
paracentesis)
−
Progression to cirrhosis
6.5. 
Secondary Objectives Assessed at End of Study 
•
To evaluate the effect of OCA compared to placebo on histological improvement in
NASH by assessing the following endpoints using NASH CRN scoring criteria:
−
Improvement in fibrosis by at least 1 stage with no worsening of NASH
−
NASH resolution with no worsening of fibrosis
−
Improvement of fibrosis by at least 1 stage AND/OR resolution of NASH,
without worsening of either
−
No worsening of fibrosis AND no worsening of NASH
−
Improvement in each key histological feature of NASH by at least 1 point
(steatosis, lobular inflammation, and hepatocellular ballooning)
−
Improvement of fibrosis by at least 2 stages


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−
Improvement in NAS by at least 2 points with no worsening of fibrosis
−
Improvement of fibrosis and resolution of NASH as a composite endpoint and as
defined by both endpoints being met in the same subject
−
Resolution of fibrosis
•
To evaluate the effect of OCA compared to placebo on liver biochemistry and
markers of liver function
6.7. 
Safety Objectives Assessed at End of Study 
•
To evaluate the effect of OCA compared to placebo on:
−
Incidence of adjudicated cardiovascular events
−
Incidence of adjudicated acute kidney injury (AKI) events
−
Incidence of adjudicated events of hepatic injury
−
Long-term safety and tolerability (TEAEs, ECGs, vital signs, and clinical
laboratory assessments)
7.
INVESTIGATIONAL PLAN
7.1. 
Overall Study Design
This Phase 3, double-blind, randomized, long-term, placebo-controlled, multicenter 
international study will evaluate the effect of OCA on histological improvements in NASH, 
all-cause mortality, and liver-related clinical outcomes.  The study will enroll approximately 
2370 subjects with NASH.  The population will comprise approximately 2085 subjects with 
biopsy-confirmed, noncirrhotic NASH and evidence of stage 2 or stage 3 liver fibrosis, including 


Protocol 747-303 
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Confidential and Proprietary 
approximately 60% with fibrosis stage 3 and approximately 40% with fibrosis stage 2; and an 
additional cohort of approximately 285 subjects with stage 1 fibrosis with at least 
1 accompanying comorbidity to gather information on the safety of OCA and progression of 
liver disease in this population.  
A planned Interim Analysis is to be performed when a minimum of 750 randomized subjects (the 
first sequential) with fibrosis stage 2 or stage 3 would have reached their actual/planned 
Month 18 Visit.  For the purpose of determining the timing of the Month 18 Interim Analysis, 
subjects that discontinue before their Month 18 visit are considered to have reached their 
Month 18 Visit and will be part of the Month 18 Interim Analysis cohort.  The cutoff for the 
Month 18 Interim Analysis cohort database lock will be defined in the SAP.  The study will be 
continued in a blinded fashion, and subjects will be followed for clinical outcomes to confirm 
clinical benefit.  Final analysis will evaluate the effect of OCA on mortality and liver-related 
clinical outcomes and long-term safety of OCA after the accrual of approximately 
291 adjudicated clinical outcomes composite events combined in the OCA 25 mg and placebo 
groups for subjects with fibrosis stage 2 or stage 3 (projected to take approximately 10 years in 
total).  Subjects are expected to have a minimum follow-up time of approximately 4 years.   
Subjects will be screened for a period of up to 12 weeks before entering the study.  
Approximately 2370 subjects with NASH who meet all eligibility criteria will be randomized to 
receive OCA 10 mg, OCA 25 mg, or matching placebo in a 1:1:1 ratio for the duration of the 
study, in conjunction with local standard of care.  Randomization of subjects with fibrosis 
stage 2 or stage 3 will be stratified by presence of type 2 diabetes at enrollment (yes/no) and use 
of thiazolidinediones (TZDs)/glitazones or vitamin E at baseline (yes/no).  Biopsy-confirmed 
NASH will be determined by central reading of liver histology at Screening, and all subsequent 
histology assessments will be performed centrally in a blinded fashion.  
Investigational product (ie, OCA or placebo) will be taken orally, with water, once daily.  
Subject safety and laboratory assessments will be evaluated at clinical visits occurring after the 
first month and once every 3 months following the initiation of treatment (Day 1) through 
Month 18.  Following the Month 18 visit, clinic visits will occur every 6 months for the 
remaining duration of the study. 
With the exception of liver transplant, if a subject experiences a suspected or confirmed clinical 
outcomes event, he or she should continue the regular visit schedule and continue taking 
investigational product as long as the subject has not met any of the criteria for discontinuation 
outlined in Section 7.7.  Subjects who discontinue investigational product are expected to be 
followed through to study closure (or at the discretion of the Sponsor).  Specific strategies to 
encourage continued subject participation in the study will be outlined in a Subject Retention 
Plan (Section 7.9).   


Protocol 747-303 
7 .1.1. 
Study Design Diagram 
Figure 1: 
Study Design Schematic 
11:1:1 Randomization 
Screening 
F12 Weeks 
EOS = end of study 
11 
0 
1 
3 
(Day 1) 
Months 
6 
9 
Standard of care 
12 
15 
Placebo 
OCA 25 mg 
18 
t 
Interim Analysis 1 
at Month 18 
(3750 subjects) 
Semi-annual l.isits 
48 
Version 11.0: 04May2021 
Pa e43 
EOS 
t 
Final Analysis 
After 291 Events• 
£ Biopsy (Subjects. without a liver biopsy performed within 6 months before Day 1 will have a biopsy at the second Screening 
Visit). 
• Number of adjudicated events accmed in placebo and OCA 25 mg groups combined.
Confidential and Proprietary 


Protocol 747-303 
7.1.2. 
Schedule of Study Procedures 
Table 1: 
Schedule of Study Procedures 
Screening
0
Study Visit (Relative to Day 1) 
1 
2•
(Day 1)
Visit Window (Relative to Visit
.$12wks
Day) 
pl'iorb 
STUDY PROCEDURES-ALL SUBJECTS
Fast ƚ8 h. Prior to Visit
X 
Informed Consent 
X
Medical History 
X
Physical Exam 
X
12-Lead Electrocardiogram
X 
Inclusion/Exclusion Criteria
X 
X 
Vital Signs and Body Weightg
X 
X 
--
I 
I 
AUDIT. Smoking Habits, Caffeine
X' 
X 
Consumption 
-
I
-
I
A&i 
X 
X 
X 
MELD Score 
X 
X 
1
±lwk
X 
X 
X 
X
CLINICAL AND LABORATORY EVALUATIONS' -ALL SUBJECTS
-t b"liary Ultrasoundk for-
and Gallbladder 
xi 
X"'
Assessment 
Confidential and Proprieta1y 
Month O to Month 18
3 
6 
9 
±2 wks 
±2wks 
±2wks
X 
X 
X 
X 
X 
X 
I 
X 
I 
I 
X 
X 
X 
X 
X 
X 
X 
12
15
18
-6wks
±2wks 
±2wks 
to +2 
wks 
X 
X 
X 
X 
X 
X 
X 
X 
I 
I 
X
X 
I 
I 
I 
I 
X 
X 
X 
X 
X 
X 
X
X 
Version 11.0: 04May2021 
Pa 0e44 
Month 24 to EOS
Semi-
Month
EOS/
Annual/
Annual 
48 
EOT'
±2wks
±4wks
±2 wksd 
x• 
X 
X 
xr
X 
X 
xr
X 
X 
x• 
X 
X 
I 
xr 
X 
X 
I 
I 
I 
x• 
X 
X 
x• 
X 
X 
x• 
X 


Protocol 747-303 
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Confidential and Proprietary 
Table 1: 
Schedule of Study Procedures (Continued) 
Study Visit (Relative to Day 1) 
Month 0 to Month 18 
Month 24 to EOS 
Screening 
0 
(Day 1) 
1 
3 
6 
9 
12 
15 
18 
Semi-
Annual/
Annual 
Month 
48 
EOS/ 
EOTc 
1 
2a 
Visit Window (Relative to Visit 
Day) 
≤12 wks 
priorb 
±1 wk 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
-6 wks
to +2
wks
±2 wks 
±4 wks 
±2 wksd 
AFP for 
X 
X 
X 
X 
X 
Xe 
X 
X 
Liver Biopsyn,aa 
X 
X 
X 
X 
Prior and Concomitant 
Medicationso 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
X 
Randomization/Treatment 
Assigned 
X 
Lifestyle Modification Counseling 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
Dispense Investigational Product 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
Administer Investigational Product 
Onsitep 
X 
Collect Bottles/Investigational 
Product 
Accountability/Compliance 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
X 
Serum Chemistry, Hematology, 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
X 
Educate Subjects on Signs and 
Symptoms of Potential Hepatic 
Injury or Decompensation 
X 
X 
X 
X 
X 
Xe,q 
Educate Subjects on Signs and 
Symptoms of Intercurrent Illness 
and/or Potential Adverse Events 
(Appendix C) 
Xe 
Evaluate Signs and Symptoms of 
Potential Hepatic Injury or 
Decompensation (Appendix C) 
X 
X 
X 
X 
X 
X 
X 
X 
Xe,q 
X 
X 
-


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Confidential and Proprietary 
Table 1: 
Schedule of Study Procedures (Continued) 
Study Visit (Relative to Day 1) 
Month 0 to Month 18 
Month 24 to EOS 
Screening 
0 
(Day 1) 
1 
3 
6 
9 
12 
15 
18 
Semi-
Annual/
Annual 
Month 
48 
EOS/ 
EOTc 
1 
2a 
Visit Window (Relative to Visit 
Day) 
≤12 wks 
priorb 
±1 wk 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
-6 wks
to +2
wks
±2 wks 
±4 wks 
±2 wksd 
Evaluate Signs and Symptoms of 
Intercurrent Illness and/or Potential 
Adverse Events (Appendix C) 
Xe 
X 
Assess Subjects per Potential DILI 
Management and Progression to 
Cirrhosisr,aa Algorithms 
X 
X 
X 
X 
X 
X 
X 
X 
Xe, q 
X 
X 
Creatine Phosphokinaseab 
X 
Thyroid Hormone (TSH) 
X 
X 
X 
Xf 
X 
X 
Free Fatty Acids 
X 
X 
X 
X 
X 
Xf 
X 
X 
Urinalysis 
X 
X 
X 
Xe 
X 
X 
Urine-Based β-hCG Pregnancy 
Testt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
X 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 


Protocol 747-303 
Version 11.0: 04May2021 
Table 1: 
Schedule of Study Procedures (Continued) 
Sh1dy Visit (Relative to Day 1) 
Visit 'Window (Relative to Visit 
Day) 
Cardiovascular Risk Scores (FRS, 
Reynolds score, SCORE, IO-year 
ASCVDRisk) 
Confidential and Proprieta1y 
Screening 
1 
2• 
Ī12 wks 
pl'io1•b 
0 
(Day 1) 
X 
Month 0 to Month 18 
1 
3 
6 
9 
12 
15 
18 
-6wks
±1 wk 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
to +2
wks
X 
X 
Pa 0e47 
Month 24 to EOS 
Semi­
Annual/ 
Annual 
Month 
48 
.EOSI 
EOT' 
±2 wks 
±4 wks 
±2 wksa 
X 
X 


Protocol 747-303 
Table 1: 
Schedule of Study Procedures (Continued) 
Study Visit (Relative to Day 1) 
Visit Window (Relative to Visit 
Day) 
Screening 
1 
2• 
::,12 wks 
prio1·b 
0 
(Day 1) 
Month O to Month 18 
1 
3 
6 
9 
12 
15 
±1 wk 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
±2 wks 
18 
-6wks 
to +2 
wks 
AST= aspartate aminotransferase: AUDIT= Alcohol Use Disorders Identific 
Test; P-hCG = beta human chorionic gonadotropin; 
Version 11.0: 04May2021 
Pa 0e 48 
Month 24 to .EOS 
Semi­
Annual/ 
Annual 
±2wks 
Month 
48 
±4wks 
EOS/ 
EOT' 
: BMI = bod mass inde 
;EOS= 
C vm • 
g=hepa 
; CP = Ch.ild-Puoh; C
RF = case re 011 form; DILi =
˥
·u 
-induced liver in"tu ; 
;h=hom·; 
; 
LD = model of en stage ver 1sease: 
; RNA= ribonucleic acid; wk(s) = week(s); 
•
ot reqmre 
or su ˦ects w o iave a a 10psy w1 un 6 mont s e ore Ran on11zahon 
ay 1 and can provide unstained slides. 
b Subjects will be enrolled in the study when informed co11Sent is obtained. Info1med co11Sent may be obtained and slides from a historical biopsy 1113Y be sent for central reading 
before conducting Visit 1 assessments and procedures without initiating the :Sl2-week Screening Period. 
c Study procedtll"es and assessments not required if done within 6 months of the EOT/EOS Visit. 
d For EOS, window is relative to the EOS date announced by the Spo11Sor, and the visit should be done as soon as possible upon study discontinuation. For EOT, visit should be as 
Confidential and Proprieta1y 


Protocol 747-303 
Version 11.0: 04May2021 
Pa 0e 49 
g Vital siims include body temperature, sitting heart rate, respiratory rate, and sitting blood pressure. 
h l
!!!l!!Lst circumference and hip circumference. Height measW"ed at Screening only. Body weight will be additionally collected at each visit that vital signs are assessed.
i AUDIT only. 
i AEs occurring after signine: of the !CF must be entered on the AE CRF. 
k For subjects who develop؛tudy, __ assessments for study visits after onset 0£111111 are not required. 
1 Hepatobiliary ultrasound؜ and؝ assessments at Screening is not required it:°from a recent historic ultrasonnd (within 3 months of screening) 
is available. 
m Ultrasound will be conducted to enhance- surveillance and for gallbladder assessment. If ultrasorn1d was not performed at Screening and the historic ultrasound is >3 
months from Day 1 pe1f01m a hepatobiliary ultrasound. 
n For subjects who develop potential liver-related clinical outcomes dW"ing the study, protocol-specified biopsies for study visits after onset of the potential outcome event may not 
be required. For any subject who develops an AE of hepatic injury or decompeusation, or if cirrhosis is suspected based on criteria other than biopsy or clinical outcomes (see 
Figure 3), a liver biopsy is recommended and should be discussed with the Medical Monitor. 
0 Prior me-dicati.ons taken within 6 months of Da 1 are to be recorded at Screenin and Da 1 onl . For all other visits, onl concomitant medications are to be recorded. 
After Month 18, subjects detennined to be at higher risk of progression or decompensation in the judgment of the Investigator may be monitored for signs and symptolllS of 
potential hepatic injury or decompensation more frequently than every 6 months (as frequently as needed) per discretion of tl1e Investigator and upon discussion with the Medical 
Monitor. 
r Perfonn targeted assessment of ascites and hepatic encephalopathy, if necessary. 
s Instruct the subject to fast ovemight (at least 8 hours) before each visit. Fasting is required before all study visits after screening, but water is permitted and subjects should 
ensure they are hydrated prior to study visits. Refer to Table 12 for a foll list of analytes to be tested.
1 Urine ؞-hCG pregnancy tests must be pe1fo11ned for females of childbearing potential before entiy. If positive, a confim1atory blood test must be pe1fo11ned. lithe blood test is 
also positive, the subject may not be enrolled in the study. (Additional testing may be conducted where required, regionally.) If a female study participant becomes pregnant 
while she is enrolled in the clinical study, she must intem1pt treatment with investigational product lllllllediately. 
u Assessed at EOT only for subjects that discontinue investigational product before or on Month 18 Visit.
v 2 PK blood samples (one colle.cted at the beginning of the visit and one at the end of the visit) should be collected at each scheduled visit after the Month 18Visit (Section 14.1).
In the days leading up to and including the visit day, subjects should maintain the regular daily tiniing of their IP dose administration ( eg, dosing every moming, dosing every 
aftemoon, dosing eve1y evening, etc). If the subject's regular daily dosing time occurs during the site visit, the subject should administer the dose at the study site and the time 
of dosing should be recorded in the eCRF. 
' ,. . 
ab Additional CPK samples may be collected if ALT, total bilirubin, or ALP are elevated (see Table 2). 
Confidential and Proprieta1y 


Protocol 747-303 
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Confidential and Proprietary 
7.1.3. 
Study Duration 
The overall study duration is event driven and will be determined by the time required to achieve 
approximately 291 adjudicated events for the clinical outcomes composite endpoint in the OCA 
25 mg and placebo groups combined for subjects with fibrosis stage 2 and stage 3, estimated to 
take approximately 10 years.   
7.2. 
Number of Subjects 
The study will enroll approximately 2370 subjects with NASH.  The population will comprise 
approximately 2085 subjects with biopsy-confirmed, noncirrhotic NASH and evidence of stage 2 
or stage 3 liver fibrosis, including approximately 60% with fibrosis stage 3 and approximately 
40% with fibrosis stage 2; and an additional cohort of approximately 285 subjects with stage 1 
fibrosis with at least 1 accompanying comorbidity to gather information on the safety of OCA 
and progression of liver disease in this population. 
At selected investigational sites, approximately 300 subjects will have the option to provide 
blood samples for measurement of OCA PK concentrations.  At selected centers where the 
devices are available, subjects may participate in 
measurements.  At study sites in the United States, subjects will have the option to provide stool 
samples for microbiome/metabolome analysis only if they provided baseline (Day 1) samples. 
7.3. 
Treatment Assignment 
Subjects will be randomized in a 1:1:1 ratio to receive placebo, OCA 10 mg, or OCA 25 mg 
(in a blinded manner) from Day 1 through study termination. 
7.4. 
Monitoring and Management of Potential Hepatic Injury and/or 
Decompensation 
AEs, signs and symptoms of potential hepatic injury or decompensation, and laboratory values 
will be reviewed at regular intervals as described in the following subsections (Section 7.4.1 to 
Section 7.4.2.1).  Based on the assessments of signs and symptoms of hepatic injury 
(Appendix C) and liver biochemistry, investigational product will be continued, interrupted, or 
discontinued per criteria discussed in Section 7.7, and close monitoring procedures will be 
implemented (refer to Section 7.4.3).  
In the event of a potential hepatic injury, the subject should be promptly brought into the clinic to 
undergo a complete evaluation including laboratory assessments, physical examinations, and 
review of signs and symptoms of potential hepatic injury or decompensation.   
The Investigator will educate each subject about recognizing the signs and symptoms of hepatic 
injury or decompensation and instruct each subject to contact the study site to report the onset of 
any of the 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. 


Protocol 747-303 
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Confidential and Proprietary 
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. 
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: 
•
Worsening or new pruritus
•
Decreased urine output, dizziness, or lethargy
Healthcare Provider (HCP) Interactions will be reported: 
•
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 (refer to Section 9.3)
•
Laboratory procedures or assessments performed by an HCP
Signs and symptoms of potential hepatic injury or decompensation should be followed by 
(1) evaluation of liver biochemistry for potential drug-induced liver injury (DILI)
(Section 7.4.1), (2) assessment for disease progression to cirrhosis (Section 7.4.2), (3) triggering
of investigational product interruption or discontinuation per criteria (Section 7.7),
(4) documentation in the AE eCRF or the SAE eCRFs (Section 15.1.5 and Section 15.1.6), and
(5) contact with the medical monitor.
7.4.1. 
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 16.11.  The specific criteria for 
identification and adjudication of potential hepatic injury events are described in the HSAC 
charter.  


Protocol 747-303 
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Confidential and Proprietary 
Liver biochemistries will be evaluated 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 in the event of signs or symptoms of potential hepatic injury,
decompensation, or if laboratory alerts have been triggered
It is important that the laboratory assessments be completed as required and that the central 
laboratory be used for assessments whenever possible.  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.  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 subjects using specific 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 2.  


Protocol 747-303 
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Confidential and Proprietary 
Figure 2: 
Potential DILI Management Algorithm for Study 747-303 
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. 
Laboratory assessments include:  ALT, ALP, direct and total bilirubin, INR. 
a Signs and symptoms of hepatic injury include severe fatigue, nausea, vomiting, right upper quadrant pain, fever, rash, and 
eosinophilia.  
b Lower severity treatment-emergent threshold criteria include the following from Table 2: 
1)
In subjects with normal/near normal ALT at baseline and treatment-emergent ALT ≥5x ULN, TB normal, or with
Gilbert’s:  no change in BL TB
2)
In subjects with elevated ALT at baseline and treatment-emergent ALT ≥3x BL or ≥300 U/L, whichever occurs first,
TB normal, or with Gilbert’s:  no change from BL TB
3)
In subjects with baseline ALP ≤ULN and treatment-emergent ALP ≥2x BL and >ULN but <250 U/L
4)
In subjects with baseline ALP >ULN and treatment-emergent ALP ≥2x BL but <300 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, the Medical Monitor should be promptly contacted upon awareness for consultation regarding management of 
the subject.
Liver Laboratory Assessment per Routine Study Site Visit or 
at Unscheduled Visit if Suspected of Hepatic lnjw-y 
Within Protocol-Specified 
Threshold Criteria 
Moolto1iog 
Outside of Protocol-Specified 
Threshold Criteria 
Prcscnce of Signs aod 
Symptoms of Hepatic 
lo' 
Lower Severity Tbn:shold Criteria Meil' 
and Subject Available for 
Prom t Evaluation< 
Outside Protocol-Specified 
Threshold Criteria 
Moolto1ing 
----------- _, 
Conduct PK Sampling; Physical Exam: 
Repeat Biochcmistty Labsc.• 
Within Protocol-Specified 
Threshold Criteria 
Monlto1ing 


Protocol 747-303 
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Confidential and Proprietary 
Table 2: 
Liver Laboratory Criteria for Monitoring for Potential Hepatic Injury 
Baseline 
Treatment Emergent 
Signs and 
Symptoms of 
Hepatic 
Injurya 
Action 
ALT Normal/Near 
Normalb
ALT ≥5x ULN 
TB normal 
Gilbert’sc:  no change in BL TB 
No 
•
Repeat laboratory testing
including CPK within 2-4 days
ALT ≥3x ULN 
Regardless of TB or DB 
Yes 
Interrupt 
• Repeat laboratory testing
including CPK within 2-4 days 
• Collect PK sample within 7 
days 
ALT ≥8x ULN 
Regardless of TB or DB 
No 
Interrupt 
• Repeat laboratory testing
including CPK within 2-4 days 
•
Collect PK sample within 7
days
ALT ≥3x ULN 
TB ≥2x ULN 
Gilbert’sc:  DB ≥2x ULN or INR 
>1.5
No 
Interrupt 
• Repeat laboratory testing
including CPK within 2-4 days 
•
Collect PK sample within 7
days
ALT Elevatedb 
ALT ≥3x BL or ≥300 U/L, 
whichever occurs first 
TB normal 
Gilbert’sc:  no change from BL 
TB 
No 
•
Repeat laboratory testing
including CPK within 2-4 days
ALT ≥2x BL or ≥300 U/L, 
whichever occurs first 
Regardless of TB or DB 
Yes 
Interrupt 
• Repeat laboratory testing
including CPK within 2-4 days 
• Collect PK sample within 7 
days 
ALT ≥5x BL or ≥500 U/L, 
whichever occurs first 
Regardless of TB or DB 
No 
Interrupt 
• Repeat laboratory testing
including CPK within 2-4 days 
•
Collect PK sample within 7
days
ALT ≥2x BL or ≥300 U/L, 
whichever occurs first 
TB ≥2x ULN 
Gilbert’sc:  DB >2x ULN or INR 
>1.5
No 
Interrupt 
• Repeat laboratory testing
including CPK within 2-4 days 
•
Collect PK sample within 7
days
TB (>1.5 mg/dL 
exclusion criterion 
747-303)
TB ≥2.0 mg/dL and DB >30% of 
TB 
Yes/No 
Interrupt 
• Repeat laboratory testing
including CPK within 2-4 days 
•
Collect PK sample within 7
days


Protocol 747-303 
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Table 2: 
Liver Laboratory Criteria for Monitoring for Potential Hepatic Injury 
(Continued) 
Baseline 
Treatment Emergent 
Signs and 
Symptoms of 
Hepatic 
Injurya 
Action 
ALP ≤ULNd 
ALP ≥2x BL and >ULN 
No 
If ALP <250 U/L, then: 
•
Repeat laboratory testing
including CPK within 2-4 days
If ALP ≥250 U/L, then: 
Interrupt  
•
Repeat laboratory testing
including CPK within 2-4 days
•
Collect PK sample within 7
days
Yes 
Interrupt 
•
Repeat laboratory testing
including CPK within 2-4 days
•
Collect PK sample within 7
days
ALP >ULNd 
ALP ≥2x BL or >300 U/L, 
whichever occurs first 
No 
If ALP <300 U/L, then: 
•
Repeat laboratory testing
including CPK within 2-4 days
If ALP ≥300 U/L, then: 
Interrupt  
•
Repeat laboratory testing
including CPK within 2-4 days
•
Collect PK sample within 7
days
Yes 
Interrupt 
•
Repeat laboratory testing
including CPK within 2-4 days
•
Collect PK sample within 7
days
ALP = alkaline phosphatase; ALT = alanine aminotransferase; BL = baseline; DB = direct bilirubin; CPK = creatine 
phosphokinase; DILI = drug-induced liver injury; INR = international normalized ratio; NASH = nonalcoholic steatohepatitis; 
OCA = obeticholic acid; PK = pharmacokinetic; TB = total bilirubin; ULN = upper limit of normal 
a Signs and symptoms of hepatic injury include severe fatigue, nausea, vomiting, right upper quadrant pain, fever, rash, and 
eosinophilia. 
b Baseline ALT is defined as an average of all pre-treatment values from Screening and Day 1.  Elevated Baseline defined as 
ALT ≥1.5x ULN.  ALT decreases are common within the first 3-6 months of treatment in NASH subjects receiving OCA.  If 
there is a decrease in ALT for all lab draws through the Month 6 Visit, then a new baseline should be established for subsequent 
DILI determination, based on the average ALT from the Month 3 and Month 6 Visits. 
c A subject will be considered to have Gilbert’s syndrome if it was established at baseline and documented in the subject’s 
medical history. 
d Baseline ALP is defined as an average of all pre-treatment values from Screening and Day 1.  Modest ALP increases (<50%) 
from baseline within the first 3 months of treatment are common in NASH subjects receiving OCA and represent an expected 
pharmacodynamic effect.  If there is an increase in ALP through the Month 6 Visit, then a new baseline should be established 
for subsequent DILI determination, based on the average ALP from the Month 3 and Month 6 Visits. 


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If any subject meets the triggering threshold limits indicated in Table 2 and experiences signs or 
symptoms of hepatic injury (severe fatigue, nausea, vomiting, right upper quadrant pain, fever, 
rash, eosinophilia) investigational product should be immediately interrupted (see Section 7.7 for 
dosing modifications). 
If no signs or symptoms of hepatic injury 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 2.  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.
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, the 
Medical Monitor should be promptly contacted upon awareness for consultation regarding 
management of the subject. 
•
If on repeat evaluation, 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 2),
investigational product must be interrupted for a minimum of 30 days, a PK sample
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 in whom close monitoring is initiated, a follow-up assessment of the subject’s 
status should be performed after approximately 12 months of monitoring. 
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 


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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.  The 
original or copies should be retained at the site as the source documents.  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, 
for example, a single abnormal laboratory analyte result may be artefactual or may clearly be 
explained for a particular subject as due to pre-existing conditions or circumstances unrelated to 
their liver function or the study; accordingly, Investigators may be allowed to implement an 
alternate follow-up procedure, based on their medical judgement, but only after documented 
consultation and 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.  
7.4.2. 
Progression of Disease to Cirrhosis 
Investigators will closely monitor subjects for potential progression to cirrhosis at every visit (or 
at unscheduled visits).  If the subject meets one or more of the criteria for potential progression 
to cirrhosis described in Figure 3 and/or any additional evidence that may be available including 
findings from targeted physical exams or from clinically indicated procedures (eg, biopsy, 
ultrasound, or esophagogastroduodenoscopy [EGD]), then the subject is considered to have 
potentially progressed to cirrhosis; Child-Pugh scores must then be assessed.  Refer to 
Section 7.4.2.1 for determination of Child Pugh Score.  If a subject may have progressed to 
cirrhosis, a Fibroscan assessment should be performed where possible (if not already part of the 
scheduled assessment) and repeated annually.  Dose adjustments or investigational product 
discontinuation may be required in subjects who meet criteria for progression to cirrhosis (see 
Table 4).  If the dose of investigational product is adjusted (Child-Pugh A) or if investigational 
product is discontinued (Child-Pugh B or C) a PK sample must be collected within 7 days.  The 
PK sample should be collected prior to receiving the reduced dose. 
If non-invasive indicators of progression to cirrhosis become evident at any time during the 
study, it is recommended that a liver biopsy should be obtained and sent for central reading to 
confirm the diagnosis of cirrhosis and for inclusion in the analysis of study outcomes.  Any 
interpretations by a local pathologist should be collected and entered in the eCRF within 2 days 
of receiving results.  If a biopsy is not performed, the reason should be stated in the eCRF.  The 
following clinical outcomes may preclude the need for a liver biopsy to confirm progression to 
cirrhosis:  presence of ascites, hepatic encephalopathy, variceal hemorrhage, or the presence of 
large esophageal varices or varices with a red wale that require treatment. 
The process for assessing disease progression to cirrhosis, the potential need for liver biopsy, and 
the implications on dosing are summarized in Figure 3.  
Potential events of progression to cirrhosis will be reviewed and adjudicated by the Hepatic 
Outcomes Committee which is described in Section 16.11.  The Hepatic Outcomes Committee 


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charter describes the specific criteria for identification and adjudication of potential events of 
progression to cirrhosis.   
Figure 3: 
Algorithm for Determining Progression to Cirrhosis 
; CP = Child–Pugh; 
; INR = international 
normalized ratio; IP = investigational product; NFS = nonalcoholic fatty liver disease fibrosis score; TE = transient elastography; 
ULN = upper limit of normal. 
Note:  To maintain blinding, dose adjustments will be handled by the investigational product supplier such that: 
•
Subjects on OCA 25 mg have the dose reduced to OCA 10 mg
•
Subjects on OCA 10 mg and placebo remain on OCA 10 mg and placebo, respectively
a It is not necessary to rule out the occurrence of varices, ascites, or hepatic encephalopathy at each visit; however, if at any time 
during the clinical management of the subject there are signs and symptoms that are suggestive of any of these events (eg, 
ascites noted on ultrasound or presence of varices noted on clinically indicated EGD), then the subject is considered to have met 
the criteria for progression to cirrhosis and a Child-Pugh screen must be assessed for that subject. 
7.4.2.1. 
Child-Pugh Assessment 
The Child-Pugh (CP) Score (Pugh 1973, Lucey 1997) will be assessed only in subjects who meet 
one or more of the criteria for progression to cirrhosis (Figure 3).  A targeted examination will be 
performed to assess ascites and hepatic encephalopathy.  CP is calculated and reported within the 
electronic data capture (EDC) system based on data entered into the eCRF by adding the scores 
from the 5 factors outlined in Table 3 and can range from 5-15.  Among subjects who meet 
criteria for progression to cirrhosis, dose adjustment (see Table 4) should be considered in those 
Is one or more of the following criteria met? 
No Confirmatory Liver Biopsy Needed 
l. Evidence of stage 4 fibrosis on biopsy (e.g., clinically indicated 
biopsy) 
2. Known evidencea of any of the following in the absence of acute 
liver failme: 
Varices with or without hem01Thage 
Ascites 
Hepatic encephalopathy 
Confirmatory Liver Biopsy Recommended 
l. Liver stiffness by TE 2':14 kPa combined with one or more of the 
following at 2 consecutive visits: 
FIB-4 >2.67 
APR! >1.5 
NFS >0.676 
2. 
Combined low platelet collllt (<140 000/nun3) with persistent 
(i.e., at least 2 consecutive visits within 6 months): 
Decrease in sernm albumin 
Elevation in prothrombin ti.me/INR (not due to 
anticoagulation therapy), or 
Elevated bili.rnbiI1 (2':2x ULN) 
Splenomegaly on abdomiiial iinagiI1g 
No 
Continue IP per 
Protocol 


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with a CP score <7, and investigational product should be discontinued in those with a CP 
score ≥7.  For the purpose of dose adjustment or discontinuation, Child Pugh Scores should 
ONLY be applied in subjects who demonstrate progression to cirrhosis based on criteria 
presented in Section 7.4.2.  Dose adjustment or discontinuation should not be considered based 
solely on the CP score, in subjects who do not meet criteria for progression to cirrhosis.  
Calculation of the CP score includes Investigator assessments of ascites and hepatic 
encephalopathy, which may be assessed during the AE 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 = mild, well compensated disease (ie, CP Class A)
•
CP Score 7-9 = moderate, significant functional compromise (ie, CP Class B)
•
CP Score ≥10 = severe, decompensated disease (ie, CP Class C)
Table 3: 
Child-Pugh Scoring System 
Factor 
Units 
Points 
1 
2 
3 
Serum bilirubin 
μmol/L 
<34 
34-50
>50
mg/dL 
<2.0 
2.0-3.0 
>3.0
Serum albumin 
g/L 
>35
28-35
<28 
g/dL 
>3.5
2.8-3.5 
<2.8 
Prothrombin time 
Seconds prolonged 
0-3
4-6
>6
INR 
<1.7 
1.7-2.3 
>2.3
Ascitesa 
None 
Mild 
Moderate-
Severe 
Hepatic encephalopathyb 
None 
Grade 1 or 2 
Grade 3 or 4 
INR = international normalized ratio 
West Haven criteria: Vilstrup 2014; Child-Pugh criteria: Pugh 1973, Lucey 1997. 
a Refer to CTCAE Appendix D for definitions of severity of ascites
b 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  
7.4.2.2. 
Model for End-Stage Liver Disease (MELD) Scoring 
MELD is a scoring system used to assess the severity of chronic liver disease.  The MELD score 
is calculated using serum creatinine (mg/dL), bilirubin (mg/dL), and INR.  The MELD-Na score 
is calculated using serum creatinine (mg/dL), bilirubin (mg/dL), INR, and sodium and is 
calculated when the MELD score is greater than 11.  The MELD calculation adjusts for subjects 
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.  


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7.4.3. 
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 
disease progression to cirrhosis or 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 of the clinical event leading to discontinuation has occurred 
(per discretion of the Investigator and upon discussion with the Medical Monitor). 
At a minimum, the following assessments should be conducted at each study visit:  
•
Exam and thorough review of subject-reported signs and symptoms of hepatic injury
or decompensation (Appendix C)
•
Liver biochemistry (including ALP, ALT, AST, GGT, total and conjugated bilirubin,
creatinine, and albumin), prothrombin time (PT)/INR, serum electrolytes, and
assessment of algorithm for progression to cirrhosis (only if the subject is at the study
site) and MELD scores
In addition, a PK 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 or 
interrupts investigational product due to potential hepatic injury (Section 7.4.1).  A PK sample 
should also be collected when the dose of investigational product is reduced (Child-Pugh A) or 
discontinued (Child-Pugh B/C) due to progression to cirrhosis (Section 7.4.2).  
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 need to 
be discussed with the Sponsor’s Medical Monitor: 
•
Repeating liver enzyme and serum bilirubin tests as described in Table 2
•
Obtaining a more detailed history of symptoms and prior or concurrent diseases
•
Obtaining a history of concomitant drug use (including nonprescription medications
and herbal and dietary supplement preparations), alcohol use, recreational drug use,
and special diets is important.  Concomitant drugs with potential hepatotoxicity
should be recorded and discontinued unless alternative therapies are not available.  In
the case of concomitant drugs that are 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 that may be associated with liver toxicity


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•
Ruling out acute viral hepatitis types A, B, C, D (in those thought to have acute HBV
infection), and E; autoimmune or alcoholic hepatitis; Wilson’s disease,
hypoxic/ischemic hepatopathy; and biliary tract disease
•
Obtaining additional tests to evaluate liver function, as appropriate (eg, INR, direct
bilirubin)
•
Seeking hepatology consultation, if the Investigator is not a hepatologist
For all subjects in whom close monitoring is initiated for potential hepatic injury, a follow-up 
assessment of the subject’s status should be performed after approximately 12 months of 
monitoring. 
7.4.4. 
Pruritus 
Pruritus is to be closely monitored.  Although pruritus itself has not been shown to be a predictor 
of hepatic injury, Investigators should be vigilant in responding to subjects’ complaints of new or 
worsening pruritus symptoms with prompt follow-up.  Pruritus grading (as with all AEs) should 
be performed in accordance with the current version of the CTCAE (Appendix D). 
For subjects with Grade 3 pruritus per the current version of the CTCAE (Section 15.1.5.1), 
instruct the subject to discontinue investigational product (Table 4).  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 pruritus ≤ Grade 2 is provided in Table 4 and Section 15.1.5.1. 
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 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). 


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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, or fever 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, 
decreased 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 estimated glomerular filtration rate (eGFR).  All local laboratory 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 4. 


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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.   
Figure 4: 
Algorithm for Monitoring Subjects for Potential Renal Impairment 
ACE = angiotensin converting enzyme; AE = adverse event; ARBs = angiotensin receptor blockers; BUN = blood 
urea nitrogen; eCRF = electronic case report form; eGFR = estimated glomerular filtration rate; IP = investigational 
product; NSAIDS = nonsteroidal anti-inflammatory drugs. 
a Baseline value is defined as the average of the two most recent serum creatinine values from study visits 
(scheduled and unscheduled) that are at least 7 days apart and are not associated with an acute event or creatinine 
increase.  Elevated results due to a renal-related AE or transient use of a nephrotoxic medication should not be 
included in the baseline calculations. 
b Laboratory assessments include:  serum chemistry (creatinine, albumin, BUN, electrolytes), urinalysis with 
microscopic examination, and assessment of eGFR.  
c Evaluation should be comprehensive and include assessments of recent medical history, changes in health status, 
changes in medications (especially ACE inhibitors, ARBs, NSAIDs, diuretics), and intercurrent illness. 
d 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. 
Above Threshold Criteria of: 
Increase In sernm crrattnlnr by ~-3 mg/dL ~ 26.5 nmol/L) within 48 honl'S 
OR 
Srrnm creattnlnr ::>:l.5x Basrllne", which Is known or presumrd to havr occurrrd 
within the p1ior 7 days 
Subject available for 
re-evaluation within 48 hours 
No 
Yes 
Repeat serum 
chemislly and 
urinalysis labsh 
Below threshold criteria 
Above threshold criteria on 
repeat test 
Inte1..-upt IP until 
subjrct Is avaUable 
for repeat trstin 
Continue IP per 
protocol 
Evaluate concomitant medications and 
underlying medical conditions'. 
Is alternatil'e etiolo 
resent? 
Yes 
Interrnpt IP and 
Initiate close 
monit01ingd 


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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. 
•
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 16.11).  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 with 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 (evidence of hematuria, flank or lower abdominal pain, nausea, vomiting, fever, 
or chills).  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 


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(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.   
7.7. 
Investigational Product Adjustment, Interruption, and 
Discontinuation Criteria 
Dosages for investigational product should be maintained constant during the study.  However, 
adjustments, interruptions, discontinuation, and any rechallenge of investigational product should 
be implemented per the criteria outlined in Table 4. 
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.  The Investigator should use their clinical judgement to determine if
more frequent assessments of laboratory tests and symptoms are necessary.
•
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.  The Investigator should use their clinical judgement to determine if more
frequent assessments of laboratory tests and symptoms are necessary until
stabilization of the clinical event leading to discontinuation has occurred (per
discretion of the Investigator and upon discussion with the medical monitor
[Section 7.4.3]).  The subjects will not be rechallenged with investigational product.
Subjects who interrupt treatment will be monitored to determine if or when investigational 
product may be restarted.  However, an interruption of investigational product may result in 
treatment discontinuation.  In this instance, an EOT or EOS visit should occur only after 
discussion of the event with the sponsor’s medical monitor.  The investigator should obtain a 
liver biopsy at the EOT visit to characterize any histological changes during the period that the 
subject was taking investigational product. 
Prior to re-starting investigational product after a prolonged interruption, the subject must be 
re-consented and new baseline visit procedures must be performed if the interval from the last 
visit was more than 3 months (+2 weeks) during the first 18 months of the study or more than 
6 months prior (+2 weeks) during the remainder of the study. 
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 investigational product; 2) in subjects 
who experience an event that is not symptomatic (such as an incidental finding of gallstones 
during an ultrasound exam); 3) in subjects who have already undergone a cholecystectomy 
following a prior event of cholelithiasis or cholecystitis (and who have no symptoms suggestive 


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Pa e66 
ofretained or recunent bile duct stones)· or 4) in subjects who have a medical histmy of 
pancreatitis and have not experienced a recunence of pancreatitis since em-olhnent into the study. 
Table 4: 
Criteria for Dose Adjustment, Interruption, Discontinuation and 
Rechallenge 
DOSE ADJUSTMENT 
Cl'itel'ia 
Action Taken with IP 
Rechallene:e 
Progress to cin-hosis and have Child Pugh A 
Adjust to a maximum 
Not applicable. Remain at maxi.tmun daily dose 
cin-hosis (CP score <7) 
daily dose of 10 mg (or 
of 10 mg (or equivalent placebo) for remainder 
equivalent placebo) in a 
of study. 
blinded fashion 
::;Grade 2Pruritus (refer to Section 15.1.5.1) 
Drug holiday or less 
Return to original daily dose if tolerated 
frequent dosing, as 
needed 
DOSE INTERRUPTION 
Cl'itel'ia 
Action Taken with IP• 
Rechallene:eb 
Liver laboratory values0 are above the upper 
Interrupt immediately 
Subjec may be rechallenged after a minimum of 
threshold criteria and signs and symptoms of 
upon initial observation 
30 days if abnonnal liver enzymes return to 
hevatic iniurv are vresenrl 
below threshold values, there are no symptoms, 
Liver laboratory values0 are above the upper 
Ac.cording to threshold 
laboratory abnonnalities are determined not to 
threshold criteria and there are no signs and 
linuts (Table 2), either 
be due to DILi and approved by the Medical 
symptoms of hepatic injury<I 
intermpt or intenupt 
Monitor and Investigator. 
after con:fumation by 
repeat testing 
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 v.-ith inte1rnption or discontinuing 
investigational product. 
Gastroenteritis (established severe abdonunal 
Interrupt 
If no evidence of liver injmy is detected, 1P may 
pain, vonuting, diall'hea) or dehydration 
be resta1ted at the same dose after resolution of 
AE categorized as 2':Grade 4 in severity and not 
Intem.1pt 
intercurrent illness. 
or unlikely related to IP 
Potential .renal impainnent (serum creatinine 
Intenupt after 
Subject may be rechallenged after a mininiUIU of 
exceeds upper threshold criteria (Section 7.6]) 
confirmation by repeat 
30 days iflaborato1y results retum to v.ritlun 
testing 
threshold criteria and approved by tl1e Medical 
Monitor and Investigaior. 
Symptomatic cholelithiasis and/or cholecystitis 
Intem1pt 
Subjects should remain in the study and 
complete all protocol-specified assessments. as 
defined in Table l, while off IP. Subjects may 
resume IP: 
•
After full resolution from a
cholecystectomy and after receiving
approval from the Investigator and
Medical Monitor provided there are no
signs or symptoms suggestive of retained
or recurrent bile duct stones
•
If it is deemed, after sW"gical consultation,
that the subject does not need to undergo
surge1y, symptoms have resolved, and
after receiv-ing approval from the
Investigator and Medical Monitor.
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Table 4: 
Criteria for Dose Adjustment, Interruption, Discontinuation and 
Rechallenge (Continued) 
DOSE INTERRUPTION 
Crite1·ia 
Action Taken with IP• 
Rechallenl!eb 
Pregnancy 
Inte1n1pt 
Subject should continue with the study visit 
schedule. The subject may rn-sta1t 
investigational product when she is no longer 
pregnant or breastfeeding at the discretion of the 
Investigator and after discussion with the 
Medical Monitor as described in 
Section 15.1.12. 
DOSE DISCONTINUATION 
Critea-ia 
Action Taken with IP 
Rechallenl!e 
Potential Hepatic Decompensation• or 
Discontinue8 / 
Continue to retum for scheduled study visits for 
Progression to Child Pugh B or C 
No Rechallenge 
safety follow up; however, the subject should 
[CP Score 2'.7] 
not be rechallenged. Monitor closely for clinical 
outcomes according to protocol assessments. 
Treatment-emergent acute or nonacute 
Discontinue8 / 
Continue to return for scheduled study visits for 
pancreatitis 
No Rechallenge 
safety follow up; however, the subject should 
>Grade 3 pn.11-itusf 
not be rechallenged. 
Other AEs :::'.Grade 3 considered possibly, 
probably. or definitely related to IP 
Liver transplantation 
Bai-iati-ic Smgerv (Gasti-ic Bypass) 
AE = adverse event; ALP= alkaline phosphatase; ALT= aspa1tate aminoti-ansferase; CP = Child-Pugh; DILi = mug-induced 
liver injllly; IP = investigational product 
• If subject is unable to be evaluated promptly, study dmg must be itmnediately interrupted.
b Requires c-omplete documentation of full resolution or nomial/baseline based on laboratory parameters and symptoms.
c ALT, ALP, dit-ect or total bilimbin, or INR.
d Signs and symptoms of hepatic it1jU1y include severe fatigue, nausea, vomiting, right upper quadrant pain, fever, rash, and
eosinophilia. 
• Clinically evident complications of portal hypertension (eg, ascites, variceal hemon-hage, hepatic encephalopathy).
f Severity per the current version of the CTCAE.
g Subjects who permanently discontinue fro111 investigational product are expected to continue iii the study and should follow the
regular visit schedule for the duration of the study. The Investigator should use clinical judgement to deteanine if more 
frequent assessments of laborat01y tests and sympto111S are necessary until stabilization of the clinical event leading to 
discontimiation has occurred (per discretion of the Investigator and upon discussion with the medical 111onitor). 
7.8. 
Criteria for Study Termination 
The Sponsor reserves the right to tenninate the study at any time. It is normal procedme 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 necessaiy to stop the study before all 
subjects have completed the study. In addition, the Sponsor may terminate the study at an 
investigation.al site at any time (eg, Good Clinical Practice [GCP] noncompliance or 
poorly performing sites, as determined by the number of subjects emolled 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 inf01med by the Sponsor as to when the final study visit is to be completed 
and should then schedule all subjects for the EOS or EOT Visit. The window of time for 
scheduling the visit will be based on a final projection of when the requisite 291 adjudicated 
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events will have been accrued in the OCA 25 mg and placebo groups combined for subjects with 
fibrosis stage 2 or stage 3. 
7.9. 
Subject Retention 
The primary objectives for the end of study analysis are to evaluate the effects of OCA compared 
with placebo on all-cause mortality and liver-related clinical outcomes.  The overall study 
duration is event driven and will be determined by the time required to observe the prespecified 
adjudicated events for the clinical outcomes composite endpoint (Section 7.8).  Therefore, it is 
very important that subjects continue to participate for the duration of the study to enable 
assessment of clinical outcomes.  
Subjects may discontinue investigational product during the study; however, these subjects are 
expected to continue in the study until study termination and every effort will be made by the 
investigator to discuss subjects’ continuation in the study.  Investigators will emphasize to 
subjects the importance of their continuation in the study after withdrawal of investigational 
product by either continuing to attend regularly scheduled visits, allowing semi-annual telephone 
visits by the investigator, or by allowing the investigator to have continued access to the 
subjects’ medical records to assess potential major adverse cardiovascular events (MACE) and 
liver-related clinical outcomes.  The site staff will encourage subjects to adopt an option that 
allows for the most data moving forward.  Subjects will be asked to provide both personal and 
primary physician(s) contact information who can provide information to the investigator about 
the clinical/medical status on the subjects’ behalf.  Additional information is described in 
Section 8.2.1.  
Please refer to specific strategies and procedures that will provide additional information to 
facilitate subject retention as described in a separate Subject Retention Plan. 
8.
SELECTION AND WITHDRAWAL OF SUBJECTS
8.1. 
Subject Population
This study will be conducted at up to 400 international sites with experience in treating patients 
with 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.  
8.1.1. 
Subject Inclusion Criteria 
1. Histologic evidence of NASH upon central read of a liver biopsy obtained no more than
6 months before Day 1 defined by presence of all 3 key histological features of NASH
with a score of at least 1 for each and a combined score of 4 or greater out of a possible
8 points according to NASH CRN criteria.
2. Histologic evidence of fibrosis stage 2 (perisinusoidal and portal/periportal) or stage 3
(bridging fibrosis) as defined by the NASH CRN scoring of fibrosis, or


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Histologic evidence of fibrosis stage 1a or stage 1b (mild or moderate, zone 
3 perisinusoidal) as defined by the NASH CRN scoring of fibrosis if accompanied by 
≥1 of the following risk factors:  
•
Obesity (BMI ≥30 kg/m2)
•
Type 2 diabetes diagnosed per 2013 American Diabetes Association criteria
(hemoglobin A1c [HbA1c] ≥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)
•
ALT >1.5× upper limit of normal (ULN).
3. For subjects with a historical biopsy, is either not taking or is on stable doses of
TZDs/glitazones or vitamin E for 6 months before Day 1.
4. Stable body weight (ie, not varying by >10% for at least 3 months) before Day 1.
5. Age ≥18 years.
6. Female subjects of childbearing potential must use ≥1 effective method of contraception
during the study and until 30 days following the last dose of investigational product.
Effective methods of contraception are considered to be those listed below (refer to
Section 9.8 for highly effective contraceptive methods):
•
Barrier method, ie, condom (male or female) with spermicide or diaphragm with
spermicide
•
Intrauterine device
•
Vasectomy (partner)
•
Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection)
•
Abstinence (defined as refraining from heterosexual intercourse).
7. 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. 
1. Current or history of significant alcohol consumption for a period of more than
3 consecutive months within 1 year before Screening (significant alcohol consumption is
defined as more than 2 units/day for females and more than 4 units/day for males, on
average).
2. 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).
3. HbA1c >9.5% within 60 days before Day 1.


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4. Evidence of other forms of known chronic liver disease including:
•
Positive test result at Screening for hepatitis B surface antigen (HBsAg)
•
Active hepatitis C virus (HCV) infection (positive for HCV ribonucleic acid [RNA] at
Screening) or history of positive HCV RNA test result
•
PBC, PSC, autoimmune hepatitis, or overlap syndrome
•
Alcoholic liver disease
•
Wilson’s 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 [LLN] or
exclusion at the Investigator’s discretion) 
•
Prior known drug-induced liver injury within 5 years before Day 1
•
Known or suspected 
•
History of liver transplant, current placement on a liver transplant list, or MELD
score >12. 
5. Histological presence of cirrhosis.
6. Total bilirubin >1.5 mg/dL (subjects with Gilbert’s syndrome may be enrolled despite a
total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5× ULN).
7. Conjugated bilirubin ≥1.5 x ULN.
8. AST or ALT ≥10× ULN, international normalized ratio (INR) ≥1.4, or serum creatinine
≥1.5 mg/dL.
9. Creatine phosphokinase >5x ULN.
10. Platelet count <100 000/mm3.
11. LDL ≥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.
12. Inability to safely undergo a liver biopsy.
13. History of biliary diversion.
14. Known positivity for human immunodeficiency virus infection.
15. Subjects with recent history (within 1 year of Day 1) of significant atherosclerotic
cardiovascular disease (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 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.
-


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−
Controlled hypertension without other recent manifestations of significant
atherosclerotic cardiovascular disease and placement of cardiac pacemaker or
defibrillator for reasons other than atherosclerotic cardiovascular disease (eg, for
treatment of atrial fibrillation subsequent to nodal ablation) is not exclusionary.
16. Other medical conditions that may diminish life expectancy to <2 years, including known
cancers (except carcinomas in situ or other stable, relatively benign carcinomas).
17. Known substance abuse in the year before Screening.
18. Pregnancy, planned pregnancy, potential for pregnancy (ie, unwillingness to use effective
birth control during the study), or current or planned breast feeding.
19. Participated in a clinical research study with any investigational product being evaluated
for the treatment of diabetes, weight loss, or NASH in the 6 months before Day 1.
20. Received any investigational product not being evaluated for the treatment of diabetes,
weight loss, or NASH 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.
21. Previous exposure to OCA.
22. Mental instability or incompetence, such that the validity of informed consent or ability
to be compliant with the study, is uncertain.
23. History of known or suspected clinically significant hypersensitivity to OCA or any of its
components.
24. Any other condition that, in the opinion of the Investigator, would impede compliance or
hinder completion of the study.
25. Acute cholecystitis or acute biliary obstruction.
26. BMI >45 kg/m2 with at least 1 of the following comorbidities:
−
Hypertension with blood pressure ≥140/90 mmHg if <60 years, ≥150/90 mmHg if
≥60 years, or on antihypertensive medication
−
Hyperlipidemia defined as LDL cholesterol ≥160 mg/dL, total cholesterol
≥200 mg/dL, or on lipid lowering medication
−
Type 2 diabetes per 2013 American Diabetes Association criteria
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.  Subjects who permanently discontinue from investigational product are not required 
to be assessed more frequently than the scheduled study visits provided 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 7.7 for withdrawal criteria related to potential hepatic injury 
and/or decompensation; progression to cirrhosis; treatment-emergent acute or nonacute 


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pancreatitis; Grade 3 pruritus, AEs ≥Grade 3 in severity and possibly, probably, or definitely 
related to investigational product; liver transplantation and bariatric surgery.  Other reasons, 
including withdrawal of consent or lost to follow-up, are described in Section 8.2.1 to 
Section 8.2.3 below. 
Bariatric Surgery (Gastric Bypass) 
Subjects must discontinue investigational product after undergoing bariatric surgery.  A liver 
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. 
8.2.1. 
Other Reasons for Discontinuation of Investigational Product 
Subjects who discontinue investigational product are expected to continue in the study until the 
end of the study or at the discretion of the Sponsor.  With the exception of liver transplant, if a 
subject experiences a suspected or confirmed clinical outcomes event, he or she should continue 
the regular visit schedule and continue taking investigational product as long as the Investigator 
assesses it as safe.  Subjects who discontinue investigational product prior to termination of the 
study need to also continue to follow the regular visit schedule through to study closure.  In 
general, subjects should be strongly encouraged to both stay on investigational product and 
remain in the study until study termination.  Specific strategies to encourage continued subject 
participation in the study will be outlined in a Subject Retention Plan.  Early termination 
procedures should only be conducted if the subject withdraws consent (see Section 9.9.9). 
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.
•
The occurrence of clinical or laboratory AEs considered by the Investigator to be
clinically important.
•
Modification of consent:
−
Consent may be modified to discontinue study visits but allow semi-annual
telephone contact of subject, subject’s primary care physician, or personal
contacts who can provide information on behalf of the subject by the investigator
•
Consent may be modified to discontinue study visits or semi-annual telephone contact
but allow continued access to medical records to assess for potential major adverse
cardiovascular events (MACE) and liver-related clinical outcomes
•
Withdrawal of consent:
−
Consent may be fully withdrawn
The Investigator must notify the Medical Monitor as soon as possible when a decision to 
discontinue a subject from treatment is made or when any subject prematurely withdraws from 
the study. 


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8.2.2. 
Withdrawal of Consent and Requirements to Re-Enter the Study 
Withdrawal of Consent 
If the subject decides that it is in his/her best interest to discontinue from the study, he or she 
may withdraw consent.  It is fully understood that all subjects volunteer for the study and that 
they may withdraw their consent to continue in the study at any time. 
A reasonable effort must be made to determine the reason(s) for subject discontinuation.  This 
information and date must be recorded in the appropriate CRF. 
Requirements to Re-enter Study after Withdrawal of Consent 
Subjects who withdraw consent and want to re-enter the study must confirm that they have not 
received any investigational product being evaluated for the treatment of diabetes, weight loss, or 
NASH within 30 days before restarting investigational product or within 5 half-lives of the 
compound (whichever was longer) before restarting investigational product.  Subjects are to be 
re-consented and new baseline visit procedures must be performed if the interval from the last 
visit was more than 3 months (+2 weeks) during the first 18 months of the study or more than 
6 months prior (+2 weeks) during the remainder of the study. 
8.2.3. 
Lost to Follow-up 
If a subject fails to return to the clinic for a study visit, and the Investigator ceases to have 
contact with the subject, he or she will be withdrawn from the study. 
A reasonable effort must be made to contact the subject and determine the reason(s) why a 
subject fails to return for a study visit or is lost to follow-up, as outlined in the Subject Retention 
Plan.  This information and date of contact must be recorded in the appropriate CRF. 
8.2.4. 
Subject Discontinuation Notification 
The Investigator must notify the Medical Monitor by telephone or email as soon as possible if 
any subject prematurely withdraws from the study.  The date when the subject is withdrawn and 
the reason for discontinuation must be recorded in the CRF.  If a subject is “lost to follow-up” 
(fails to return for a visit), a reasonable effort should be made to contact the subject in order to 
determine why the subject failed to return.  This information must be documented in the CRF.  If 
a subject is withdrawn from the study early (regardless of the cause), all of the EOT/EOS 
evaluations should be performed at the time of withdrawal, as appropriate (see Section 9.9.9).  
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, and OCA 25 mg.  Each dose 
will be made up of 1 tablet (ie, one placebo tablet, one OCA 10 mg tablet, or one OCA 25 mg 
tablet). 


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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. 
For subjects participating in the PK portion of the study:  All assessments, except for the 
post-dose collection of blood samples for the subset of subjects participating in the PK 
assessment, must be completed before administration of investigational product. 
Refer to Section 7.7 and Table 4 for adjustments, interruptions, and discontinuation of 
investigational product per safety criteria. 
9.2. 
Lifestyle Modification Counseling 
Despite the serious nature of the disease, there are currently no approved therapies for the 
treatment of NASH nor accepted standard of care.  The therapeutic options for NASH are largely 
limited to lifestyle modifications, generally encompassing diet and physical activity, and 
treatment of concurrent conditions such as type 2 diabetes, obesity, hypertension, and 
dyslipidemia.  Lifestyle modifications can be very effective in patients who make significant 
adjustments to their lifestyle.  Therefore, in accordance with the current standard of care, all 
subjects will receive counseling on lifestyle modification with regard to diet and exercise.  
Owing to the regional and cultural differences in diet and lifestyle across investigational sites, 
Investigators will be asked to counsel subjects on ways to maintain a healthy diet and to 
encourage subjects to engage in an appropriate form of exercise. 
9.3. 
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 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, between Day 1 and Month 18, unless the baseline 
therapy is no longer considered clinically appropriate by the Investigator.  In general, 
Investigators will be encouraged to follow guidelines for care based upon local and institutional 
practice patterns and any relevant published practice guidelines. 


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Exceptions to this general requirement are noted below. 
•
Subjects providing historical biopsies to determine study eligibility should either not
be taking any drugs with potential NASH-modifying properties (specifically,
TZDs/glitazones or vitamin E) or should be on a stable dose of these medications for
6 months before Day 1 through Month 18.  Changes to these drugs with potential
NASH-modifying properties are not permitted, for all subjects, for the first 18 months
of the study.  Ideally, subjects should generally remain on baseline TZDs/glitazones
or vitamin E from Month 18 through the end of the study, unless the baseline therapy
is no longer considered clinically appropriate by the Investigator.
9.3.1. 
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 sequestrants) 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 15.1.5.1. 
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.   
9.3.2. 
Other Concomitant Medications 
The effect of OCA on drug metabolizing enzymes has been evaluated in both in vitro and clinical 
studies.  The PK profile of caffeine, a sensitive CYP1A2 substrate, showed weak effect of OCA 
on CYP1A2.  Based on these results, OCA may increase the exposure of narrow therapeutic 
index drugs that are substrates for CYP1A2, such as theophylline and tizanidine. 
If non-invasive indicators of progression to cirrhosis become evident at any time during the 
study, it is recommended that a liver biopsy should be obtained and sent for central reading (refer 
to Section 7.4.2). 
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). 
9.3.3. 
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 participants as indicated via appropriate 
medicinal interventions (eg, statins).  Recent guidelines stress the importance of evaluating 
atherosclerotic cardiovascular disease (ASCVD) risk in all patients to help guide decisions in 
recommending therapies and reducing LDLc to reduce the risk and prevent onset or recurrence 


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of ASCVD.  As such, reducing lipids, particularly low-density lipoproteins, are part of a 
comprehensive cardiovascular 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 5). 
Figure 5: 
Therapeutic Targets for LDLc Based on Subject ASCVD Risk 
ASCVD = atherosclerotic cardiovascular disease; LDLc = low-density lipoprotein cholesterol. 
Adapted from: 2019 ESC/EAS guidelines (Mach 2020). 
9.3.4. 
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; 
Therapy that achieves :::;50% LDLc reduction 
from baseline and an LDLc goal of 
<1.4 DllDOI/L (<55 mtvdL) 
o current sratin: consider high-intensity 
LDL-loweriog therapy 
• CWTelll LDL-lowering therapy; increase 
treatment inteusi 
Drug '.'lame 
Atorvastaiin 
Rosuvasrn1in 
imva tatin 
Pravas1a1in 
Lovastatin 
Fl11vas1a1in XL 
Fluvastatin 
Pitav:1slalin 
Assess subject' ASCVD risk profile 
High Risk 
Therapy that achieves :::;50% 
LDLc red11clio11 from baseline 
and an LDLc goal of 
< 1.8 DllDOI/L ( <70 mg/dL) 
Moderate Risk 
LDLc goal of 
<2.6 DllDOI/L (<100 mg/dL) 
Statin Dose Intensity 
High Intensity Dose 
Moderate Intensity 
Dose 
• 
Low Intensity Dose 
40 - 80 mg 
10- 20 mg 
20-40 mg 
5- 10mg 
20 - 40mg 
10mg 
40-80 mg 
10-20mg 
40-80 mg 
20mg 
80mg 
40mg BIO 
20- •I0m~ 
l - 4mg 
LDLc goal of 
<3.0 DllDol/L (<100 mg/dL) 


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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 
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 the 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 an endocrinologist if 
they experience new onset type 2 diabetes mellitus. 
9.4. 
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.  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. 
9.5. 
Randomization and Blinding 
This study will be conducted in a double-blind, placebo-controlled manner.  Subjects will be 
randomized 1:1:1 to placebo, OCA 10 mg, or OCA 25 mg.  Randomization of subjects with 
fibrosis stage 2 or stage 3 will be stratified by presence of type 2 diabetes at enrollment (yes/no) 
and use of TZDs/glitazones or vitamin E at baseline (yes/no).  The randomization will be based 


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on a predefined randomization code (generated by the Sponsor or designee) using an interactive 
web response system (IWRS), which the Sponsor intends will serve as a computer-based subject 
registration system at Screening and Day 1.  The IWRS will serve as an investigational product 
inventory and management system and may be integrated with the study database.  
The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide subject data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned and investigational product dispensing 
information (ie, bottle number[s]) will be provided.   
The Sponsor will have access to aggregate event rates (blinded) to perform sample size 
re-estimation, but will remain blinded to actual adjudicated outcomes throughout the entire study 
until the final analysis or intervention. 
Data flow, access, process and disclosure of unblinded data will be described in a data access 
plan (DAP) in order to preserve the integrity of the final analysis of the ongoing study.   
9.5.1. 
Emergency Unblinding Procedures 
Randomization codes and corresponding treatment assignment will be made available to the 
Investigator and the Medical Monitor for emergency use only through the IWRS system.  When 
possible, the Medical Monitor should be consulted in the event that a medical emergency 
necessitates unblinding (ie, in situations where knowledge of the blinded treatment is necessary 
for further medical management of the subject).  If it is not reasonable to inform the Medical 
Monitor in advance of unblinding, the Investigator must promptly document in the subject’s 
source record and should subsequently contact the Medical Monitor to explain any premature 
unblinding of treatment assignment (such as accidental unblinding or unblinding due to a serious 
adverse event [SAE]).  Procedures for unblinding a subject’s treatment will be provided 
separately to the Investigator.  The Medical Monitor will document within study correspondence 
the rationale, circumstances, and the person or persons being informed about the unblinding.   
The DMC (refer to Section 16.10) will be provided unblinded data to review during closed 
sessions.  The DMC will document, in the closed session DMC minutes (which will be made 
available to the Sponsor only after the database is locked and the study is unblinded), details 
about any unblinded subject data reviews.  Cases of premature unblinding (as noted above) will 
be reviewed by the DMC. 
Access to randomization codes and corresponding treatment assignment will also be made 
available through the IWRS system to the appropriate, named individual(s) responsible for 
unblinding suspected unexpected serious adverse reactions (SUSARs) for reporting to the 
Regulatory Authorities. 
9.6. 
Assignment of Site and Subject Numbers 
9.6.1. 
Site Numbers 
Each study site selected to participate in this study will be assigned a site number by the Sponsor. 
The site number will be used to categorize subject data and to identify the site and/or Investigator 
within study documents.  This number will be recorded in the CRF. 


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9.6.2. 
Subject Numbers 
Subjects will be identified by a unique 6-digit number, independent of the randomization 
number.  The first 3 digits will represent the site number and the last 3 digits will represent the 
Screening number. 
9.7. 
Restrictions 
No additional restrictions. 
9.8. 
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 
747-303 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.
•
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).
9.9. 
Visit Procedures
9.9.1. 
Visit Windows
Visits should be based on Day 1 (not on the prior visit) unless stated otherwise.  For example, 
Month 3 should ideally occur 3 months (±2 weeks) following Day 1.  A month is defined as 
4 weeks (ie, 28 days).  The visit windows are as follows: 


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Table 5: 
Visit Windows and/or Intervals 
Visit 01· Prncedure
Screening
Day 1
Month 1
Months 3 through 15
Month 18
Semi-Annual/Annual
(Months 24, 30, 36, 42, 54, 60, 66, 72, 78
and continued eve1y 6 or 12 months until the
EOS) 
Month48
EOS
EOT 
EOS = end of study; EOT = end of treatment 
Visit Window and/or Interval
Visit(s) are to occur :Sl2 weeks before Day 1. Subjects
will be enrolled in the study when informed consent is 
obtained. 
This is the day of randomization and day of the first
dose of investigational product. On-treatment visit 
scheduling should be calculated from this oint going
f 01ward unless stated othe1wise. 
- measurements may e
p
eening Visit 1 through Day 1.
±1 week (7 days)
±2 weeks (14 days)
±6 weeks to+ 2 weeks (56 days)
±2 weeks (14 days)
±4 weeks (28 days)
±2 weeks (14 days) relative to the EOS date annotmced
by the Sponsor and the visit should be done as soon as 
possible upon study discontinuation 
Visit should be done as near as possible to last dose
taken 
Sites should attempt as much as possible to schedule each visit within a 100-day window during 
the first 18 months of treatment and within the scheduled visit window per protocol based on the 
Day 1 Visit. If a known visit schedule departure is planned for a time frame greater than 
100 days from previous visit during the first 18 months of treatment, an unscheduled bottle 
should be proactively dispensed and provided to the subject. 
9.9.2. 
Informed Consent Procedures 
The Investigator or designee will explain the nature, purpose, possible risk and benefit of the 
study to the subject and will provide him/her with a copy of the written info1mation and 
informed consent f01m (ICF). The subject will be given sufficient time to consider the study 
before deciding whether or not to pa1iicipate. The subject will be infonned that paiiicipation is 
voluntaiy and that her/his future medical treatment will not be compromised by pa1ticipation 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 inf01med consent before entering the study. The Investigator 
or a medically qualified designee is responsible for administering and documenting the written 
informed consent of the subject. The subject will be given a copy of the written information and 
his/her signed and dated consent f mm. 
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Subjects must provide written informed consent if investigational product is re-sta.Ited after a 
prolonged intenuption of 3 months or more during the firnt 18 months or after an intenuption of 
more than 6 months at any time after the Month 18 study visit. 
9.9.3. 
Screening Visit Procedures (.12 weeks before Day 1) 
An initial Screening Visit must be perfo1med :::12 weeks before Day 1 to dete1mine 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 emolled 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 to confnm that early rescreening will not affect safety or efficacy for the subject. 
For rescreening, all Screening procedures should be repeated and a new 3-digit Screening 
number assigned. Subjects should be re-consented, as appropriate, at this time. 
Subjects will be emailed in the study when info1med consent is obtained. Screening Visit 1 
procedures for all subjects are as follows: 
•
Review ICFs and obtain signatures before perfmming any study-related procedures,
including Screening procedures
•
Collect medical histmy
•
Verify inclusion and exclusion criteria for eligibility
•
Perf mm a physical examination
•
and vital signs (body temperature, sitting heai-t rate, 
respirato1y rate, and sitting blood pressure) 
• 
• 
Determine alcohol consumption (Alcohol Use Disorders Identification Test [AUDIT] 
questionnaire) 
•
Assess and record any pretreatment-emergent AEs (after the ICF has been signed)
•
Record prior (if within 6 months of Day 1) and cunent concomitant medications
•
Perfmm hepatobiliaiy ultrasound for- screening and for gallbladder assessment
unless data from a recent historic ultrnsound (within 3 months of screening) is
available
•
Obtain blood samples for
Semm chemistty, hematology, and coagulation 
Creatine phosphokinase 
Glucose and HbA 1 c 
Virology screen (HCV and HBsAg) 
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•
Calculations will be performed by the Sponsor or designee for
−
MELD score
− 
•
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 and subjects should ensure they are hydrated prior to study visits)
Screening Visit procedures for a subset of subjects are as follows: 
•
Provide kits and instructions for collection of stool specimens at home prior to the
Day 1 visit (only completed for a subset of subjects enrolled prior to Version 7 of the
protocol)
• 
For subjects without a recent liver biopsy with unstained slides, a second Screening Visit 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).   
Laboratory test results must be available and reviewed by the investigator before the liver 
biopsy.  
Screening Visit 2 procedures for all subjects without a recent liver biopsy with unstained slides 
are as follows: 
•
Assess and record any pretreatment-emergent AEs
•
Obtain liver biopsy
9.9.4. 
Day 1 Procedures (Randomization) 
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 CRF
−
If the subject reports having eaten within 8 hours, document accordingly in the
source and CRF and remind the subject that fasting is required before all study
visits after screening.
•
Perform a standard 12-lead electrocardiogram (ECG)
•
Review inclusion and exclusion criteria for eligibility
• 
 and vital signs (body temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure) 
•


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•
Detennine alcohol consumption (AUDIT questionnaire), smoking habits, and caffeine
consumption
•
Educate subjects about signs and symptoms of potential hepatic injmy or
decompensation
•
Evaluate signs and symptoms of potential hepatic injmy or decompensation
(Appendix C) and assess subjects per Potential DILI Management (Figure 2) and
Progression to Cinhosis (Figme 3) Algorithms
• 
In subjects who progress to cirrhosis and have a CP score <7, I PK blood sample 
will be obtained at the next scheduled visit prior to dose adjustment. Subjects 
who discontinue investigational product due to progression to cinhosis and Child 
Pugh score ?.7 or due to hepatic injmy, will provide a PK blood sample if the site 
visit is within 7 days from dose intenuption or discontinuation. The time of the 
last dose of investigational product prior to the PK blood sample will be rep011ed . 
•
Assess and record any pretreatment-emergent AEs
•
Record prior (if within 6 months of Day 1) and cunent concomitant medications
•
Randomize the subject only ifs/he meets all inclusion criteria and no exclusion
criteria
•
If hepatobiliaiy ultrasound for 
and for gallbladder assessment was not
I 
performed at Screening and the historic ultrasound is > 3 months from Day 1, perf 01m
a hepatobiliaiy ultrasound.
Serum chemistry, hematology, and coagulation 
Thyroid hormones 
Free fatty acids 
Insulin, c-peptide, and HOMA-IR 
Glucose and HbAlc 
Apoptosis mai·kers (CK-18 M30 and CK-18 M65) 
Noninvasive assessments of liver fibrosis: ELF, Fibrotest/Fibrosure 
Inflammation mai·ker (hs-CRP) 
•
Calculations will be perf 01med by the Sponsor or designee for:
-
MELD score
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•
Obtain urine sample for urinalysis
•
Perfmm a urine-based ˤ-hCG pregnancy test for females of childbearing potential
•
Provide lifestyle modification counseling
•
Access the IWRS and dispense investigational product. NOTE: All Day 1
assessments, except for the post-dose collection of blood samples for the subset of
subjects paiticipating in the PK assessment, must be completed before administration
of the first dose of investigational product on Day 1.
•
Administer the first 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 crnsh
the tablet.
•
Schedule the next visit, reiterate dosing instiuctions, and advise the subject:
To bring the investigational product bottle( s) 
To fast overnight (at least 8 hours) before the next visit, but water is pe1mitted and 
subjects should ensme they am hydrated prior to study visits 
Day 1 Visit procedures for the various subsets of subjects are as follows: 
• 
• 
Obtain blood samples for 
-
PK assessment
The following Day 1 Visit procedures were only completed for a subset of subjects em·olled prior 
to Version 7 of the protocol: 
9.9.5. 
•
Obtain stool sample (collected at home) for microbiome/metabolome analysis
• ·­
Month 1, 3, 9, and 15 Procedures 
Month 1, 3, 9, and 15 Visit procedures for all subjects ai·e as follows: 
•
Verify that the subject has fasted for at least 8 hours
-
Record fasting status in the source and CRF
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−
If the subject reports having eaten within 8 hours, document accordingly in the
source and CRF and remind the subject that fasting is required before all study
visits after screening.
• 
 and vital signs (body temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure)  
•
Assess and record AEs
•
Review and record concomitant medications
•
Obtain blood samples for
−
Serum chemistry, hematology, and coagulation
−
Free fatty acids (Month 1 only)
−
Insulin, c-peptide, and HOMA-IR (Month 1 only)
−
Glucose and HbA1c
− 
•
Educate subjects about signs and symptoms of potential hepatic injury or
decompensation (Month 1 Visit and as frequently as needed per Investigator
discretion)
•
Evaluate signs and symptoms of potential hepatic injury or decompensation and
assess subjects per Potential DILI Management and Progression to Cirrhosis
Algorithms
−
In subjects who progress to cirrhosis and have a CP score <7, 1 PK blood sample
will be obtained at the next scheduled visit prior to dose adjustment.  Subjects
who discontinue investigational product due to progression to cirrhosis and Child
Pugh score ≥7 or due to hepatic injury, will provide a PK blood sample if the site
visit is within 7 days from dose interruption or discontinuation.  The time of the
last dose of investigational product prior to the PK blood sample will be reported.
•
Calculations will be performed by the Sponsor or designee for:
−
MELD score
− 
•
Perform a urine-based β-hCG pregnancy test for females of childbearing potential
•
Provide lifestyle modification counseling
•
Collect used bottles of investigational product, assess investigational product
compliance, and perform investigational product accountability
•
Access the IWRS and dispense investigational product
•
Schedule the next visit, reiterate dosing instructions, and advise the subject:
−
To swallow the tablet whole with water; s/he must not chew, divide, or crush the
tablet


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To bring the investigational product bottle(s) 
To fast overnight (at least 8 hours) before the next visit, but water is pemntted and 
subjects should ensure they are hydrated prior to study visits 
The following Month 1, Month 3, and Month 15 Visit procedures were only completed for a 
subset of subjects emolled prior to Version 7 of the protocol: 
•
Obtain stool sample ( collected at home) for microbiome/metabolome analysis
(Month 3 only and only US subjects who provided baseline [Day 1] sample)
•
Provide kits and instmctions for collection of stool specimens at home at the Month 1
visit for the Month 3 visit and Month 15 visit for the Month 18 visit (Only US
subjects who provided baseline [Day l] sample)
For Months 9 and 15, for subjects participating in the PK assessments, instruct the subject: 
•
NOT to take investigational product on the morning of the next visit
•
To bring the investigational product bottle(s)· s/he will dose at the clinic (subjects
paiiicipating in the PK assessments only)
If non-invasive indicators of progression to cinhosis become evident at any time during the 
study, it is recommended that a liver biopsy should be obtained and sent for central reading. 
9.9.6. 
Month 6 and Month 12 Procedures 
Month 6 and 12 Visit procedures for all subjects ai·e as follows: 
•
Verify that the subject has fasted for at least 8 hours
Record fasting status in the source and CRF 
If the subject repmis having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required before all study 
visits after screening. 
• 
and vital signs (body temperature sitting heai't rate 
respirato1y rate, and sitting blood pressure) 
• 
• 
Dete1mine alcohol consumption (AUDIT questionnaire), smoking habits, and caffeine 
consumption 
• 
• 
Perfo1m hepatobiliaiy ultrasound for 
•
Assess and record AEs
•
Review and record concomitant medications
• 
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for gallbladder assessment 


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−
Serum chemistry, hematology, and coagulation
−
Thyroid hormones (Month 6 only)
−
Free fatty acids
−
Insulin, c-peptide, and HOMA-IR
−
Glucose and HbA1c
−
Apoptosis markers (CK-18 M30 and CK-18 M65)
−
Noninvasive assessments of liver fibrosis (ELF, Fibrotest/Fibrosure)
−
Inflammation marker (hs-CRP)
− 
•
Educate subjects about signs and symptoms of potential hepatic injury or
decompensation (as needed, per Investigator’s discretion)
•
Evaluate signs and symptoms of potential hepatic injury or decompensation and
assess subjects per Potential DILI Management and Progression to Cirrhosis
Algorithms
−
In subjects who progress to cirrhosis and have a CP score <7, 1 PK blood sample
will be obtained at the next scheduled visit prior to dose adjustment.  Subjects
who discontinue investigational product due to progression to cirrhosis and Child
Pugh score ≥7 or due to hepatic injury, will provide a PK blood sample if the site
visit is within 7 days from dose interruption or discontinuation.  The time of the
last dose of investigational product prior to the PK blood sample will be reported.
•
Calculations will be performed by the Sponsor or designee for
−
MELD score
− 
− 
•
Perform a urine-based β-hCG pregnancy test for females of childbearing potential
•
Provide lifestyle modification counseling
•
Collect used bottles of investigational product, assess investigational product
compliance, and perform investigational product accountability
•
Access the IWRS and dispense investigational product
•
Schedule the next visit, reiterate dosing instructions, and advise the subject:
−
To fast overnight (at least 8 hours) before the next visit, but water is permitted and
subjects should ensure they are hydrated prior to study visits
−
To bring the investigational product bottle(s)


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•
Inst:iuct the subject to swallow the tablet whole with water; s/he must not chew,
divide, or crush the tablet
Month 6 and 12 Visit procedures for the various subsets of subjects are as follows: 
For subjects who develop- during the study, - screening assessments for study visits 
after onset of- are not required. 
If non-invasive indicators of progression to cinhosis become evident at any time during the 
study, it is recommended that a liver biopsy should be obtained and sent for central reading. 
9.9.7. 
Month 18 Procedures 
Note: Month 18 liver biopsy was performed for subjects who were enrolled in the interim 
analysis cohort. Subjects randomized on or after 16 Jul 2017 who have not had a Month 18 
biopsy are no longer required to have a biopsy at this visit unless progression to cinhosis is 
suspected. 
Month 18 Visit procedures for all subjects are as follows: 
•
Verify that tl1e subject has fasted for at least 8 hours
Record fasting status in the source and CRF 
If the subject repmts having eaten within 8 hours document accordingly in the 
source and CRF and remind the subject tl1at fasting is required before all study 
visits after screening. 
•
Perfmm a physical examination
•
Perform a standard 12-lead ECG
•
and vital signs (body temperahue, sitting heart rate, 
respiratory rate, and sitting blood pressure) 
• 
• 
Detennine alcohol consumption (AUDIT questionnaire), smoking habits and caffeine 
consumption 
• 
Confidential and Proprietary 


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•
Perform hepatobiliary ultrasound for 
 screening and for gallbladder assessment 
•
Assess and record AEs
•
Review and record concomitant medications
−
Serum chemistry, hematology, and coagulation
−
Thyroid hormones
−
Free fatty acids
−
Insulin, c-peptide, and HOMA-IR
−
Glucose and HbA1c
−
Apoptosis markers (CK-18 M30 and CK-18 M65)
−
Noninvasive assessments of liver fibrosis (ELF, Fibrotest/Fibrosure)
−
Inflammation marker (hs-CRP)
− 
•
Educate subjects about signs and symptoms of potential hepatic injury or
decompensation (as needed, per Investigator’s discretion)
•
Evaluate signs and symptoms of potential hepatic injury or decompensation and
assess subjects per Potential DILI Management and Progression to Cirrhosis
Algorithms
−
In subjects who progress to cirrhosis and have a CP score <7, 1 PK blood sample
will be obtained at the next scheduled visit prior to dose adjustment.  Subjects
who discontinue investigational product due to progression to cirrhosis and Child
Pugh score ≥7 or due to hepatic injury, will provide a PK blood sample within
7 days from dose interruption or discontinuation.  The time of the last dose of
investigational product prior to the PK blood sample will be reported.
•
Calculations will be performed by the Sponsor or designee for
−
MELD score
•
Obtain urine sample for urinalysis
•
Perform a urine-based β-hCG pregnancy test for females of childbearing potential
•
Provide lifestyle modification counseling
•
Collect used bottles of investigational product, assess investigational product
compliance, and perform investigational product accountability
-


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•
Access the IWRS and dispense investigational product
•
Schedule the next visit, reiterate dosing instructions, and advise the subject:
−
To fast overnight (at least 8 hours) before the next visit, but water is permitted and
subjects should ensure they are hydrated prior to study visits
−
To bring the investigational product bottle(s)
•
Instruct the subject to swallow the tablet whole with water; s/he must not chew,
divide, or crush the tablet.
Month 18 Visit procedures for the various subsets of subjects are as follows: 
•
Obtain stool sample (collected at home) for microbiome/metabolome analysis (only
completed for a subset of US subjects who provided baseline [Day 1] sample and
were enrolled prior to Version 7 of the protocol)
For subjects who develop potential liver-related clinical outcomes during the study, 
protocol-specified biopsies for study visits after onset of the potential outcome event may not be 
required.  For subjects who develop 
 during the study, 
 assessments for study 
visits after onset of 
 are not required. 
9.9.8. 
Semi-Annual Visit Procedures 
If clinical indicators of progression to cirrhosis become evident at any time during the study, it is 
recommended that a liver biopsy be obtained and sent for central reading. 
9.9.8.1. 
Semi-Annual Procedures (Months 24, 30, 36, 42, 48, 54, 60, 66, 72, 78 and every 6 
months until the EOS) 
After Month 18, subjects determined to be at higher risk of progression or decompensation in the 
judgment of the Investigator may be monitored for signs and symptoms of potential hepatic 
- -


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injury or decompensation as frequently as needed per discretion of the Investigator and upon 
discussion with the Medical Monitor. 
Semi-Annual Visit procedures for all subjects are as follows: 
•
In the days leading up to and including the visit day, subjects should maintain the
regular daily timing of their investigational product dose administration (eg, dosing
every morning, dosing every afternoon, dosing every evening, etc).  If the subject’s
regular daily dosing time occurs during the site visit, the subject should administer the
dose at the study site and the time of dosing should be recorded in the eCRF.
•
Verify that the subject has fasted for at least 8 hours
−
Record fasting status in the source and CRF
−
If the subject reports having eaten within 8 hours, document accordingly in the
source and CRF and remind the subject that fasting is required before all study
visits after screening.
• 
and vital signs (body temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure) 
•
Assess and record AEs
•
Review and record concomitant medications
• 
• Perform hepatobiliary ultrasound for 
 and for gallbladder assessment 
•
Obtain blood samples for
−
− Serum chemistry, hematology, and coagulation 
−
Glucose and HbA1c
−
PK (2 sparse samples):  the first sample should be collected when the subject
arrives at the study site and the second sample should be collected at the end of
the study visit.  The times of the last dose of investigational product, the last meal,
and collection of the 2 sparse samples will be recorded in the eCRF.
•
Educate subjects about signs and symptoms of hepatic injury or decompensation (as
needed, per Investigator’s discretion) and intercurrent illness and/or potential adverse
events (Appendix C)
•
Evaluate signs and symptoms of hepatic injury or decompensation and assess subjects
per Suspected DILI Management and Progression to Cirrhosis Algorithms
intercurrent illness and/or potential adverse events (Appendix C)
−
In subjects who progress to cirrhosis and have a CP score <7, 1 PK blood sample
will be obtained at the next scheduled visit prior to dose adjustment.  Subjects
who discontinue investigational product due to progression to cirrhosis and Child
Pugh score ≥7 or due to hepatic injury, will provide a PK blood sample within


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7 days from dose interruption or discontinuation.  The time of the last dose of 
investigational product prior to the PK blood sample will be reported. 
•
Calculations will be performed by the Sponsor or designee for:
−
MELD score
− 
•
Obtain urine sample for urinalysis
•
Perform a urine-based β-hCG pregnancy test for females of childbearing potential
•
Provide lifestyle modification counseling
•
Collect used bottles of investigational product, assess investigational product
compliance and perform investigational product accountability
•
Access the IWRS and dispense investigational product
•
Schedule the next visit, reiterate dosing instructions, and advise the subject:
−
To bring the investigational product bottle(s)
−
To fast overnight (at least 8 hours) before the next visit, but water is permitted and
subjects should ensure they are hydrated prior to study visits 
For subjects who develop 
 during the study, 
 assessments for study visits 
after onset of 
 are not required. 
9.9.8.2. 
Month 48 Visit Procedures 
Subjects determined to be at higher risk of progression or decompensation in the judgment of the 
Investigator may be monitored for signs and symptoms of potential hepatic injury or 
decompensation as frequently as needed per discretion of the Investigator and upon discussion 
with the Medical Monitor. 
•
Verify that the subject has fasted for at least 8 hours
−
Record fasting status in the source and CRF
−
If the subject reports having eaten within 8 hours, document accordingly in the
source and CRF and remind the subject that fasting is required before all study
visits after screening.
•
Perform a physical examination
•
Perform a standard 12-lead ECG
•
 and vital signs (body temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure) 
•
Determine alcohol consumption (AUDIT questionnaire), smoking habits, and caffeine
consumption
• 
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•
Perform hepatobiliary ultrasound for
 and for gallbladder assessment 
•
Obtain liver biopsy
•
Assess and record AEs
•
Review and record concomitant medications
−
Serum chemistry, hematology, and coagulation
−
Thyroid hormones
−
Free fatty acids
−
Insulin, c-peptide, and HOMA-IR
−
Glucose and HbA1c
−
Noninvasive assessments of liver fibrosis: ELF, Fibrotest/Fibrosure
−
Inflammation marker (hs-CRP)
•
Evaluate signs and symptoms of potential hepatic injury or decompensation and
assess subjects per potential DILI Management and Progression to Cirrhosis
Algorithms
−
In subjects who progress to cirrhosis and have a CP score <7, 1 PK blood sample
will be obtained at the next scheduled visit prior to dose adjustment.  Subjects
who discontinue investigational product due to progression to cirrhosis and Child
Pugh score ≥7 or due to hepatic injury, will provide a PK blood sample within
7 days from dose interruption or discontinuation.  The time of the last dose of
investigational product prior to the PK blood sample will be reported.
•
Calculations will be performed by the Sponsor or designee for
−
MELD score
•
Obtain urine sample for urinalysis
•
Perform a urine-based β-hCG pregnancy test for females of childbearing potential
•
Provide lifestyle modification counseling
•
Collect used bottles of investigational product, assess investigational product
compliance and perform investigational product accountability
•
Access the IWRS and dispense investigational product
•
Schedule the next visit, reiterate dosing instructions, and advise the subject:
−
To bring the investigational product bottle(s)


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−
To fast overnight (at least 8 hours) before the next visit, but water is permitted and
subjects should ensure they are hydrated prior to study visits
Month 48 Visit procedures for the various subsets of subjects are as follows: 
For subjects who develop potential liver-related clinical outcomes during the study, protocol-
specified biopsies for study visits after onset of the potential outcome event may not be required. 
9.9.8.3. 
Additional Annual Procedures (Months 30, 42, 54, 66, 78 and every 12 Months 
until the EOS) 
For Months 30, 42, 54, 66, 78 and every 12 months until the EOS the following Annual Visit 
procedures are to be conducted in addition to those specified in Section 9.9.8.1 for all subjects as 
follows: 
•
Perform a physical examination
•
Perform a standard 12-lead ECG
•
Determine alcohol consumption (AUDIT questionnaire), smoking habits, and caffeine
consumption
•
Obtain blood samples for
−
Thyroid hormones
−
Free fatty acids
−
Insulin, c-peptide, and HOMA-IR
−
Inflammation marker (hs-CRP)
•
Calculations will be performed by the Sponsor or designee for
−
Cardiovascular risk scores (FRS, Reynolds score, SCORE, 10-year ASCVD Risk)
Annual procedures for the various subsets of subjects are as follows: 
9.9.9. 
End of Study and/or End of Treatment Procedures for Subjects that Withdraw 
from Investigational Product or Withdraw Consent 
Subjects who discontinue investigational product are expected to continue in the study until the 
end of the study or at the discretion of the Sponsor.  Additional strategies to encourage continued 
subjects participation in the study will be outlined in a Subject Retention Plan.   
EOT procedures will be required whenever subjects discontinue treatment with investigational 
product.  The EOT visit and procedures listed below must be performed as close as possible to 
the subject’s last dose of investigational product.  When a subject discontinues investigational 
product but continues with regularly scheduled study visits, the EOS visit will be completed later 


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in the study as the subject’s final study visit.  The actual investigational product discontinuation 
scenario (Table 6) will determine the sequence of the EOT and EOS visits and procedures.  In 
some cases, the EOT visit and procedures will precede the EOS visit; in others, the EOT and 
EOS visits will be combined and performed as close as possible to the subject’s last dose of 
investigational product.   
When a subject ends her/his participation in the study (eg, at a point between standard study 
visits) either due to early termination (withdrawal of consent) or discontinuation, an EOT/EOS 
visit must be performed as near as possible to her/his last dose of investigational product and the 
procedures, listed below, performed.  The purpose of this visit is to conduct complete and/or 
final assessments on or as near as possible to the final day of dosing.  In some cases, the subject 
may discontinue on the day of a scheduled study visit.  In these cases, EOT/EOS visit procedures 
should be performed in place of the scheduled study visit procedures.  The data will be recorded 
as EOT and EOS procedures in the CRF.  
Table 6: 
Early Discontinuation Scenarios 
Investigational 
Product 
Consent 
Study Visit Status 
EOT Visita 
EOS Visita 
Early 
Termination 
Discontinued 
Withdrawn 
No additional visits 
except EOT/EOS 
Combined visit, completed as close as 
possible to last dose of investigational 
product 
Treatment 
Discontinuation 
Discontinued 
Active 
Regular Visit 
Schedule 
Complete as close as 
possible to last dose of 
investigational product 
Complete at 
final study 
visit 
Discontinued 
Semi-annual 
contactb 
Telephone contact 
every 6 months 
(±2 weeks) 
Combined visit, completed as close as 
possible to last dose of investigational 
product 
Discontinued 
Record 
review onlyb Record review only 
Combined visit, completed as close as 
possible to last dose of investigational 
product 
Sponsor 
Termination 
Discontinued 
N/A 
No additional visits 
except EOT/EOS 
Combined visit, completed as close as 
possible to last dose of investigational 
product 
Lost to 
Follow-Up 
Discontinued 
LTF 
None 
Unable to complete due to LTF status 
EOS = end of study; EOT = end of treatment; LTF = lost to follow-up 
a Refer to Section 9.9.9 and Schedule of Study Procedures for all procedures and evaluations required at the EOS and EOT 
Visits. 
b Outcomes data to be discussed or collected include data related to adjudicated event-related data.  No additional data (eg, AE, 
concomitant medication, etc.) data will be collected, except as indicated in Section 15.1.9. 
Some assessments noted below may be omitted if they have been completed within 6 months 
(or the timeframe otherwise specified) and so long as safety issues do not warrant repeat testing. 
EOS and/or EOT 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 CRF


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If the subject repmts having eaten within 8 hours, document accordingly in the 
source and CRF and remind the subject that fasting is required before all study 
visits after screening. 
•
Perfmm a physical examination
•
Perfmm a standard 12-lead ECG
• 
and vital signs (body temperature, sitting heart rate, 
respiratory rate, and sitting blood pressure) 
• 
• 
Dete1mine alcohol consumption (AUDIT questionnaire), smoking habits and caffeine 
consumption 
•
Assess and record AEs
•
Review and recmd concomitant medications
• 
• 
Perfmm hepatobilia1y ultrasound for 
and for gallbladder assessment 
(not required at EOT/EOS if done within 6 months of visit) 
•
Obtain liver biopsy (not required if biopsy has been done within 6 months of the
• 
EOT /EOS Visit
Serum chemistiy, hematology and coagulation 
Thyroid hmmones 
Free fatty acids 
Insulin, c-peptide, and HOMA-IR 
Glucose and HbAlc 
Apoptosis markers (CK-18 M30 and CK-18 M65; only for subjects that 
discontinue investigational product before or on Month 18 visit) 
Noninvasive assessments ofliver fibrosis: ELF, Fibrotest!Fibrosure 
Inflammation marker (hs-CRP) 
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•
Evaluate signs and symptoms of hepatic injury or decompensation and assess subjects
per Suspected DILI Management and Progression to Cirrhosis Algorithms and
intercurrent illness and/or potential adverse events (Appendix C)
•
Calculations will be performed by the Sponsor or designee for
−
MELD score
− 
− 
•
Obtain urine sample for urinalysis
•
Perform a urine-based β-hCG pregnancy test for females of childbearing potential
•
Collect all used and unused bottles of investigational product, assess investigational
product compliance, and perform investigational product accountability
EOS and/or EOT Visit procedures for the various subsets of subjects are as follows: 
• 
• Obtain stool sample (collected at home or in office if the subject did not receive a kit 
and instructions at the last visit) for microbiome/metabolome analysis (only 
completed for a subset of US subjects who provided baseline [Day 1] sample and 
were enrolled prior to Version 7 of the protocol) 
For subjects who develop potential liver-related clinical outcomes during the study, 
protocol-specified biopsies for study visits after onset of the potential outcome event may not be 
required.  For subjects who develop
 during the study, 
 assessments for study 
visits after onset of 
are not required. 
9.9.10. 
Unscheduled Safety Visit 
The Investigator may schedule an at-clinic Unscheduled/Safety Visit at any time if clinically 
warranted (refer to Section 7.4).  Unscheduled and/or repeat assessments, including additional 
laboratory tests or investigations, may be conducted.  Evaluations may include a physical exam, 
serum biochemistry, serum electrolytes, assessment of MELD scores, and imaging and/or 
Fibroscan at Investigator’s discretion.  In these cases, where a local laboratory is used, it is 
important that all local laboratory data, including the reference ranges, are collected and entered 
in the eCRF within 2 days of receiving results.  Further monitoring outside of regular scheduled 
visits should be based on the Investigator’s assessment of the subject’s clinical status. 
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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 
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 within 2 days of
receiving results.  Note:  Investigational product can only be dispensed if central or
local laboratory values are available.
−
Minimum testing required to support the protocol:  Liver safety labs of direct and
total bilirubin, AST, ALT, GGT, ALP, coagulation panel (INR, aPTT), platelets,


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albumin and serum creatinine and non-liver safety labs of CBC & Diff, standard 
electrolytes, lipid panel 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.
•
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 the 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 the pediatric population suffering from 
biliary atresia (BA), there are no safety data available specific to 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, vaccine name, and 
manufacturer should be recorded as a concomitant medication for each dose.   


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11.
INVESTIGATIONAL PRODUCT MATERIALS AND
MANAGEMENT
11.1. 
Investigational Product 
The investigational product is a white, round, film-coated tablet containing 25 mg or 10 mg of 
OCA or placebo.  All tablets are identical in size and appearance.  The tablets contain the 
following inactive ingredients:  microcrystalline cellulose, sodium starch glycolate, and 
magnesium stearate.  The OCA 25 mg tablet also contains silicon dioxide. 
11.2. 
Investigational Product Packaging and Labeling 
The packaging and labeling of investigational product supplies will be performed according to 
Good Manufacturing Practice standards by a designated qualified vendor.  All investigational 
product will be provided as tablets for oral administration and provided in high-density 
polyethylene bottles with heat induction seals and child resistant closures.  The bottle packaging 
will not reveal any information about the treatment dose contained in the bottle.  Multiple bottles 
may be dispensed to the subject according to the visit schedule in Table 1 to provide enough 
tablets for daily dosing until the next time drug is dispensed.  If a known visit schedule departure 
is planned for a time frame greater than 100 days from previous visit during the first 18 months 
of treatment, an unscheduled bottle should be proactively dispensed and provided to the subject. 
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 
All OCA tablet strengths provided to clinical trial sites in support of clinical study are to be 
shipped and stored at 15°C to 25°C.  Temperature excursions within the range of 2°C and 30°C 
for no more than a 6 month period are acceptable, and the OCA tablet continues to be suitable 
for use in clinical studies.  Additionally, temperature excursions within the range -20°C to 40°C 
for no more than 7 days are acceptable, and the OCA tablet continues to be suitable for use in 
clinical studies.  
11.4. 
Investigational Product Administration 
Refer to Section 9.1. 
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.  


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All investigational product will be provided for use only in this study and is not to be used for 
any other purpose. The Investigator or designee will maintain a full record of investigational 
product accountability, including records of individual subject dispensing and final return or 
disposition (as directed by the Sponsor). 
The study monitor, also known as the Clinical Research Associate (CRA) will review 
accountability records against investigational product dispensed and that remaining in stock, 
during on site monitoring visits and when the study is completed, or if it is prematurely 
tenninated. The CRA will retrieve documentation detailing and confinning the return or 
destruction of the investigational product. If the investigational product is to be returned to the 
Sponsor's vendor for destruction, the CRA will also prepare the investigational product for 
shipment. 
12.
OVERVIEW OF ASSESSMENTS
The assessments supporting the objectives for the Interim Analysis at Month 18 are as follows: 
Interim Analyses Variables 
Assessments 
PrimaIJ: Objective Assessed at the Month 18 Interim Anal1sis (All Subjects) 
Improvement in fibrosis w-ith no 
A reduction in fibrosis stage of at least 1 with no increase in hepatocellular 
worsening of NASH 
ballooning, lobular inflammation, or steatosis from baseline based on liver biopsy 
using NASH CRN criteria 
Resolution of ASH Iv-ithno 
NASH resolution defined as the overall histopathologic inte1pretation of l) "no fatty 
worsening of fibrosis 
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 with no 
increase in fibrosis stage from baseline based on liver biopsy using NASH CRN 
criteria 
Secondac: Objectives Assessed at the Month 18 Interim Anal:1:sis £All Subjects} 
Improvement of fibrosis by at least 
A reduction in fibrosis stage of at least 1 with no increase in hepatocellular 
l stage. AND/OR resolution of
ballooning, lobular inflammation or steatosis from baseline base.cl 011 liver biopsy 
ASH. without worsening of either
using NASH CRN criteria AND/OR NASH resolution defined as the overall 
histopathologic inte1pretation of 1) 'no fatty liver disease" or 2) "fatty liver disease. 
(simple or isolated steatosis) without steatohepatitis" AND a NAS of 0 for ballooning 
a11d 0-1 for inflanunatio11 with no increase in fibrosis stage from baseline based on 
liver biopsy using NASH CRN criteria 
o worsening of fibrosis AND 110
No increase from baseline in fibrosis stage AND 110 increase in hepatocellular 
worsening of ASH 
ballooning, lobular inflammation or steatosis based on liver biopsy using ASHCRN 
criteria 
lmprovemen in each key 
A reduction in score of at least l from baseline for steatosis, lobular inflanunation, or 
histological feature of NASH 
hepatocellular ballooning based on liver biopsy using ASH CRN criteria 
Improvement of fibrosis by at least 
A reduction from baseline in fibrosis of at least 2 stages baseJ on liver biopsy using 
2 stages 
NASH CRN criteria 
Improvement in AS by at least 
A reduction in NAS by at least 2 points with no increase in fibrosis stage from 
2 points with no worsening of 
baseline based on liver biopsy using NASH CRN criteria 
fibrosis 
Improvement of fibrosis and 
A reduction from baseline in fibrosis stage of at least 1 using NASH CRN criteria and 
resolution of ASH as a composite 
resolution of ASH as defined above 
C11dpoint and as defined by both 
endpoints being met in the same 
subject 
Histological progression to cirrhosis 
A fibrosis stage of 4 based on liver biopsy using NASH CRN c1-ite1-ia 
Confidential and Proprietary 


Protocol 747-303 
Interim Analy-ses V aiiables 
Resolution of fibrosis 
Liver biochem.istty and markers of 
liver function 
Adjudicated cardiovascular events 
for cardiovascular outcomes 
assessment 
Safety and tolerability 
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Page 102 
A fibrosis stage of O based on liver biopsy using NASH CRN criteria 
ALT, AST, GGT, ALP, total and direct bilirubin, albumin, INR, and platelets 
Cardiovascular events including core MACE (cardiovascular death, nonfatal 
myocardial infarction, nonfatal stroke), expanded MACE (unstable angina requiring 
hospitalization, transient ischemic attack, peripheral or c.orona1y revascularization 
procedures. hospitalization for congestive heart failme ). Other events potentially 
related to adverse cardiovascular outcomes as defined in Appendix E and included in 
the CAC charter w-ill be sent to the CAC for adjudication 
TEAEs, ECGs. vital signs, clinical laborato1y assessments (including lipid profile 
changes) 


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The assessments supp01ting the objectives for the final analysis at the end of the study are as 
follows: 
EOS Analyses Val'iables 
Assessments 
Primary Obje.ctiYe Assessed at EOS {All Subjects) 
Clinical outcomes composite 
endpoint 
Tin1e to first occurrence of any of the following adjudicated events: death ( all cause); 
MELD score 2:15; liver transplant; hospitalization (as defined by a stay of2:24 hours) 
for onset of variceal bleed, hepatic encephalopathy (as defined by a West Haven 
score of2:2). or spontaneous bacterial peritonitis (confinned by diagnostic 
paracentesis); ascites seconda1y to cin·hosis and requiring medical intervention ( eg, 
dim·etics or paracentesis); or progression to ciirhosis 
Se.condary Objectins Assessed at EOS (All Subjects) 
Improvement in fibrosis '"·ith no 
worsening of ASH 
Resolution of ASH w-ith no 
worsening of fibrosis 
Improvement of fibrosis by at least 
1 stage AND/OR resolution of 
ASH. without worsening of either 
o worsening of fibrosis AND no
worsening of ASH 
Improvement iii each key histological 
feature of ASH 
Improvement of fibrosis by at least 
2 stages 
Improvement in AS by at least 
2 points with no worsening of 
fibrosis 
Improvement of fibrosis and 
resolution of ASH as a composite 
endpoint and as defined by both 
endpoillts beillg met in the same 
subject 
Resolution of fibrosis 
Liver biochemistry and markers of 
liver function 
Confidential and Proprietary 
A reduction in fibrosis stage of at least 1 and no increase in hepatocellular balloonii1g, 
lobular inflammation, or steatosis from baseline based on liver biopsy using NASH 
CRN criteria 
NASH resolution defined as the overall histopathologic inte1pretation of 1) "no fatty 
liver disease" or 2) "fatty liver disease (siniple or isolated steatosis) without 
steatohepatitis" AND a NAS of0 for ballooning and 0-1 for inflammation with no 
ii1crease in fibrosis stage from baseline based on liver biopsy usii1g ASH CRN 
criteria 
A reduction ill fibrosis stage of at least 1 with no increase in hepatocellular 
ballooning, lobular iirllammation or steatosis from baseline based on liver biopsy 
using NASH CRN criteria AND/OR NASH resolution defined as the overall 
histopathologic inte1pretation of 1) "no fatty liver disease" or 2) "fatty liver disease 
(siniple or isolated steatosis) without steatohepatitis" AND a NAS of 0 for ballooning 
and 0-1 for inflammation with no illcrease in fibrosis stage from baseline based on 
liver biopsy using NASH CRN criteria 
No increase from baseline iii fibro&is stage AND no increase in hepatocellular 
ballooning, lobular inflammation or steatosis based 011 liver biop&y usmg ASH 
CRN criteria 
A reduction in score of at least 1 from baseline for steatosis, lobular inflammation, or 
hepatocellular ballooning based on liver biopsy using 
ASH CRN criteria 
A reduction from baseline in fibrosis of at least 2 stages based on liver biopsy using 
NASH CRN criteria 
A reduction ill NAS by at least 2 poillts with no increase iii fibrosis stage from 
baseline based on liver biopsy using NASH CRN criteria 
A reduction from baseline in fibrosis stage of at least 1 using NASH CRN criteria and 
resolution of NASH as defined above 
A fibrosis stage of 0 based on liver biopsy using NASH C
RN criteria 
ALT. AST, GGT, ALP, total and direct bilimbm, albtunm, INR, and platelets 


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Safety Objecth,es at EOS (All Subjects) 
Adjudicated cardiovascular events 
for cardiovascular outcomes 
assessment 
Adjudicated events of AKI 
Cardiovascular events including core MACE (cardiovascular death, nonfatal 
myocardial infarction, nonfatal stroke) and expanded MACE (unstable angina 
requiring hospitalization, transient ischem.ic attack, peripheral or coronary 
revascularization procedures, hospitalization for congestive heart failure, and 
an-hythm.ias). Any hospitalization (2:24 hours) where a cause has not been identified 
by the Investigator will be treated as a cardiovascular eveut and seut for adjudication. 
Other events potentially related to adverse cardiovascular outcomes as defined in 
Appendix E and included in the CAC charter ·will be sent to the CAC for adjudication 
Evaluate the effect of OCA compared to placebo on the incidence of adjudicated AKI 
events 
Adjudicated events of hepatic injury 
Evaluate the effect of OCA compared to placebo on the incidence of adjudicated 
events ofhepatic injury 
Long-term safety and tolerability 
TEAEs, ECGs, vital signs, clinical laboratory assessments (including lipid profile 
changes) 
AKI= acute kidney in\ 
; ALT= alanine aminotransferase; 
aminotransferase; 
Adjudication Co1ll1111tfe,e; 
Fibrosis; EOS = end of sl:I. y; 
events; MELD = model of en stage 
-; NAFLD = nonalcoholic fat 
treatment-emergent adverse event; 
13.
ASSESSMENTS OF EFFICACY
13.1. 
Liver Biopsies 
T = aspartate 
Given that historical biopsies are to be obtained no more than 6 months before Day 1, slides 
should be sent for centrnl 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. 
Liver biopsies will generally be obtained from the right lobe of the liver as described in a study 
speǶ manual. Liver biopsies are to be performed after the hepatobiliaiy ultrasound 
for __ If the initial biopsy was obtained from the left lobe, then subsequent 
biopsies must be obtained from the left lobe. Biopsies should be at least 2 cm in length. If a 
serial liver biopsy is required, the biopsy should not be perfo1med within 6 months of a prior 
liver biopsy, unless clinically indicated. For subjects who develop potential liver-related clinical 
outcomes during the study, protocol-specified biopsies for study visits after onset of the potential 
outcome event may not be required. 
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The investigator will assess the clinical criteria for progression of fibrosis to cirrhosis for each 
subject during the study.  If non-invasive indicators of progression to cirrhosis become evident at 
any time during the study, it is recommended that a liver biopsy should be obtained and sent for 
central reading.  Updated guidance on criteria to trigger an unscheduled liver biopsy in subjects 
with potential progression to cirrhosis may be provided to investigators separately. 
If possible, a PK blood sample should be collected at the time of the liver biopsy. 
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 biopsy assessments will be performed centrally, including assessments from biopsies to 
determine study eligibility and unscheduled biopsies, and biopsies that may be performed to 
confirm cirrhosis according to criteria described in Section 7.4.2. 
To determine eligibility at enrollment, a central pathologist must confirm histological presence 
of NASH and a minimum NAS of 4 with a score of at least 1 in each component of NAS.  For 
each biopsy, key features of NASH (ie, steatosis, lobular inflammation, and hepatocellular 
ballooning) and fibrosis staging will be graded in accordance with the NASH CRN criteria for 
scoring (Kleiner 2005) as summarized in Table 7.   
Table 7: 
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% 
2 = >33% - 66% 
3 = >66%  
Stage 0 
No Fibrosis 
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, persinusoidal 
Moderate, zone 3, perisinusoidal 
Portal / periportal   
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 
In addition to the primary scoring system of NASH CRN, biopsy samples from the Month 18 
Interim Analysis will also be scored based on modified Ishak scoring (Ishak 1995) and SAF 
scoring (Bedossa 2014) for all subjects as well as for quantitative collagen for a subset of 
subjects as exploratory assessments.  Any extra biopsy tissue may undergo exploratory 
histological evaluations such as alpha-smooth muscle actin or bile acid transporter analysis. 


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13.2. 
Prospective Surveillance 
 screening will include a hepatobiliary ultrasound and AFP assessment according to the 
schedule presented in Table 1.  For subjects who develop 
during the study, 
screening 
assessments for study visits after onset of 
are not required. 
13.4. 
Efficacy Laboratory Assessments 
Refer to Section 15.2.6 for instructions regarding sample collection and Table 12 for a full list of 
analytes to be tested. 
-
-
-


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13.7. 
Assessments for the Various Subsets of Subjects 
At selected investigational sites, at least 300 subjects will have the option to provide blood 
samples for measurement of OCA PK concentrations.   
At study sites in the United States, subjects will have the option to provide stool samples for 
microbiome/metabolome analysis only if they provided baseline (Day 1) samples.   
PK and microbiome/metabolome assessments are optional, and subjects may decline to 
participate without affecting their involvement in the rest of the study. 
At selected centers where the devices are available, subjects may participate in 
.  Biopsy samples will be scored for quantitative -


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collagen for a subset of subjects as described in Section 13.1.1.  The schedule of assessments is 
presented in Table 1. 
14.
CLINICAL PHARMACOLOGY ASSESSMENTS


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14.1.2. 
Subjects Who Develop Cirrhosis and Child-Pugh Class A 
Subjects who develop cirrhosis and are Child-Pugh Class A (CP score <7) will have their dose 
adjusted (refer to Table 4).  These subjects will provide 1 blood sample for PK assessment prior 
to dose adjustment, at the next scheduled visit.  The PK assessment will measure serum 
concentrations of OCA, its conjugates (glyco-OCA and tauro-OCA), and OCA-glucuronide.  The 
time of the last dose of investigational product and the time of the last meal will be recorded.  
The subject will then begin taking the adjusted dose of investigational product, thereafter, at the 
appropriate time. 
14.1.2.1. Subjects Who Interrupt or Discontinue Investigational Product due to Cirrhosis 
or Hepatic Injury 
Subjects who are considered to have potentially progressed to cirrhosis and discontinue 
investigational product due to progression to cirrhosis and due to Child Pugh score ≥7 or 
interrupt investigational product due to hepatic injury will provide a PK blood sample within 
≤7 days from interruption or discontinuation of the investigational product (refer to Table 4). 


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15.
ASSESSMENTS OF SAFETY
15.1. 
Adverse Events and Serious Adverse Events 
15.1.1. 
Definition of Adverse Events 
15.1.1.1. Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of the 
investigational product in humans, whether or not considered related to investigational product.  
An AE (also referred to as an adverse experience) can be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom, or disease temporally associated with any use of 
the investigational product, without any judgment about causality and irrespective of route of 
administration, formulation, or dose, including an overdose. 
AEs include, but are not limited to: (1) a worsening or change in nature, severity, or frequency of 
condition(s) present at the start of the study; (2) subject deterioration due to primary illness; 
(3) intercurrent illness; and (4) drug interaction.  For reporting purposes, pregnancy is not
considered an AE.
Subjects should be questioned in a general way, without leading the subject or asking about the 
occurrence of any specific symptom.   
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  The diagnosis and not the individual signs/symptoms should 
be documented as the AE.  For example, if the underlying disease process is a stroke, it would 
not be appropriate to record the AE by describing the symptoms “sudden numbness, dizziness, 
and difficulty speaking.”  The AE medical term of “stroke or cerebrovascular accident” should 
be recorded as it more accurately describes the AE. 
Subjects should be instructed to contact the site promptly if they develop any of the signs and 
symptoms of intercurrent illness and/or potential adverse events listed in Appendix C.  
15.1.1.2. Treatment-Emergent Adverse Event 
A treatment-emergent AE (TEAE) is any event not present before the initiation of the 
investigational product or any event already present that worsens in either intensity or frequency 
following exposure to the investigational product. 
15.1.1.3. 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-subject hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability or incapacity
•
Results in a congenital abnormality or birth defect


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•
Is an important medical event that may jeopardize the subject or may require medical
intervention to prevent one of the outcomes listed above
Events not considered to be SAEs are hospitalizations for: 
•
Routine monitoring of the studied indication and not associated with any deterioration
in condition or AE
•
Elective treatment for a pre-existing condition that did not worsen
•
Respite care or observation when there is no AE associated with the hospitalization
A PK blood sample should be collected in subjects who experience a 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 will be recorded in the eCRF.  If a PK sample cannot be 
collected within 7 days, the reason should be recorded in the eCRF. 
15.1.2. 
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 
product that are brought to its attention are recorded.  The Sponsor shall also inform all 
participating Investigators, as applicable to the local regulations. 
15.1.3. 
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,” “possible” or “probable,” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting. 


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Table 8: 
Relationship of Adverse Events to Investigational Product 
Relationship 
Description 
Definite 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product or in which the investigational product level has been established in 
body fluids or tissue; that follows a known or expected response pattern to the suspected 
investigational product; and that is confirmed by improvement on stopping or reducing the 
dosage of the investigational product, and reappearance of the reaction on repeated 
exposure. 
Probable 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product; that follows a known or expected response pattern to the suspected 
investigational product; that is confirmed by stopping or reducing the dosage of the 
investigational product; and that could not be reasonably explained by the known 
characteristics of the subject’s clinical state. 
Possible 
A reaction that follows a reasonable temporal sequence from administration of the 
investigational product; that follows a known or expected response pattern to the suspected 
investigational product; but that could readily be produced by a number of other factors. 
Unlikely 
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. 
15.1.4. 
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. 
15.1.5. 
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 10, must be entered on the AE CRF.  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 current version of the CTCAE 
manual for guidance on appropriate grading. 


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Table 10: 
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. 
15.1.5.1. Severity of Pruritus (as an AE) 
To ensure consistency in reporting, pruritus AEs must be graded for severity (ie, intensity) using 
the current version of the CTCAE (Appendix D) the category definitions are included in 
Table 11 for reference.  As pruritus is a subjective symptom, clinical judgment should be used to 
determine its management.   
Table 11: 
Severity of Pruritus 
Pruritus Grade 
Clinical Description of Severity for Pruritus 
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, the occurrence and magnitude of which are not readily 
measured objectively, 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.  Guidance for 
the management of subjects experiencing significant pruritus are provided in Table 4 
(Section 7.7) and includes: 
•
Pruritus ≥Grade 3 in severity:  Discontinue investigational product
•
Pruritus ≤Grade 2 in severity:  One or more of the following may be considered:
−
Drug holiday or less frequent dosing at the discretion of the Investigator.
−
Short-term use of BAS


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•
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.
•
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 9.3.
−
Other medical therapies may be considered, as deemed clinically appropriate and
based on current practice guidelines (EASL 2017) or literature (Hegade 2015).
15.1.6. 
Reporting of Adverse Events and Serious Adverse Events 
15.1.6.1. Reporting of Adverse Events 
AE data will be collected from the time that signed informed consent is obtained until the subject 
fully completes her/his study participation of the study. 
All AEs, whether believed by the Investigator to be related or unrelated to the investigational 
product, must be documented in the subject’s medical records, in accordance with the 
Investigator’s normal clinical practice and on the AE CRF.  Each AE is to be evaluated for 
duration, intensity, frequency, seriousness, outcome, other actions taken, and relationship to the 
investigational product.  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 promptly when any signs 
or symptoms of hepatic decompensation are observed in any subject. 
15.1.6.2. Reporting of Serious Adverse Events 
In agreeing to the provisions of this protocol, the Investigator accepts all legal responsibilities for 
immediate reporting of SAEs to the Sponsor.  Immediate reporting implies within 24 hours of 
becoming aware of the occurrence of an SAE. 
All SAEs must be reported to the Sponsor (including potential liver-related clinical outcome 
events that qualify as serious).   


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SAEs are reported by entering the SAE data into the study specific EDC system.  Entering the 
SAE data into the EDC system will automatically notify the Sponsor of the event.  In the event 
that the EDC system is inaccessible, an SAE may be reported by: 
If an SAE is reported by fax, an SAE Report form must also be completed in the EDC system as 
soon as the EDC system is accessible.  At a minimum, the following information should be 
provided at the time of the initial report:   
•
Subject number
•
Event term
•
At least 1 criterion classifying the event as serious
•
Name and title of the reporting individual
•
Causal relationship to the investigational product
The Investigator will assess whether the event is causally related to the investigational product.  
The Sponsor will also assess whether the event is causally related to the investigational product, 
in addition to assessing the overall safety profile of the investigational product.  The Sponsor will 
notify the appropriate regulatory agencies as well as all participating Investigators of 
investigational new drug (IND) Safety Reports/Expedited Safety Reports that occur during the 
study within the time frames required by each regulatory agency.  
Following the initial report, any additional information obtained by the Investigator about the 
SAE must be reported promptly to the Sponsor in the same manner as described above for the 
initial SAE report.  Any supporting source documentation should be faxed to 
 or 
emailed to 
 as soon as possible.   
The Investigator is responsible for submitting information on IND Safety Reports/Expedited 
Safety Reports received from the Sponsor to her/his local IRB/IEC, as directed by the 
local-country requirements.  Documentation of the submissions to IECs/IRBs must be retained in 
the appropriate study file(s).  As instructed by the Sponsor, IND Safety Reports/Expedited Safety 
Reports should be retained in the appropriate investigative site study files, or with the IB. 
SAEs involving potential liver-related clinical outcome events will be processed and reported by 
the Sponsor as described in Section 15.1.7.  
15.1.7. 
Potential Liver-Related Clinical Outcome Events 
Specified liver-related clinical outcome events may, by definition (see Section 15.1.1.3) qualify 
as SAEs.  The Sponsor must be notified of any SAEs within 24 hours of the site becoming aware 
of the event (see Section 15.1.6.2).  The Sponsor is responsible for regulatory reporting of SAEs, 
including expeditious reporting of SUSARs, refer to Section 15.1.2 for definition of SUSAR.  
Given that the liver-related clinical outcome events could also meet the criteria of a SUSAR, 
which would necessitate unblinding for expedited reporting, the Sponsor will not expeditiously 
report potential liver-related clinical outcome events in order to retain the study blind and 
preserve the integrity of the clinical outcomes endpoint.  These events will be selected as a 


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“study event” on the Adverse Event CRF and will be submitted for adjudication to the Hepatic 
Outcomes Committee as described in Section 16.11. 
The Sponsor will consider the following list of clinical outcome events (MedDRA preferred 
terms) to be disease related and exempt from expeditious regulatory reporting, but will continue 
to report them in a non-expeditious manner:  death, end-stage liver disease (preferred term: 
chronic hepatic failure), liver transplant (preferred term: liver transplant), 
, variceal bleeding (preferred terms: gastroesophageal variceal 
haemorrhage, esophageal varices haemorrhage), hepatic encephalopathy (preferred term: hepatic 
encephalopathy), spontaneous bacterial peritonitis (preferred term: peritonitis bacterial), ascites 
secondary to cirrhosis (preferred term: ascites), and progression to cirrhosis (preferred term: 
hepatic cirrhosis). 
15.1.8. 
Additional Investigator Responsibilities for SAEs 
The safety data recorded in the CRF represent the official record of all AEs and SAEs reported in 
the study.  The Investigator should comply with requests by the Medical Monitor or other 
Sponsor personnel to record the SAE on the subject’s AE CRF.  Other supporting documents 
such as radiology reports, hospital discharge summaries, and autopsy reports should also be 
provided, when appropriate.  Additionally, upon request by the 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. 
15.1.9. 
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 15.1.6.2. 
15.1.10. 
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 15.1.6.2. 
All SAEs that occur within 30 days of discontinuation from the study, whether or not they are 
related to investigational product, should be reported to the Sponsor within 24 hours by 
following the instructions provided in Section 15.1.6.2. 
15.1.11. 
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.  


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If resolved, a resolution date for the AE should be documented on the CRF.  The Investigator 
must ensure that follow-up includes any supplemental investigations indicated to elucidate the 
nature and/or causality of the AE.  This may include additional laboratory tests or investigations, 
or consultation with other healthcare professionals, as considered clinically appropriate by the 
Investigator. 
All subjects showing possible drug-induced liver injury 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 CRF.  Note that longer follow-up can sometimes reveal an off-drug repetition 
of what had appeared to be drug-induced liver injury, indicating that liver injury was related to 
underlying liver disease. 
If a subject experiences symptoms consistent with cholelithiasis 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. 
15.1.12. 
Pregnancy and Follow-Up 
Pregnancies are not considered AEs in and of themselves; however, if a female study participant 
becomes pregnant while she is enrolled in the clinical study, she must interrupt treatment with 
investigational product immediately (see Table 4) and the Sponsor must be notified within 
24 hours of the Investigator’s awareness of the pregnancy by completing the Pregnancy CRF in 
the EDC system and downloading and completing the Pregnancy Report Form.  The Pregnancy 
Report Form must be emailed to 
.  The 
subject and neonate must be followed for outcome information and/or as considered appropriate 
by the Investigator and the Sponsor. 
The subject may re-start investigational product when she is no longer pregnant or breastfeeding 
at the discretion of the Investigator and after discussion with the Medical Monitor.  The subject 
must have a negative pregnancy test before restarting investigational product.  If a subject’s 
pregnancy is terminated early (planned or unplanned), she must have termination of the 
pregnancy confirmed by a serum β-hCG test before restarting investigational product. 
Completing the Pregnancy Report Form is not a substitute for reporting an AE/SAE when an 
AE/SAE has occurred.  In the situation when an AE/SAE has occurred, the AE/SAE reporting 
procedures described in Section 15.1.6 must also be followed. 


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15.2. 
Other Safety Parameters 
15.2.1. 
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, 
gender, race, and ethnicity) will be recorded. 
15.2.2. 
Physical Examination 
To assess for clinical findings, the Investigator or designee will perform a physical examination 
at the visits specified in Table 1.  A basic physical examination should be performed, including 
all body systems pertinent to the subject.  Any clinically significant abnormality should be 
reported on the AE CRF page.   
15.2.3. 
Vital Signs 
Vital signs will be assessed at the visits specified in Table 1.  Vital signs include body 
temperature, sitting heart rate, respiratory rate, and sitting blood pressure.  When taking heart 
rate, respiratory rate, and blood pressure readings, subjects should be seated quietly for a 
minimum of 3 minutes before the readings are taken.   
15.2.4. 
Electrocardiogram 
Standard 12-lead ECGs will be collected at the visits specified in Table 1.  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 CRF as normal, abnormal but not clinically 
significant, or abnormal and clinically significant.  Any clinically significant abnormality on 
ECGs should be reported on the AE CRF page.  
Investigative sites must retain a copy of all 12-lead ECGs.  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.
15.2.5. 
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 using the AUDIT, smoking habits, and 
caffeine consumption CRFs.  AUDIT is a 10-item questionnaire that uses the domains of alcohol 
consumption, drinking behavior, and alcohol-related problems (Saunders 1993) 
15.2.6. 
Laboratory Assessments 
Except for Screening and safety lab visits between regularly scheduled visits, 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 CRF.  If the subject reports having eaten (water is 
permitted) within 8 hours, the Investigator or designee will document accordingly in the source 


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and CRF and remind the subject that fasting is required before all regularly scheduled study 
visits after screening ( exception - safety lab visits). 
Blood, urine, and stool samples for laborat01y assessments will be collected at the visits specified 
in Table 1. Full instrnctions 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 separate procedural manuals. All necessaiy collection supplies will 
be provided by the appropriate laborato1y 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 laborat01y is required. In 
these cases, the Investigator will obtain the laborat01y results and the laborat01y n01mal ranges. 
All local laborat01y data, including the reference ranges, ai·e to be collected and entered in the 
eCRF within 2 days ofreceiving 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 laborat01y tests containing clinically significant abnormal values ai·e to be 
followed regularly until the values return to n01mal ranges· until a valid reason, other than 
investigational product-related AE is identified; or until further follow-up is deemed medically 
unnecessaiy. 
The list of laborat01y analytes to be tested is shown in Table 12. 
Table 12: 
List of Laboratory Analytes to be Tested 
Labor-atory Assessment 
All Subjects 
Serum chemistry 
Hematology 
Confidential and Proprietary 
Analyte 
Albumin, BUN, direct bilimbin (ie, conjugated bili.rubin), indirect bilimbin 
total bilimbin, AST, ALT, ALP, GGT, creatinine, electrolytes (calcium, 
chloride magnesiwn, phosphorns, potassimn, sodilllll), total protein, 
bicarbonate, free fatty acids ( only at visits that specify analysis of this analyte ), 
creatine phosphokinase ( only at visits that specify analysis of this analyte ), 
LDL, HDL, VLDL, total cholesterol, triglycerides, and calculation of eGFR 
Hemoglobin, hematocrit, white blood count with differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils), platelets, red blood cell 
count includin MCV. MCH MCHC 
ilimbin, blood, 
, leucocytes, nitrates, 


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Table 12: 
List of Laboratory Analytes to be Tested (Continued) 
Labol'atory Assessment 
Virology 
Pregnancy Test (female subjects 
of childbearing potential) 
Ana1yte 
HbsAg, HCV 
ı-hCG 
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Microbiome/Metabolome 
Analysis 
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 
AFP = 
-fetoprotein; ALP= alkalin.e phosphatase; ALT= alanine aminotr
= 
•
• 
onadotro •
-
-
mational nmmalized ratio; LDL = low-dens1 
0lobin: MCHC = mean corpuscular hemoglobin concentra 
corpuscular vohune; AFLD = nonalcoholic fa 
• ; NFS = NAFLD fibrosis
score; PAI-I= plasminogen activator inhibitor-I; 
PT= prothrombi.i1 ti.ine;
PTT = partial thromboplastin time; RNA= ribom 
. 
H = thyroid stinmlating
hormone; VLDL = ve1y low-density lipoprotein 
The Investigator should proactively monitor and manage lipid levels in all subjects as indicated 
via appropriate medical interventions (eg, statins). Recent guidelines stress the impo11ance 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 recmTence of ASCVD (refer to 
Section 9.3.3 and Appendix A). 
Urine-based ͘-hCG pregnancy tests will be perfmmed for female subjects of childbearing 
potential at the visits specified in Table 1. If a mine pregnancy test is positive, a se1um 
pregnancy test must be perfo1med to confom the result. If positive the Sponsor must be notified 
and the subject will be followed, as outlined in Section 15.1.12 through pregnancy outcome. 
International normalized ratio (INR) will be calculated based on prothrombin time value by the 
central laborato1y. MELD scores will be calculated based on creatinine, bilirnbin, INR, and 
sodium values as appropriate, collected at the same visit, with modification by United Network 
for Organ Sharing. If only I component of MELD needs to be repeated, all other components 
should also be repeated. 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, tam-o-OCA, and glyco-OCA concentrations. Laboratory analyte results may be 
used to calculate various cardiovascular risk and fibrosis measw·ement scores. 
16.
STATISTICS
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
hypothesis tests, will be prepared and approved by the Sponsor and its designees before study 
database lock. 
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Data flow, access, process and disclosure will be described in a DAP.  The DAP will cover the 
process by which an independent statistical group will conduct analyses, including the Month 18 
Interim Analyses to support regulatory filing for conditional marketing approval. 
16.1. 
Primary Analysis Populations (For End-of-Study Analysis) 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
•
The Intent-to-Treat (ITT) Population will include all randomized subjects with
fibrosis stage 2 or stage 3 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.
•
The Full Analysis Population will include all randomized subjects, all fibrosis stages,
who receive at least 1 dose of investigational product (OCA or placebo).  Treatment
assignment will be based on the randomized treatment.
•
The Per-Protocol (PP) Population will include all ITT subjects who do not have any
major protocol violations that potentially affect the efficacy conclusions.  Treatment
assignment will be based on the randomized treatment.
•
The Safety Population will include all randomized subjects, all fibrosis stages, 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.
•
The PK Population will include all OCA subjects who have at least 1 confirmed
fasted analyzable sample.  Subjects must have been fasting for approximately 8 hours
before the visit and must not have any major protocol deviations that potentially
affect exposure levels.  The PK Population will be used for OCA PK and PK/PD
analyses.
Additional details regarding the cutoff for the Month 18 Interim Analysis population will be 
defined in the SAP.  


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16.3. 
Efficacy Analysis at Month 18 Interim Analysis 
16.3.1. 
Primary Efficacy Analysis 
All efficacy analysis will be conducted using the ITT population (only including fibrosis stage 2 
and stage 3 subjects).  The hypothesis testing of primary and (key) secondary endpoints will be 
conducted with control of Type 1 error (OCA 25 mg, then 10 mg).  The 2-sided alpha allocated 
to all testing in this single study will be 0.05.  The histological endpoints will be tested at the 
Month 18 Interim Analysis with an alpha level of 0.02.  The primary clinical outcomes endpoint 
will be tested with a minimum alpha level of 0.03, and this may be augmented by recycled alpha 
from the Month 18 Interim Analysis.  Adjustments for multiplicity are specified in Section 16.7, 
and additional details on the testing will be provided in the SAP. 
The primary endpoints at the Month 18 Interim Analysis are: 
•
Improvement in fibrosis by 1 stage or more, with no worsening of hepatocellular
ballooning, no worsening of lobular inflammation and no worsening of steatosis
•
NASH resolution with no worsening of fibrosis
The primary efficacy analysis for fibrosis improvement at the Month 18 Interim Analysis will 
test the following hypotheses using the ITT population (the ITT population for the Month 18 
Interim Analysis is not the same as that for the overall study and is defined in the SAP): 
•
H01:  The percentage of subjects with fibrosis improvement by 1 stage or more, no
worsening of hepatocellular ballooning, and no worsening lobular inflammation is
equal between placebo and OCA.
•
H11:  The percentage of subjects with fibrosis improvement by 1 stage or more, no
worsening of hepatocellular ballooning, and no worsening lobular inflammation is
different between placebo and OCA.
The primary efficacy analysis for the resolution of NASH with no worsening of fibrosis at 
Month 18 Interim Analysis will test the following hypotheses using the ITT population: 
•
H02:  The percentage of subjects with NASH resolution and no worsening of fibrosis
is equal between placebo and OCA.
•
H12:  The percentage of subjects with NASH resolution and no worsening of fibrosis
is different between placebo and OCA.
NASH resolution is defined as the 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.  The primary efficacy analyses at 
the Month 18 Interim Analysis will compare placebo and OCA using a 
Cochran-Mantel-Haenszel (CMH) test stratified by the randomization strata (type 2 diabetes 
at enrollment [yes/no] and use of TZDs/glitazones or vitamin E at baseline [yes/no]).   
Supportive analyses will be conducted using PP population and all fibrosis stages (Full Analysis 
Population).  Additional supportive and sensitivity analyses along with analysis populations of 
interest will be defined in the SAP. 


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16.3.2. 
Secondary Efficacy Analyses 
16.3.2.1. Histology Analysis 
Secondary efficacy endpoints at the Month 18 Interim Analysis are: 
•
Improvement of fibrosis by at least 1 stage AND/OR resolution of NASH, without
worsening of either
•
No worsening of fibrosis AND no worsening of NASH
•
Percentage of subjects with improvement in each key histological feature of NASH
by at least 1 point (steatosis, lobular inflammation, and hepatocellular ballooning).
•
Percentage of subjects with improvement of fibrosis by at least 2 stages
•
Percentage of subjects with improvement in NAS by at least 2 points with no
worsening of fibrosis
•
Improvement of fibrosis and resolution of NASH as a composite and as defined by
both endpoints being met in the same subject
•
Histological progression to cirrhosis
•
Resolution of fibrosis
16.3.2.2. Liver Biochemistry and Liver Function 
The following laboratory parameters will be summarized by treatment group:  ALT, AST, 
gamma-glutamyl transferase (GGT), ALP, total and direct bilirubin, albumin, INR, and platelets. 
Analyses of change from baseline and percent change from baseline will be performed as 
specified in the SAP. 
Descriptive statistics of the laboratory values will be summarized by treatment group and visit.  
The results, change from baseline, and percentage change from baseline values as well as 
estimates of least-square (LS) means, standard errors, and 95% confidence intervals (CIs) will be 
presented by treatment group.  Estimates of the mean difference between each active treatment 
group and placebo group, the standard error of the difference, and 95% CI of the difference will 
be presented.  Baseline is defined as the mean of all available evaluations before treatment. 


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16.4. 
Efficacy Analyses at End of Study 
16.4.1. 
Primary Efficacy Analysis 
All efficacy analysis at EOS will be conducted using the ITT population (only including 
fibrosis stage 2 and 3 subjects).  The hypothesis testing of primary and (key) secondary 
endpoints will be conducted in with control of Type 1 error (OCA 25 mg, then 10 mg).  
Adjustments for multiplicity are specified in Section 16.7 and additional details on the testing 
at EOS will be provided in the SAP. 
The primary efficacy endpoint at the EOS will be the time to first occurrence of one of the 
following post-randomization:  
•
Death (all-cause)
•
MELD score ≥15
•
Liver transplant
•
Hospitalization (as defined by a stay of 24 hours or greater) for onset of:
−
Variceal bleed
−
Hepatic encephalopathy (as defined by a West Haven score of ≥2)
−
Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
•
Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or
paracentesis)
•
Progression to cirrhosis


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The primary efficacy analysis for clinical outcomes at EOS will test the following hypothesis: 
•
H01:  The time to first occurrence of any of the adjudicated events for all-cause
mortality and liver-related clinical outcomes are equal between placebo and OCA.
•
H11:  The time to first occurrence of any of the adjudicated events for all-cause
mortality and liver-related clinical outcomes are different between placebo and OCA.
Only adjudicated events (including progression to cirrhosis) will be included in analyses.  
Placebo and each OCA dose will be compared separately using a log rank test stratified by the 
randomization stratification factor.  Kaplan-Meier (KM) estimates of the distribution of the time-
to-event will be tabulated and graphed by treatment group.  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. 
16.4.2. 
Secondary Efficacy Analyses 
16.4.2.1. Histology Analysis 
•
Improvement in fibrosis by 1 stage or more, with no worsening of hepatocellular
ballooning, no worsening of lobular inflammation, and no worsening of steatosis
•
NASH resolution with no worsening of fibrosis
•
Improvement of fibrosis by at least 1 stage AND/OR resolution of NASH, without
worsening of either
•
No worsening of fibrosis AND no worsening of NASH
•
Percentage of subjects with improvement in each key histological feature of NASH
by at least 1 point (steatosis, lobular inflammation, and hepatocellular ballooning).
•
Percentage of subjects with improvement of fibrosis by at least 2 stages
•
Percentage of subjects with improvement in NAS by at least 2 points with no
worsening of fibrosis
•
Improvement of fibrosis and resolution of NASH as a composite endpoint and as
defined by both endpoints being met in the same subject
•
Resolution of fibrosis
16.4.2.2. Liver Biochemistry and Liver Function 
The following laboratory parameters will be summarized by treatment group:  ALT, AST, GGT, 
ALP, total and direct bilirubin, albumin, INR, and platelets.   
Analyses of change from baseline and percent change from baseline will be performed as 
specified in the SAP. 


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Descriptive statistics of the laboratory values will be summarized by treatment group and visit. 
The results, change from baseline, and percentage change from baseline values as well as 
estimates of least-square (LS) means, standard errors, and 95% Cis, will be presented by 
treatment group.  Estimates of the mean difference between each active treatment group and 
placebo group, the standard error of the difference, and 95% CI of the difference will be 
presented.  Baseline is defined as the mean of all available evaluations before treatment. 
Each active OCA treatment group will be compared to placebo using the log rank test stratified 
by the randomization stratification factor.  KM estimates of the distribution of the time-to-event 
will be tabulated and graphed by treatment group.  The tabulation will include the KM 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.  Subjects without any documentation of events will be 
censored at the date of last contact. 
16.5. 
Interim Analyses Post Month 18 Interim Analysis 
There will be 2 planned interim analyses to be conducted using group sequential approach in 
accordance to the SAP and DMC Charter at the accumulation of 50% and 80% of the total 
planned 291 adjudicated clinical outcome events.  The primary efficacy endpoint for these 
planned interim analyses will be the clinical outcomes composite endpoint.  
If either of these 2 Interim Analysis are significant, then all analyses described in Section 16.4 
will be carried out. 
16.6. 
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. 


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16.6.1. 
Time to Event Endpoints 
For the time-to-event analyses, including the primary clinical outcomes composite endpoint, only 
adjudicated events (including biopsy confirmed progression to cirrhosis) will be included.  
Subjects who do not experience an adjudicated event will be censored at the time of their last 
contact.  Sensitivity analyses will be described in the SAP. 
16.6.2. 
Quantitative Endpoints 
For other efficacy endpoints utilizing an ANCOVA model, mixed-effect repeated measures 
model or the Wilcoxon Rank Sum Test, observed cases will serve as the primary analysis.   
16.6.3. 
Responder Endpoints 
For the analyses of the primary and key secondary histological efficacy endpoints, in which 
subjects are classified as either a responder or a non-responder (binary outcome), any subject 
who does not provide any assessment at the specified timepoint and after baseline 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.  Subjects who early terminate before Month 18, biopsy results at the time of early 
termination, if available, will be included in Month 18 histological endpoints analyses. 
A completer analysis will also be conducted, 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. 
Additional sensitivity analysis will be described in the SAP. 
16.7. 
Multiple Comparisons/Multiplicity 
The 2-sided alpha allocated to all testing in this single study will be 0.05.  The histological 
endpoints will be tested at the Month 18 Interim Analysis with alpha level of 0.02.  The 
primary clinical outcomes endpoint will be tested with a minimum alpha level of 0.03, which 
may be augmented by recycled alpha from the Month 18 Interim Analysis.  Further details 
are provided in the SAP. 
16.7.1. 
Multiplicity Adjustment for the Month 18 Interim Analysis 
For the Month 18 Interim Analysis, testing methods to control overall Type 1 error will be 
implemented.  The sequential testing order will be:  primary endpoints in 25 mg versus 
placebo, followed by primary endpoints in 10 mg versus placebo; details will be provided in 
the SAP. 
16.7.2. 
Multiplicity Adjustment for Interim (Post Month 18 Interim Analysis) and EOS 
Analyses 
For the interim and EOS analyses of the primary and (key) secondary endpoints, OCA will 
be compared to placebo.  O’Brien-Fleming type alpha-spending function will be used to 
control overall alpha level allocated for clinical outcomes for DMC analysis at 50% and 80% 
information fraction and at EOS. 


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The SAP will specify the methods and alpha levels for the interim analyses and EOS final 
analysis.  The DMC will review the interim criterion for efficacy in conjunction with detailed 
safety data and other relevant information to determine whether to continue the study.  
16.8. 
Examination of Subgroups 
Both at the interim and final analyses, the primary and key secondary efficacy endpoints will be 
analyzed for subject subgroups (eg, age, sex, and race) using the ITT population.  Subgroups will 
be assessed at Baseline and only if there are a sufficient number of subjects in each group 
(eg, >5 subjects per group). 
Key subgroups of interest are fibrosis stage and diabetes status.  Additional parameters for 
subgroup analyses include, but are not limited to:  age, sex, race, BMI, NAS, ballooning, FRS, 
statin or antihypertensive medication use, ALT, AST, GGT, and geographic region.  Further 
details regarding subgroups analyses will be specified in the SAP. 
16.9. 
Safety Analysis 
Safety data, including AEs and clinical laboratory observations, will be summarized by treatment 
group using the Safety Population.  The evaluation of safety data will be conducted at both the 
interim and final analyses.  
16.9.1. 
Adverse Events 
AEs will be coded using the Medical Dictionary of 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. 
16.9.2. 
Hepatic and Renal Safety Adjudication 
Potential events of hepatic injury and AKI will be adjudicated during the study (Section 16.11).  
The adjudication of the events of hepatic injury will be separate from the adjudication of events 
for assessment of the primary outcomes endpoint 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. 
16.9.3. 
Cardiovascular Event Adjudication 
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 treated 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 
(CAC) Charter for adjudication.  The adjudication of these events will be handled separately 
from the adjudication of events for assessment of the primary endpoint in this study (See 


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Section 16.11).  Undetermined cause of death will be classified as a cardiovascular death by the 
CAC. 
There will be no formal hypothesis testing of MACE at the Month 18 Interim Analysis.  The 
EOS assessment of MACE will include all MACE events occurred from the start of the study. 
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.  
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 the 2 dose levels of 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.   


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16.9.4. 
Cardiovascular Risk Assessments 
Cardiovascular risk scores will be calculated for assessments including: 
•
FRS
•
Reynolds score
•
SCORE
•
10-year ASCVD Risk based on Pooled Cohorts Equation
Each score is derived from a subject’s age, sex, smoking status, total cholesterol and HDL levels, 
systolic blood pressure, and other factors including family history, BMI, ethnicity, and 
medications. 
These cardiovascular assessments will be summarized by treatment group using descriptive 
statistics at Baseline and at each on-study evaluation.  The change and percentage change from 
Baseline will also be summarized.  Baseline is defined as the last assessment before treatment.  
Further analysis details will be specified in the SAP. 
16.9.5. 
Clinical Laboratory Evaluations 
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.   
16.9.6. 
Lipoprotein Evaluations 
Lipoprotein samples, separate from the serum chemistry samples, collected for a subset of 
subjects up to Version 7 of the protocol, will be assayed in addition to serum lipid analyses 
performed as part of the serum chemistry panel.  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. 
16.9.7. 
Additional Safety Analysis 
16.9.7.1. Vital Signs 
The results and change from Baseline to each on-study evaluation visit will be summarized for 
body temperature, sitting heart rate, and respiratory rate.  Baseline is defined as the mean of all 
available evaluations before treatment. 


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16.9.7.2. Electrocardiograms 
The ECG data analysis will be conducted based on methodology recommended in the ICH E14 
guideline, The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential 
for Nonantiarrhythmic Drugs.   
Baseline is defined as the mean of all available evaluations before treatment.  Descriptive 
statistics of ECG parameters (time between 2 consecutive R waves [RR], PR, QRS, QT, and QT 
interval corrected by the 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 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.   
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. 
16.10. 
Data Monitoring Committee 
An independent DMC that includes 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.  The DMC will have oversight 
over the study conduct as defined by the DMC charter.  All members will have considerable 
experience with clinical study conduct and DMCs.  Any candidate found to have a conflict of 
interest or whose name is listed on the Food and Drug Administration (FDA) debarment list will 
not be offered membership.  Conflicts of interest will be assessed regularly, and if members are 
found to have a new conflict of interest they will be replaced.   
The DMC will meet approximately quarterly at scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review safety and efficacy data as well as the adjudication 
assessments from the 4 adjudication committees listed in Section 16.11.  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. 
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, 


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specific summary data focused on hepatic and renal safety are reviewed by the DMC, including 
an aggregate unblinded summary of adjudicated cases of potential 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. 
Data flow, access, process and disclosure will be described in a DAP.  The DAP will cover the 
process by which an independent statistical group will conduct analyses and provide to the 
DMC, including the Month 18 Interim Analyses to support regulatory filing for conditional 
marketing approval. 
16.11. 
Adjudication Committees 
All potential liver-related clinical outcomes and potential events of hepatic injury, AKI, MACE, 
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: 
•
CAC:  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 including clinical events and histological findings of potential
disease progression to cirrhosis
•
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.   
Specific details of the events that will be adjudicated by the CAC, Hepatic Outcomes Committee, 
HSAC, and 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 outside of a protocol 
amendment. 
The adjudication committee members will include experts with relevant adjudication experience; 
they will not be involved in the study as Investigators, DMC members, or consultants.  Any 
candidate found to have a conflict or whose name is listed on the FDA debarment list is not 


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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.   
Histological progression to cirrhosis will be determined by central reading of liver biopsies. A 
biopsy evaluation form signed by one of the study-specific central pathologists will be necessary 
to confirm histological progression to cirrhosis.  Clinical events and histological findings of 
potential disease progression to cirrhosis will be adjudicated by the Hepatic Outcomes 
Committee.  The end of study primary efficacy endpoints of clinical composite outcome events 
are described in Section 16.4.1.  
17.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
17.1. 
Study Monitoring
Study records at each site will be monitored at regular intervals by a representative of the 
Sponsor, the CRA.  The role of the CRA is to aid the Investigator in the maintenance and 
documentation of complete, accurate, legible, well organized and easily retrievable data.  In 
addition, the CRA will ensure the Investigator's understanding of all applicable regulations 
concerning the clinical evaluation of the investigational product and will ensure an understanding 
of the protocol, reporting responsibilities and the validity of the data.  This will include ensuring 
that full and appropriate essential documentation is available. 
In order to perform this role, the CRA must perform source data verification and as such must be 
given access to the subject’s primary source documentation (eg, paper or electronic medical 
records such as consent to participate in the study, visit dates, screening and randomization 
numbers, demographic information, medical history, disease history, physical examination, vital 
signs, laboratory assessments [copy of laboratory reports], AEs, concomitant medications, dates 
of dispensing investigational product, ECGs, etc) that support data entries in the CRF.  The CRF 
must be completed promptly after each visit to allow the progress and results of the study to be 
closely followed by the Medical Monitor. 
The Investigator may exercise judgment in allowing the CRA access to particular sections of the 
subject's medical records if these are deemed irrelevant to the performance, observations or 
conduct of this study. 
17.2. 
Audits and Inspections 
The Investigator should understand that it may be necessary for the Sponsor, the IRB/IEC and/or 
a regulatory agency to conduct one or more site audits during or after the study and agrees to 


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allow access to all study related documentation and information and be available for discussion 
about the study.   
17.3. 
Documentation Associated with Interim Data 
To ensure continued unbiased conduct during the study and unbiased analysis at the end of the 
study, a select group of unblinded personnel will be identified and charged with producing the 
associated unblinded documents to support regulatory submissions for conditional marketing 
approval.  All other personnel, including those charged with completing the study, will remain 
blinded to individual subject treatment assignments and unblinded aggregated data as described 
in the DAP.   
18.
QUALITY CONTROL AND QUALITY ASSURANCE
Logic and consistency checks will be performed on all data entered into the CRF or ultimately 
transferred into the database to ensure accuracy and completeness.   
Training sessions, regular monitoring of the study at the study site by the Sponsor or designated 
personnel (eg, CRA), instruction manuals, data verification, cross checking and data audits will 
be performed to ensure quality of all study data.  Investigators’ meetings and/or onsite study 
initiations will be performed to prepare Investigators and other study site personnel for 
appropriate collection of study data. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit.  Please see Section 17.2 for more details regarding the audit 
process. 
19.
ETHICS
19.1. 
Ethics Review
The final study protocol, including the final version of the ICF and/or other subject information, 
must be approved or given a favorable opinion in writing by an IRB/IEC as appropriate.  The 
Investigator must submit written IRB/IEC approval to the Sponsor before he or she can enroll 
any subject into the study.  The Investigator is responsible for providing the IB and any other 
available safety information and information about payments and compensation available to 
study subjects to the ethics committee for review. 
The Investigator is responsible for informing the IRB/IEC of any revisions to the protocol in 
accordance with local requirements.  A favorable opinion on revisions will be obtained before 
implementation, unless the revisions are necessary to reduce immediate risk to study participants. 
In addition, the IRB/IEC must approve all advertising used to recruit subjects for the study.  The 
protocol must be reapproved by the IRB or IEC upon receipt of revisions and annually, as local 
regulations require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product.  
The Sponsor will provide this information to the Investigator. 


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Progress reports and notifications of SARs will be provided to the IRB/IEC according to local 
regulations and guidelines.  Investigators or the Sponsor or its designee will provide reports to 
the IRB/IEC as requested, at a minimum annually, and after the study is complete. 
19.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013) and are 
consistent with ICH/GCP, applicable regulatory requirements and the Sponsor’s policies. 
19.3. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided.  
The subject’s signed and dated ICF(s) must be obtained before conducting any study procedures. 
The Investigator(s) must maintain the original, signed ICF(s).  A copy of the ICF(s) must be 
given to the subject. 
19.4. 
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 reports and communications relating to subjects in this 
study that are disclosed to an authorized third party will identify subjects only by protocol and 
assigned number and will be shared in a secure manner.  All data shall be secured against 
unauthorized access. 
The Investigator will maintain a list of subject’s names and identifying information (eg, subject’s 
hospital number, unique subject number).  This list will not be collected by the Sponsor. 
The written information sheet will explain that study data will be stored in a computer database, 
maintaining confidentiality in accordance with national data protection legislation.  All data 
computer processed by the Sponsor or designee will be identified by unique subject 
number/randomization code/site number, only. 
When personal data on subjects are stored or processed by computer, the data must be protected 
to prevent their disclosure to unauthorized third parties.  The pertinent sections of the data 
protection laws in which the country is being conducted will be complied with in full. 


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The written ICF will explain that, for data verification purposes, authorized representatives of the 
Sponsor, a regulatory authority, or an IRB/IEC may require direct access to parts of the hospital 
or study site records relevant to the study, including subject’s medical history. 
20.
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 at 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. 
20.1. 
AE Reporting 
The Investigator is responsible for recording AEs reported by the subject or discovered by any 
other means during the study.  In agreeing to the provisions of this protocol, the Investigator 
accepts all legal responsibilities for immediate reporting of SAEs to the Sponsor. 
20.2. 
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 revise 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 revision 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. 
20.3. 
Regulatory Documentation 
The following regulatory documentation must be completed or provided, and maintained: 
•
Approved ICF (all versions)
•
IRB/IEC approvals (of protocol/subsequent revisions, subject questionnaires, etc)
•
Form FDA 1572
•
Current medical license
•
Curriculum vitae
•
Laboratory certification and reference ranges
•
Financial disclosure forms
20.4. 
Ethics Review (IRB or IEC) 
Please see Section 19.1 for the Investigator’s responsibilities regarding ethics review. 


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20.5. 
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. 
21.
PUBLICATION POLICY
The Sponsor intends to publish the results of all of the clinical studies that it Sponsors consistent 
with the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil, 
October 2013).  Consistent with the recommendations of the editors of several leading medical 
journals, the International Committee of Medical Journal Editors (ICMJE), authorship of 
publications resulting from Intercept sponsored studies should fairly recognize the activities of 
those that have made a significant contribution to the study (http://www.icmje.org).  Thus, it is 
anticipated that authorship will reflect the contribution made by the Sponsor personnel, the 
Investigators and others involved, such as statisticians. 
In recent years, issues about conflicts of interest and accuracy of the study data have been raised 
in the medical press.  Accordingly, the Sponsor has developed publication guidelines for clinical 
studies that are appropriate for this study.  Key issues include the following: 
•
Clinical Study Registries (eg, clinicaltrials.gov):  A description of the study and
relevant design elements (eg, basic design, objectives and endpoints, sample size,
study population, and key inclusion/exclusion criteria) and results (when available)
will be published online in a manner consistent with applicable regulatory guidelines.
•
Overview:  Investigators, reviewers and editors will have the right to audit the data to
verify its accuracy.
•
Responsibility:  Each Investigator is responsible for the accuracy and completeness of
all data from her/his site.  The Sponsor (or its representatives) is responsible for the
accuracy of the data entered into the study databases and the analyses conducted.


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•
Data Management:  The Sponsor will establish data management and SAP.  The
Investigators will have the opportunity to provide input into the plans.  The
Investigators will have the right to review the audit reports and data resolution
decisions before 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 before the establishment of a clean file.  The Investigators must
provide adequate notice (at least 2 months) to the Sponsor of their intention to audit a
study.  The audit should be conducted in a timely manner to allow the resolution of
discrepancies before a clean file is established.  The Investigators will bear all the
costs for the conduct of audits that they initiate, except those related to the resolution
of data queries which the Sponsor will bear.  Such audits must be conducted in such a
manner as to minimize the time to create the clean file.
•
Authorship:  The Sponsor, in collaboration with the Investigators, will establish the
appropriate authorship and responsibility for drafting study documents in accordance
with the principles of the ICMJE.  All manuscripts will be reviewed and agreed upon
before submission for publication by all authors.
•
Single Center Publication and Additional Publications:  This is a multicenter study
and is designed to be published with complete data from all the study sites.  Single
center publications are therefore not considered appropriate.  Any such publications
should clearly state that the data are “extracted” from a multicenter study and that the
study was not intended, or statistically powered, for data presentation by a single
study site.
•
Intercept Review of External Manuscripts:  Consistent with this, Investigators must
submit any drafts of any publications or presentations that may arise from this study
to the Sponsor for review and approval and to ensure consistency with the policy in
this protocol at least 30 days before 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 subsequent revisions, 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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22.
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APPENDIX A. MANAGEMENT OF CHANGES IN CHOLESTEROL 
In previous studies evaluating obeticholic acid (OCA) for nonalcoholic fatty liver disease 
(NAFLD) and nonalcoholic steatohepatitis (NASH), changes in lipid profile were observed in 
response to OCA therapy.  As described in the Investigator’s Brochure, data from these studies 
suggest that any OCA-induced increase in low-density lipoprotein (LDL) cholesterol can be 
managed by statins.  While there are no long term data with OCA in NASH to assess any 
long-term increase in cardiovascular risks, given the increased cardiovascular mortality in NASH 
patients in general, it is important to monitor for changes in cholesterol levels, and manage LDL 
levels in the context of other risk factors.  
Statins are sometimes reluctantly used by healthcare professionals in patients with NAFLD or 
NASH, which may in part be due to the contraindication in statin package inserts for use in 
patients with active liver disease.  There is growing evidence of the safety of statins in patients 
with elevated baseline liver enzymes, including in subjects with compensated NAFLD/NASH.  
During the conduct of Study 747-303, routine study visits provide an opportunity to detect any 
adverse effects that may arise due to blinded or open-label study drug or concomitant medication 
use such as statins through various assessments of the liver.  Liver enzyme elevations are usually 
reversible with continued use or after discontinuing treatment without evidence of long-term 
injury. 
The purpose of this guidance document is to provide participating Investigators a uniform 
approach for monitoring LDL concentrations and considering treatment of LDL cholesterol 
increases during the study.  The Investigator may consider alternate cholesterol management 
strategies on a case-by-case basis.  This guidance summarizes recommendations for the 
management of LDL cholesterol based on the ACC/AHA 2019 Guideline on the Primary 
Prevention of Cardiovascular Disease (Arnett 2019) and the European Guidelines for the 
Management of Dyslipidaemias: Lipid Modification to Reduce Cardiovascular Risk 
(Mach 2020).   
Investigators should closely monitor subjects’ LDL concentrations and evaluate each subject 
with respect to:  
•
Magnitude of LDL increase (ie, absolute LDL value in the context of individual
cardiovascular risk profile)
•
Cardiovascular risk factors
•
Risk-benefit assessment of statin or other appropriate dyslipidemia therapy
•
Any other factors that are relevant to dyslipidemia management
Recommended LDL Management Algorithm (Figure A1): 
•
Investigators and/or study staff will be alerted by the central laboratory when a ≥15%
increase from baseline is detected in a subject’s LDL concentration as part of the
standard lab panel conducted at every study visit.
−
If an LDL value is elevated and the subject reports having eaten within 8 hours
before the blood draw, the Investigator may repeat the assessment under fasting
conditions to better assess the magnitude of the increase.


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•
If the LDL cholesterol increase of ≥15% relative to study baseline is confirmed,
Investigators should also assess any other cardiovascular disease risk factors that may
be present.  A subject may be considered at high risk for cardiovascular disease if any
of the following factors are present:
−
History of atherosclerotic cardiovascular disease (eg, prior myocardial infarction,
angina) or cerebrovascular disease
−
High LDL and/or low high-density lipoprotein values
−
Age >50
−
Diabetes mellitus
−
Hypertension
−
Tobacco smoker
−
Male gender
•
If the Investigator determines that intervention is warranted after a risk-benefit
analysis for statin versus non-statin dyslipidemia therapy, the Investigator may:
−
Initiate statins at an appropriate dose (high-, moderate-, or low-intensity statin
depending on the subject’s cardiovascular risk profile) in subjects who are not
currently taking a statin
−
Up-titrate statin dose in subjects who are already taking a statin at less than
maximum (or maximum tolerated) dose or switch to a more potent statin in
subjects taking maximum dose of a low or moderate intensity statin
−
Initiate or up-titrate non-statin dyslipidemia therapy in subjects for whom statin
use is not preferred or are already on a maximum (or maximum tolerated) statin
therapy (eg, ezetimibe, fibrates, PCSK9 inhibitors, and bile acid sequestrants [see
protocol for instructions regarding dosing of investigational product and bile acid
sequestrants])
•
If any dyslipidemia therapy is initiated or up-titrated:
−
The new concomitant medication or change in dose must be documented on the
case report form (CRF);
−
Dyslipidemia therapy initiation or dose adjustments may be considered
appropriate to achieve LDL concentrations at or below baseline
−
If treatment with statins is initiated, women of childbearing potential must be
informed that statin use is contraindicated during pregnancy.  Methods of
contraception should be reviewed and modified if necessary to ensure highly
effective methods with failure rates <1% per year, such as implants, injectables,
combined oral contraceptives, some intrauterine devices, sexual abstinence, or
history of vasectomy of partner are used.


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•
If the Investigator determines that intervention is not necessary, based on LDL
evaluation and assessment of other risk factors, this decision and the reason for the
decision must be documented on the CRF.
This guidance may be updated over the course of the study as cardiovascular disease prevention 
guidelines evolve over time.  New lipid findings as a result of ongoing evaluations will be 
included in the Investigator’s Brochure during periodic updates. 
Figure A1: 
LDL Management Flow Chart 
a  If a subject is unable to tolerate statins other lipid-lowering modalities may be considered and must be 
documented, including reason for choice of medication.
Investigator deci si oo -
Need to add lipid 
lowering medication 
:2:15% increase ii:om ba&eline 
(central lab alert)in fasting 
LDL confirmed 
Asses,s subject's <Nerall risk 
factors for CVD 
i 
Subject not ona 
1i pid lowering 
medication 
Subject already on 
lipid 1 owering 
medication 
Initia le lipid lowering 
medication if 
appropriate• 
Document medication, 
dose, &art dale, elc. on 
CRF 
C-0nsider dose 
escalatioo' 
Inve&.igator decision -
Further intervention 
no! neoe ssary 
Documenl 
reason fur 
decision on 
CRF 


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APPENDIX B. MANAGEMENT OF HYPERGLYCEMIA 
The selection of the appropriate individualized therapy is described in current guidelines to assess risk of hyperglycemia (Figure B1; 
Buse 2020) 
Figure B2: 
Glucose-Lowering Medication in Type 2 Diabetes: Overall Approach 
RA = receptor agonist; SU = sulfonylureas; TZD = thiazolidinediones. 
Source: Buse 2020. 
GLUCOSE-LOWERING MEDICATION IN TYPE 2 DIABETES: OVERALL APPROACH • 
. 
FIHT•LINE THERAPY IS METFORMIN AND COMPREHENSIVE LIFEmU !INCLUDING WEl&HT MANAGEMENT AND PHYSICAL ACTIVITY) 
' ' 
,&, 
NO 
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: ............ ,I, -········ HbA,, abo,e lnd;,id.,Uztd 11,gct P'°'t
' btlow ................
... ··---: 
• h bibli1hed ASCVD 
• lndiatorsofhighASCYO 
riskl•g1 iSS )'t'ats•lYH 
or coronary,c.trolid, law,r 
t.rlremity •rtery stenosi,.,50%) 
r -·-· P;!;BLY --·- . 
: 
: GLP-1 RA with primn CVD bt1ttflt 1 
: 
r --------- DR ---------i 
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llfurlhtr inttnfflit•tioniirtquirtdor 
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• forp,11litnhono116LP-l RA. 
considero11ddingSGll21wilhprovtn 
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• AYoidil0 il tht$tllingofHF 
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• DPP-4i&,otsa~liplll)inthe$t1l!ng 
ofHF(~nolon6l.P-I IW 
• Baulinsulin" 
• SU' 
I. PllffenC'/Dbt.!.t·-rt rwi:s it li.n!ibtlindir•DNlot rtdl;,:ingCVOf'lents. 
2. 8~ llllJrtth•I S5L12111bt!ir.g ¥1111$ by11gion 1nd individu1I 1g~nt wll!icgil.1a lndit.1\ed Ind M ,UR 
for inifa1ion1nd <ffllinued use 
3. Ullpagtl1l~ll1, w..,.._ftluln. ,nd d•~•gb'l~bl llm iM-wn rNlltUm ill MF 1nd tt rtdu,;:, ctD,.-~ruR 
in CYOT1. l:IM;.itlc,1in hu pfWl'IMY IMIII 6ul.tome dHI fTora CIEDENII.D1,Mq'.ifwin hH Jrin.irr hnn 
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Degl.~ilndVlOOtbrgiM~mdf:~m,'Ti:dC\'Dn~r, 
5. 1.4'# dowrr,1y H bntt1 l,1tr~td ~lm ,.,U. ,tuidlJICl1or C\'Dttl,cl$ 
COMPELLIIIG NEED TO MINIMIZE HYPOGLYCEMIA 
• Choo$eliter genffi11ionSUwilhlo'werri~ofhypog\yceml,1 
• Considerbml~wlinwit!rlo'tlll'1risliof hypoglycenrla' 
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1. ~l,udr,r;/f11 
!1300•gl•r1tineUUlO/d,t,m1t •NPll ill1u 
t. Sem~glir.ide lirJ11ul:ft ~ ~lutl:ft . Htn,1idt • liJiWN1ide 
t. II tM11pKillu.111Wbld1liu (i,'-NHU~hfd C'/0.'"' ruk Q( 1po1jlycffllil 
91ilitity 10 ,rwt 
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lfOPP-4inottoletiiledor 
((lnlri11nd1Uled or ~tl~nl alrudy on 
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• Con\iderDPP-4iOR SGtr2iwith 
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z hf'l\ltiltr~ H»-rtr• 
Kff(f 11,i,~rthilure rt~utlHI fietttta rr.kli,n 
U~ • Urin~Alt 
ill~~-Cmuininei.ti:i; LVEF • LatlYi'ltriM!lar ~tmfuHi:wl 


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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 Section 7.5.1)
•
Significant upper abdominal pain with nausea, vomiting, or
fever, jaundice
Hyperglycemia 
(Protocol Section 9.3.4) 
•
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


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•
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: 
•
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?


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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:
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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APPENDIX E. STANDARDIZED DEFINITIONS FOR CARDIOVASCULAR ENDPOINT EVENTS 
Event 
Definitions 
Cardiovascular (CV) Death:
Death due to Acute :MI 
Sudden Cardiac Deatl1 
Confidential and Proprieta1y 
Death due to Acute MI refers to a death by any CV mechanism (eg, all'hytlunia, sudden death, HF, stroke, 
pulmomuy embolus, peripheral arterial disease) ::;30 days• after a MI related to the immediate consequences of 
the Ml, such as progressive HF or recalcitrant a1Thythmia. There may be assessable mechanisms of CV death 
during this time period but for simplicity, if the CV death occms ::;30 days of the Ml, it will be considered a 
death due to MI. 
Acute MI should be verified to the extent possible by the diagnostic criteria outlined for acute MI (Clinical Data 
Interchange Standards Consortium [CDISC], Chapter 4) or by autopsy findiugs showiug recent :MI or recent 
coronary thrombosis. 
Death resulting from a procedure to treat a MI (percutaneous coronruy iutervention (PCI), coromuy aite1y bypass 
graft surge1y [CABG]), or to treat a complication resultiug from Ml, should also be considered death due to acute 
MI. 
Death resultiug from an elective coronaty procedure to treat myocardial ischetnia (ie, chronic stable angiua) or 
death due to a MI that occurs as a direct consequence of a CV investigation/procedure/operation should be 
considered as a death due to a CV procedure. 
Sudden Cai·diac Death refers to a death that occurs unexpectedly, not following an acute Ml, and iucludes the 
following deatlis: 
a.
Death witnessed and occurriug without new or worsening symptoms
b.
Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, unless tlie
symptoms suggest acute MI
c.
Death witnessed and attributed to an identified a1Thythmia ( eg, captured on at1 electrocai·diographic
(ECG) recordiug, witnessed on a monitor, or unwitnessed but found on implantable cardioverter­
defibrillator review)
d.
Death after unsuccessful resuscitation from cardiac arrest ( eg, implantable cardiove1ter defibrillator (ICD)
unresponsive sudden cai·diac death, pulseless electrical activity a!l'est)
e.
Death after successful resuscitation from cardiac an·est at1d without identification of a specific cai·diac or
non-cru·diac etiology
f.
Unwitnessed death iu a. subject seen alive and clinically stable ::;24 hours prior to being found dead
without any evidence supporting a specific non-CV cause of death (infonnation regardiug the subject's
clinical status preceding deatl1 should be provided, if available).
Unless additional infomiation suggests an alternate specific cause of deatli (eg, death due to Other CV Causes), if 
a subject is seen alive ::;24 hours of being found dead, sudden cardiac deatl1 (criterion f above) should be 
recorded. For subjects who were not obsenred alive within 24 hours of death, undetermiued cause of deatli 
should be recorded (eg, a subject found dead iu bed, but who had not been seen by family for several days). 


Protocol 747-303 
Event 
Death due to HF 
Death due to Stroke 
Death due to CV Procedures 
Death due to CV Hemonhage 
Death due to Other CV Causes 
Non-CV Death: 
The following is a suggested list of non-
CV causes of death: 
•
Puhnonary
•
Renal
•
Gastrointestinal
•
Hepatobiliary
•
Pancreatic
•
Infection (includes sepsis)
•
Inflanunatory ( eg, Systemic
Inflanunatory Response
Syndrome (SIRS) / inunune
(including autoimmune; may
include anaphylaxis from
environmental [ eg, food]
allergies)
•
Hem01Thage that is neither CV
bleeding nor a stroke (see
Chapter 1, Section 6, and
Chapter 6)
Confidential and Proprieta1y 
Definitions 
Version 11.0: 04May2021 
Page235 
Death due to HF refers to a death in association with clinically worsening symptoms and/or signs of HF 
regardless of HF etiology (CDISC, Chapter 7). Deaths due to HF can have various etiologies, including single or 
recunent Mls, ischemic or 11011-ischemic cardiomyopathy, hypertension, or valvular disease. 
Death due to Stroke refers to death after a stroke (hemorrhagic, ische1n.ic, or undete1mined) that is either a direct 
consequence of the stroke or a complication of the stroke. Acute stroke should be verified to the extent possible 
by the diagnostic criteria outlined for stroke (CDISC, Chapter 6). 
Death due to CV Procedures refers to death caused by the immediate complications of a cardiac procedure. 
Death due to CV Hemonhage refers to death related to hemonhage such as a non-stroke intracran.ial hemonhage 
(CDISC, Chapter 6), non-procedural or non-traumatic vascular mpture (eg, aortic aneurysm), or hemorrhage 
causing cardiac tamponade. 
Death due to Other CV Causes refers to a CV death not included in the above categories but with a specific, 
known cause (eg, pulmonary embolism or peripheral arterial disease). 
Non-CV death is defined as any death with a specific cause that is not thought to be CV in nature, as listed in 
CDISC Chapter 1, or as listed for CV Death. 


Protocol 747-303 
Event 
•
Non-CV procedure or surge1y
•
Trauma
•
Suicide
•
Non-prescription drug reaction
or overdose
•
Prescription drug reaction or
overdose (may include
anaphylaxis)
•
Neurological (non-CV)
•
Malignancy
•
Other non-CV
Undetermined Cause of Death: 
Undete1·mined Cause of Death (will 
be classified as a CV death) 
Cardiovascular Events: 
Myocardial Infarctionb 
Confidential and Proprieta1y 
Definitions 
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Page236 
Undetermined cause of death refers to a death not attributable to one of the above categories of CV death or is 
due to a non-CV cause. Inability to classify the cause of death may be due to lack of infonnation ( eg, the only 
available information is "subject died") or there is insufficient supporting infonnation or detail to assign the cause 
of death. In general, most deaths should be classifiable as CV or non-CV, and the use of this category of death 
therefore, should be discouraged and should apply to few subjects in well-nm clinical trials. 
a)
Clinical Presentation
The clinical presentation should be consistent with diagnosis of myocardial ischemia and infarction. Other
findings that might suppmt the diagnosis of MI should be taken into account because a number of conditions are
associated with elevations in cardiac biomarkers (eg, trauma, surge1y, pacing, ablation, HF. hypertrophic
cardiomyopathy, pulmonary embolism, severe pulmonary hype1tension stroke or subarachnoid hemoIThage
infiltrative and inflammat01y disorders of cardiac muscle drug toxicity, bums, critical illness, extreme exertion,
and chronic kidney disease).
Supporting infmmation can also be considered from myocardial imaging and coronary imaging. The totality of
the data may help differentiate acute MI from the bac.kground disease process.
b)
Biomarker Elevations
For cardiac biomarkers, laboratories should repmt an upper reference limit (URL). If the ninety-ninth percentile
of the URL from the respective laboratmy perfom1ing the assay is not available, then the URL for myocardial
necrosis from the laboratmy 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 paiticular laboratory should be used as the URL.
Laboratories cai1 also report both the ninety-ninth percentile of the upper reference limit and the MI decision


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Event 
Definitions 
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
−
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:


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Event 
Definitions 
−
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: 
1.
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 
2.
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 
3.
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).
•
And believed to be responsible for the myocardial ischemic symptoms/signs.


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Event 
Definitions 
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 
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 


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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
iii. Non-invasive diagnostic evidence of clinically significant elevated left- or right-sided
ventricular filling pressure or low cardiac output.  For example, ECG criteria could include:
E/e’ >15 or D-dominant pulmonary venous inflow pattern, plethoric inferior vena cava with
minimal collapse on inspiration, or decreased left ventricular outflow tract (LVOT) minute
stroke distance (time velocity integral [TVI])
OR 


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1v. Invasive diagnostic evidence with right heart catheterization showing a pulmonary capillary 
wedge pressure (pulmonru.y artery occlusion pressure) 2:18 nunHg, central venous pressure 
2:12 nunHg, or a cardiac index <2.2 L/min/m2 
Note: All results from diagnostic tests should be reported, if available, even if they do not meet the above criteria, 
because they provide important infom1ation for the adjudication of these events. 
5.
The subject receives initiation or intensification of treatment specifically for HF, including at least ONE
of the following:
a.
Augmentation in oral diuretic therapy
b.
Intravenous diuretic or vasoactive agent ( eg, inotrope, vasopressor, or vasodilator)
c. 
Mechanical or surgical intervention, including:
1. 
Mechanical circulatory support ( eg, intra-aortic balloon pump ventriculru.· assist device,
extracorporeal membrane oxygenation, total artificial heart)
11. 
Mechanical fluid removal (eg, ultrafiltrntion, hemofiltration, dialysis)
Au urgent HF visit is defined as an event that meets all of the following: 
6.
The subject has an urgent, unscheduled office/practice or emergency depru.tment visit for a primru.-y
diagnosis of HF, but not meeting the criteria for a HF hospitalization (ie, urgent outpatient visit)
7.
All signs and symptoms for HF hospitalization (ie, symptoms and physical examination
findings/laboratory evidence of new or worsening HF, as indicated above) must be met
8.
The subject receives initiation or intensification of treatment specifically for HF, as detailed in the above
section with the exception of oral diuretic therapy, which will not be sufficient.
Interventional Cardiology: Clinical Definitions 
Clinically-Driven Target Lesion 
Revascularization: 
Confidential and Prop1i.eta1-y 
Revasculaii.zation is clinically-driven if the target lesion diru.neter stenosis is >50% by quantitative coronai-y 
angiography (QCA) and the subject has clinical or functional ischemia which cannot be explained by another 
native corona1y or bypass graft lesion. Clinical or functional ischemia includes any of the following: 
a.
A history of angina pedoris, presun1ably related to the target vessel
b.
Objective signs of ischemia at rest ( electrocardiographic changes) or during exercise test ( or
equivalent), presumably related to the target vessel
c.
Abnonnal 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. 


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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 coronary lesions with the 
use of intravascular ultrasound, coronary flow reserve (CFR), or fractional flow reserve (FFR), insertion of a 
guide wire will NOT be considered PCI. 


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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. 


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Event 
Target Vessel Revascularization 
(TVR): 
Vascular Complications: 
Definitions 
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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. 
•
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.
•
Arteriovenous fistula: Development of a new, unintended communication between an a1ie1y and a vein
occurring at a vascular access site within 72 hours of a procedure.
•
Periphernl ischemia: Development of new arterial insufficiency sufficient to produce clinical signs or
symptoms of ischemia (pallor, pain, paresthesia) distal to a vascular access site within 72 hours of a
procedure.
•
Periphe1·al nerve injury: Development of new sensmy or motor loss of peripheral nerve function from
extemal nerve compression (eg, as a result of positioning during a procedure), or internal compression or
direct nerve damage from the procedure, occmring within 72 hours of a procedure.
•
Pseudoanem·ysm: Development of a new localized collection of blood with a persistent communication
(neck) originating at a vascular access site and occw1i.ng within 72h of a procedme.
•
Retroperitoneal hemo1Tbage: Development of new bleeding into the retroperitoneal space originating
at a vascular access site and occurring within 72 hours of a procedure.
Interventional Cardiology: Angiog1·aphi.c Definitions 
Abrupt Closm·e: 
New intra-procedural severely reduced flow (TIMI grade 0-l) within the target vessel that persists and requires 
intervention by stenting or other treatment, or results in MI or death. Abrnpt closme requires an association with a 
vascular dissection, thrombus, or severe spasm at the treatment site or within the instmmented vessel. 
Coronary Lesions Treated 
Coronary Arter·y Segments 
Definitions 
Right coronaiy artery ostium 
Origin of the right coronaiy arte1y, including the first 3 mm of the 
arte1y 
Proxin1al right coronary artery 
Proximal portion of the right coronaiy arte1y, from the ostimn of the 
right coronaiy artery to the origin of the first right ventricular branch 
(pRCA) 
Confidential and Proprieta1y 


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Mid right coronary artery 
Middle portion of the right coronary artery, from the origin of the first 
right ventricular branch to the acute margin (mRCA) 
Distal right coronary artery 
Distal portion of the right coronary artery, from the acute margin to the 
origin of the posterior descending artery (dRCA) 
Right posterior descending artery 
In right dominant and mixed circulations, the vessel that runs in the 
posterior interventricular groove and supplies septal perforator 
branches (PDA) 
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 
bifucation (LM) 
Left main coronary artery bifucation 
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) 


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Definitions 
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 
desending artery to supply the anterolateral wall of the left ventricle 
(D1) 
First diagonal lateral branch 
Branch of the first diagonal branch 
Second diagonal branch 
Second of the three longest branches originating from the left anterior 
desending 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 
desending 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) 


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Definitions 
First obtuse marginal branch 
First of the three longest branches originating from the left circumflex 
artery to supply the laterall 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 laterall 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 laterall wall of the left ventricle (OM3) 
Third obtuse marginal lateral branch 
Branch of the third marginal branch 
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 


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Event 
Definitions 
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. 
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. 


Protocol 747-303 
Event 
TIMI (Thrombolysis in Myociudial 
Infarction) Flow Grades: 
Vessels 
Peripheral Vascular Intervention 
Peripheral Vascular Intervention 
(PVI): 
Confidential and Proprieta1y 
Definitions 
Version 11.0: 04May2021 
Page249 
•
Grade O (no perfusion): There is no antegrade flow beyond the point of occlusion.
•
Grade 1 (penetration without perfusion): TI1e contrast material passes beyond the area of obstmction but
"hangs up" and fails to opacify the entire coronary bed distal to the obstruction for the dm·ation of the
cineangiographic filming sequence.
•
Grade 2 (partial perfusion): The contrast material passes across the obstruction and opacifies the
coromuy bed distal to the obstruction. However, the rate of enhy 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 entJ.y into
or clearance from comparable areas not perfused by the previously occluded vessel (eg, the opposite
corona1y artery or the coronaty bed proximal to the obstmction).
•
Grade 3 (complete pe1·fusion): Antegrade flow into the bed distal to the obstruction occurs as promptly as
antegrade flow into the bed proxin1al to the obstmction and clearance of contrast material from the involved
bed is as rapid as from atl uninvolved bed in the same vessel or the opposite artery.
• • • 
• • • • • 
Left main coronruy arte1y (LMCA)
Left anterior descending at1eiy (LAD) with septal and diagonal branches
Left circumflex arte1y (LCX) with obtuse marginal brat1ches
Ramus intennedius artery
Right coronary a11e1y (RCA) at1d at1y of its branches
Postei·ior descending arte1y
Saphenous vein bypass graft( s)
At1erial bypass graft(s): Right internal mammary graft, left internal mamma1y graft, radial at1ery graft and
gastroepiploic arte1y graft.
Peripheral vasculat· interventiond is a catheter based or open surgical procedure designed to improve ruierial or 
venous blood flow or othe1wise modify or revise vascular conduits. Procedm-es may include, but are not liniited 
to, percutaneous trruisluminal balloon angioplasty. stent placement, thrombectomy, embolectomy, atherectomy, 
dissection repair, anemysm exclusion, treatment of dialysis conduits, placement of various devices intravasculru· 
thrombolysis or other phrumacotherapies. and open surgical bypass or revision. 
In general, the intention to perform percutaneous peripheral vascular intervention is denoted by the insertion of a 
guide wire into a peripheral atie1y or vein. 


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Event 
Definitions 
The target vessel(s) and the type of revascularization procedure (eg, surgical bypass, thrombectomy, 
endarterectomy, percutaneous transluminal angioplasty, stent placement, thromboembolectomy, and 
thrombolysis) should be specified and recorded. For the sake of simplicity, this definition applies to the 
extracranial carotid artery and other non-cardiac arteries and veins and excludes the intracranial vessels and 
lymphatics. 
Procedural Success: 
In the case of percutaneous intervention for obstructive lesions, procedural success is defined as the achievement 
of a satisfactory final residual diameter stenosis by angiography at the end of the procedure (and without flow 
limiting dissection or hemodynamically significant translesional pressure gradient).  The specific parameter for 
final percent residual stenosis is typically between <30% and <50%; selection of the appropriate percentage may 
vary depending upon the specific intervention applied, the vascular territory, and anticipated or desired 
therapeutic response.  Procedural success also implies absence of in-hospital major adverse events (eg, death, 
stroke, myocardial infarction, acute onset of limb ischemia, need for urgent/emergent vascular surgery, and other 
procedure-specific major adverse events).  The balloon inflation, stent placement, or other therapeutic 
intervention may be preceded by use of adjunctive devices (eg, percutaneous mechanical thrombectomy, 
directional or rotational atherectomy, laser, and chronic total occlusion crossing device), as predefined in the 
protocol. 
Procedural Status: Non-Elective and 
Elective: 
a.
Non-Elective:  Non-elective procedures include emergent and urgent procedures.  A non elective
procedure is a procedure that is performed without delay, because there is clinical consensus that the
procedure should occur imminently. Non-elective procedures imply a degree of instability of the subject,
urgency of the medical condition, or instability of the threatening lesion.
−
Emergent:  A procedure that is performed immediately because of the acute nature of the medical
condition (eg, acute limb ischemia, acute aortic dissection), and the increased morbidity or mortality
associated with a temporal delay in treatment.
−
Urgent:  An urgent procedure is one that is not an emergency but is required to be performed on a
timely basis (≤24 hrs) (eg, a 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). 


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Event 
Definitions 
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 lesion revascularization occurs 
in the absence of protocol-directed surveillance ultrasound or angiography. 
Vessel Patency: 
Vessel patency at a given time point will be determined by the absence of clinically-driven target lesion 
revascularization and/or absence of recurrent target lesion diameter stenosis >50% by imaging (eg, invasive 
angiography or most commonly, duplex ultrasonography). If patency data are incorporated within the primary 
endpoint of a clinical trial, the angiographic images or duplex ultrasonographic images should be assessed by 
appropriate core laboratories and made available to the AC for review upon request. 


Protocol 747-303 
Event 
Restenosis: 
Stent Thrombosis 
Stent Thrombosis: Timing 
Stent Thrombosis Categories 
Confidential and Proprietaiy 
Definitions 
Re-nairnwing of the aiteiy following the treatment of a prior stenosis 
Version 11.0: 04May2021 
Page252 
Binary restenosis: A diameter stenosis of>50% at the previously treated lesion site, including the originally 
treated site plus the adjacent vascular segments 10 mm proximal and 10 mm distal to the site ( or as otherwise 
defined by the protocol, as noted above). 
In-stent restenosis (ISR): A previously stented lesion that has >50% diameter stenosis. 
Stent thrombosis should be reported as a cumulative value over time and at the various individual time points as 
specified below. Time 0 is defined as the time point after the guiding catheter has been removed and the subject 
has left the cardiac catheterization laboratory. 
Stent Thrombosis: Timing 
Acute stent thrombosis1 
0-24 hours post stent in1plantation
Subacute stent tluombosis1 
>24 hours - 30 days post stent in1plantation
Late stent thrombosis2 
>30 days - 1 yeai· post stent implantation
Vety late stent thrombosis2 
> 1 year post stent implai1tation
I 
Acute or subacute can also be replaced by the tenn early stent thrombosis. Early stent thrombosis (0-30 days) will be 
used herein. 
2 
Includes "primary" as well as "secondary" late stent thrombosis: 'seconda1y ' late stent thrombosis is a stent thrombosis 
after a target lesion revascularization. 
1.
Definite Stent Thrombosis
Definite stent thrombosis is considered to have occurred by either angiographic or pathological
confirmation:
a.
Angiographic confirmation of stent thrnmbosis•
•
The presence of a thrombusf that originates in the stent or in the segment 5 mm proximal or distal to
ilie stent and presence of at least 1 of the following criteria within a 48-hour time window:
-
Acute onset of ischemic symptoms at rest
-
ew ischemic ECG changes that suggest acute ischemia
-
Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous MI)


Protocol 747-303 
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Confidential and Proprietary 
Event 
Definitions 
−
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,%202014.pdf). 


Protocol 747-303 
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Confidential and Proprietary 
APPENDIX F. SUMMARY OF CHANGES: PROTOCOL 747-303 VERSION 11.0 
(DATED 04 MAY 2021) 
Protocol 747-303 was revised to include the following information: 
1) Update to the end-of-study primary objective for progression of cirrhosis to include all clinical evidence beyond only
histological changes
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 due to
suspected hepatic injury and progression to cirrhosis, within 7 days of experiencing a serious adverse event, and at the time of
liver biopsy.  Additional PK sparse sample collection was added to each study visit after Month 18 to adequately capture the
OCA exposure-response relationships for efficacy and safety
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
to each study visit after Month 18.
6) Inclusion of local laboratory results and reference ranges into the eCRF and inclusion local pathology reports 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) Study duration was updated from 7 to 10 years based on current estimates for outcome accrual
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 10.0 is crossed out and revised text in Version 11.0 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 11.0 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. 


Protocol 747-303 
Section 
Title Page 
Sponsor's 
Approval 
Study 
Personnel 
Contact 
Information 
Section 5.3 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Sponsor 
Intercept Phannaceuticals, Inc. 
4 7eQ EasEg:a.t@ :uaU 
San Diego, CA 92121 
USA 
, Clinical Development 
Intercept Pharmaceuticals, Inc. 
Primaiy 
Contact: 
Secondaiy 
Contact: 
Email: 
_, MD 
L@ad M@aisal M01Ht0Fl1>.4"@aisal E,ˋ@li 
PR.'\ H@alˌ Ssi@es@s 
.ˍamiD,HS 
Intercept Phaimaceuticals, Inc. 
Sh1dy 747-209-is- fmther e•ralHa.tiHg the effect of 
OCA and atorvastatin treatment on LDL 
metabolism in subjects with NASH to better 
understand the lipid profile changes obse1ved in 
the FLINT sh1dy. Subjects with biopsy­
confirmed NASH and :fibrosis received placebo 
or OCA 5mg, 10 mg, or 25 mg once daily, for up 
to 4 weeks. 
Confidential and Proprieta1y 
Revise.d Text (Vel'sion 11.0, 04 May 2021) 
Sponsor 
Intercept Phamiaceuticals, Inc. 
9520 Towne Centr·e Drive, Suite 200 
San Diego, CA 92121 
USA 
_,MD 
, Clinical Development 
Intercept Pharmaceuticals, Inc. 
Primruy 
Contact: 
PRA Health Sciences Medical Monitol' 
Team 
_,MD 
,MD 
_,MD(Lead) 
Secondary 
-• M.D. 
Contact: 
Intercept Phaimaceuticals, Inc. 
Email: 
Telephone 
Study 747-209 fmther evaluated the effect of OCA 
and atmvastatin treatment on LDL metabolism in 
subjects with NASH to better understand the lipid 
profile changes observed in the FLINT study. 
Subjects with biopsy-confirmed NASH and fibrosis 
received placebo or OCA 5mg, 10 mg, or 25 mg 
once daily, for up to 4 weeks. 
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Key Change 
Reasons/ 
Justification fol' 
Chane 
Sponsor address 
updated to reflect new 
location 
Sponsor wet signature 
approver updated to 
reflect change in 
personnel 
Primary contact 
infonnat.ion expanded 
to include the entire 
PRA medical monitor 
teain 
Secondary contact was 
updated to reflect 
change in personnel 
Updated language to 
reflect completion of 
Study 747-209 


Protocol 747-303 
Section 
Section 5.4 
and22 
Section 5.5 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
The incidence of NASH is increasing and NASH 
is lik:@ly to b@ the leading cause of liver 
transplant by 2020, highlighting the need for 
development of effective therapies that can 
improve steatohepatitis and resulting fibrosis, 
potentially delaying liver transplant or death. 
The rate of progression and risk of 
decompensation is vaiiable and may be rapid in 
ce1tain patients, necessitating closer smveillance 
of patients at 1isk. Recent safety findings in 
NASH clinical trials .include ӕ cases of hepatic 
decompensation reported as SUSARs, 1 of which 
resulted in death. Qa@ Eas@ 1,i,ias HlfOft@Ӗ iH a 
sHtJ:i@Et 1.ii1ith ao s11iӗ@ilc@ of Eii:raosis at eas@liH@; 
th@ sHbj@Et's a·@ate:l:@at assigam@Ht 1·@maiBs 
elmd@d. The s@rnad (fatalt case was repo1ted in 
a subject with cinhosis and hepatic impa.innent 
at baseline; the subject was in the OCA 25 mg 
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
The incidence of NASH is increasing and NASH 
has berome one of the leading causes of liver 
transplant (Wong 2020, Younossi 2020), 
highlighting the need for development of effective 
therapies that can improve steatohepatitis and 
resulting fibrosis, potentially delaying liver 
transplant or death. 
References: 
Wong RJ, Singal AK. Trends in Live1· Disease 
Etiology Among Adults A waiting Liver 
Transplantation in the United States, 2014-2019. 
JAMA Netw Open. 2020 Feb;3(2):e1920294. 
Younossi ZM, Stepanova M, Ong J, et al 
Nonalcoholic Steatohepatitis is the most rapidly 
increasing indication for liver transplantation in 
the United States. Clio Gastroenterol Hepatol. 
2020 Jun 9. 
The rate of progression and 1isk of decompensation 
is variable and may be rapid in certain patients, 
necessitating closer surveillance of patients at risk. 
Recent safety findings in NASH clinical uials 
include 9 cases of hepatic decompensation reported 
as SUSARs, 1 of which resulted in death. The 
signs of hepatic decompensatiou included death 
due to a hepatic event; MELD sc01·e Ә15; liver 
transplant; ascites; or an SAE ofvariceal bleed, 
hepatic encephalopathy, 01· spontaneous bacterial 
peritonitis. The fatal case was reported in a subject 
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Page256 
Key Change 
Reasons/ 
Justification fol' 
Change 
Updated the language 
and references to 
provide suppo11 for 
statement regarding 
cunent rate of liver 
transplantation 
Known potential risks 
with investigationaJ 
product and DMC 
recommendations 
were updated to reflect 
the language in the 
cunent version of the 
OCA Investigational 
Brochme 0/ l 9 
27Mar2020) 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
treatment group. Both cases ifl11olv:ed IR¼mernas 
coe:foHHGHlg factors that mah ev:aluatioH of 
associatioH with a·eatnieHt diffirnlt. 
Key liver-related findings: 
•
eDISH analyses show no evidence of hepatic
injmy with OCA compared to placebo.
•
ill PBC hepatic AEs evaluated by
Standardized MedDRA c1ite1ia showed a rate of
hepatic AEs higher in OCA-treated subjects
compared with those treated with placebo.
•
Given that the liver is the p1imary site of
action for OCA safety and efficacy, liver
concentrations for total OCA were predicted for
subjects with hepatic impailment based on Child­
Pugh Classification. While 1.5- and 1.7-fold
increases in liver concentrations of OCA are
predicted for subjects with Child-Pugh Class B
and C, respectively, liver concentrations of OCA
in subjects with Child-Pugh A are predicted to be
similar to those of healthy control subjects (1.1-
fold increase).
•
Serious liver-related adverse reactions have
been rep01ted in postmarketing in PBC patients
with decompensated cinhosis or Child-Pugh
Class B or C hepatic impai.iment when Ocaliva
was dosed more frequently than the
recommended staiting dosage of 5 mg once
weekly.
ChaHges .i:B liflid profiles .have also b@@n obs@1v@a 
with OCA aosiflg, .i:BclHGHlg an mcr@as@ in low 
,I--• : ... 1•--- •-•-•- /T T'\T \ %L-1--•---.1 nnrl n 
-
--
--
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
with cirrhosis and hepatic impai1ment at baseline; 
the subject was in the OCA 25 mg treatment group. 
Key liver-related findings: 
•
eDISH analyses show no evidence of hepatic
injmy with OCA compared to placebo.
•
ill PBC, hepatic AEs evaluated by Standardized
MedDRA criteria showed a rate of hepatic AEs
higher in OCA-treated subjects compai·ed with those
treated with placebo. In NASH clinical tiials, the
incidence of hepatic TEAEs was similar between
OCA and placebo groups. Serious hepatic
TEAEs, however, occurred more frequently with
OCA 25 mg, as compared to OCA 10 mg and
placebo
•
Given that the liver is the plimary site of action
for OCA safety and efficacy, liver concentrations
for total OCA were predicted for subjects with
hepatic i.inpainnent based on Child-Pugh
Classification. While 1.5- and 1. 7-fold increases in
liver concentrations of OCA are predicted for
subjects with Child-Pugh Class B and C,
respectively, liver concentrations of OCA in
subjects with Child-Pugh A are predicted to be
similai· to those of healtl1y control subjects (1.1-fold
increase). In a hepatic impairment study in
NASH subjects with compensated ci1Thosis
(Child-Pugh Class A), plasma exposure was
apprnximately 4- to 10-fold higher, and liver
exposni-e was approximately 2-fold higher as
compared to NASH subjects with liver fibrnsis.
OCA has not been evaluated in ASH subjects
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Key Change 
Reasons/ 
Justification fol' 
Change 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Eleenias@ iB high Elensity hpopro+ein (HDL) 
ehol@steFol. The di,e,ieal sigmfieane@ of these 
lipia fl±laings remaias YHekar ans is being 
stHEli@El furth€i·. 
An independent data monitoring committee 
(DMC) has perf01med detailed reviews of 
individual subject and aggregate data from both 
the Phase 3 clinical outcomes study in subjects 
witl1 PBC (Study 747-302) and the Phase 3 
pivotal studies in subjects with NASH fibrosis 
(Study 747-303) and NASH cilThosis (Sn1dy 
747-304) on a qruuterly basis, in an unblinded
fashion, and in closed sessions (without the
Sponsor's participation). Ia the f!UR11@Fly DMC
meetings to dat@, th@ DMC has r@coma1@0El@El th@
stHd:ies eotttiIBie 1.vidtottt fB:odtfieatioH.
Following a request from the FDA, an ad hoc 
DMC review was held and the DMC 
recommended that: 
•
For subjects in Study 747-303,
investigational product should be intenupted in
subjects who experience symptomatic
cholelithiasis and/or cholecystitis.
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
with decompensated cirrhosis (Child-Pugh Class 
Band Child-Pugh Class C). 
•
Serious liver-related adverse reactions have
been rep01ted in post:marketing in PBC patients with
decompensated cirrhosis or Child-Pugh Class B or
C hepatic in1pairment when Ocaliva was dosed
more frequently than the recommended starting
dosage of 5 mg once weekly.
OCA-related changes in serum lipids (decrease 
in high-density lipoprotein cholesterol [HDLc) 
and increase in LDLc) have been observed in 
healthy volunteers, in subjects with PBC and 
NASH, and in subjects with other underlying 
conditions. However, the pattern and 
magnih1de, as well as the clinical significance of 
these changes, are not well understood and 
dearly depend on a subject's underlying 
condition and other comorbidities. Although 
increases in LDLc have generally been 
considered to be associated with increased 
cardiovascular risk, it is not possible to draw 
conclusions regarding the cardiovascular effect 
of OCA-related changes in lipid proftle given the 
concurrent positive effects of OCA on other 
metabolic factors such as a decrease in hs-CRP 
(in PBC studies), and relative improvement of 
triglyceride and very low-density lipoprotein 
(VLDL) cholesterol levels. In order to better 
assess cardiovascular risk, longer treatment 
periods and larger numbers of subjects are 
necessary and an being studied fm1her. 
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Justification fol' 
Change 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise.d Text (Version 11.0, 04 May 2021) 
In ASH clinical studies, treahnent with OCA 
was associated with a generally modest and 
transient rise in glycemic parameters (fasting 
plasma glucose, fasting serum insulin, and 
HbAlc, 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 apprnximately 6 
months of treatment. 
An independent data monitoring committee (DMC) 
has pe1f01med 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 (SU1dy 747-303) and NASH
cinhosis (Study 747-304) on a qua1terly 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: 
.
For subjects in Study 747-303, investigational 
product should be intem1pted 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.
Confidential and Proprieta1y 
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Key Change 
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Justification fol' 
Change 


Protocol 747-303 
Section 
Synopsis 
Section 6.4 
Section 12 
Section 15.1.7 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
6.4. Plimary Objective Assessed at End of Study 
To evaluate the effect of OCA compared to 
placebo on all-cause m011ality and liver related 
clinical outcomes as measured by the time to first 
occmTence of any of the following adjudicated 
events (clinical outcomes composite endpoint): 
Death ( all cause) 
Model of end stage liver disease 
(MELD) score :::::15 
Liver transplant 
Hospitalization (as defined by a stay of 
:::::24 hours) for onset of: 
• V aiiceal bleed
• Hepatic encephalopathy (as defined
by a West Haven score of :::::2)
• Spontaneous bacte1ial peritonitis
(con.fumed by diagnostic paracentesis)
Ascites seconda1y to cinhosis and 
requiring medical inte1vention (eg, 
diuretics or paracentesis) 
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
6.4. Pt·imaiy Objective Assessed at End of Study 
•
To evaluate the effect of OCA compared to
placebo on all-cause mo11ality and liver related
clinical outcomes as measured by the time to first
occUITence of any of the following adjudicated
events (clinical outcomes composite endpoint):
Death (all cause) 
Model of end stage liver disease (MELD) 
score :::::15 
Liver transplant 
Hospitalization (as defined by a stay of :::::24 
hours) for onset of: 
• Variceal bleed
• Hepatic encephalopathy (as defined by
a West Haven score of:::::2)
• Spontaneous bacterial pe1itonitis
(con.fumed by diagnostic paracentesis)
Ascites secondaty to ciIThosis and requiting 
medical intervention (eg, diuretics or 
paracentesis) 
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Key Change 
Reasons/ 
Justification fol' 
Chan e 
The definition of 
progression to 
ciJThosis was made 
broader to not only 
include histology 
findings, but also 
laboratory parameters 
and clinical features as 
indicators of 
progression to 
ci.tThosis. These 
broader criteria will 
now be used to 
identify events for 
adjudication by the 
Hepatic Outcomes 
Committee 


Protocol 747-303 
Section 
Synopsis 
Section 7.1 
Section 7.1.3 
Section 16.2 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Leng t.@lm safety and tel@rability 
(TEAEs, EGGs, vital sigas, and dinical 
Final analysis will evaluate the effect of OCA on 
mmtality and liver-related clinical outcomes and 
long-tenn safety of OCA after the accrual of 
approximately 291 adjudicated clinical outcomes 
Confidential and Proprieta1y 
Revise.d Text (Vel'sion 11.0, 04 May 2021) 
6.7. Safety Objectives Assessed at End of Study 
•
To evaluate the effect of OCA compared to
placebo on:
o
Incidence of adjudicated cardiovascular
events
o
Incidence of adjudicated acute kidney
injury events
o
Incidence of adjudicated events of
hepatic injm-y
o
Long-term safety and tolerability
(TEAEs, ECGs, vital signs, and clinical
laboratory assessments)
Final analysis will evaluate the effect of OCA on 
mmtality and liver-related clinical outcomes and 
long-term safety of OCA after the accmal of 
approximately 291 adjudicated clinical outcomes 
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Key Change 
Reasons/ 
Justification fo1· 
Sh.1dy duration 
updated to 10 yea.rs 
based on cmTent 
estimates for outcome 
accmal 


Protocol 747-303 
Section 
Section 7 .1.2, 
Table 1 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
composite events combined in the OCA 25 mg 
and placebo groups for subjects with fibrosis 
stage 2 DI stage 3 (projected to take 
approximately+ years in total). Subjects aJe 
expected to have a minimum follow-up time of 
approximately 4 years. 
Schedule of Study Procedures 
Revise.d Text (Version 11.0, 04 May 2021) 
composite events combined in the OCA 25 mg and 
placebo groups for subjects with fibrosis stage 2 DI 
stage 3 (projected to take approximately 10 years in 
total). Subjects are expected to have a minimmn 
follow-up time of approxin1ately 4 years. 
For Clinical and Laboratory Evaluations -All Subjects 
•
Urinalysis was updated from annual procedures to semi-annual procedmes
•
Additional row was added for "Educate Subjects on Signs and Symptoms oflntercurrent
Illness (Appendix C)" which occurs at all semi-annual visits
•
Additional row was added for "Evaluate Signs and Symptoms of Intercurrent Illness" which
occurs at all semi-annual visits and EOS/EOT
• 
For Clinical Evaluations - For Subset of Subjects 
• 
(Only at sites where 
Footnotes 
e co umn "Semi-Annual/Annual" with 
footnote specifying "These assessments are to be pei·formed only annually (M:onths 30, 42, 54, 66, 78 and 
every 12 months until EOS).'' 
Confidential and Proprieta1y 
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Key Change 
Reasons/ 
Justification fol' 
Chan e 
Schedule of study 
procedm-es was 
updated to reflect 
changes to renal 
monitoring including 
the frequency of the 
urinalysis to occm­
semi-annually 
Education and 
assessment of 
intercunent illness at 
each study visit (semi­
annual) was added to 
reflect increased 
subject education and 
monitoring 
Fibroscan was updated 
to occm- annually to 
support changes in 
hepatic injury 
monitoring 


Protocol 747-303 
Section 
Section 7.4 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise.d Text (Version 11.0, 04 May 2021) 
ab Additional CPK samples may be collected if ALT, total bilirubin, or ALP are elevated (see Table 
2). 
AEs signs and symptoms of suspeeted hepatic 
AEs, signs and symptoms of potential hepatic 
injmy or decompensation and laboratmy values 
injmy or decompensation, and laboratmy values 
will be reviewed at regular inte1vals as described 
will be reviewed at regular inte1vals as described in 
in the following subsections (Section 7.4.1 to 
the following subsections (Section 7.4 .1 to Section 
Section 7.4.2.1). Based on the assessments of 
7.4.2.1). Based on the assessments of signs and 
signs and symptoms of hepatic injmy (Appendix 
symptoms of hepatic injury (Appendix C) and liver 
C) and liver biochemistry, investigational
biochemistiy, investigational product will be 
product will be continued, intem1pted, or
continued, interrupted, or discontinued per c1ite1ia 
discontinued per crite1ia discussed in Section 7. 7, discussed in Section 7. 7, and close monitoring 
and close monitming procedures will be 
procedures will be implemented (refer to Section 
implemented (refer toSection 7.4.3). 
7.4.3). 
In the event hepatic injmy is susfHlct@a, the 
h1 the event of a potential hepatic injmy, the 
subject should be promptly brought into the 
subject should be promptly brought into the clinic to 
Confidential and Proprieta1y 
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Key Change 
Reasons/ 
Justification fol' 
Change 
Instructions added to 
encourage subjects to 
seek immediate 
medical attention 
Symptoms update to 
reflect changes in 
DILI algorithm and for 
consistency with 
Appendix.C 


Protocol 747-303 
Section 
Original Text (Version 10.0, 03 Feb 2020) 
clinic to undergo a complete evaluation including 
laborat01y assessments, physical examinations, 
and review of signs and symptoms of Sl¼Sflectea 
hepatic injmy or decompensation. 
The Investigator will educate each subject about 
recognizing the signs and symptoms of suspected 
hepatic injmy or decompensation and instruct 
each subject to contact the study site to repo1i the 
onset of any of the signs and symptoms dming 
the study. 
Appendix C provides guidance for review of 
signs and symptoms of hepatic injury or 
decompensation desc1ibed below to be evaluated 
at each study visit, or as frequently as needed per 
Investigator's discretion. 
Signs and Symptoms of Hepatic Injmy or 
Decompensation: 
•
Specific signs and symptoms of liveI
impailmeut: yellowing of the skin or the whites
of eyes, pale-colored stools_, mine colm change
from pale to deep amber [dark] (ld-lect:i:ag
m½fllHi'ea 9iHillBiH meffi.90HSIH)
•
More general signs and symptoms of ascites
and encephalopathy: confusion, or abmpt
abnorn1al behavim, s,,1,1elliHg of the legs or
eeaomeB
•
Non-specific signs and symptoms of
inlpail'ed health: nausea, vomitiI1g, abdominal
pain dianhea, weight loss, fever and chills,
worsening, or new, or severe fatigue, weakness,
loss of appetite
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
undergo a complete evaluation including laboratory 
assessments, physical examinations, and review of 
signs and symptoms of potential hepatic injmy or 
decompensation. 
Tue Investigator will educate each subject about 
recognizing the signs and symptoms of suspected 
hepatic iI1jmy or decompensation and instruct each 
subject to contact the study site to repo1t the onset of 
any of the signs and symptoms dming the study. 
The Investigator will instruct subjects to seek 
immediate medical attention if they experience 
signs or symptoms of hepatic injm)' or 
decompensation. 
Appendix C provides guidance for review of signs 
and symptoms of hepatic injmy or decompensation 
described below to be evaluated at each study visit, 
or as frequently as needed per Investigator's 
discretion. 
Signs and Symptoms of Hepatic Injmy or 
Decompensation: 
•
Specific signs and symptoms of liver
inlpailment: 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, rnsh, 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 impaiI·ed
health: nausea, vomiting, abdominal pain, diaIThea,
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Protocol 747-303 
Section 
Section 7.4.1 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
. 
Significant intercmTent illnesses such as 
gastroente1itis may exacerbate hepatic injury or 
decompensation ( eg, established severe 
abd01ninal pain, vomiting, and dianhea for morn 
thas 4 da:,rs) and should be an indication for 
prompt investigational product intenuption and 
complete subject evaluation 
Other Symptoms: 
.
Worsening or new prnritus 
. WofsMing of rnaal fuectioa or liksly 
dsk3,dfatioH 
Liver biochemistry will be evaluated to assess 
biochemical niggers that will prompt an 
immediate reevaluation of subjects. Thus, these 
assessments will be pe1fo1med at: 
.
Each protocol-specified visit 
. Unscheduled visits in the event of signs or 
symptoms of saspsctsd hepatic injllly, 
decompensation, or if laboratory ale1ts have been 
n·iggered 
It is important that the laborato1y assessments be 
completed as required and that the central 
laboratory be used for assessments whenever 
possible. If a subject callllot 1etum to the clinic 
for a scheduled or unscheduled visit, or there is 
an event that triggers a need for an illlillediate 
assessment the use of a local lab is p@fffiissԗle 
at the discr@tioa of th@ 1H-¥@stigateL In these 
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
weight loss, fever and chills, worsening, or new, or 
severe fatigue, weakness, loss of appetite 
. 
Significant intercmTent illnesses such as 
gastroente1itis may exacerbate hepatic injllly or 
decompensation (eg, established severe abdominal 
pain, vomiting, and dianhea) and should be an 
indication for prompt investigational product 
intem1ption and complete subject evaluation 
Other Symptoms: 
. Worsening or new pnuitus 
.
Decreased urine output, dizziness, or 
lethargy 
Events of potential as hepatic injury will be 
reviewed and adjudicated by the Hepatic Safety 
Adjudication Committee (HSAC), as described 
in Section 16.11. The specific criteria for 
identification and adjudication of potential 
hepatic injm)' events are desuibed in the HSAC 
charte1·. 
Liver biochemistries will be evaluated to assess 
biochemical triggers that will prompt an immediate 
reevaluation of subjects. Thus, these assessments 
will be perfonned at: 
.
Each protocol-specified visit 
.
Unscheduled visits in the event of signs or 
symptoms of potential hepatic injury, 
decompensation, or if laboratory alerts have been 
triggered 
It is imp01tant that the laborato1y assessments be 
completed as required and that the central laboratory 
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Change 
Process for identifying 
potential hepatic 
injury and the action 
taken with IP was 
updated to align with 
published guidance 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
cases, the Investigator will obtain the laborat01y 
results and the laborat01y nonnal ranges. 
The process for assessing subje.cts using specific 
criteria is presented in Figure 2, and the specific 
threshold(s) for each laborat01y analyte to tJ.igger 
mandatory repeat testing and potentially a 
complete subject evaluation (depending on the 
repeat result) are summarized in Table 2. 
. . .
If any subject meets the niggering threshold 
limits fur @i؛h؜ COHjHgat@d hilirat3in or 
cr@atiain@, investigational product should be 
immediately inte1rupted (see Section 7.6 for 
dosing modifications). I-'.or th@ r@maming li:i.i@1· 
hioch؝BHS؞ ass@ssm@Hts, if a sabj@ct is om;sid@ 
of ffie ffflflet" er le•.'♦'et' Htfeshela IHflfl's, ffie 
laeora1;0؟ ass@ssm@Hl shoHld h@. r@p@at@d ia ؠ to 
3 days (with th@ s;ire@ptioa of aJJ.calm@ 
phosphatas@ [,AI:,Pl, \¥hi:ch is + days➔ aad 
@:i.ial:aat@d i,.ih@a th@ 1·ssHlts ar@ ai;ailaek If a 
repeat laborato1y test cannot be pe1fom1ed within 
ء days, the subject should be instJ.ucted to 
intem1pt investigational product until repeat lab 
results have been reviewed. 
.
If on repeat evaluation, values ar@ withia th@ 
epfll:i:eeele HH"eshela Efilefie, no dosing 
modifications are required and the subject should 
continue to be monitored. 
. If on repeat evaluation آ remain om;sid@ 
th@ sp@cifi@d thr@shold (see Table 2), 
investigational product أ be int.enupted for 
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
be used for assessments whenever possible. If a 
subject cannot retmn 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 nquin-d. In these cases, the 
Investigator will obtain the laborat01y results and 
the laborat01y n01mal 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 
aJtemative processes under which subjects may 
complete the protocol-specified assessments 
unde1· 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 subjects using specific 
c1iteria is presented in Figure 2, and the specific 
threshold(s) for each laborato1y analyte to trigger 
mandatory repeat testing and potentially a complete 
subject evaluation (depending on the repeat result) 
are summarized in Table 2. 
. . .
If any subject meets the niggering threshold limits 
indicated in Table 2 and experiences signs or 
symptoms of hepatic injury (severe fatigue, 
nausea, vomiting, right upper quadrant pain, 
fever, rash, eosinophilia) investigational product 
should be immediately intenupted (see Section 7. 7 
for dosing modifications). 
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Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
a minimum of30 days Sf mNil th@ lab0,1,at01:,' 
l"@SHIE5 f@ffifH ts J,¥it1Ha th@ a1313lieabl@ EIH:@5hela 
EFit@fia ل5@@ مsetiea +.a HH. aesiag 
meai!ieatieas). 1B this eass, a m@Elieal hist01:,t 
aBQ 13hysieal @*am sheHla b@ E8HaHEt@a aHa ,'½e 
ififeHHeنise Eiftek¼EHBه siو l!fia sىيtsHts s{ 
liY@f iB:jffiy a.5 0@5Clib@a ia ً@Etien +.4) sheula b@ 
cell@Et@a. TI1e Medical Monitor should be 
promptly contacted upon awareness for 
consultation regarding management of the 
subject. :U:symptems 13st·si5t Sf f@psat tssti:Hg 
588'\¥5 ps1·si5tsat abHeflBaliٌ· a5 0@5El"ib@a abe:i.z@, 
it is Ri3131·s13Fiet@ ts iftititN@ elss@ sbs@Pi'!Nistt t;s 
astsrHHH@ vA1@th@f th@ ab11:01malitiss al"@ 
. 
. 
. 
HHf)f8l/lHg Sf W8l"S@n1Hg. 
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 eaB have repeat ( or 
any safety) laboratory tests perfonned at a local 
laborato1y, but nmmal laborato1y ranges and the 
results should be made available to the 
Investigator. The original or copies €aH be 
retained at the site as the source documents. 
It should be noted that it is difficult to recognize 
every potential marker of hepatic er Ietlftl 
detelioration. TI1ere is no substitute for good 
medical judgment. Investigators will be 
reminded to be cautious and mindful in their 
evaluation of subjects' symptoms, signs, and 
laboratory results. However, for example, a 
single abnormal laboratmy analyte result may be 
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
If no signs or symptoms of hepatic injm)' are 
present, but liver biochemistries are above the 
triggering threshold limits, the subject should 
either inteHupt investigational product or 
laboratory assessments including ueatine 
phosphokinase (CPK) should be repeated within 
2-4 days according to the threshold limits
specified in Table 2. If a repeat laboratmy test
cannot be perfmmed within 7 days of receiving
results, the subject should be instructed to intenupt 
investigational product until repeat lab results have 
been reviewed. 
If investigational product is interrupted, 
laboratory assessments including CPK should be 
repeated within 2-4 days, a PK sample must be 
collected (within 7 days), and close monitoring 
should be initiated (repeat labs and physical 
exam should occur as often as deemed 
approp1iate 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, the Medical Monitor 
should be promptly contacted upon awareness 
for consultation regarding management of the 
subject. 
. If on repeat evaluation 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, live1· biochemistries 
remain elevated (see Table 2), investigational 
product must be intem1pted for a minimum of 30 
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Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
artefactual or may clearly be explained for a 
particular subject as due to pre-existing 
conditions or circumstances unrelated to their 
liver function or the study; accordingly, 
Investigators may be allowed to implement an 
alternate follow-up procedure, based on their 
medical judgement, but only after documented 
consultation and agreement with the Sponsor's 
Medical Monitor. 
Specific aspects of the SHspt1ctt1El DILI 
Management Alg01ithm may be adjusted, in 
which case specific guidelines will be provided 
to the sites for implementation. 
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
e 
promp y contactea upon awareness for consultation 
regarding management of the subject. 
In any subject for whom interrnpted 
investigational product fo1· reasons other than 
the inability to promptly repeat laboratory 
testing (within 7 days) for non-safety reasons, a 
rechallenge may be considered afte1· 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 
1·estarted 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 
nsolved, the Investigat01· should consult with the 
Medical Monitor to determine a treatment plan. 
This may include continuing close monitoring 
with interruption 01· discontinuing 
investigational product. 
For all subjects in whom close monitoring is 
initiated, a follow-u assessment of the sub· ect's 
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Chan e 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise.d Text (Version 11.0, 04 May 2021) 
status should be performed after apprnximately 
12 months of monit01ing. 
Subjects should wherever possible, come back to 
the site. It may be difficult for subjects who are 
distant from their smdy site to return to the site 
promptly. Such subjects must have repeat (or any 
safety) laborato1y tests perfom1ed at a local 
laborato1y, but n01mal laborato1y 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. The 01iginal or 
copies should be retained at the site as tl1e source 
documents. 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 
eve1y potential marker of hepatic deterioration. 
There is no substimte for good medical judgment. 
h1vestigators will be reminded to be cautious and 
mindful in their evaluation of subjects' symptoms, 
signs and laborat01y results. However, for 
example, a single abn01mal laboratmy analyte result 
may be a1tefach1al or may clearly be explained for a 
particular subject as due to pre-existing conditions 
or circumstaiices unrelated to their liver :function or 
the sh1dy; accordingly, hlvestigators may be 
allowed to implement an alternate follow-up 
procedure, based on their medical judgement, but 
only after documented consultation and agreement 
with the Sponsor's Medical Monitor. 
Confidential and Proprieta1y 
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Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise.d Text (Version 11.0, 04 May 2021) 
Specific aspects of the Potential DILI Management 
Algo1ithm may be adjusted, in which case specific 
guidelines will be provided to the sites for 
implementation. 
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Change 
7.4.I Figure 2 
Figure 2: 
SaSfJ@Ct@d Potential DILI Management Algorithm for Study 747-303
The fo/1011 ing major changes were made to the figure: 
• "Conjugated bilirubinlcreatinine" 11 as replaced with "presence of signs and symptoms of hepatic injwy ", which if present
leads to immediate IP interruption and initiation of close monitoring
• An additional step was added to confirm if the threshold met from Table 2 is a lower severity, as noted in the footnote.
• An additional box (with footnote) was added below interruption of IP to highlight the importance and timeliness of PK
sample collection and to clarify that close monitoring requires a physical exam and repeat biochemishy labs
• Footnotes were updated to reflect the new proposed algorithm
Section 7.4. l, 
Table 2: Liver Laboratory Criteria for Monitoring for SHSf)@Ct@d Potential Hepatic Injmy or D@comp@asation 
Table 2 
Section 7.4.2 
Section 9.9.5 
Section 9.9.6 
Section 13 .1 
Existing table and footnotes were replaced with new criteria and is updated to reflect updated threshold criteria, and guidance 
on PK sampling, use of local labs, and monitoring. 
Investigators will closely monitor subjects for 
potential progression to ciIThosis at eve1y visit 
( OI at unscheduled visits in th@ @¥@Ht of sigas or 
symptoms of SHSfJ@Ct@d h@f)atic iajwy or 
d@comp@nsatioa). If the subject meets one or 
more of the c1iteria for progression to ciIThosis 
described in Figure 3 sases oH F@¥tew of 
laeoratm.y vaJH@s, .BORHP1asiv@ scor@s of liv@r 
fibrosis, transi@nt @lastography rnading (if 
BVflila.13le), and any additional evidence that may 
be available it1cludit1g findings from targeted 
physical exams or from clinically indicated 
procedures (eg, biopsy, ultrasound, or 
Investigators will closely monitm subjects for 
potential progression to ciIThosis at every visit (or at 
unscheduled visits in the event of signs or 
symptoms of suspected hepatic injmy or 
decompensation). If the subject meets one or more 
of the criteria for potential progression to ciIThosis 
described in Figure 3 and/or any additional 
evidence that may be available including findings 
from targeted physical exams or from clitlically 
indicated procedures (eg, biopsy, ultrasound or 
esophagogastroduodenoscopy [EGD]), then the 
subject is considered to have potentially progressed 
to ciIThosis; Child-PuE!h scores must then be 
Section updated to 
distinguish when a 
confirmatory liver 
biopsy is 
recommended. 
Stronger language was 
added to emphasize 
the need and 
importance of 
obtaining a liver 
biopsy to confim1 
citrhosis and for 
inclusion in the 
Confidential and Proprieta1y 


Protocol 747-303 
Section 
Original Text (Version 10.0, 03 Feb 2020) 
esophagogastroduodenoscopy [EGD]), then the 
subject is considered to have progressed to 
cinhosis; Child-Pugh scores must then be 
assessed. Refer to Section 7.4.2.1 for 
detennination of Child Pugh Score. Dose 
adjustments or investigational product 
discontinuation may be required in subjects who 
meet crite1ia for progression to cirrhosis (see 
Table 5). 
If diaical indicators of progression to cinhosis 
become evident at any time dming the study, it is 
recommended that a liver biopsy be obtained and 
sent for central reading. 
The process for assessing disease progression to 
cirrhosis and the implications on dosing½£ 
summarized Figure 3. 
Confidential and Proprieta1y 
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Chan e 
assessed. Refer to Section 7.4.2.1 for determination 
analysis of study 
of Child Pugh Score. If a subject may have 
outcomes 
progressed to cirrhosis, a Fibroscan assessment 
should be performed when· possible (if not 
already part of the scheduled assessment) and 
repeated annually. Dose adjustments or 
investigational product discontinuation may be 
required in subjects who meet criteria for 
ro ·ession to cirrhosis see Table 4 . 
If non-invasive indicators of progression to 
cinhosis become evident at any time during the 
su1dy, it is recommended that a liver biopsy should 
be obtained and sent for central reading to conrum 
the diagnosis of ciIThosis and for inclusion in the 
analysis of study outcomes. Any interpretations 
by a local pathologist should be collected and 
entered in the eCRF within 2 days of receiving 
results. If a biopsy is not performed, the reason 
should be stated in the eCRF. The following 
clinical outcomes may preclude the need for a 
liver biopsy to confirm progression to ciIThosis: 
presence of ascites, hepatic encephalopathy, 
variceal hemorrhage, or the presence of large 
esophageal varices or varices with a red wale that 
require treatment. 


Protocol 747-303 
Section 
Section 7.4.2, 
Figure 3 
Section 7 .4.3 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise.d Text (Version 11.0, 04 May 2021) 
The process for assessing disease progression to 
cinhosis, the potential need for liver biopsy, and 
the implications on dosing is summarized Figure 3. 
Potential events of progression to cirrhosis will 
be 1·eviewed and adjudicated by the Hepatic 
Outcomes Committee which is described in 
Section 16.11. The Hepatic Outcomes Committee 
charter describes the specific criteria for 
identification and adjudication of potential 
events of prognssion to cirrhosis. 
Figure 3: 
Algorithm for Determining Progression to Cirrhosis 
New.figure to clarify when a confinnatory liver biopsy i.s recommended. 
Definition of ''persistent" expanded to include 2 consecutive visits within 6 months. 
Version 10 Section 7. 7 Close Observation 
At a minimum, the following assessments should 
be conducted at each study visit 
•
Physieal exam and thorough review of
subject reported signs and symptoms (Appendix
C)
In addition, a phannacokinetic sample for 
assessment of OCA serum chug levels and its 
major metabolites sl1ould be obtained in any 
subject who develops an AE of hepatic injmy or 
decompensation 
Version 11 Section 7.4.3 Close Observation 
At a mininmm, the following assessments should be 
conducted at each study visit: 
•
Exam and thorough review of subject-repo1ted
signs and symptoms of hepatic injury or
decompensation (Appendix C),
In addition, a phannacokinetic sample for 
assessment of OCA sernm ch11g levels and its major 
metabolites should be obtained in any subject who 
develops an AE of hepatic injmy or decompensation 
or interrupts investigational product due to 
suspected hepatic injm)' (Section 7.4.1). 
For all subjects in whom close monitoring is 
initiated for potential hepatic injury. a follow-up 
Confidential and Proprieta1y 
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Key Change 
Reasons/ 
Justification fol' 
Change 
The close observation 
section is specific to 
potential hepatic 
injmy and was 
therefore reorganized 
back into this section 
header 
Updated based on 
actions taken with IB 
due to potential 
hepatic injury 
Inclusion of follow-up 
assessment per 
guidance in DILI 
algorithm 


Protocol 747-303 
Section 
Section 7.5.1 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
NASH is associated with several known 1isk 
factors for cholelithiasis such as obesity, type 2 
diabetes, and other metabolic abn01malities. 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 hist01y of gallstones, it is 
imp01tant 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 sae:j@EE @)*@R@HESS s+,t8ffi5 5:ygg@sEi¥@ sf 
ehel@Htai:asis aea,le,1: Ehel@Eđsti:tis, 5.lh@ sh0Ē0 
HHS@fge a ESHlj:ll@t@ @¥alaati:ee eeesist@HE Ji1itith 
th@ leeal staH0a:f0 Sf Ea:f@, 13@ 055@55@0 HH' 
ēf8fl1·iat@ tf@at.ffi@Ht, i:HelaEliBg fl0t@Btial 
ieaieat:iee :fef 5m·g@fj' E@g, ehel@ey5t@eteĔt aBa 
13@ meeitenĕEi 1:IBtil rnselatiee Sf eH:H:ieal 5iges 
aEl:0 5-t01BS. 
If sĖtemat;ie ehel@lithiasis aea/ef Eh0l@e;1stiti:s 
is Eiiagees@El, ie·.issti:gatieeal fl1'8£k-¼Et sh0al0 13@ 
i:Btm1lflt@0 Es@@ S@etiee ). 
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
assessment of the subject's status should be 
performed after approximately 12 months of 
monitoring 
NASH is associated with several known risk factors 
for cholelithiasis, such as obesity, type 2 diabetes, 
and other metabolic abn01malities. The prevalence 
of gallstone disease in NASH is higher than in the 
general population. The maj01ity 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 hist01y of gallstones, it is 
imp01tant that all subjects be ( 1) monitored for signs 
and symptoms suggestive of gallstone disease and 
(2) cmmseled to recognize and seek immediate
medical attention if they expe1ience symptoms
suggestive of cholelithiasis and/or cholecystitis.
Subjects who develop signs or symptoms 
suggestive of symptomatic cholelithiasis and/or 
complications related to gallstone disease (eg, 
cholecystitis) should have investigational product 
interrupted while undergoing fm1her 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 1·esume 
investigational product after approval from the 
Investigator and Medical Monitor (see 
Section 7.7) 
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Clarification added to 
capture when subjects 
are allowed to re-
initiate IP 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Section 7.5.2 
h1vestigational product must be pe1manently 
Section 
discontinued in any subject diagnosed with 
15.1.11 
u·eatment-emergent acute, OI nonacute (chronic
or recurrent) pancreatitis (see Section 7.7). TI1e
evidence used to diagnose pancreatitis, including
symptoms, laborat01y test results, and/or imaging
results, 5heakl 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. TI1e
h1vestigator should contact the Medical Monitor
upon awareness of treatment-emergent acute or
nonacute pancreatitis.
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
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. 
References: 
Sakorafas GH, Milingos D, Peros G. 
Asymptomatic cholelithiasis: is cholecystectomy 
really needed? A critical reappraisal 15 years 
after the introduction of Iaparnscopic 
cholecystertomy. Dig Dis Sci 2007 May; 52:1313-
25. 
Stinton LM, Shaffer EA. Epidemiology of 
gallbladder disease: cholelithiasis and cancer. 
Gut Liver. 2012 Apr;6(2): 172-87. 
h1vestigational product must be pe1manently 
discontinued in any subject diagnosed with 
treatment-emergent acute or nonacute (chronic or 
recunent) pancreatitis (see Section 7. 7). TI1e 
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. 
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Revised to emphasize 
that data used to 
diagnose pancreatitis 
must be collected 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise.d Text (Version 11.0, 04 May 2021) 
Section 7.6 
New Section 
7 .6. Monitoling for Renal Impairment and 
N ephrolithiasis 
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, decreased 
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 J'ecorded as well as all 
centrnl lab data (scheduled or unscheduled visits) 
to adequately capture events. Repeat laboratory 
assessments should include albumin, serum 
chemistry (creatinine, BUN, elech·olytes),
urinalysis with microscopic examination, and 
assessment of estimated glomerular f'Iltration 
rate (eGFR). All local laboratory 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 impail'ment 
and the actions to be taken with investigational 
product are outlined in Figure 4. 
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Key Change 
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Justification for 
Change 
Guidance provided on 
monitoring and actions 
for IP intem1ption and 
PK sample collection 
for renal impainnent 
and nephrolithiasis 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise,d Text (Version 11.0, 04 May 2021) 
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 . 
... 
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 laborato111 reference ranges and the 
results should be made available to the 
Investigator. All local laboratory data, including 
reference ranges, should be entered into the 
eC
RF within 2 days of receiving the results. 
. 
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 intercun:ent illness 
should be conducted. If no alternative 
cause of serum creatinine elevation can 
be identified investie:ational product 
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Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
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 16.11). The specific criteria for
identification and adjudication of
potential AKI events are desuibed in the
Renal Adjudication Committee charter.
be recorded in the eCRF. 
A rechallenge may be considered after a 
minimum of 30 days if serum creatinine 
returns to below thnshold values and if 
approved by the Medical Monitor and 
Investi ator. If semm creatinine remains 
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Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise,d Text (Version 11.0, 04 May 2021) 
above threshold values after 30 days, the 
subject should be referred to a 
nephrologist for further evaluation. 
7.6.2. 
Neplu:olithiasis 
The development of signs or symptoms 
suggestive of kidney stones (nephrolitWasis) 
should be monitored. Standard of ca.re inrluding 
adherence to ncommended dietary measures, 
adequate fluid intake, and other measures 
presrribed should be employed to prevent 
recurrent episodes of kidney stones (Pearle 
2014). Subjects should be asked if they have 
experienced symptoms of nephrolithiasis 
(evidence of hematuria, flank or lower 
abdominal pain, nausea, vomiting, fever, or 
chills). 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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Protocol 747-303 
Section 
Section 7.6, 
Figure 4 
Section 7.7 
Section 7. 7, 
Table 4 
Section 8.2 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise.d Text (Version 11.0, 04 May 2021) 
Reference: 
Peade MS, Goldfal'b DS, Assimos DG, et al. Medical 
management of kidney stones: AUA Guideline. J Urol. 
2014;192:316-24. 
Figure 4: 
Algorithm for Monitoring Subjects for Potential Renal lmpainnent. 
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Chan e 
New figure clarifies creati.nine threshold and the steps taken by the Investigator to monitor subjects with potential acute kidney injury 
including repeat testing, i.nvestigationa1 product intenuption, and monitoring. 
Subjects can be tempornrily or permanently 
discontinued from investigational product by the 
Investigator at any time for clinical safety 
concerns. 
Subjects can be temporarily or pe1manently 
discontinued from investigational product by the 
h1vesti ator at an time for clinical safe 
Table 4: Criteria for Dose Adjustment, Intenuption, Discontinuation and Rechallenge 
Added PK sample 
collection to better 
understand exposure­
response relationship. 
The criteria for Dose Iutem1ption and its related footnotes were updated to reflect changes in monitoring for renal impairment, hepatic 
m 
, cholelithiasis and/or cholec stitis 
Refer to Section 7.4 and Section 7.7 for 
withdrawal crite1ia related to sHspect@d hepatic 
injmy and/or decompensation; progression to 
cirrhosis; treatment-emergent acute or nonacute 
pancreatitis; Grade 3 pruritus AEs ;:::Grade 3 in 
severity and possibly, probably or definitely 
related to investigational prnduct; AEs ˖Gi;ade 4 
m. se1.i:etity aad NOT or twikely re!ated to
iHJ.'@sligatioaal prnchct; liver transplantation, and
bariatric surgery, aad rregaaecy. Other reasons,
Refer to Section 7 .4 and Section 7. 7 for withdrawal 
criteria related to potential hepatic injury and/or 
decompensation; progression to ciIThosis: treatment­
emergent acute or nonacute pancreatitis; Grade 3 
prmitus, AEs ˗Grade 3 in severity and possibly 
probably, or definitely related to investigational 
product; liver transplantation, and bariattic surgery. 
Other reasons, including withdrawal of consent OI 
lost to follow up, are described in Section 8 .2.1 to 
Section 8.2.3 below. 
CotTected to align with 
Section 7. 7 as AEs >= 
Grade4 and 
pregnancy are listed as 
interruptions not as 
withdrawal/discontinu 
ation 
Confidential and Proprieta1y 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
including withdrawal of consent or lost to follow 
up, are described in Section 8.2.1 to Section 8.2.3 
below. 
Section 9.3 
Subjects taking bile acid sequestFaats (BASt 
(including colestyramine and its derivatives, 
colestipol, colesevelam, or other sequestrants) or 
aluminum hydroxide- or smectite-containing 
antacids should be instructed to stagger their 
dosing of investigational product, 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). 
The effect of OCA on mug metabolizing 
enzymes has been evaluated in both in vitro and 
clinical studies. The PK profile of caffeine, a 
sensitive CYPIA2 substrate, showed weak effect 
of OCA on CYPIA2. Based on these results 
OCA may increase the exposure of narrow 
therapeutic index drngs that are substrates for 
CYPIA2, such as theophylline and tizanidine. 
If dimcal indicators of progression to ciIThosis 
become evident at any time dming the study, it is 
recommended that a bjopsy be obtained and sent 
for central reading. 
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
9.3.1. 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 de1ivatives, colestipol, 
colesevelam, or other sequestrants) or aluminum 
hydroxide- or smectite-containing antacids should 
be instrncted to stagger their dosing of 
investigational product in temporal relation.ship to 
these agents, ensming 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 ti·eat pruritus ԘGrade 
2 in seve1ity refer to Section 15.1.5.1. 
Due to the potential of BAS to affect the 
disposition of OCA, long-term llse of BAS should 
be avoided where possible while taking 
investigational prnduct. In subjects taking long-
term BAS for other medical conditions ( eg, 
hypercholesteremia), other therapies to replace 
the BAS should be considered. 
9.3.2. Other Concomitant Medications 
The effect of OCA on mug metabolizing enzymes 
has been evaluated in both in vitro and clinical 
studies. The PK profile of caffeine, a sensitive 
CYPIA2 substrate, showed weak effect of OCA on 
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Key Change 
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Change 
Since the long-terrn 
use of BAS can affect 
the exposure to OCA 
and its metabolites, 
guidance was added to 
encournge 
Investigators to limit 
use of longer-tenn 
BAS. 
Other concomitant 
medications update ot 
reflect changes in 
progression to 
ciiThosis and guidance 
regai·ding COVID-19 
vaccination was 
added. 


Protocol 747-303 
Section 
Synopsis 
Section 9.3.3 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
•
Gi¥@B th@ fll"@1,1al@HE@ et: ElyslifliEl@m:ia iH
patiE!Bts i.¥ith Nli:gl-1 aBEl th@ fl et@atial
i:ae1·@as@ ia tetal aaEl bilb ehel@st@rnl
fellewi:ag tf@aEEH@Bt i.i.tith QGA, it is
H!E8HHB@ft8@8 {Be,t, lfili1@St88FS ft'88Ett1r@l;i
meB:iteF a:00 maaag@ l:ifliB l@:i,z@ls 1;ia
Bflfll,9flFiat@ ffi@Eliei:aal i:at@F¥@Htieas E@g,
statm5j. •úfl@Hû A pFe1,1is@s a g@H@Fal
gaisa:HE@ feF Ehel@st@rnl EHaBag@ffi@HE
i:aclHEliBg ffieBiteriHg, trigg€fs fur
i:at@FVE!Btiea, aeEl tFE!atffi@et geals.
New Section and Figure 
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
CYP1A2. Based on these results, OCA may 
increase the exposure of murnw thernpeutic index 
drngs that are substrates for CYP1A2, such as 
theophylline and tizanidine. 
If non-invasive indicators of progression to 
cinhosis become evident at any time during the 
study, it is recommended that a liver biopsy should 
be obtained and sent for central reading (refer to 
Section 7.4.2). 
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 close (refer to 
Section 10). 
9.3.3 
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 monito1· and manage lipid levels in all 
participants as indicated via appropriate 
medicinal inte1--ventions (eg, statins). Recent 
guidelines stress the importance of evaluating 
atherosclerotic cardiovasculu disease (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 
low-density lipoproteins, are part of a 
comprehensive cardiovascular risk reduction 
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Key Change 
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Change 
Guidance on the 
management of 
dyslipidemia 
according to current 
guidelines 
(ACC/ AfWESC/EAS 
) and based on 
ASCVD risk was 
added to optimize and 
proactively manage 
subjects based on 
cardiovascular risk 
factors before and 
when LDLc elevations 
occur. Existing bullet 
was removed 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise,d Text (Version 11.0, 04 May 2021) 
strntegy. Results from meta-analyses have 
con.finned t.he dose-dependent reduction in 
ASCVD with LDLc-lowering agents; the greater 
the absolute LDLc reduction, the greate1· 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 treahnents and each subject's overall 
ASCVD risk proflle. The tai·geted approach to 
lipid management is aimed at reducing 
atherosclerotic risk by substantially lowering 
LDLc to levels that have been achieved in recent 
large-scale h·ials (Figure 5). 
Section 9 .3 .4 
New Section 
9.3.4. 
Standard of Care: Management of 
Hyperglycemia 
Subjects with type 2 diabetes mellitns 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 histo11' 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, polyphae:ia, blurred 
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Key Change 
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Change 
Guidance on the 
management of 
hyperglycemia 
according to ctm·ent 
guidelines (ADA and 
EASD) was added to 
optimize and 
proactively manage 
subjects before 
elevations occur 
Additional language 
refeITing subjects to 
their treating physician 
and/or endocrinologist 
was added for subjects 
who develop 
hyperglycemia 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise,d Text (Version 11.0, 04 May 2021) 
vision, fatigue and headaches should also be 
monitored. 
Subjects who experience treatment-emergent 
hyperglycemia should be closely monitored and 
treatment should be based on cunent 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 seve1ity 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 
undel'lying risk factors including underlying 
cardiovascular and renal disease. According to 
these guidelines, glycemic treatment ta1·gets 
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 measming 
HbAlc 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 the patient-cente1·ed 
care. 
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Protocol 747-303 
Section 
Section 9.5.1 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
The DMC (refer to Section 16.10) 1,vil:l ha,v@ 
0EE@55 te th@ ϫJRϬ 8:HB 'i¥ill e@ ael@ te :mlhli:aa 
mravidual sm:>j@ets . Th@ DMC will be provided 
unblinded data to Ieview dming closed sessions. 
The DMC will docmnent, in the closed session 
DMC minutes (which will be made available to 
the Sponsor only after the database is locked and 
the study is unblinded), details about any 
unblinded subject data reviews. Cases of 
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
While criteria for initiating therapy requires 
individualizing HbAlc targets, a reasonable 
HbAlc target is approximately Ϫ7% (53 
mmol/mol) (Davies 2018). The selection of the 
approptiate individualized thernpy is desCI'ibed 
in current guidelines from ADA and EASD for 
management of hyperglycemia (Appendix B). 
Subjects displaying increasing fasting glucose, 
HBAlc, or HOMA-IR levels should be 1·eferred 
to either theh· treating physician, if already 
under care for diabetes, or to an endocrinologist 
if they experience new onset type 2 diabetes 
mellitus. 
Reference: 
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. 
The DMC (refer to Section 16.10) will be provided 
unblinded data to Ieview dming closed sessions. 
The DMC will document, in the closed session 
DMC minutes (which will be made available to the 
Sponsor only after the database is locked and the 
study is unblinded), details about any unblinded 
subject data reviews. Cases of premanire 
unblinding (as noted above) will be reviewed by the 
DMC. 
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Change 
CoITected per changes 
in Section 16.10. 


Protocol 747-303 
Section 
Section 7 .1.2, 
Table 1 
Section 9.9.1, 
Table 5 
Section 9.9.8.1 
Section 9.9.8.3 
Section 9.9.9 
Section 7 .1.2 
Section 9.9.3 
Section 9.9.4 
Section 9.9.5 
Section 9.9.6 
Section 9.9.7 
Section 9.9.8 
Section 9.9.8.1 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
premature unblinding (as noted above) will be 
reviewed by the DMC. 
Semi-Annual Procedures (Months 24, 30, 36, 42, 
48, 54, 60, 66, 72, iffi0 78) 
Additional Annual Procedures (Months 30, 42, 
54, 66, iffi0 78) 
t 
Instruct the subject to fast overnight (at least 
8 hours) before the next visit (water is pennitted) 
Semi-Annual Visit procedures for all subjects are 
as follows: 
•
Ve1ify that the subject has fasted for at
least 8 hours
Obtain blood samples for 
Sel1llll chemistry, hematology, 
and coagulation 
•
Glucose and HbAlc
Educate subjects about signs and 
symptoms of hepatic injmy or 
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
Semi-Annual Procedures (Months 24, 30, 36, 42, 
48, 54, 60, 66, 72, 78 and every 6 months until the 
EOS) 
Additional Annual Procedures (Months 30, 42, 54, 
66, 78 and every 12 months until the EOS) 
Instrnct the subject to fast overnight (at least 8 
hours) before the next visit (water is permitted and 
subjects should ensure they are hydrated prior to 
study visits) 
Semi-Annual Visit procedures for all subjects are as 
follows: 
In the days leading up to and including the 
visit day, subjects should maintain the regulal' 
daily timing of their investigational prnduct 
dose administration (eg, dosing every morning, 
dosing every afternoon, dosing eve1·y evening, 
etc). If the subject's l'l'gulal' daily dosing time 
occurs during the site visit, the subject should 
administer the dose at the study site and the 
time of dosing should be l'ecorded in the eCRF. 
Verify that the subject bas fasted for at least 
8homs 
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Chan e 
Semi-annual and 
annual procedm-es 
updated to remove 
Month 78 as last 
timepoint. Study is 
ongoing until number 
of clinical outcome 
events is documented. 
Instructions for 
subjects to stay 
hydrated updated to 
encourage accurate 
mmiitoring for renal 
impainnent and 
nephrolithiasis 
Section updated to 
reflect changes in 
education of 
intercmTent illnesses 
other than hepatic 
lll 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
decompensation (as needed, per 
fuvestigator's discretion) 
Evaluate signs and symptoms of iiltǜeetea 
hepatic injllly or decompensation and assess 
subjects per Suspected DILI Management 
and Progression to Cinhosis Algorithm 
In subjects who progress to cirrhosis 
and have a CP score <7, 1 PK blood 
sample will be obtained at the next 
scheduled visit prior to dose 
adjustment. Subjects who 
discontinue investigational product 
due to progression to citThosis and 
Child Pugh score ?_7 or due to 
hepatic injlllY, will provide a PK 
blood sample if the siǝe visit is 
within 7 days from dose intem1ption 
or discontinuation. The time of the 
last dose of it1vestigational product 
prior to the PK blood sample will be 
repmied. 
Calculations will be perfonned by the 
Sponsor or designee for: 
•
MELD score
Perfonu a urine-based ŧ-hCG pregnancy 
test for females of childbeaiing potential 
Confidential and Proprieta1y 
Revise.d Text (Vel'sion 11.0, 04 May 2021) 
•
Obtain blood samples for
Sernm chemistiy, hematology, and 
coagulation 
Glucose and HbAlc 
•
Educate subjects about signs and symptoms
of hepatic injmy or decompensation (as
needed, per fuvestigator's discretion) and
intercurrent illness and/or potential
adverse events (Appendix C)
I 
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Justification fol' 
Chan e 
Frequency of 
urinalysis updated to 
reflect changes to 
renal monitoring 


Protocol 747-303 
Section 
Section 9.9.8.3 
Section 9.9.9 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Calculations will be perfonned by the 
Sponsor or designee for 
Cardiovascular risk scores (FRS, 
Reynolds score, SCORE, 10-year 
ASCVD Risk) 
ObtaiB 1:1:l.ins samph fer HiiBaljrsi-s 
Obtain blood samples for 
Semm chemistry, hematology, and 
coagulation 
Thyroid hormones 
Free fatty acids 
Confidential and Proprieta1y 
Revise.d Text (Vel'sion 11.0, 04 May 2021) 
Calculations will be perfonned by the 
Sponsor or designee for: 
MELD score 
Obtain urine sample for minalysis 
•
Perfonn a urine-based Ƙ-hCG pregnancy
test for females of childbearing potential
Calculations will be perfonned by the
Sponsor or designee for
Cardiovascular 1isk scores (FRS, 
Reynolds score, SCORE, 10-year 
ASCVDRisk) 
Annual procedures fo1· the various subsets of 
subjects are as follows: 
Obtain blood samples for 
Semm chemistry, hematology, and 
coagulation 
Thyroid h01mones 
Free fatty acids 
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Key Change 
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Justification fol' 
Added annual 
Fibroscan assessment 
to better monitor 
subjects for 
progression to 
ci.1Thosis. 
Frequency of 
urinalysis updated to 
reflect changes to 
renal monitoring 
Procedure for 
evaluation of 
intercmTent illness 


Protocol 747-303 
Section 
Section 9.9.10 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
The Investigator may schedule an at-clinic 
Unscheduled/Safety Visit at any time if clinically 
warranted (refer to Section 7.4). Unscheduled 
and/or repeat assessments, including additional 
laborat01y tests or investigations, may be 
conducted. Evaluations ma include a h sical 
Confidential and Proprieta1y 
Revised Text (Vel'sion 11.0, 04 May 2021) 
Tue Investigator may schedule an at-clinic 
Unscheduled/Safety Visit at any time if clinically 
wananted (refer to Section 7.4). Unscheduled 
and/or repeat assessments, including additional 
laborat01y tests or investigations, may be conducted. 
Evaluations ma include a h sical exam, serum 
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Key Change 
Reasons/ 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise.d Text (Version 11.0, 04 May 2021) 
exam, semm biochemistry, semm electrolytes, 
biochemistry, sernm electrolytes, assessment of 
aaa assessment of MELD scores at fuvestigator's 
MELD scmes, and imaging and/or Fibroscan at 
discretion. Fm1her monitoring outside of regular 
h1vestigator's discretion. In these cases, where a 
scheduled visits should be based on the 
local laboratory is used, it is impo1tant that all 
fuvestigator's assessment of the subject's clinical 
loral laboratory data, including the reference 
status. 
ranges, are collected and entered in the eCRF 
within 2 days of receiving the results. Fmther 
monitoring outside ofregular scheduled visits 
should be based on the fuvestigator' s assessment of 
the subject's clinical status. 
Section 10 
New Section. 
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 an unable 
to return to study sites for evaluations and/or to 
receive continued supply of investigational 
product. Enforcement of many 1·estl'ictions by 
local autho1ities have also affected the site 
monitor's ability to pe1·fonn on-site monitoring 
duting 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 nreive 
investigational product until in-person site visits 
can resume. To ensure the continued safety 
monitoring of the participating subject and to 
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Change 
Guidance to 
Investigators on 
acceptable procedures 
and necessary 
documentation 
required dmi.ng 
COVID-19 pandemic 
and vaccine 
info1mation were 
added to ensw-e the 
safety of the subject in 
the study as well as the 
integrity of the study. 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise,d Text (Version 11.0, 04 May 2021) 
minimize the potential adverse impact on 
achieving the objectives of the study due to the 
restrictions from the COVID-19 pandemic, the 
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 c.ontinued 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
electrnnic 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 a
qualified healthcare professional who is
currently authorized to undertake examinations
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Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise,d Text (Version 11.0, 04 May 2021) 
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 laboratOI)' tests are to be sent to the
Investigator and entered in to the eCRF within
2 days of receiving 1·esults. Note: Investigational
product can only be dispensed if central or local
laboratory values are available.
-
Minimum testing required to support
the protocol: Liver safety labs of
direct and total bilirubin, AST, ALT,
GGT, ALP, coagulation panel (INR,
aPTT), platelets, albumin and serum
creatinine and non-liver safety labs of
CBC & Diff, standard elech·olytes,
lipid panel and urine-based Jl-hCG
pregnancy test.
•
Investigational Product Dishibution:
Investigational product may be sent dinctly to
the subject from either the study site or a thlrd-
party vendor via a comier service if subjects are
not able to attend study site visits. Dinct
shipment ofinvestigational product from the
Investigator site to subjects must adhere to the
site's institutional and pharmacy procedures and
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Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise,d Text (Version 11.0, 04 May 2021) 
counh1' specific requirements. If the 
Investigator is unable to evaluate safety and 
tolerability and assess the benefit-risk for the 
individual subject, the .subject must intenupt 
investigational prnduct until the assessment can 
be completed. 
•
Home Visits: If laboratory tests cannot be
obtained from local laboratories, home nursing
support (where available and permitted) is an
accepted option that may be employed to
supplement telemedkine 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 requiJ·ed subject
questionnaires).
•
Monitoring: Cancelling or postponing of on-
site monitoring visits and extension of the period
between monito1ing 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 
Investieator, maintain subject participant 
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Protocol 747-303 
Section 
Section 13.1 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
The investigator will assess the clinical crite1ia 
for progression of fibrosis to cinhosis for each 
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
confidentiality and be compliant with 
IDPP A/GDPR and 21 CFR Part 11 guidance. 
In addition to regularly collected n·ial data, 
available COVID-19 related data such as 
COVID-19 testing will also be collected for all 
subjects. Any subject that contracts the SARs­
Co V-2 vims 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 counh1' where you 
practice) is allowable for pa11icipants enrolled in 
the Intercept-sponso1·ed PBC and NASH clinical 
trials. Of note, as the currently approved 
COVID-19 vaccines have not been specifically 
tested in the ASH or PBC subjed population, 
nor the pediah·ic population suffering from 
biliary atresia (BA), there are no safety data 
available specific to 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, vaccine name and 
manufachll'er should be i-ecorded as a 
concomitant medication for each dose. 
The investigator will assess the clinical niteria for 
progression of fibrosis to cirrhosis for each subject 
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Protocol 747-303 
Section 
Synopsis 
Section 13 .1.1 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
subject during the study. If clinical indicators of 
progression to cinhosis become evident at any 
time during the study, it is recommended that a 
liver biopsy be obtained and sent for central 
reading. Updated guidance on criteria to trigger 
an unscheduled liver biopsy in subjects with 
susfJ@CΊ@a progression to cinhosis may be 
provided to investigators separately. 
In addition to the p1ima1y scoring system of 
NASH CRN, biopsy samples will also be scored 
based on modified Ishak scoring (Ishak 1995) 
and SAF scoring (Bedossa 2014) for all subjects 
as well as for quantitative collagen for a subset of 
subjects as exploratmy assessments. Any extra 
biopsy tissue may undergo exploratory 
histological evaluations such as alpha-smooth 
muscle actin or bile acid transpmter analysis 
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
during the study. If clinical indicators of 
progression to cinhosis become evident at any time 
during the smdy, it is recommended that a liver 
biopsy be obtained and sent for central reading. 
Updated guidance on criteria to trigger an 
unscheduled liver biopsy in subjects with potential 
progression to cinhosis may be provided to 
investigators separately. 
hi addition to the primary scoring system of NASH 
CRN biopsy samples from the Month 18 Interim 
Analysis will also be scored based on modified 
Ishak scoring (Ishak 1995) and SAF scoring 
(Bedossa 2014) for all subjects as well as for 
quantitative collagen for a subset of subjects as 
exploratmy assessments. Any extra biopsy tissue 
may undergo exploratmy histological evaluations 
such as alpha-smooth muscle actin or bile acid 
trans 01ter anal sis 
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Added language to 
clarify additional 
scoring on biopsy 
sample was for Month 
18 Interim Analysis 
only 


Protocol 747-303 
Section 
Original Text (Ve1·sion 10.0, 03 Feb 2020) 
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Protocol 747-303 
Section 
Section 
15.1.1.1 
Original Text (Version 10.0, 03 Feb 2020) 
Subjects should be instrncted to contact the site 
promptly if they develop signs and symptoms of 
SH5f)e.cte.d liƔatic Ele.compe.-B5atioa s:Ycli as: f)ale. 
colore.El stools, \:l:fHle. color ti·offl. f)ale. te ae, 
affl.8e.r [Elark], llfR-¼S@a, vornitiHg, abaoffl.i.Hal 13aiH, 
Elianhe.a, we.iglit loss, fe,,;:e,	· aaa chills, fatig;ye., 
1,ve.akHe.ss loss of af)f)e.tite. co1m1sioH:, swe.lliHg of 
the. le.gs or aeaoffl.e.H, ye.Uowiag of the. skiH or the. 
white.s of e.ye.s, aaa lm:iisiHg e.asily. 
Confidential and Proprieta1y 
Revised Text (Version 11.0, 04 May 2021) 
Subjects should be instructed to contact the site 
promptly if they develop any of the signs and 
symptoms of intercurrent illness and/or potential 
adverse events listed in Appendix C. 
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Language expanded to 
include full list of 
symptoms subject and 
Investigator should be 
aware of per Appendix 
C.


Protocol 747-303 
Section 
Section 
15.1.1.3 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
An AE is considered "se1ious" if, in the view of 
either the Investigator or Sponsor, it results in 
any oftl1e following outcomes: 
Death 
•
Is tHlfBeaiately life threatening
Requires in-subject hospitalization or
prolongation of existing hospitalization
Results in persistent or significant
disability or incapacity
•
Results in a congenital abnormality or
birth defect
•
Is an important medical event that may
jeopardize the subject or may require
medical intervention to prevent one of
the outcomes listed above
Events not considered to be SAEs are 
hospitalizations for: 
•
Routine monit01ing of the studied
indication and not associated with any
dete1ioration 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
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
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-subject hospitalization or
prolongation of existing hospitalization
Results in persistent or significant disability
or incapacity
•
Results in a congenital abnormality or birth
defect
•
Is an important medical event that may
jeopardize the subject or may require
medical intervention to prevent one of the
outcomes listed above
Events not considered to be SAEs are 
hospitalizations for: 
•
Routine monit01ing 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 obse1vation when there is no
AE associated with the hospitalization
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Removal of 
immediately, as any 
life threatening event 
is considered serious 


Protocol 747-303 
Section 
Section 
15.1.5.1 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Since prnritus is a subjective symptom, the 
occunence and magnih1de of which are not 
readily measured objectively, clinical judgment 
needs to be applied in the management of each 
subject. Managing QC.A-related prnrih1s may 
help improve tolerance in those subjects who 
expe1ience problematic pnnitus and may 
otherwise discontinue from the study 
prematurely. Guidance for the management of 
subjects experiencing significant pnuitus are 
provided in Table 4 (Section 7.4.2.1) and 
includes: 
•
Pnnitus 2':Grade 3 in severity: Discontinue
investigation.al product
Pnu-itus ::::Grade 2 in severity: One OT more 
of the following may be considered: 
Drng holiday or less frequent dosing at 
the discretion of the Investigator. 
"BAS f)f@scrif)tioa: SHIJ:i@cts takiag R'\S 
(iacl-1.¼diag chol@sŷ'n1miae aHa its 
e@rivati1,,es, col@stif)ol, col@s@v:dam, or 
other s@qy@straats) shoald 1:>@ H:l::Stmctee 
to stagger th@ir dosiag of ia11estigati0Hal 
fll·oaact, SH&'.:lring at least 4 hoars 
b@tvt@@H eos@s of th@ "BAS aHd 
in-v@stiga:tio0al fl'roduct. 
Confidential and Proprieta1y 
Revi.se.d Text (Version 11.0, 04 May 2021) 
Since pruritus is a subjective symptom, the 
occUITence and magnitude of which are not readily 
measmed objectively, clinical judgment needs to be 
applied in the management of each subject. 
Managing OCA-related prnritus may help improve 
tolerance in those subjects who experience 
problematic pnuih1s and may othe1wise discontinue 
from the study prematurely. Guidance for the 
management of subjects expeliencing significant 
prrnitus are provided in Table 5 (Section 7.7) and 
includes: 
•
Pnnitus 2':Grade 3 in severity: Discontinue
investigational product
Pnnitus :SGrade 2 in severity: One or more of 
the following may be considered: 
Dmg holiday or less frequent dosing at the 
discretion of the Investigator. 
Shott-term use of BAS 
o
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
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Since the long-tetm 
use of BAS can affect 
the exposme to OCA, 
guidance was added to 
encourage 
Investigators to limit 
the use of BAS to 2 
weeks at a time and 
possible rechallenge of 
OCA. Additional 
guidance was provided 
on when IP 
discontinuation should 
be considered 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
-
Other therapies may be .. as deemed
clinically appropriate.
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
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. 
0 
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 h·eatment plan. 
This may include continuing 
every other day dosing, 
interrupting or discontinuing 
investigational product. 
0 
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. 
0 
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 9.3. 
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Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Section 
If a subject experiences symptoms consistent 
15.1.11 
with cholelithiasis or pancreatitis, the subject 
should HHGMgo a complete evaluation for both 
conditions consistent with local standards of 
care. If symptomatic cholelithiasis and/or 
cholecystitis is diagnosed, ia·.isstigaheaal 
prnciHct sheHIEl bs iatsn:aptsci, anci the subject 
should be managed and monitored as desc1ibed 
in Section 7.5.1. 
Section 15.2.6 
Blood, urine and stool samples for laboratory 
assessments will be collected at the visits 
specified in Table 1. Full instructions 
concerning the number and type of samples to be 
collected at each visit, the required sample 
volumes, sample collection methods, sample 
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
-
Other medical therapies may be
considered, as deemed clinically
approp1iate and based on current practice
guidelines (EASL 2017) or literature
(Hegade 2015) ..
References: 
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. 
Hegade VS, Kend1ick SF, Jones DE. Drng 
treatment of pruritus in liver diseases. Clin Med. 
2015 Aug;15(4):351-7. 
If a subject experiences symptoms consistent with 
cholelithiasis 01 pancreatitis, the subject should 
have investigational product interrnpted while 
undergoing a complete evaluation foI 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. 
Blood, urine, and stool samples for laborat01y 
assessments will be collected at the visits specified 
in Table 1. 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 
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Change 
Updated to reflect 
changes in guidance 
for cholelithiasis 
and/or cholecystitis 
(section 7 .5.1) 
Section updated to 
provide clarification 
on use oflocal lab and 
inclusion or 
results/reference 
ranges into the eCRF 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
processing, labeling, and shipping will be 
provided in separate procedural manuals. All 
necessaiy collection supplies will be provided by 
the approp1iate laborato1y 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 laborat01y is 
required. In these cases, the Investigator will 
obtain the laboratory results and the laborat01y 
normal ranges. All local laborat01y 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 resuictions refer to Section 10. 
All subjects with laboratmy tests containing 
clinically significant abnonnal 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 
unnecessa1y. 
. . .
The Investigator should maaag@ sHej@Els 1,1it:h 
ElilHEally sigmfi:Ea:at li13e13fet:@ffi aeaemialiti@s 
Hsmg leEal staaElafa ef EB£@ 131·eE@EH1:1:·@s as 
af)f)f8l3i'iat@ aft@¼· ass@ssmg th@ ffi(:Jiiliaual 
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
will be provided in separate procedural manuals. 
All necessary collection supplies will be provided 
by the appropriate laborat01y and will be 
approp1iately assembled for the specific evaluations 
required at each visit. 
If a subject cannot ntum 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 nsults 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 altemative 
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 abnom1al 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 indicate via 
appropriate medical interventions (eg, statins). 
Recent guidelines stress the impo11ance of 
evaluating ASCVD 1isk in all subjects to help 
euide decisions in recommendine therapies and 
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Monitoring of lipids 
language updated to 
reflect changes in 
Section 9.3.3 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
subj set's total cai:diovascular risk profile as 
d@scria@d in .f..f)f)t1HdHE ,"z. 
Revise,d Text (Version 11.0, 04 May 2021) 
reducing LDLc to reduce the risk and prevent 
onset or recurnnce of ASCVD (refer to Section 
9.3.3 and Appendix A). 
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Section 15.2.6, 
Table updated to include calc11lation of eGFR and PK analytes added for clarity based off updated renal monit01ing and additional PK 
Table 12 
assessments. 
Section 16.4.1 
All efficacy analysis at EOS will be conducted 
using the ITT population (only including fibrnsis 
stage 2 and 3 subjects). The hypothesis testing 
of primary and (key) seconda1y endpoints will be 
conducted in with control of Type 1 enor (OCA 
25 mg, then 10 mg). Adjustments for 
multiplicity are specified in Section 16. 7 and 
additional details on the testing at EOS will be 
provided in the SAP. 
The primaiy efficacy endpoint at the EOS will be 
the time to first occunence of one of the 
following post randomization: 
•
Death (all-cause)
•
MELD score 2:15
•
Liver transplant
•
Hospitalization (as defined by a stay of 24
hams or greate1) for onset of:
-
V aiiceal bleed
-
Hepatic encephalopathy (as defined by a
West Haven score of2:2)
-
Spontaneous bacterial peritonitis
(confmned by diagnostic paracentesis)
Confidential and Proprieta1y 
All efficacy analysis at EOS will be conducted using 
the ITT population ( only including fibrosis stage 2 
and 3 subjects). The hypothesis testing of primary 
and (key) secondaiy endpoints will be conducted in 
with control of Type 1 enor (OCA 25 mg, then 
10 mg). Adjustments for multiplicity are specified 
in Section 16.7 and additional details on the testing 
at EOS will be provided in the SAP. 
The primary efficacy endpoint at the EOS will be 
the time to first occunence of one of the following 
post randomization: 
•
Death (all-cause)
MELD score 2:15
Liver transplant
•
Hospitalization (as defined by a stay of 24 hours
or greater) for onset of:
-
V ariceal bleed
-
Hepatic encephalopathy (as defined by a
West Haven score of 2:2)
-
Spontaneous bacte1ial peritonitis (confinned
by diagnostic paracentesis)
•
Ascites secondaiy to cinhosis and requiring
medical intervention (eg, diuretics or paracentesis)
Prngression to cinhosis 
The definition of 
progression to 
ciIThosis was made 
broader to not only 
include histology 
findings, but also 
laborat01y parameters 
and clinicĕ! features as 
indicators of 
progression to 
ciIThosis. These 
broader criteria will 
now be used to 
identify events for 
adjudication by the 
Hepatic Outcomes 
Committee 


Protocol 747-303 
Section 
Section 16.9.2 
Section 16.9 .3 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Ascites secondruy to cirrhosis and requiiing 
medical intervention ( eg, dimetics or 
paracentesis) 
New Section 
Adjudicated cru·diovascular events include core 
MACE (cardiovasculru· death, nonfatal 
myocardial infru-ction, and nonfatal stroke) and 
expanded MACE (unstable angina re.quiring 
hospitalization, transient ischemic attack, 
peripheral or corona1y revascula1ization 
procedures hospitalization for congestive heart 
failme). Other events potentially related to 
adverse cardiovascular outcomes are defined in 
Appendix D and will be included in the 
Cru·diovascular Ad"udication Committee CAC 
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Revise,d Text (Version 11.0, 04 May 2021) 
16.9.2. Hepatic and Renal Safety Adjudication 
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Section added to 
reflect additional 
Potential eYents of hepatic injury and AKI will 
adjudication 
be adjudicated during the study (Section 16.11). 
committees. 
The adjudication of the events of hepatic injury 
will be separate from the adjudication of events 
for assessment of the primru1' outcomes endpoint 
in this study. The adjudication of potential 
events of hepatic injm1' and AKI will be further 
defined in the HSAC charter and the Renal 
Adjudication Committee charter, respectively. 
Adjudicated cardiovasculru· events include core 
MACE (cardiovascular death, nonfatal myocardial 
infru-ction, and nonfatal stroke) and expanded 
MACE (m1stable angina requiring hospitalization, 
transient ischemic attack peripheral or coronruy 
revascularization procedures, hospitalization for 
congestive bea1t failme and arrhythmias). Any 
hospitalization (Ѹ24 hours) where a cause has not 
been identified by the Investigator will be treated 
as a cardiovascular event and sent for 
ad·udication. Other events otentiall related to 
Definition of CV 
events for adjudication 
was updated to be 
consistent with the 
criteria defined in the 
CAC charter. 


Protocol 747-303 
Section 
Section 16.10 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Chaiter for adjudication. The adjudication of 
these events will be handled sepai·ately from the 
adjudication of events for assessment of the 
prima1y endpoint in this study (See Section 
16.11). Undetemlined cause of death will be 
classified as a cardiovascular death by the CAC. 
The time-to-event endpoints include: 
Tue DMC will meet approximately qUaJ.terly at 
scheduled meetings and ad hoc meetings will be 
convened, as approp1iate, to review safety and 
efficacy data as well as the adjudication 
assessments from the Ӹ adjudication committees 
listed in Section 16 .11. Based on review of these 
data, the DMC will advise the Sponsor on the 
validity and scientific merit of continuing the 
sh1dy. 
Written minutes of both the open and closed 
DMC sessions will be prepared. The closed 
minutes will be made available to the appointed 
Sponsor representatives only after the database is 
locked. 
Data. listings ti1·0¥icfod te thti DMC de aet ceataia 
inciiv:idual sӹtict tniatmSBt infeHBat;iea; 
hew@¥er, th@ DMC wiU ha•rti access te the 
,I 
_1., ______ ,1 ---· 
, .. 1..1· 
,l : .. ..1: .. :,1 .• _1 
_,_" 
_.._ ..l-+-
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
adverse cardiovascular outcomes are defined in 
Appendix D and will be included in the 
Cardiovascular Adjudication Committee (CAC) 
Charter for adjudication. The adjudication of these 
events will be handled separately from tl1e 
adjudication of events fm assessment of the p1ima1.y 
endpoint in this su1dy (See Section 16.11). 
Undete1mined cause of death will be classified as a 
cardiovascular death by the CAC. 
Tue time-to-event endpoints include: 
•
Time from randomization to the first
occurrence of anhythmia
The DMC will meet approximately quruterly at 
scheduled meetings and ad hoc meetings will be 
convened, as appropriate, to review safety and 
efficacy data as well as the adjudication assessments 
from the 4 adjudication committees listed in Section 
16.11. 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 prepai·ed. The closed minutes will 
be made available to the appointed Sponsor 
representatives only after the database is locked. 
Summa1y tables reviewed by the DMC during 
dosed sessions will be unblinded and include an 
overall column contailling inf01mation regai·ding all 
subjects and separate treatment columns with fake 
labels, ie, the actual treatment groups ai·e used, but 
are not identified. Data reviewed during the 
Version 11.0: 04May2021 
Page 304 
Key Change 
Reasons/ 
Justification fol' 
Change 
DMC responsibilities 
expanded to include 
review of aggregate 
analyses for all 
adjudication 
committees. 


Protocol 747-303 
Section 
Synopsis, 
Section 16.11 
Original Text (Version 10.0, 03 Feb 2020) 
as apprnpriat@. Summruy tables reviewed by the 
DMC dming closed sessions will include an 
overall column containing information regru·di.ng 
all subjects and sepru·ate treatment columns with 
fake labels, ie, tl1e actual treatment groups are 
used, but are not identified. Data reviewed 
dming tl1e meetings will include, at a minimum, 
disposition, demographics, exposme, clinical 
laboratmy results, MedDRA coded AEs, and 
AEs leading to eru·ly withdrawal of 
investigational product. At each meeting, 
detailed nanatives of inte1val SAEs (including 
events resulting in death) ru·e reviewed by the 
DMC in addition to a cumulative list of all SAEs. 
All s:asp@ct@e liver-related clinical outcomes aH4 
MACE that occm 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 ־ committees and 
event types tl1ey are responsible for adjudicating 
are as follows: 
•
CAC: Adjudicates all suspected MACE,
including all deaths
•
Hepatic Outcomes Committee: Adjudicates
all deaths and s:asp@ct@e liver-related clinical
outcomes
Each adjudication committee will have a chruter 
that documents the repmting of events by tl1e 
study site, definition of the susp@ct.sa events to 
be adjudicated, suoolv of source documentation 
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
meetings will include, at a minimum, disposition, 
demographics, exposure clinical laboratmy results, 
MedDRA coded AEs, and AEs leading to early 
withdrnwal 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 hor as appropriate. 
All potential liver-related clinical outcomes, and 
potential events of hepatic injury, AKI, MACE, 
and hospitalizations (depending on the cause) 
that occur after administrntion of the first dose of 
investigational prnduct 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: 
•
CAC: 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
including clinical events and histological findings
that are suspected as progression to liver
cinhosis
Version 11.0: 04May2021 
Pacae 305 
Key Change 
Reasons/ 
Justification for 
Change 
Section updated to 
reflect initiation of 
renal and hepatic 
injwy adjudication 
committees. 
Clarification added to 
CAC and Hepatic 
Outcomes Committee 
to more accurately 
define events that are 
being sent for 
adjudication per the 
chatter. 
Clarification added to 
confirm no protected 
health information will 
be provided to the 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
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 procedmes of the 
committee. 
Specific details of the events that will be 
adjudicated by the CAC, {H½Q Hepatic Outcomes 
Committee are desc1ibed in the respective 
adjudication chatters. Any changes to either the 
adjudication process or changes to specific 
events to be adjudicated will be addressed in the 
chatters and will be colllIIlunicated to all study 
sites outside of a protocol amendment. 
. . .
The adjudication of suspsctsd events will be 
based on available source documentation, 
including but not limited to individual clinical 
study data, hospital records, histology, discharge 
sulllIIlaries, atH1/or death ce1tificates. Tue 
adjudication committees will not receive any 
individual subject treatment or site-specific 
infonnation. 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 regulato1y requirements, 
including the archiving of essential documents. 
Histological progression to ciIThosis will be 
detennined by central reading of liver biopsies. 
A biopsy evaluation fo1m signed by one of the 
study-specific central ::-Ո'-Չ1-- :-=-=--- will be 
Confidential and Proprieta1y 
Revise,d Text (Version 11.0, 04 May 2021) 
. 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, 
rep01ting of the final assessment, and the working 
procedures of the committee. 
Specific details of the events that will be adjudicated 
by the CAC, Hepatic Outcomes Committee, HSAC, 
and Renal Adjudication Committee are described 
in the respective adjudication chatters. Any chat1ges 
to either the adjudication process or changes to 
specific events to be adjudicated will be addressed 
in the charters at1d will be communicated to all 
study sites outside of a protocol amendment. 
... 
The adjudication of potential events will be based 
on available source documentation, including but 
not linuted to individual clinical study data, hospital 
records, histology, discharge summaries, anc1/or 
death ceitificates. The adjudication committees will 
not receive any individual subject treatment or site-
specific infonnation. All protected health 
information will remain confidential and will not 
be available to the adjudication committee. The 
assessment of events will be conducted in 
Version 11.0: 04May2021 
Pacae 306 
Key Change 
Reasons/ 
Justification fol' 
Chamte 
adjudication 
committees. 


Protocol 747-303 
Section 
Original Text (Version 10.0, 03 Feb 2020) 
necessaiy to confirm histological progression to 
cinhosis. This cliaical outcom@ @adf>oiBt will 
џ adjudicated by the Hepatic Outcomes 
Committee but 11,iill e@ iaclHa@Ei iH th@ 
aѠuaicat@Ei h@patic cliaical outcomes t11r@Hts. 
Appendix A 
This guidance summarizes recommendations for 
the management of LDL cholesterol based on the 
ACC/AHA ѡ Guideline on the Tf@atm@at of 
IUooa Ghol@st@rnl to R@auc@ ,A_th@rnscl@rntic 
G1H·aio1,1ascula:F &isk iH Adults ER,ay ѢQl 41 and 
the European Gaia@lia@s oa Ga:Faio1rascula:F 
Dis@as@ Pr€¥@Htioa iH Glinical Practic@ (P@1·k 
J-
Confidential and Proprieta1y 
Revise.d Text (Version 11.0, 04 May 2021) 
compliance with study-specific procedmes, 
manuals, GCP, and all other applicable regulat01y 
requirements, including the ai·chiving of essential 
documents. 
Histological progression to cinhosis will be 
detemlined by central reading of liver biopsies. A 
biopsy evaluation fo1m signed by one of the study-
specific central pathologists will be necessa1y to 
confum llistological progression to cinhosis. 
Clinical events and histological findings of 
potential disease progression to cirrhosis will be 
adjudicated by the Hepatic Outcomes Committee. 
The end of study primary efficacy endpoints of 
clinical composite outcome events are descl'ibed 
in Section 16.4.1. 
This guidance summarizes recommendations for the 
management of LDL cholesterol based on the 
ACC/AHA 2019 Guideline on the Primai-y 
Prevention of Cardiovascular Disease (Arnett 
2019) and the European Guidelines for the 
Management of Dyslipidaemias: Lipid 
Modification to Reduce Cardiovascular Risk 
(Mach 2020). 
References: 
Arnett DK, Blumenthal RS, Albert MA, et al. 
2019 ACC/AHA Guideline on the Primai·y 
Prevention of Ca1·diovascular Disease: A Report 
of the Amelican College of Cardiology/American 
Hea11 Association Task Force on Clinical 
Version 11.0: 04May2021 
Page 307 
Key Change 
Reasons/ 
Justification for 
Change 
Appendix was 
reviewed and 
updated based on 
more recent US and 
Emopean 
guidelines. 


Protocol 747-303 
Section 
Appendix B 
AppendixC 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
Revise.d Text (Version 11.0, 04 May 2021) 
Practice Guidelines. Circulation. 2019 
Sep;140(11):e596-e646. 
Mach F, Baigrnt C, Catapano AL, rt 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 Eurnpean 
Society of Cardiology (ESC) and European 
Atherosclerosis Society (EAS). European Heart 
Journal. 2020 Jan;41(1):111-88. 
New Appendix. 
Version 11.0: 04May2021 
Page 308 
Key Change 
Reasons/ 
Justification fol' 
Change 
Inclusion of management of hyperglycemia appendix as a guidance to Investigators on the appropriate therapy be cun-ent 
guidelines. 
Reference: 
Buse JB, Wexle1· DJ, Tsapas A, et al. 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Repol't 
by the American Diabetes Association (ADA) and the European Association for· the Study of Diabetes (EASD). Diabetes Care. 2020 
Feb;43(2) :487-93. 
EDUCATION AND ASSESSMENT OF 
SIGNS/SYMPTOMS OF IrnPl • .TIC INJURY 
,΍,'QR: :ggcGi<IPΎSA'.J:±Gflii: 
SHl:>j@ct gducatieH: 
Subjects should be educated eH Ώ@ sigHs aHd 
sΐtems ef hepatie i:ajm:y aHd d@eemp@Hsatiea 
,,1,IHel½ El£@ hsΑ@e s@le,.-,,. Βi!f ΓleBΔ Hl, SH8ji!EΕ5 
detsnniB@El te b@ at IHgh@I 1isk ef prngnssiea er 
d@Eemp@asatiea ia th@ jHdgm@Ht ef th@ 
lffi•esΖgttl:er fflBJ' se H1:eHtterea fef sij;fts ttaa 
sΗΘems ef sasp@et@a hepatie i:ajm:y 01· 
EDUCATION AND ASSESSMENT OF 
Appendix C updated 
SIGNS/SYMPTOMS OF INTERCURRENT 
to consolidate 
ILLNESS AND/OR POTENTIAL ADVERSE 
education and 
EVENTS AT EACH STUDY VISIT 
assessments for 
Subjects should be educated to understand and 
interctment illness
that have been added
recognize the signs and symptoms of intercurrent 
to the protocol into 
illnesses and/01· potential adverse events listed 
one location for ease 
below. Investigators should instrurt subjects to 
of use for the 
seek immediate medical attention if they 
experience any of these signs or symptoms. 
Investigator. 
Confidential and Proprieta1y 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
El@EemfHiasatiea me1·@ fl:@ɢ@atJy ɣaB: @11@fj' a 
EBeatJ¼s Eas fl:@ɤɥdy as H@@EI@ɦ p@1· aisEntiea 
ef th@ lEP1@stiga-ter aaEI UflSH aisrnssiea with th@ 
M@EliEaJ MeHitor. 
gigHS aB:EI gɧtmptoms ofIIɨaEiE Iaj:ary 01· 
Q@EOffifH!HSatioa: 
I 
g13 @EiiiE siges aaEi sɩtmptoHl:5 of l:ill@r 
iHlpairm@Ht: y@Uewiag of Hi@ skiH er ID@ w-kit@s 
of ɪ'@5, pal@ eolor@Ei steals, :arm@ Eolo1: Ehaeg@ 
from paJ@ to Ei@ɫ ame@J.· [ciark] (rdl@etiag 
impai1·@Ei silifHeiB m@ta.so1ism1 
I 
Mer@ g@a@J.·aJ siges aaEi SYffiptoms of asEit@s 
BBQ @HEi!f!B8IOf18ID,-: eoti4tisioH, sweHiag of lit@ 
l@gs 01· asEiem@H 
I 
Noa sp@Eitie siges aaEI symptoms of 
impB:ifeti health: aaHSea, •reffl:iɬ, abtieffl:iaal 
paiB, dianh@a, 1.night loss, rel/@J.' aHEI Ehills, 
wors@aiag or H@W fatigu@, w@akH@ss, less of 
apf)et=iJe 
I 
gigeiHEaHt iBt@l'EHH·@J.lt illH@ss@s R½Eh as 
gasti:o@at€ritis may ɭaE@dɮat@ h@patiE iaj:Yry 01· 
El@Eomp@asatioe E@g, @staslish@EI s@11@r@ 
asEloHHB:al paia, vemitiag, and aiauh@a fur EBor@ 
ffiaH 4 Ela;i:51 aHEI shoHlEI s@ aa iBaiEatioa fu1· 
p1·0mpt- iw1@st.igatioaal fl'OGYEt-iBt@ffUf)tiea aHe 
eemplete stibjeet e•ralHfttteB 
GID@r gymptoEBs: 
I 
Vlors@HiBg er a@v.r pHHims 
I 
W01·s@aiag ofrnaal fuaEtioa or li:k:@ly 
El@hyElratioa 
Confidential and Proprieta1y 
Revise.d Text (Vel'sion 11.0, 04 May 2021) 
At each visit, study site staff shouJd 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 
Sii!!s and Svml!toms 
Cholelithiasis 
•
Upper abdominal pain
(P1·otocol Section 
01· tenderness
7.5.1) 
(particnlal'ly post-
prandial), abdominal 
swelling, nansea, 
vomiting, 01· fever
Acute 
•
Symptoms of these
cholecystitis, or 
events may be similar to
Acute 
symptomatic
pancreatitis 
cholelithiasis (see Section 
(Protocol Section 
7.5.1) 
7.5.2) 
•
Significant upper
abdominal pain with 
nausea, vomiting, or
fever, janndice 
Hype1·glycemia 
•
Polyul'ia, polydipsia, 
polwhae:ia. blnl'l'ed
Version 11.0: 04May2021 
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Key Change 
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Justification fol' 
Change 


Protocol 747-303 
Section 
Original Text (Vel'sion 10.0, 03 Feb 2020) 
IBt@H,HH@Bt nlB@55: 
1B tJaftieH:lB:f, iBt@m:HnBt: illa@ss@s saeh as 
gasl:fS@Bt@Fies HJ:ay @̖̕ae@d̗at;@ h@flal;lE H½JffiJ• 01· 
S@€9H¼f3@R50:liee E@g, @staelish@a 5@1,•@f@ 
aeaeffi:H¼aJ flaiB, 1,•SHHtmg, 0:RS,'Sf aiafffi@a fEn· 
HJ:ot·e dtea 1 0£1)'5) RBEl seoula be RB iBElieetioa :for 
fl£9H¼f3t amg mt@HaptiS:B 0:RQ ESH¼f3l@t@ sabj@Et 
@¥alaatiea. 
£abj@et Ass@ssm@Bt: 
i"A @aeh 11isit, staEl;' sit@ staff sheala il½Ef..¾H@ if th@ 
s:¾bj@et has E:i@¥@lsfl@S BB;' sf th@ aee¥@ siges aeEl 
s̘tems, 1·@e@i1,•@a a̙1 B@li\1 E:ifag flt·@sHifltieBS, 
Elf!,,• Beli\l oi,ier (;He EOffBt@r HteEHERtioes Of eerbei 
s:¾J)fll@m@ats frnm h@altll ea:r@ fllWriEl@fs (HCP&), 
Sf ha.El BBY labefatery flt·ee@Elm,@s 01· ass@ss1H@Bts 
f)er:forffl.ed by ae HCP. 
PesitPr@ f@5flSBs@s ts ̚, B@l,lf sf 1,-.,e1·s@RiBg 
s̛teffis ameeg thes@ list@a aee1;@ sheulEl 
selieit :foUew Hfl Elff@StieBs. Fel-lew :¾fl E1ff@stiem 
H1:a,1 melff a@ fHrtli:@1· Elff@stieBS ea E:iaf·atiee sf 
@̜!:fl@Fi@eeiBg th@ s,lffifltSffi, asseeiat@a siges aea 
symfltSffiS, 1,1ffi@th@r this is B@w Sf 1,11e1·s@BiBg 
frnm fll·@11ieas @̝@1·i@BE@ Sf eth@r E1ff@stieBS as 
aflfll"Sflfiat@. £em@ @*0:H¼f3l@s am tJrn¥iEl@a e@le:w. 
Follow up Questions for Positive Response to 
Signs/Symptoms of Hepatic Injwy or 
Decompensation 
. . .
5.
Example 5: If subject has noticed feeling
dehydrated or is not urinating as often as usual,
follow up question may include:
Confidential and Proprieta1y 
Revise.d Text (Vel'sion 11.0, 04 May 2021) 
(Protocol Section 
,ision, fatigue and 
9.3.4) 
headaches 
Renal 
•
New onset 
Impafrment 
fatigue/asthenia, nausea,
(P1·otocol Section 
7.6.1) 
01· confusion and to
assess signs such as 
decl'eased skin turgor 
(dehydration), inc1·eased
heart 1·ate, lower
exh·emity edema, 
decreased mine output
01· dark urine 
N ephrolitbiasis 
•
Evidence ofhematuria,
(Protocol Section 
flank or lower 
7.6.2) 
abdominal pain, nausea, 
vomiting, feve1·, or chills 
Hepatic Injm1' 
•
Specific signs and 
aud/or 
symptoms of liver
decompeusation 
impairment: yellowing
(Protocol Section 
7.4) 
of the skin or the whites 
of eyes, pale-colored
stools, Ul'ine color c.hange
Questions to ask 
from pale to deep ambe1·
subjects a1·e listed 
[dark])
below 
•
Mo1·e genet·al signs and 
svmptoms of ascites ancl
Version 11.0: 04May2021 
Page 310 
Key Change 
Reasons/ 
Justification fol' 
Change 


Protocol 747-303 
Section 
Original Text (Version 10.0, 03 Feb 2020) 
a.
Are you excessively thirsty?
Confidential and Proprieta1y 
Revised Text (Version 11.0, 04 May 2021) 
encephaJopathy: 
swelling of the legs 01· 
abdomen, confusion or 
abrupt abnormal 
behavio1· 
•
on-spedfic signs and 
symptoms of impail'ed 
health: nausea,
vomiting, abdominal
pain, diarrhea, weight
loss, fever and chills,
worsening or new
fatigue, weakness, loss of
appetite 
•
Significant inte1·cwTent
illnesses such as
gastl'Oenteritis may
exacerbate hepatic injury 
or decompensation (eg, 
established severe
abdominal pain,
vomiting, and diarrhea)
and should be an 
indication for pl'Ompt 
investigational product
intel'l'uption and 
complete subject 
evaluation
Version 11.0: 04May2021 
Page 311 
Key Change 
Reasons/ 
Justification for 
Change 


Protocol 747-303 
Section 
Original Text (Version 10.0, 03 Feb 2020) 
soc 
Removal of all previous SOCs 
Revised Text (Version 11.0, 04 May 2021) 
Other Symptoms: 
• 
\Vorsening or new
prudtus
•
Decreased urine output, 
dizziness, 01· lethargy 
5.
Example 5: If subject has noticed feeling
dehydrated or is not minating as often as usual,
follow up question may include:
a.
Are you excessively thiisty?
b.
Are you fet>ling dizzy or lethargic and weak?
Moving fo,ward only the most recent SOC ,viii be included in the protocol. 
Confidential and Proprieta1y 
Version 11.0: 04May2021 
Page 312 
Key Change 
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Justification for 
Change 

SAP_001.pdf: 
Intercept J 
Statistical Analysis Plan for Protocol 747-303 
A Phase 3, Double-Blind, Randomized, Long-Term, Placebo-Controlled, 
Multicenter Study Evaluating the Safety and Efficacy of Obeticholic Acid in 
Subjects with Nonalcoholic Steatohepatitis 
The REGENERATE Study 
RandomizEd Global Phase 3 Study to Evaluate the Impact on NASH with 
FibRosis of Obeticholic Acid Ireatm,Ent 
OBETICHOLIC ACID (OCA) 
Protocol Version and Date: 
11.0: 04 May 2021 
Phase: 
Phase 3 
Methodology: 
Double-Blind, Randomized, Placebo-Controlled Study 
Sponsor: 
Intercept Phaimaceuticals, Inc. 
305 Madison A venue 
MoITistown, NJ 07960 
Sponsor Representative: 
Analysis Plan Date: 
Analysis Plan Version: 
Tel: 
646-747-1000 
Fax: 
858-558-5961 
31 Janmuy 2023 
2.0 
CONFIDENTIAL 
The infonnation contained herein is the property of Intercept Phannaceuticals, Inc. and may not be 
reproduced, published, or disclosed to others without written authorization of Intercept Phannaceuticals, Inc. 
NCT Number: NCT02548351
This NCT number has been applied to the document for purposes of posting on Clinicaltrials.gov


Statistical Analysis Plan 
Protocol 747-303 
APPROVALS: 
Authored by: 
MD,MPH,PhD 
, Biostatistics 
Intercept Pha1maceuticals, Inc. 
B iostatistician 
Intercept Phaimaceuticals, Inc. 
Approved by: 
,PhD 
, Biostatistics & Data Management 
aimaceuticals, Inc. 
, Clinical Development 
Intercept Phaimaceuticals, Inc. 
, Regulat01y Affairs 
Intercept Phaimaceuticals, Inc. 
Confidential and Proprietary 
Date 
Date 
Date 
Date 
Date 
3lJan2023 
Pa_g;e2 


Statistical Analysis Plan 
 31Jan2023
Protocol 747-303 
Page 3
Confidential and Proprietary 
TABLE OF CONTENTS 
APPROVALS: .................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................8 
1.
INTRODUCTION ......................................................................................................12 
2.
INFORMATION FROM THE STUDY PROTOCOL ...............................................12 
2.1. 
Study Objectives .........................................................................................................12 
2.1.1. 
Month 18 Interim Analysis .........................................................................................12 
2.1.1.1. 
Primary Objective Assessed at 18 Months .................................................................12 
2.1.1.2. 
Secondary Objectives Assessed at 18 Months ............................................................13 
2.1.2. 
End of Study Analysis: ...............................................................................................14 
2.1.2.1. 
Primary Objective Assessed at End of Study .............................................................14 
2.1.2.2. 
Secondary Objectives Assessed at End of Study ........................................................14 
2.1.2.4. 
Safety Objectives Assessed at End of Study ..............................................................15 
2.2. 
Study Design ...............................................................................................................16 
2.2.1. 
Overall Study Design ..................................................................................................16 
2.2.2. 
Study Design Diagram ................................................................................................17 
2.2.3. 
Randomization Methodology .....................................................................................17 
2.2.4. 
Monitoring Guidelines and Unblinding ......................................................................18 
2.3. 
Study Endpoints ..........................................................................................................18 
2.3.1. 
Efficacy Analysis at Month 18 Interim Analysis .......................................................18 
2.3.1.1. 
Primary Efficacy Endpoints ........................................................................................18 
2.3.1.2. 
Secondary Efficacy Endpoints ....................................................................................19 
2.3.2. 
Efficacy Analysis at End of Study ..............................................................................21 
2.3.2.1. 
End of Study Primary Estimands and Efficacy Endpoints .........................................21 
2.3.2.2. 
Secondary Efficacy Endpoints ....................................................................................22 


Statistical Analysis Plan 
 31Jan2023
Protocol 747-303 
Page 4
Confidential and Proprietary 
2.4. 
Safety Evaluations at Month 18 and End of Study .....................................................24 
3.1. 
Sample Size for Clinical Outcomes Composite Endpoint ..........................................24 
3.2. 
Interim Analyses of Clinical Outcomes Post Month 18 Interim Analysis .................25 
3.3. 
Sample Size for Month 18 Interim Analysis ..............................................................26 
3.4. 
Analysis Populations ..................................................................................................27 
3.4.1. 
Month 18 Interim Analysis Populations .....................................................................27 
3.4.2. 
End of Study Analysis Populations ............................................................................28 
4.
GENERAL STATISTICAL METHODS ...................................................................29 
4.1. 
Computing Environment ............................................................................................30 
4.2. 
Baseline Definitions ....................................................................................................30 
4.3. 
Visit Windows ............................................................................................................31 
4.4. 
Examination of Subgroups .........................................................................................31 
5.
STUDY POPULATION .............................................................................................33 
5.1. 
Subject Disposition .....................................................................................................33 
5.2. 
Demographics and Baseline Characteristics ...............................................................33 
5.3. 
Baseline NASH Disease Characteristics ....................................................................35 
5.4. 
Medical and Cardiovascular Medical History ............................................................35 
5.5. 
Protocol Deviations ....................................................................................................36 
5.6. 
Impact of COVID-19 Pandemic .................................................................................36 
6.
EFFICACY ANALYSES ...........................................................................................36 
6.1. 
Adjustments for Covariates ........................................................................................36 
6.2. 
Handling of Subject Discontinuations and Missing Data ...........................................37 
6.2.1. 
Quantitative Endpoints ...............................................................................................37 
6.2.2. 
Responder Endpoints ..................................................................................................37 
6.2.3. 
Sensitivity Analyses ....................................................................................................38 
6.3. 
Control of Type I Error ...............................................................................................39 
6.3.1. 
Histological Primary Endpoints: .................................................................................39 
6.3.2. 
End of Study Primary Endpoints: ...............................................................................41 
6.4. 
Interim Analyses and Data Monitoring ......................................................................42 
6.4.1. 
Interim Analysis of Clinical Outcomes ......................................................................42 
6.4.2. 
Data and Safety Monitoring Committee .....................................................................42 


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6.4.3. 
Adjudication Committees ...........................................................................................43 
6.4.4. 
Primary Efficacy Analysis ..........................................................................................44 
6.4.4.1. 
Primary Efficacy Analysis at Month 18 .....................................................................44 
6.4.4.2. 
Primary Efficacy Analysis at End of Study ................................................................45 
6.4.5. 
Secondary Efficacy Analyses at Month 18 and End of Study ....................................46 
6.4.6.10. 
Change from Baseline in MELD ................................................................................49 
6.4.7. 
End of Study Time to Event Analyses ........................................................................50 
6.4.7.1. 
Time to Each Component of the Clinical Outcome Endpoint ....................................50 
10.
SAFETY ANALYSES ...............................................................................................56 
10.1. 
Extent of Exposure .....................................................................................................56 
10.2. 
Prior and New Concomitant Medications ...................................................................57 


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10.3. 
Adverse Events ...........................................................................................................58 
10.4. 
Adverse Events of Special Interest .............................................................................60 
10.4.1. 
Pruritus ........................................................................................................................61 
10.4.2. 
Hepatic Safety Analysis ..............................................................................................62 
10.4.3. 
Dyslipidemia ...............................................................................................................64 
10.4.4. 
Gallbladder Disease and Related Complications ........................................................64 
10.4.5. 
Pancreatitis ..................................................................................................................65 
10.4.6. 
Renal Injury ................................................................................................................65 
10.4.7. 
Urolithiases .................................................................................................................66 
10.4.8. 
Hyperglycaemia/New Onset Diabetes Mellitus ..........................................................66 
10.4.9. 
Cardiovascular Risk ....................................................................................................67 
10.4.9.1. 
Adjudicated Cardiovascular Events ............................................................................67 
10.4.9.2. 
Cardiovascular Adverse Events ..................................................................................68 
10.4.9.4. 
Serum Chemistry Lipids .............................................................................................69 
10.5. 
Clinical Laboratory Evaluations .................................................................................69 
10.5.1. 
Serum Chemistry, Hematology, and Coagulation ......................................................70 
10.5.2. 
Shifts in CTCAE Toxicity Grade ...............................................................................70 
10.5.3. 
Urine Chemistry and Urinalysis .................................................................................70 
10.5.4. 
Liver Laboratory Criteria for Monitoring for Suspected Hepatic Injury or 
Decompensation .........................................................................................................70 
10.5.5. 
Lipoprotein Evaluations ..............................................................................................72 
10.5.6. 
Renal Function Evaluations ........................................................................................73 
10.6. 
Pregnancies .................................................................................................................74 
10.7. 
Vital Signs ..................................................................................................................74 
10.8. 
Electrocardiograms .....................................................................................................74 
11.
CHANGES TO PLANNED ANALYSES ..................................................................75 
12.
REFERENCES ...........................................................................................................77 
APPENDIX A. DATA CONVENTIONS AND STANDARD PROGRAMMING ...................78 
APPENDIX B. ANALYSIS WINDOWS ...................................................................................86 
APPENDIX C. PREFERRED TERMS TO IDENTIFY POTENTIAL KIDNEY 
INJURY .............................................................................................................88 


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APPENDIX D. LIVER LABORATORY CRITERIA FOR MONITORING FOR 
POTENTIAL HEPATIC INJURY ....................................................................90 
LIST OF TABLES 
Table 1: 
Estimands for Clinical Composite Outcome ..............................................................22 
Table 2: 
O’Brien-Fleming Boundaries .....................................................................................26 
Table 3: 
Analysis Populations for the Month 18 Interim Analysis and End of Study 
Analysis ......................................................................................................................29 
Table 4: 
End of Study Type 1 Error ..........................................................................................42 
Table 6: 
Bile Acid Totals and Individual Bile Acids with Molecular Weights ........................55 
Table 7: 
Stages of CKD ............................................................................................................74 
Table 8: 
Cutoffs of Albumin to Creatinine Ratio .....................................................................74 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................17 
Figure 2: 
Statistical Testing for the Month 18 Interim Analysis ................................................40 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
AESI 
adverse events of special interest 
AKI 
acute kidney injury 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
AUDIT 
Alcohol Use Disorders Identification Test 
BLQ 
below limit of quantitation 
BMI 
body mass index 
CEC 
clinical events committee 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRL 
Complete Response Letter 
CRP 
C-reactive protein
CRN 
Clinical Research Network 
CS 
clinically significant 
CSR 
clinical study report 
CV 
cardiovascular 
CV% 
coefficient of variation 
DAP 
Data Access Plan 
DCO 
Data cutoff Date 
DILI 
drug induced liver injury 
DMC 
Data Monitoring Committee 
DOB 
date of birth 
DOIC 
date of informed consent 
eCRF 
electronic case report form 


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Abbreviation 
Term 
EAIR 
Exposure adjusted incidence rate 
ECG 
electrocardiogram 
EDC 
Electronic Data Capture 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
FDA 
Food and Drug Administration 
FRS 
Framingham Risk Score 
GGT 
gamma-glutamyl transferase 
glyco-OCA 
glycine 6α-ethyl chenodeoxycholic acid 
HDL 
high density lipoprotein 
IA 
Interim analysis 
ICH 
International Conference on Harmonization 
IE 
Intercurrent Event 
in 
inches 
IgM 
immunoglobulin M 
IIEF-15 
International Index of Erectile Function-15 
INR 
international normalized ratio 
IQR 
interquartile range 
ITT 
Intent-to-Treat 
IWQoL-Lite 
Impact of Weight on Quality of Life-Lite 
IWRS 
interactive web response system 
kg 
kilogram 
KM 
Kaplan-Meier 
lb 
pounds 
LDL 
low density lipoprotein 
LLN 
lower limit of normal 
LS 
least-square 
MACE 
major adverse cardiovascular events 
MELD 
Model for End Stage Liver Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Term 
mITT 
modified Intent-to-Treat 
µmol 
micromole 
mg 
milligram 
MMRM 
mixed-effect repeated measures model 
MW 
molecular weight 
NAFLD 
nonalcoholic fatty liver disease 
NAS 
nonalcoholic fatty liver disease activity score 
NASH 
nonalcoholic steatohepatitis 
NCS 
not clinically significant 
NDA 
New Drug Application 
NEC 
Not Elsewhere Classified 
NFS 
nonalcoholic fatty liver disease fibrosis score 
ng 
nanogram 
OCA 
obeticholic acid 
PBC 
primary biliary cirrhosis 
PT 
preferred term 
QTcF 
QT interval corrected by the Fridericia’s formula 
RR 
time between 2 consecutive R waves 
SAE 
serious adverse event 
SD 
standard deviation 
SEM 
standard error of the mean 
SI 
standard international unit 
SMQ 
Standardized MedDRA Query 
SOC 
system organ classes 
TEAE 
treatment-emergent adverse event 
TNF-α 
tumor necrosis factor-alpha 


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Abbreviation 
Term 
TZD 
thiazolidinedione 
U/L 
units per liter 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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1.
INTRODUCTION
This document outlines the statistical methods to be implemented for the Month 18 Interim 
Analysis and End of Study Analysis of Study 747-303 (Phase 3 data collected within the scope 
of the Intercept Pharmaceuticals, Inc. [the Sponsor], sponsored protocol).  Access to unblinded 
analyses is specified in the data access plan (DAP) and Unblinding Plan (24 Mar 2022).  Any 
deviations from the methods specified in this Statistical Analysis Plan (SAP) will be documented 
in the clinical study report (CSR). 
On 26 Jun 2020, the Food and Drug Administration (FDA) issued a Complete Response Letter 
(CRL) to New Drug Application (NDA) 212833.  Resolution of deficiencies outlined in the CRL 
required additional histological and safety analyses, which are outlined in SAP Addendum V2.0 
(Dated 25 Apr 2022).  
It is important to note that all analyses following the CRL that were used to support a re-
submission are described in the SAP addendum dated 25 Apr 2022.  The Month 18 Interim 
Analyses that refer to sections in this document (Section 2.1.1, Section 2.3.1, Section 3.4.1) were 
done for the original NDA submission.  The updates in this SAP document are relevant to End of 
Study analyses.   
Key changes in this document compared to SAP V1.0 (dated 24 Jan 2019) are summarized in 
Section 11. 
2.
INFORMATION FROM THE STUDY PROTOCOL
2.1. 
Study Objectives
This section provides the study objectives at the Month 18 Interim Analysis and at the End of 
Study Analysis.  
2.1.1. 
Month 18 Interim Analysis 
2.1.1.1. 
Primary Objective Assessed at 18 Months 
To evaluate the effect of obeticholic acid (OCA) compared to placebo on histological 
improvement of nonalcoholic steatohepatitis (NASH) by assessing the following endpoints using 
NASH Clinical Research Network (CRN) scoring criteria: 
•
Improvement of fibrosis by at least 1 stage with no worsening of NASH (no
worsening of hepatocellular ballooning, no worsening of lobular inflammation and no
worsening of steatosis)
•
Resolution of NASH with no worsening of fibrosis
NASH resolution is defined as the overall histopathologic 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.  


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2.1.1.2. 
Secondary Objectives Assessed at 18 Months 
•
To evaluate the effect of OCA compared to placebo on histological improvement of
NASH by assessing the following using NASH CRN scoring criteria:
−
Improvement of fibrosis by at least 1 stage AND/OR resolution of NASH,
without worsening of either
−
No worsening of fibrosis AND no worsening of NASH
−
Progression to cirrhosis
−
Improvement of fibrosis by at least 2 stages
−
Improvement of each key histological feature of NASH by at least 1 point
(steatosis, lobular inflammation, and hepatocellular ballooning)
−
Improvement of NAS by at least 2 points with no worsening of fibrosis
−
Improvement of fibrosis and resolution of NASH as a composite endpoint and as
defined by both endpoints being met in the same subject
−
Resolution of fibrosis
•
To evaluate the effect of OCA compared to placebo on liver biochemistry and
markers of liver function


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−
Incidence of adjudicated cardiovascular events
−
Safety and tolerability (treatment-emergent adverse events (TEAEs),
electrocardiograms (ECG), vital signs, clinical laboratory assessments)
2.1.2. 
End of Study Analysis: 
2.1.2.1. 
Primary Objective Assessed at End of Study 
•
To evaluate the effect of OCA compared to placebo on all-cause mortality and
liver-related clinical outcomes as measured by the time from randomization to the
first occurrence of any of the following adjudicated events (clinical outcomes
composite endpoint):
−
Death (all cause)
−
Model of end stage liver disease (MELD) score ≥15
−
Liver transplant
−
Hospitalization (as defined by a stay of ≥24 hours) for onset of:
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)
−
Histological progression to cirrhosis
2.1.2.2. 
Secondary Objectives Assessed at End of Study 
•
To evaluate the effect of OCA compared to placebo on histological improvement of
NASH by assessing the following endpoints using NASH CRN scoring criteria:
−
Improvement of fibrosis by at least 1 stage with no worsening of NASH


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−
Resolution of NASH with no worsening of fibrosis
−
Improvement of fibrosis by at least 1 stage AND/OR resolution of NASH,
without worsening of either
−
No worsening of fibrosis AND no worsening of NASH
−
Improvement of fibrosis by at least 2 stages
−
Improvement of each key histological feature of NASH by at least 1 point
(steatosis, lobular inflammation, and hepatocellular ballooning)
−
Improvement of NAS by at least 2 points with no worsening of fibrosis
−
Improvement of fibrosis and resolution of NASH as a composite endpoint and as
defined by both endpoints being met in the same subject
−
Resolution of fibrosis
•
To evaluate the effect of OCA compared to placebo on liver biochemistry and
markers of liver function
2.1.2.4. 
Safety Objectives Assessed at End of Study 
•
To evaluate the effect of OCA compared to placebo on:
−
Incidence, exposure adjusted incidence rate and time to treatment-emergent
pruritus
−
Incidence, exposure adjusted incidence and time to adjudicated cardiovascular
events
−
Incidence and exposure adjusted incidence adjudicated acute kidney injury (AKI)


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−
Incidence, exposure adjusted incidence and time to adjudicated events of hepatic
injury
−
Long-term safety and tolerability (TEAEs, AESIs, ECGs, vital signs, clinical
laboratory assessments)
2.2. 
Study Design 
2.2.1. 
Overall Study Design 
This Phase 3, double-blind, randomized, long-term, placebo-controlled, multicenter international 
study will evaluate the effect of OCA on histological improvements of NASH, all-cause 
mortality, and liver-related clinical outcomes.  According to the original design, the study will 
enroll approximately 2370 subjects with NASH.  The population will comprise approximately 
2085 subjects with biopsy-confirmed, precirrhotic NASH and evidence of liver fibrosis, 
including approximately 60% with fibrosis stage 3 and 40% with fibrosis stage 2.  An additional 
cohort of approximately 285 subjects with fibrosis stage 1, and at least 1 accompanying 
comorbidity, will also be enrolled to gather information on the safety of OCA and progression of 
liver disease in this population as detailed in this document.  A planned interim analysis (Month 
18 Interim Analysis) will be performed after a minimum of 750 randomized subjects (the first 
sequential) with fibrosis stage 2 or stage 3 would have reached their actual/planned Month 18 
Visit (including subjects who discontinued before reaching the planned Month 18 Visit). 
Following the Month 18 Interim Analysis, the study will be continued in a blinded fashion, and 
subjects will be followed over an extended period for clinical outcomes to confirm clinical 
benefit as part of the End of Study Analysis.  The End of Study Analysis will evaluate the effect 
of OCA on mortality and liver-related clinical outcomes, as well as the long-term safety of OCA 
as described in the protocol after accrual of approximately 288 adjudicated clinical outcome 
composite events combined in the OCA 25 mg and placebo groups for subjects with fibrosis 
stage 2 or stage 3 based on the group sequential design with one Interim Analysis at 66% of 
information fraction.  The sample size required for the updated analysis can be found in 
Section 3.1. 
Subjects will be screened for a period of up to 12 weeks before entering the study.  
Approximately 2480 subjects with NASH who meet all eligibility criteria will be randomized to 
receive OCA 10 mg, OCA 25 mg, or matching placebo in a 1:1:1 ratio for the duration of the 
study, in conjunction with local standard of care.  Randomization of subjects with fibrosis 
stage 2 or stage 3 will be stratified by presence of diabetes at enrollment [yes/no] and use of 
thiazolidinediones (TZDs) or vitamin E at baseline [yes/no].  Biopsy-confirmed NASH will be 
determined by central reading of liver histology at Screening, and all subsequent histology 
assessments will be performed centrally in a blinded fashion.  At Month 18 or early termination, 
biopsy slides will be paired-read with the screening biopsy in a blinded fashion to minimize 
temporal bias of the Month 18 biopsy read.  
Following Month 18 visits, clinical visits will occur every 6 months for the remaining duration of 
the study.  For any subject who develops an AE of hepatic injury or decompensation, or if 
cirrhosis is suspected based on criteria other than liver biopsy or clinical outcomes, a liver biopsy 
is recommended and will be read using Consensus Method except that in a case where a biopsy 


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was already obtained within 6 months of the suspected liver injury or decompensation event.  All 
deaths and potential liver-related clinical outcomes including clinical events and histological 
findings of potential disease progression to cirrhosis adjudicated by independent Hepatic 
Outcome Committee will be used for the End of Study analysis. 
Investigational product (ie, OCA or placebo) will be taken orally, with water, once daily.  
Subject safety and laboratory assessments will be evaluated at clinical visits as detailed in the 
protocol.   
With the exception of liver transplant, if a subject experiences a suspected or confirmed clinical 
outcome event, he or she should continue the regular visit schedule and continue taking 
investigational product as long as none of the criteria for discontinuation outlined in the protocol 
have been met.  Subjects who discontinue investigational product due to Investigator or Sponsor 
decision are expected to be followed through to study closure (or at the discretion of the 
Sponsor).   
Details of study procedures and assessments are described in the protocol. 
2.2.2. 
Study Design Diagram 
Figure 1: 
Study Design Schematic 
EOS = End of study; OCA=obeticholic acid 
▲Biopsy (Subjects without a liver biopsy performed within 6 months before Day 1 will have a biopsy at the second
Screening Visit).
* Number of hepatic clinical outcomes adjudicated events accrued in placebo and OCA 25 mg groups combined
with one Interim Analysis at 66% of information fraction.
2.2.3. 
Randomization Methodology 
This study will be conducted in a double-blind, placebo-controlled manner.  Subjects will be 
randomized 1:1:1 to placebo, OCA 10 mg, or OCA 25 mg.  Randomization will be stratified by 
presence of diabetes at enrollment [yes/no] and use of TZDs or vitamin E at baseline [yes/no].  


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The randomization will be based on a predefined randomization code (generated by the Sponsor 
or designee) using an interactive web response system (IWRS), which the Sponsor intends will 
serve as a computer-based subject registration system at Screening and Day 1.  The IWRS will 
serve as an investigational product inventory and management system and may be integrated 
with the study database.  
The Investigator or designee will be required to register the subject in the IWRS and may be 
prompted to provide subject data necessary to properly randomize and allocate the subject to 
treatment.  A randomization number will be assigned and investigational product dispensing 
information (ie, bottle number[s]) will be provided.   
2.2.4. 
Monitoring Guidelines and Unblinding 
Once enrolled, subjects will be monitored closely by reviewing their AEs, signs and symptoms, 
and laboratory values especially for potential hepatic injury and/or decompensation, pruritus, 
gallstone disease, symptomatic cholelithiasis and/or cholecystitis or pancreatitis, renal 
impairment and nephrolithiasis.  Dosages for investigational product should be maintained 
consistent with the protocol during for the duration of the study.  Any dose adjustments, 
interruptions, discontinuation, and any rechallenge of investigational product should be 
implemented per the criteria outlined in the protocol based on safety or tolerability concerns (see 
Appendix D).  
Subjects that discontinue investigational product are expected to continue in the study until study 
termination, and the study will only terminate at the time when the required number of 
adjudicated events has accrued (Section 3).   
Subjects who discontinue investigational product are expected to continue in the study and 
complete all scheduled study visits and assessments and are to be followed for the occurrence of 
outcome (hepatic) events.  
The study will be conducted in a blinded manner with the exception a selected group of 
individuals who are unblinded for the Month 18 Interim Analysis as described in the DAP and 
Unblinding Plan.  After the End of Study database lock, the study data will be completely 
unblinded. 
2.3. 
Study Endpoints 
2.3.1. 
Efficacy Analysis at Month 18 Interim Analysis 
2.3.1.1. 
Primary Efficacy Endpoints 
The primary efficacy analysis for the Month 18 Interim Analysis will compare subjects treated 
with OCA (10 mg and 25 mg) versus placebo on histological improvement of nonalcoholic 
steatohepatitis (NASH) by assessing both of the following using NASH Clinical Research 
Network (CRN) scoring criteria: 
•
The percentage of subjects with improvement of fibrosis by 1 stage or more, no
worsening of hepatocellular ballooning, no worsening of lobular inflammation, and
no worsening of steatosis


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•
The percentage of subjects with resolution of NASH and no worsening of fibrosis
The study will meet its primary objective if either of the above primary endpoints is met. 
2.3.1.2. 
Secondary Efficacy Endpoints  
2.3.1.2.1. Histological Analysis: 
The analysis of the secondary histological efficacy endpoints for the Month 18 Interim Analysis, 
including the key secondary endpoint will compare subjects treated with OCA (10 mg and 
25 mg) versus placebo on histological improvement by assessing the following using NASH 
CRN scoring criteria: 
Key Secondary Endpoint: 
•
Percentage of subjects with improvement of fibrosis by at least 1 stage AND/OR
resolution of NASH, without worsening of either
Secondary Endpoints: 
•
Percentage of subjects with no worsening of fibrosis AND no worsening of NASH
•
Percentage of subjects with progression to cirrhosis
•
Percentage of subjects with improvement of fibrosis by at least 2 stages
•
Percentage of subjects with improvement of each key histological feature of NASH
by at least 1 point (steatosis, lobular inflammation, and hepatocellular ballooning)
•
Percentage of subjects with improvement of NAS by at least 2 points with no
worsening of fibrosis
•
Percentage of subjects with improvement of fibrosis and resolution of NASH as a
composite endpoint and as defined by both endpoints being met in the same subject
•
Percentage of subjects with resolution of fibrosis


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2.3.2. 
Efficacy Analysis at End of Study 
2.3.2.1. 
End of Study Primary Estimands and Efficacy Endpoints 
The primary estimands at the end of study (EOS) will be the difference in time from 
randomization to the first occurrence of one of the post-randomization events listed below 
(clinical outcome composite endpoints).  This will be assessed between OCA and placebo in 
adult subjects with (NASH) at fibrosis stage 2 or 3. 
•
Death (all-cause)
•
MELD score ≥15
•
Liver transplant
•
Hospitalization (as defined by a stay of 24 hours or greater) for onset of:
−
Variceal bleed
−
Hepatic encephalopathy (as defined by a West Haven score of ≥2)


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−
Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
•
Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or
paracentesis)
•
Histological progression to cirrhosis
For subjects who had an intercurrent event like investigational product interruption or dose 
adjustment or investigational product discontinuation and continued in the study, the events after 
those intercurrent events will still be evaluated for the analysis following Treatment Policy.  If an 
intercurrent event like study discontinuation due to various reasons, withdrawal from study, or 
lost-to-follow-up occurred, the last available assessment prior to the intercurrent events will be 
used for the analysis following the While on Treatment Policy. 
Table 1: 
Estimands for Clinical Composite Outcome 
Estimands 
Population 
Endpoint 
Intercurrent 
Events 
Strategy for 
IEs 
Population-
Level Summary 
Primary 
ITT 
Time to the 
first occurrence 
of the specific 
clinical 
composite 
outcomes   
Investigational 
Product 
discontinuation 
or interruption 
or dose 
adjustment 
Treatment 
Policy 
Difference in 
time to the first 
occurrence of the 
clinical outcome 
events between 
OCA and placebo 
at end of study 
Same as above Same as above 
Study 
discontinuation 
due to various 
reasons or 
death, or 
withdrawal or 
lost to follow 
up  
While on 
treatment 
policy 
Difference in 
time to first 
occurrence of the 
events including 
death, and 
clinical outcomes 
before study 
discontinuation, 
withdrawal or 
lost to lost to 
follow.  
Otherwise, it will 
be censored. 
IE=intercurrent events; ITT=intent-to-treat; OCA=obeticholic acid 
2.3.2.2. 
Secondary Efficacy Endpoints 
2.3.2.2.1. Histological Analysis 
The analysis of the histological efficacy endpoints at End of Study will be based on the following 
endpoints analyzed for all post-baseline biopsies. 
•
Percentage of subjects with Improvement of fibrosis by at least 1 stage with no
worsening of NASH
•
Percentage of subjects with Resolution of NASH with no worsening of fibrosis


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•
Percentage of subjects with improvement of fibrosis by at least 1 stage AND/OR
resolution of NASH, without worsening of either
•
Percentage of subjects with no worsening of fibrosis AND no worsening of NASH
•
Percentage of subjects with histological progression to cirrhosis
•
Percentage of subjects with improvement of fibrosis by at least 2 stages
•
Percentage of subjects with improvement of each key histological feature of NASH
by at least 1 point (steatosis, lobular inflammation, and hepatocellular ballooning)
•
Percentage of subjects with improvement of NAS by at least 2 points with no
worsening of fibrosis
•
Percentage of subjects with improvement of fibrosis and resolution of NASH as a
composite endpoint and as defined by both endpoints being met in the same subject
•
Percentage of subjects with resolution of fibrosis


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2.4. 
Safety Evaluations at Month 18 and End of Study 
Safety-related evaluations include: 
•
Vital signs
•
12-lead electrocardiograms (including central reading ECGs)
•
Clinical laboratory evaluations, including
−
Hematology
−
Serum chemistry
−
Urinalysis
•
Lipoprotein concentrations and
•
TEAEs including AESIs, including pruritus, hepatic disorders, renal disorders
(including acute kidney injury), pancreatitis, gallbladder diseases and related
complications, dyslipidemia, hyperglycaemia/new onset diabetes, and urolithiases,
and cardiovascular events
•
Adjudicated cardiovascular events
•
Adjudicated hepatic safety events
•
Adjudicated acute kidney injury events


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3.4. 
Analysis Populations 
Analysis populations for the Month 18 Interim Analysis and the End of Study Analysis are 
summarized in Table 3. 
3.4.1. 
Month 18 Interim Analysis Populations 
The Month 18 Interim Analysis data cutoff date (DCO) has been pre-specified to include all 
subjects’ data for visits (scheduled or unscheduled) occurring on or before that date.  The Interim 
Analysis Cohort (original Month 18 IA Cohort) will include all randomized subjects who 
received at least one dose of investigational product by the DCO.  The original Month 18 IA 
Cohort will include all fibrosis stages (stages 1, 2 and 3). 
The following analysis populations will be evaluated and used for presentation and 
analysis of Month 18 Interim Analysis data: 
•
The Safety Population will include the entire IA Cohort, all fibrosis stages (stages 1, 2
and 3), who received at least 1 dose of investigational product (OCA or placebo) by
the DCO.  Treatment assignment will be based on the treatment actually received.
•
The Full Efficacy Analysis Population will include all original Month 18 IA Cohort
subjects, randomized by 15 July 2017, including all fibrosis stages (stages 1, 2, and
3), who received at least 1 dose of investigational product.  The selected
randomization cut-off date ensures an adequate sample size for the efficacy
assessment, considering that subjects randomized by 15 July 2017 would have
reached their Month 18 biopsy visit by December 2018 based on 72 week treatment
period.  Treatment assignment will be based on the randomized treatment.
•
The Intent-to-Treat (ITT) Population will include a subset of the Full Efficacy
Analysis Population, limited to those subjects with fibrosis stage 2 or stage 3.
Treatment assignment will be based on the randomized treatment.  The ITT
Population will be the primary efficacy analysis population.
•
The modified ITT (mITT) Population will include all subjects from the ITT
Population, with the exception of a subgroup of subjects who discontinued treatment
(before the Month 18 Visit and without an end of treatment biopsy) between
13 Sep 2017 and 19 Dec 2017 for the following reasons:  withdrawal of consent, lost
to follow-up, and due to other reasons.  The observed increase in the number of
discontinuations during the above-mentioned period was an unintended consequence
of 1) safety communications eliciting concern from subjects and physicians and 2)
increased subject and site burden due to the safety amendment.  Treatment
assignment will be based on the randomized treatment.  The mITT population will
serve as a supportive analysis population.
•
The Per Protocol (PP) Population will include all subjects from the ITT Population
who completed at least 15 months of treatment, had a Month 18/ end of treatment
biopsy, were on investigational product for at least 30 days immediately preceding
the biopsy, and did not have any major protocol deviation (Section 5.5) that could


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potentially affect the efficacy conclusions.  Treatment assignment will be based on 
the randomized treatment. 
•
The PK Population will include all subjects who received OCA and have at least one
confirmed fasted analyzable sample.  Subjects must have been fasting for
approximately 8 hours before the visit and must not have any major protocol
deviations that potentially affect exposure levels.  The PK Population will be used for
OCA PK analysis.
3.4.2. 
End of Study Analysis Populations
•
The Safety Population will include all randomized subjects who received at least
1 dose of investigational product (OCA or placebo).  Treatment assignment will be
based on the treatment actually received.
•
The Full Efficacy Analysis Population will include all randomized subjects, all
fibrosis stages (stages 1, 2 and 3), who received at least 1 dose of investigational
product.  Treatment assignment will be based on the randomized treatment.
•
The Intent-to-Treat (ITT) Population will be a subset of the Full Efficacy Analysis
Population, limited to those subjects with fibrosis stage 2 or stage 3.  Treatment
assignment will be based on the randomized treatment.  The ITT Population will be
the primary efficacy analysis population.  The Per Protocol (PP) Population will
include all subjects from the ITT Population who did not have any major protocol
deviation (Section 5.5) that could potentially affect the efficacy conclusions and at
least 80% compliance with investigational product (Section 10.1).  Treatment
assignment will be based on the randomized treatment.
•
The PK Population will include all subjects who received OCA and have at least one
confirmed fasted analyzable sample.  Subjects must have been fasting for
approximately 8 hours before the visit and must not have any major protocol
deviations that potentially affect exposure levels.  The PK Population will be used for
OCA PK.


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Table 3: 
Analysis Populations for the Month 18 Interim Analysis and End of Study 
Analysis 
Population 
Fibrosis Stage 
Description 
Month 18 Interim Analysis 
End of Study 
Safety 
1,2 and 3 
Randomized subjects who 
received at least one dose of 
investigational product by the 
DCO (IA Cohort) 
Randomized subjects who 
received at least one dose of 
investigational product. 
Full Efficacy 
Analysis 
1,2 and 3 
All subjects, randomized by 
15 July 2017, all fibrosis 
stages (stages 1, 2 and 3), who 
received at least 1 dose of 
investigational product. 
Randomized subjects who 
received at least one dose of 
investigational product. 
ITT 
2 and 3 
Subset of Full Efficacy 
Analysis Population 
Subset of Full Efficacy Analysis 
Population 
mITT 
2 and 3 
Subset of ITT Population 
which excludes treatment 
discontinuation (before the 
Month 18 Visit and without an 
end of treatment biopsy) 
between 13 Sep 2017 to 19 
Dec 2017 due to withdrawal of 
consent, lost to follow up and 
other reasons 
Not applicable 
Per Protocol 
2 and 3 
Subset of ITT Population who 
completed at least 15 months 
of treatment, had a Month 18/ 
end of treatment biopsy, were 
on investigational product for 
at least 30 days just preceding 
the biopsy, and did not have 
any major protocol deviation 
Subset of ITT Population with no 
major protocol deviation and at 
least 80% compliance with 
investigational product 
(Section 10.1) 
4.
GENERAL STATISTICAL METHODS
Individual subject data obtained from electronic case report forms (eCRFs), local laboratories, 
central laboratories, external sources, and any derived data will be presented in data listings by 
subject.  All data listings that contain an evaluation date will contain a relative study day.  Pre-
treatment and on-treatment study days are numbered relative to the day of the first dose of 
investigational product which is designated as Day 1.  The preceding day is Day -1, the day 
before that is Day -2, etc.   
For categorical variables, summary tabulations of the number and percentage of subjects within 
each category (with a category for missing data) of the parameter will be presented.  Percentage 
calculations will be based on non-missing data unless otherwise specified.   


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In response analysis [yes/no] of histological endpoints, the comparison between treatment groups 
will be performed using CMH test stratified by the randomization strata (type 2 diabetes at 
enrollment [yes/no] and use of TZDs/glitazones or vitamin E at baseline [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 and percentage 
change from baseline over time will be analyzed using mixed-effect repeated measures 
(MMRM) model with treatment, baseline, visit, visit by treatment interaction and 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 who do not experience an 
event will be censored.  Subjects who do not experience an event will be censored at the date of 
last contact for clinical outcome endpoints and will be censored at the earliest date of last dose 
date+30 days, end of study, death date or date cut-off date for treatment-emergent adverse events 
(TEAEs).  The censor date for time to resolution events will be the earliest date of end of study, 
death date or date cut-off date.   
4.1. 
Computing Environment 
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).  Concomitant medications will be coded using 
World Health Organization (WHO) Drug Dictionary. 
4.2. 
Baseline Definitions 
The baseline value for statistical analyses of quantitative parameters (except lipoprotein 
evaluations and markers of glucose metabolism) is defined as the mean of all available 
evaluations, at the individual subject level, prior to the first administration of investigational 
product, unless otherwise specified.  If there is only one evaluation prior to the first 
administration of investigational product, then the available data from this evaluation will be 
used as the baseline value.  Quantitative parameters include, but are not limited to, lab 
parameters (except lipoprotein evaluations and markers of glucose metabolism), 
electrocardiogram measures, exploratory biomarkers, pharmacodynamic parameters, and vital 
signs. 


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The baseline value for analyses of lipid parameters and markers of glucose metabolism is defined 
as the last fasted evaluation prior to the first administration of investigational product, unless 
otherwise specified. 
The baseline value for analyses of qualitative parameters (eg, normal/abnormal), cardiovascular 
risk assessments, and patient-reported outcomes is defined as the last evaluation prior to the first 
administration of investigational product.  Baseline definition of each assessment is provided in 
Appendix A.  
4.3. 
Visit Windows 
Visit 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).  Month 18 
(Week 72) biopsy window is Week 60 to Week 96.  For all assessments, other than biopsy, each 
visit window will have the target date as the center and the lower bound is the midway between 
the target date of this window and the preceding one.  The upper bound is the midway 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 with the same distance from the target date, then the last assessment 
will be used. “Last” will be based on sorting by date, time, record number/sequence number.  
Appendix B shows the visit windows of each visit up to Month 78.  
4.4. 
Examination of Subgroups 
There will be 3 types of analyses: 
1. Subgroup analyses for the primary and key secondary efficacy endpoint using the ITT,
mITT, and PP Populations will include the following factors:
a.
Baseline diabetes status:  Yes, No
b. BMI ( < 30 kg/m2, ≥ 30 kg/m2 and < 35 kg/m2, ≥ 35 kg/m2 )
c.
Baseline Vitamin E or TZD use:  Yes, No
d. Age categories:  <65, ≥ 65 years and <75, ≥75 years
e.
Gender:  Male, Female
f.
Race:  White, Non-White (Black or African American, Asian, Native Hawaiian or
Other Pacific Islander, American Indian or Alaska Native)
g. Geographic Region:  North America, Europe, and the Rest of the World (ROW);
including Asia as a subgroup
h. Baseline Fibrosis Score:  F1, F2 and F3
i.
Baseline NAS:  (<6, ≥6) (Only for the NASH primary efficacy endpoint)
j.
Baseline and concomitant statin medication use (no concomitant use, prior and
concomitant use, new concomitant use)
k. Baseline and concomitant use of anti-diabetic medications (no concomitant use, prior
and concomitant use, new concomitant use)


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2. Subgroup analyses for safety (selected safety endpoints) will be generated using the
Safety Population and will include the following factors:
a.
Baseline diabetes status; Yes, No
b. Baseline Fibrosis Score:  F1, F2 and F3
c.
Age categories:  <65, ≥65 years, ≥75 years
d. Gender:  Male, Female
e.
Baseline in BMI (< 30 kg/m2, ≥ 30 kg/m2  and < 35 kg/m2, ≥ 35 kg/m2 )
f.
Baseline cardiovascular medical history:  Yes, No
g. Baseline Framingham (FRS) risk score:  ≤10, >10 - ≤20, >20
h. Baseline eGFR
i.
Baseline and concomitant statin medication use (no concomitant use, prior and
concomitant use, new concomitant use)
j.
Baseline and concomitant medication use of antidiabetic medication (no concomitant
use, prior and concomitant use, new concomitant use)
k. Baseline and concomitant medication use of antihypertensive medication (no
concomitant use, prior and concomitant use, new concomitant use)
l.
Quartiles of the mean HDL values after first dose of investigational product for
adjudicated cardiovascular event
m. Quartiles of the mean LDL values after first dose of investigational product for
adjudicated cardiovascular event
n. Baseline gallbladder (ultrasound): Cholecystisis (yes vs no)
3. The change from baseline in the following parameters will be analyzed by response to the
primary endpoints and treatment group.  These summaries will be based on subjects with
Month 18 biopsy.
a.
Liver biochemistry:  ALT, AST, ALP, and GGT
b. Lipids:  LDL, HDL, VLDL and total cholesterol


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5.
STUDY POPULATION
5.1. 
Subject Disposition
Subject disposition will be tabulated by treatment group and overall and will include the number 
randomized, the number randomized but not treated, the number treated in total, the number of 
subjects in the specified analysis population, the number of subjects who completed Month 18 
Visit, the number of subjects who completed Month 18 Visit with a biopsy, the number of 
subjects who withdrew from investigational product but remained in the study, the number of 
subjects who withdrew from study prior to completing the study and reason(s) for withdrawal, 
and the number of subjects who were contacted for follow-up. 
Disposition summaries will be presented for each analysis population and will be tabulated by 
treatment group and overall.   
Subject enrollment by study site will be tabulated by treatment group and overall. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented. 
5.2. 
Demographics and Baseline Characteristics 
Demographic variables will include the following: 
•
Age and groups (<65 years, ≥65 years, ≥75 years) at the time of informed consent
•
Gender
•
Race
•
Ethnicity
•
Geographic Region: North America, Europe, and ROW (including Asia as a
subgroup)
Other baseline characteristics will include the following: 
•
Liver fibrosis stage (NASH CRN scoring criteria) by central read and consensus read
as available.
•
Liver fibrosis stage (Modified Ishak scoring criteria)
•
Hepatocellular Ballooning by central read and consensus read as available.
•
Lobular Inflammation by central read and consensus read as available.
•
Steatosis by central read and consensus as available
•
Nonalcoholic fatty liver disease activity score (NAS: <6, ≥6)
•
Weight (kg)
•
Height (cm)
•
BMI (kg/m2): Continuous and Categorical:  ( <30 kg/m2, ≥30 kg/m2 , <35 kg/m2,
≥35 kg/m2 Diabetes Status (Yes/No)


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•
Diabetes Status (Yes/No)
•
Hemoglobin A1c (HbA1c; ≤5.6%, 5.7-6.4%, ≥6.5%)
•
Low density lipoprotein (LDL: mg/dL) (≥100 mg/dL, ≥190 mg/dL)
•
Triglycerides (mg/dL) (≥150 mg/dL)
•
High density lipoprotein (HDL; mg/dL) (<40 mg/dL [men] or <50 mg/dL [women])
•
Baseline Concomitant Medication Use
−
Lipid-lowering medications, including Statins
−
Statins only
−
Antihypertensive medications
−
Antidiabetic medications
−
Thiazolidinedione (TZD) only
−
Vitamin E
−
Anticoagulants/antiplatelets
−
Bile acid sequestrants
•
Baseline Caffeine Intake
•
Baseline Alcohol Consumption as assessed by AUDIT Questionnaire (AUDIT Score
≤7, >7)
•
Baseline Smoking Habits and Status
• 
Liver biochemistry, liver function and estimated glomerular filtration rate (eGFR) results 
at baseline will be summarized as continuous variables and as frequencies for 
categorizations.  The upper limit of normal (ULN) for liver functions suggested by FDA 
will be used: ALT – 30 U/L, AST – 35 U/L, Total Bilirubin – 1.25 mg/dL, Conjugated 
(Direct) Bilirubin – 0.3 mg/dL, ALP – 120 IU/L.  
•
eGFR (chronic kidney disease epidemiology collaboration [CKD-EPI] calculation)
and groups (G1/Normal, G2, G3)
•
ALT and AST: ≤ upper limit of normal (ULN), >ULN to ≤3x ULN, >3x ULN
•
Total Bilirubin and Conjugated (Direct) Bilirubin:  ≤ULN, >ULN
•
ALP and GGT: ≤ULN, >ULN
•
Model for end stage liver disease (MELD) Score
Demographics and Baseline characteristics will be summarized and presented by treatment group 
and overall for the, ITT, mITT, Full Efficacy Analysis, PP, Safety, and PK Populations.   


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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. 
5.3. 
Baseline NASH Disease Characteristics 
Baseline NASH disease characteristics will be summarized using data collected from the NASH 
Disease History eCRF.  Variables from the NASH Disease History eCRF include the following: 
•
Age at NASH diagnosis
•
Duration of NASH in years at time of informed consent
Baseline NASH disease characteristics will be summarized and presented by treatment group and 
overall for the ITT, mITT, Full Efficacy Analysis, PP, Safety, and PK Populations.  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 NASH disease characteristics will be presented in by-subject data listings. 
5.4. 
Medical and Cardiovascular Medical History 
Verbatim terms on electronic case report forms (eCRFs) will be mapped to preferred terms (PT) 
and system organ classes using Medical Dictionary for Regulatory activities (MedDRA).  
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 SOC.   
The following cardiovascular (CV) variables from the CV Medical History eCRF will be 
summarized by preferred term: 
•
Types and number of CV conditions/events
•
Types and number of CV treatment procedures received
Lastly, separate summaries will be provided by SOC and PT for the number and percentage of 
subjects with medical history in the following categories: 
•
Pruritus
•
Hepatic Disorders
•
Gallbladder disease and Related Complications
•
Pancreatitis
•
Glycemic control
•
Dyslipidemia
•
Renal Disorders
•
Urolithiases


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Medical and CV medical history will be presented in a by-subject data listing. 
5.5. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any significant way without 
notification to the Sponsor (or designee) as described in the protocol.   
All eligibility deviations specified in the protocol will be considered major deviations and 
subjects meeting any of these deviations will not be included in the PP Population.  Major 
on-study protocol deviations that could potentially affect the efficacy or safety conclusions of the 
study will be identified through programming and identifying selected categories from the list of 
protocol deviations collected during the study: 
•
Investigational product dosing, including subjects who receive treatment different
from what they were randomized to.
•
Taking investigational product after bariatric surgery (gastric bypass)
All major protocol deviations will be summarized and listed by treatment group. 
5.6. 
Impact of COVID-19 Pandemic 
The percentage and number of subjects with protocol deviations related COVID-19 will be 
summarized by randomized treatment and by deviation type in Full Efficacy Analysis Population 
and Safety Population. 
The incidence of COVID-19 related TEAEs, serious TEAEs, severe TEAEs, relationship to 
OCA and fatal TEAE will be summarized by treatment group, by SOC and PT in Safety 
Population.  A listing of subjects with the COVID-19 related TEAEs will be generated. 
6.
EFFICACY ANALYSES
Primary efficacy will be based on the ITT Population.  The sections below provide further details 
on the methods and populations to be used in analyzing each of the efficacy endpoints.  All 
efficacy endpoints will be presented in by-subject data listings.   
6.1. 
Adjustments for Covariates 
For histological endpoints; primary, secondary, and exploratory endpoints; the comparison 
between treatment groups will be performed using CMH test stratified by the randomization 
strata (type 2 diabetes at enrollment [yes/no] and use of TZDs/glitazones or vitamin E at baseline 
[yes/no]). 
For continuous secondary and exploratory endpoints, change from baseline and percentage 
change from baseline over time will be analyzed using the MMRM model with treatment, 
baseline, visit, visit by treatment interaction, and stratification factors to be included in the 
model.  


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6.2. 
Handling of Subject Discontinuations and Missing Data 
Subjects who discontinue investigational product for any reason other than withdrawal of 
consent 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. 
6.2.1. 
Quantitative Endpoints 
For exploratory efficacy endpoints utilizing an analysis of covariance (ANCOVA), MMRM 
model, observed cases will serve as the primary analysis.   
6.2.2. 
Responder Endpoints 
For the primary endpoint analysis, the centrally read screening biopsy will be used as baseline 
histology data.  The Month 18 or post-baseline biopsy that is centrally read as part of the paired 
read (ie, paired with a new slide from the screening/baseline biopsy tissue to minimize temporal 
bias) will be compared with the baseline biopsy (screening) to determine efficacy, ie, responder 
status for primary endpoints as well as other histology efficacy endpoints.  Additional analyses 
may be conducted using the baseline biopsy slide that was used as part of the paired reading for 
primary endpoints as well as other histology efficacy endpoints. 
The protocol requires a Month 18 biopsy even for subjects who discontinued treatment but are 
on-study (in addition to the end of treatment biopsy, if applicable, by the protocol).  For each 
post-baseline biopsy, a paired reading will be performed.  If a subject has more than one paired 
reading by the Month 18 Visit, only one paired reading will be reported in Electronic Data 
Capture (EDC) based on the biopsy preceded by the longest (and least interrupted) 
investigational product exposure. 
The biopsy consensus based read methodology by a three pathologists panel will be implemented 
for all baseline and all subsequent histology data using whole slide image (WSI) technology.  
The stained slides were digitized (scanned by ICON and other vendor) and the WSI were sent to 
PathAI (vender) to be read by pathologists using the consensus method using their research 
platform.  In cases where a previously stained slide was either missing OR could not be read by 
the Consensus panel, a new slide was requested to be stained, scanned and read.  A two-stage 
approach will be utilized to reach a consensus.  At stage one, all three pathologists at each panel 
will independently read each subject’s slide image and enter the results in the database.  If the 
two pathologists matched the score for a specific component, it is chosen as the consensus score 
for the component.  If the scores from all 3 pathologists for a specific parameter are discordant, a 
single consensus score will be provided by a joint panel read at stage two and flagged as Joint 
panel decision (refer to histology manual).  
Panel A of 3 pathologists will read images of slides stained with H&E to characterize NAS 
(ballooning, inflammation, steatosis) score and Panel B pathologists will read images of slides 
stained with Trichrome to characterize NAS CRN fibrosis score.  The endpoint regarding the 
improvement or worsening of fibrosis stage and NASH will be derived based on the results from 
the consensus values at baseline and any post-baseline liver biopsy collection. 


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For the analyses of histological efficacy endpoints, in which subjects are classified as either 
responders or non-responders (binary outcome), any subject who discontinues from the study 
prior to the Month 18 biopsy Visit and does not have a post-baseline biopsy assessment will be 
considered a non-responder.  Biopsies collected for subjects who discontinued treatment before 
the Month 18 visit will be included in the Month 18 Interim Analysis of histological endpoints 
regardless of the timing of the biopsy. 
Similar conventions and statistical methodologies will be used for analyses of other exploratory 
histological-based responder analyses.  Responder endpoint analyses will be carried out for the 
primary and secondary endpoints using the ITT, mITT, Full Efficacy Analysis Population and PP 
Populations. 
A complete summary and description of the analysis plan and populations for histological data 
based on the consensus method can be found in SAP Addendum V2 (dated 25 Apr 2022). 


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6.3. 
Control of Type I Error 
6.3.1. 
Histological Primary Endpoints: 
The 2-sided Type I error (alpha) allocated to all testing in this single study will be 0.05.  The 
histological endpoints at the Month 18 Interim analysis will be performed with an alpha level of 
0.02.  The primary clinical outcomes composite endpoint will be tested with an alpha level of 
0.03 which may be augmented by recycled alpha from the Month 18 Interim Analysis. 
As shown in Figure 2, the inferential testing will start with the two primary endpoints in 
comparing the OCA 25 mg dose group versus placebo using the Truncated-Hochberg procedure 
(Gamma=0.1) and Type I error of 0.02.  


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Figure 2: 
Statistical Testing for the Month 18 Interim Analysis 
I) Scenario 1:  Both Primary Endpoints Achieve Statistical Significance at the OCA 25 mg
Dose Level
a.
Primary Endpoints at the OCA 25 mg Dose Level:  Placebo and OCA 25 mg
groups will be compared with respect to the fibrosis and NASH primary efficacy
endpoints, using the Truncated-Hochberg procedure, with critical values of 0.011 and
0.01 against which the larger and smaller P-value are to be compared respectively.  If
the larger P-value is less than 0.011 then both primary efficacy endpoints achieve
statistical significance in favor of the OCA 25 mg group.  Consequently, the full
alpha fraction is preserved and will be carried to compare placebo and OCA 10 mg
groups with respect to the primary endpoints using the Truncated-Hochberg
procedure (Gamma = 0.1).
b. Primary Endpoints at the OCA 10 mg Dose Level: Placebo and OCA 10 mg
groups will be compared, using the Truncated Hochberg procedure, with respect to
the fibrosis and NASH primary efficacy endpoints with critical values of 0.011 and
0.01 against which the larger and smaller P-value are to be compared respectively.
c.
Key Secondary Endpoint at the OCA 25 mg Dose Level:  Placebo and OCA 25 mg
groups will be compared with respect to the key secondary endpoint sequentially after
the primary endpoint at OCA 10 mg dose level.
d. Key Secondary Endpoint at the OCA 10 mg Dose Level:  Placebo and OCA 10 mg
groups will be compared with respect to the key secondary endpoint sequentially after
the key secondary endpoint at OCA 25 mg dose level.


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II) Scenario 2:  One Primary Endpoint Achieves Statistical Significance at the OCA 25 mg
Dose Level
a.
Primary Endpoints at the OCA 25 mg Dose Level: If the larger P-value is greater
than 0.011 but the smaller P-value is < 0.01 then only one of the two primary efficacy
endpoints achieves statistical significance in favor of the OCA 25 mg group.
Preserved alpha of 0.009 will be carried to compare placebo and OCA 10 mg groups
with respect to the primary endpoints using the Truncated Hochberg procedure
(Gamma = 0.1).
b. Primary Endpoints at the OCA 10 mg Dose Level:  Placebo and OCA 10 mg
groups will be compared, using the Truncated Hochberg procedure, with respect to
the fibrosis and NASH primary efficacy endpoints with critical values of 0.00495 and
0.0045 against which the larger and smaller P-value are to be compared respectively.
c.
Key Secondary Endpoint at the OCA 25 mg Dose Level:  Placebo and OCA 25 mg
groups will be compared with respect to the key secondary endpoint sequentially after
the primary endpoint at OCA 10 mg dose level.
d. Key Secondary Endpoint at the OCA 10 mg Dose Level:  Placebo and OCA 10 mg
groups will be compared with respect to the key secondary endpoint sequentially after
the key secondary endpoint at OCA 25 mg dose level.
6.3.2. 
End of Study Primary Endpoints:
For the analyses of the clinical outcomes composite endpoint at the End of Study, OCA doses 
will be compared to placebo in a sequential closed gate-keeping manner using Type I error of 
0.03.  
•
First placebo and OCA 25 mg will be compared with respect to the clinical outcomes
composite endpoint.  If the comparison achieves statistical significance at the 2-sided
alpha level in favor of OCA 25 mg, then
•
Placebo and OCA 10 mg will be compared with respect to the clinical outcomes
composite endpoint.
The possible scenarios of testing the End of Study, depending on Month 18 Interim Analysis 
results, are provided in Table 4. 


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Table 4: 
End of Study Type 1 Error 
Month 18 Interim Analysis 
End of Study 
OCA 25 mg 
OCA 10 mg 
Testing for Clinical Outcomes Endpoint 
Primary Endpoints 
Primary Endpoints 
α 
Achieve Statistical 
Significance 
α 
Achieve Statistical 
Significance 
α 
Clinical 
Outcomes 
Both Dose Groups 
Hierarchal * 
Only OCA 10 mg** 
0.02 
Both 
0.02 
Both 
0.05 
OCA 25 mg →10 mg 
at α=0.05 
OCA 10 mg at 
α=0.05 
Only one 
0.039 
OCA 25 mg →10 mg 
at α=0.039 
OCA 10 mg at 
α=0.039 
Only one 
0.009 
Both 
0.039 
OCA 25 mg →10 mg 
at α=0.039 
OCA 10 mg at 
α=0.039 
Only one 
0.03405 
OCA 25 mg →10 mg 
at α=0.03405 
OCA 10 mg at 
α=0.03405 
α for Clinical Outcomes endpoint is 0.03 + carried alpha from the Month 18 Interim Analysis depending on the statistical success 
of primary endpoints at OCA 25 mg and OCA10 mg dose level  
* Following Month 18 Interim Analysis, both OCA arms are continued for Clinical Outcomes.
** Following Month 18 Interim Analysis, only the OCA 10 mg arm is continued for Clinical Outcomes.
6.4. 
Interim Analyses and Data Monitoring 
6.4.1. 
Interim Analysis of Clinical Outcomes 
The clinical outcome events adjudicated by independent hepatic outcome committee will be 
closely monitored in a blinded manner until 100% of the required events have been captured.  
The projections for the total number of events in three groups (placebo, OCA 10mg, and 
OCA 25mg) will be generated and reviewed following the Performance Standard Plan.  
When 288 events in all three groups are expected to be observed based on the modeling 
projections, it is assumed that the targeted 190 events for 66% IA analysis in two groups 
(placebo and OCA 25) will have accrued.  This will trigger the 66% interim analysis 
evaluations as presented in Section 3.2. 
One interim analysis of the clinical composite outcomes endpoint, including all-cause 
mortality and liver-related clinical outcomes will be conducted when 66% of the 288 clinical 
outcomes events are accrued in the placebo and OCA 25 mg groups using the Lan-DeMets 
O’Brien-Fleming boundaries for efficacy (Reboussin 2000).  Further details on the 
boundaries and alpha spent in the interim analysis are provided in Section 3.2. 
6.4.2. 
Data and Safety Monitoring Committee 
An independent DMC will include hepatologists, physicians, epidemiology/cardiology expert(s), 
and statistician(s) who will not be involved in the study as Investigators, adjudication committee 
members, or consultants will have oversight over the study conduct as defined by the DMC 
charter.   


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The DMC will meet approximately quarterly, and at least every 6 months, at scheduled meetings 
and ad hoc meetings, as appropriate, to review safety and efficacy data as well as the 
adjudication assessments from the adjudication committees as specified in the charter.  Based on 
the unblinded review of these data, the DMC will advise the Sponsor on the validity and 
scientific merit of continuing the study.   
Written minutes of both the open and closed DMC sessions will be prepared.  The closed 
minutes will be made available to the appointed Sponsor representatives only after the database 
is locked. 
Data flow, access, process, and disclosure will be described in a DAP and Unblinding Plan.   
6.4.3. 
Adjudication Committees 
All suspected liver-related clinical outcomes and major adverse cardiovascular events (MACE) 
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 committees and event types they are responsible for adjudicating are as 
follows: 
•
Cardiovascular Adjudication Committee:  Adjudicates all suspected MACE,
including all deaths following the CV Adjudication Charter.
•
Hepatic Outcomes Adjudication Committee:  The role of the HOC is to review and
adjudicate all deaths and suspected liver-related clinical outcomes following the pre-
specified criteria described in the HOC Charter.
•
Renal Adjudication Committee (RAC) – The role of the RAC is to review potential
Acute Kidney Injury (AKI) events and adjudicate an event as AKI following the pre-
specified criteria included in the RAC Charter.
•
Hepatic safety Adjudication Committee (HSAC) - The role of the HSAC is to review
potential hepatic injury triggers to determine whether they meet the pre-specified criteria
for hepatic injury as described in the HSAC Charter.
Each adjudication committee will have a charter that documents the reporting of events by the 
study site, definition of the suspected events to be adjudicated, supply of source documentation 
to the committee, entire data flow and process from committee membership, review of the events 
by the committee, reporting of the final assessment, and the working procedures of the 
committee.   
All potential liver-related clinical outcome events, hepatic safety, renal and major cardiovascular 
adverse events (MACE) will be reviewed by adjudication committees before inclusion in any 
analysis.  The adjudication committee members will be independent hepatologists, nephrologists  
(cardiologists for MACE) not involved in the study as investigators, DMC members, or 
consultants.  All adjudication committee members will remain blinded to treatment group 
throughout the study.  The data coordinating center will remove all subject identification on the 
eCRF data and source documentation, as specified in the charter. 


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6.4.4. 
Primary Efficacy Analysis 
6.4.4.1. 
Primary Efficacy Analysis at Month 18 
The primary efficacy analysis at Month 18 will compare OCA to placebo.  The primary efficacy 
analysis will be conducted using the ITT Population.   
The primary endpoints for the Month 18 Interim Analysis are: 
•
Improvement of fibrosis by at least 1 stage with no worsening of NASH (no
worsening of hepatocellular ballooning, no worsening of lobular inflammation and no
worsening of steatosis)
•
Resolution of NASH with no worsening of fibrosis
The primary efficacy analysis at OCA 25 mg dose will test the following hypotheses using the 
ITT Population: 
•
H01:  The percentage of subjects with fibrosis improvement by 1 stage or more, no
worsening of hepatocellular ballooning, no worsening of lobular inflammation, and
no worsening of steatosis is equal between placebo and OCA 25 mg groups.
•
H11:  The percentage of subjects with fibrosis improvement by 1 stage or more, no
worsening of hepatocellular ballooning, no worsening of lobular inflammation, and
no worsening of steatosis is different between placebo and OCA 25 mg groups.
•
H02:  The percentage of subjects with NASH resolution and no worsening of fibrosis
is equal between placebo and OCA 25 mg groups.
•
H12:  The percentage of subjects with NASH resolution and no worsening of fibrosis
is different between placebo and OCA 25 mg groups.
The primary efficacy analysis at OCA 10 mg dose will test the following hypotheses using 
the ITT Population: 
•
H01:  The percentage of subjects with fibrosis improvement by 1 stage or more, no
worsening of hepatocellular ballooning, no worsening of lobular inflammation, and
no worsening of steatosis is equal between placebo and OCA 10 mg groups.
•
H11:  The percentage of subjects with fibrosis improvement by 1 stage or more, no
worsening of hepatocellular ballooning, no worsening of lobular inflammation, and
no worsening of steatosis is different between placebo and OCA 10 mg groups.
•
H02:  The percentage of subjects with NASH resolution and no worsening of fibrosis
is equal between placebo and OCA 10 mg groups.
•
H12:  The percentage of subjects with NASH resolution and no worsening of fibrosis
is different between placebo and OCA 10 mg groups.
The primary efficacy analyses at Month 18 will compare placebo and each OCA dose, 
adjusting for multiplicity as described in Section 6.3 and using a CMH test stratified by the 
randomization strata (diabetes at enrollment [yes/no] and use of TZDs or vitamin E at 
baseline [yes/no]).   


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These analyses, in addition to the sensitivity analyses described in Section 6.2.3, will also be 
conducted using the mITT, PP, and Full Efficacy Analysis Populations. 
6.4.4.2. 
Primary Efficacy Analysis at End of Study  
The primary efficacy endpoint at the End of Study will be the time to first occurrence of one of 
the following hepatic adjudicated events (and progression to cirrhosis based on post baseline 
biopsy including Month 48 biopsy) post-randomization:  
•
Death (all-cause)
•
MELD score ≥15
•
Liver transplant
•
Hospitalization (as defined by a stay of 24 hours or greater) for onset of:
−
Variceal bleed
−
Hepatic encephalopathy (as defined by a West Haven score of ≥2)
−
Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
•
Ascites secondary to cirrhosis and requiring medical intervention (eg, diuretics or
paracentesis)
•
Histological progression to cirrhosis
The hypotheses testing for the primary efficacy endpoint at the End of Study is: 
•
H01: The time to first occurrence of any of the hepatic adjudicated events for all-cause
mortality and liver-related clinical outcomes are equal between placebo and OCA
25 mg groups.
•
H11: The time to first occurrence of any of the hepatic adjudicated events for all-cause
mortality and liver-related clinical outcomes are different between placebo and OCA
25 mg groups.
•
H02: The time to first occurrence of any of the hepatic adjudicated events for all-cause
mortality and liver-related clinical outcomes are equal between placebo and OCA
10 mg groups.
•
H12: The time to first occurrence of any of the hepatic adjudicated events for all-cause
mortality and liver-related clinical outcomes are different between placebo and OCA
10 mg groups.
The primary efficacy analysis will be conducted using the ITT Population, only including 
fibrosis stage 2 and 3 subjects.  Placebo and each OCA dose will be compared separately using a 
log rank test stratified by the randomization stratification factor.  Kaplan-Meier (KM) estimates 
of the distribution of the time-to-event will be tabulated and graphed by treatment group.  The 
tabulation will include the KM estimate of the 25th, 50th (median), and 75th percentiles and 
corresponding 95% confidence intervals (CIs), if the medians can be estimated.  The number and 
percentage of subjects censored and with events will be presented.  The hazard ratio and 95% CI 


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will be estimated using a Cox regression model stratified by randomization strata to estimate the 
magnitude of the effect. 
6.4.5. 
Secondary Efficacy Analyses at Month 18 and End of Study 
The secondary efficacy analysis will be conducted using the ITT Population.  The secondary 
endpoints for the Month 18 Interim Analysis are: 
Key Secondary Endpoint: 
•
Percentage of subjects with improvement of fibrosis by at least 1 stage AND/OR
resolution of NASH, without worsening of either
Secondary Endpoints: 
•
Percentage of subjects with no worsening of fibrosis AND no worsening of NASH
•
Percentage of subjects with progression to cirrhosis
•
Percentage of subjects with improvement of fibrosis by at least 2 stages
•
Percentage of subjects with improvement of each key histological feature of NASH
by at least 1 point (steatosis, lobular inflammation, and hepatocellular ballooning)
•
Percentage of subjects with improvement of NAS by at least 2 points with no
worsening of fibrosis
•
Percentage of subjects with improvement of fibrosis and resolution of NASH as a
composite endpoint and as defined by both endpoints being met in the same subject
Percentage of subjects with resolution of fibrosis.
The analyses will compare placebo and each OCA dose separately (10 mg and 25 mg), using a 
CMH test stratified by the randomization strata (diabetes at enrollment [yes/no] and use of TZDs 
or vitamin E at baseline [yes/no]).   
These analyses will also be conducted using the mITT, PP and Full Efficacy Analysis 
Populations. 
At the End of Study Analysis, all Month 18 histological endpoints will be analyzed. 


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s 


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6.4.6.10. Change from Baseline in MELD 
MELD score is a scoring system for assessing the severity of chronic liver disease.  Higher 
scores on MELD indicate worse disease severity.  
MELD during treatment will be compared to baseline values to determine if there was an 
increase in MELD score, and this information will be summarized by treatment group and visit.  
MELD score, change and percentage change from baseline values will be summarized and 
analyzed as described in the General Statistical Methods (Section 4).   
Individual factors contributing to the MELD score will be presented in a listing. 


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6.4.7. 
End of Study Time to Event Analyses 
In addition to the primary analysis (Section 6.4.4.2) and secondary analyses (Section 6.4.5) and 
exploratory analyses (Section 6.4.6), the following analyses will be performed at the End of 
Study. 
6.4.7.1. 
Time to Each Component of the Clinical Outcome Endpoint 
Time to each of the following components of the clinical outcome endpoint and time to HCC 
will be analyzed by treatment group using ITT and Full Efficacy Analysis Populations: 
•
Death: date of death
•
Liver transplant: date of first liver transplant
•
MELD score ≥15: date of first occurrence of MELD ≥15
•
Hospitalization (as defined by an inpatient stay of 24 hours or greater) for new onset
or recurrence of:  variceal bleed, encephalopathy (as defined by a West Haven grade
≥2), spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis): date of
earliest hospitalization admission.
•
Ascites secondary to cirrhosis and requiring medical intervention: date of earliest
ascites start date as an adverse event that required medical intervention.
•
Histological progression to cirrhosis: date of biopsy
Only adjudicated events (and biopsy confirmed progression to cirrhosis) will be included in the 
analyses.  The time to event of each of the components of the clinical outcome endpoint are 
defines as follows:  
•
Time to death (all-cause), first MELD score ≥15 and first liver transplant will be
calculated in days as the date of the event minus the date of randomization plus 1.
Subjects who do not experience an event will be censored at the date of last contact.
•
Time to the first occurrence of onset of ascites (secondary to cirrhosis and requiring
medical intervention), will be calculated in days as the first time for onset of the
ascites minus the date of randomization plus 1.
•
Time from randomization to the date of biopsy confirming histological progression to
cirrhosis will be calculated in days as the date of the diagnosis minus the date of
randomization plus 1.  Subjects who do not experience an event will be censored at the
date of last contact.
•
Time to the first occurrence of hospitalization for new onset or recurrence of variceal
bleed, encephalopathy, spontaneous bacterial peritonitis will be calculated in days as
the first hospitalization admission date/time for new onset or recurrence of the event
minus the date of randomization plus 1.  The duration between the hospitalization
admission date/time and discharge date/time (discharge date/time – admission
date/time) must be greater than or equal to 24 hours (1 day).  Subjects who do not
experience an event will be censored at the date of last contact.


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KM estimates of the time-to-event will be tabulated and graphed by treatment group.  The 
tabulation will include the KM estimate of the medians and corresponding 95% CIs, if the 
medians can be estimated.  The number and percent of subjects censored and with events will be 
presented.  All summaries of incidence will include the associated exact binomial 95% 
confidence Interval (CI).  Listing of adjudicated events, including progression to cirrhosis will be 
provided.  At the Month 18 Interim Analysis, a listing of adjudicated events will be prepared by 
DMC vendor without unblinding the Sponsor as described in the DAP. 


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10.
SAFETY ANALYSES
Safety analyses will be conducted using the Safety Population including by treatment groups and 
total OCA (both OCA 25 mg and OCA 10 mg combined).  If a subject is randomized to placebo 
and subsequently receives OCA, each TEAE (Section 10.3) will be attributed to the administered 
OCA dose.   
No inferential comparison of safety endpoints will be performed, unless otherwise specified.  
There will be 2 sets of safety summaries presenting the safety profile of the following 
populations:  
1. The Safety Population as defined in Section 3.4
2. The ITT population as defined in Section 3.4
Frequencies of adverse events 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 for the safety population. 
Selected safety summaries will be prepared including all subjects in the mITT Efficacy 
Population.  Summaries and listings will be presented by actual treatment received. 
10.1. 
Extent of Exposure 
The extent of exposure will be summarized both continuously using descriptive statistics and 
categorically (n and % for ≤4 weeks, >4 and ≤12 weeks, >12 and ≤24 weeks, >24 and ≤36 
weeks, >36 and ≤48 weeks, >48 and ≤72 weeks, >72 and ≤96 weeks, >96 weeks ≤120 weeks; 
>120 weeks ≤144 weeks, >144 weeks ≤168 weeks, >168 weeks ≤192 weeks).  After Month 48
(Week 192) until the end of the study, exposure will be presented by 48 weeks periods.
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, drug holidays 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, drug holidays 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. 


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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 (including drug holiday) 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: 
•
(# of tablets consumed during study / # of tablets expected to be consumed during
study) * 100
where # of tablets consumed during study = # of tablets dispensed- # of tablets returned or  
•
total investigational product (mg) exposed to subject/ total investigational product
(mg) planned
where total investigational product planned = (End date of IP exposure – Start date of IP 
exposure + 1) 
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. 
10.2. 
Prior and New Concomitant Medications 
Verbatim terms on eCRFs will be mapped to Anatomical Therapeutic Chemical (ATC) class and 
Preferred Name using the WHO Drug Dictionary Enhanced. 
Pretreatment concomitant medications are those medications with start and stop prior to the 
initial dose of investigational product also classified as no concomitant medication.  Prior 
concomitant medications are those medications started prior to and continued after the initial 
dose of investigational product.  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. 
No concomitant, 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 
medications at that level.  Each summary will be ordered by descending order of incidence of 
ATC level and preferred name within each ATC level. 


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Extent of exposure of newly initiated use (after the 1st dose) of vitamin E, thiazolidinediones, 
bile acid sequestrants (BABR), statins and other lipid-lowering medications, will be calculated as 
follows: 
Exposure to the concomitant medication = {[(Date of last dose –Date of 1st dose)+1] 
– Total duration of temporary interruptions}
Missing start and end dates will be imputed as described in Appendix A.  Extent of exposure will 
be summarized by treatment group as described in the General Statistical Methods (Section 4). 
10.3. 
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.  AEs will be reported and categorized 
using the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03). 
All AE summaries will be restricted to TEAEs, which are defined as any AEs that newly appear, 
increase in frequency, or worsen in severity following randomization up to 30 days from the last 
dose date of permanent investigational product discontinuation up to new data cut-off date.  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 18.1 or later version. 
Each AE summary will be displayed by treatment group.  Summaries that are displayed by SOC 
and PT will be ordered by descending order of incidence (OCA 25 mg, followed by OCA 10 mg, 
followed by placebo) of system organ class and preferred term 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 MedDRA 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 MedDRA
SOC and PT.
•
Subject incidence of TEAEs leading to investigational product withdrawal by
MedDRA SOC and PT.
•
Subject incidence of TEAEs leading to study discontinuation by MedDRA SOC and
PT.
•
Subject incidence of TEAEs by MedDRA SOC, PT, and highest severity (CTCAE
grade).  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
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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 MedDRA SOC
and PT.  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 MedDRA SOC and PT.  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 MedDRA SOC and PT with frequency at
least 5% within any treatment group.
•
Subject incidence of TEAEs by MedDRA SOC, PT, and closest relationship to biopsy
(Related/Not Related).  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
MedDRA SOC and PT
The following listings will be presented by treatment group and subject: 
•
All TEAEs
•
Serious TEAEs (This is a subset of the TEAEs where serious is marked as “Yes”)
•
CTCAE Grade 3 or higher TEAEs (This is a subset of TEAEs where severity is
marked as CTCAE grade 3, 4, or 5)
•
Study Drug Related TEAEs (This is a subset of the TEAEs where relationship to
study drug marked as “Definite,” “Probable,” or “Possible”)
•
Biopsy-related TEAEs (This is a subset of the TEAEs where relationship to biopsy
marked as “Definite”, “Probable”, or “Possible”)
•
TEAEs leading to Study Drug Withdrawal or Study Discontinuation (This is a subset
of the TEAEs where Action Taken with Study Treatment is checked as “Drug
Withdrawn” or “Subject Discontinued from Study)
•
TEAEs leading to death (This is a subset of the TEAEs where outcome is indicated as
“Fatal” or the CTCAE grade is 5)


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10.4. 
Adverse Events of Special Interest 
The following treatment-emergent AESIs will be summarized: 
•
Pruritus
•
Hepatic
•
Cardiovascular
•
Dyslipidemia
•
Gallbladder disease and related complications
•
Pancreatitis
•
Renal
•
Urolithiases
•
Hyperglycaemia/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 of 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 AESIs by PT
•
Exposure-adjusted incidence of serious AESIs by PT
•
Exposure-adjusted incidence of AESIs by baseline diabetes status
•
Exposure-adjusted incidence of severe (Grade 3+) AESIs by PT
•
KM statistics and plot for time to first onset of treatment-emergent AESI
•
KM statistics and plot for time to onset of first severe (Grade 3+) or serious
treatment-emergent AESI
•
KM statistics and plot for duration of first treatment-emergent AESI
•
KM statistics and plot for duration of most severe treatment-emergent AESI
•
Percentage of subject-days with treatment-emergent AESIs per subject exposure year
(SEY), by severity


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All summaries noted above will include crude incidence rates for each level of summation.  For 
overall incidence summary of AESI, analyses will be performed separately for AESI collected 
on-treatment only and during study. 
Exposure-adjusted incidence rate (EAIR) difference (with corresponding 95% Cis) will be 
calculated for the number of subjects with any event by subcategory of interest as well as for 
each PT.  EAIR will be calculated to correct for differences in investigational product exposure 
by using person-time in the denominator.  Adjusted incidence per 100 SEY is defined as the 
number of subjects with an event for whom person-time is available divided by the total SEY for 
each treatment group and multiplied by 100.  If a subject experiences the event of interest, the 
subject’s SEY will be calculated as (first event onset date, minus the first dose date plus 1) 
divided by 365.25 days/year.  If a subject does not experience the event of interest, the subject’s 
SEY will be calculated as (earliest date of the last dose date plus 30 days or study 
discontinuation date or death date or date cut-off date minus the first dose date plus 1) divided by 
365.25 days/year.  One SEY is the equivalent of one subject exposed to investigational product 
for one year.  Two subjects who are exposed to investigational product for half a year together 
contribute one SEY.  The total SEY of a treatment group is the sum of the SEY for each subject 
in that treatment group.  Exposure-adjusted incidence rates will be calculated for each treatment 
group.  Exposure-adjusted incidence rate difference and the corresponding 95% CI will be 
derived from Poisson regression model with treatment as explanatory variables. 
The time to onset of first treatment-emergent AESI, including onset of first treatment-emergent 
AESI with different categories, will be estimated using the KM method by calculating the time 
from the first dose date to the first occurrence of a specific category of treatment-emergent AESI.  
Subjects who do not experience an event will be censored as described in General Statistical 
Methods (Section 4). 
The duration of first treatment-emergent AESI and most severe treatment-emergent AESI will be 
estimated using the KM method by calculating the time from the start date of first occurrence of 
a given treatment-emergent AESI or most severe AESI to its resolution (AE outcome being 
“recovered/resolved” in the eCRF).  If the AESI remains ongoing, subjects will be censored as 
described in General Statistical Methods (Section 4).  Only subjects with the events will be 
included in the analysis. 
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 with an event. 
A by-subject data listing will be provided for AEs of special interest (AESI) by category 
including the Standardized MedDRA query (SMQ) where applicable.   
Specific analyses for each AESI will be described in the subsequent sections. 
10.4.1. 
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 


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overall pruritus TEAEs will be provided.  These summaries will be generated for the Safety and 
ITT Populations.  
For subjects reporting an AE of pruritus, the various strategies for management of pruritus (listed 
below) will be summarized (per FDA request).  Frequencies per treatment group will be 
reported.  In addition, interruption of investigational product and decreased dose frequency will 
be summarized and presented in the following ways: 
1. each subject represented only once,
2. average interruptions per subject,
3. number of interruptions lasting: 1-5 days, 6-10 days, >10 days.
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 earliest 
date of last dose date plus 30 days, study discontinuation date, death date and data cut-off date 
minus the first dose date plus 1) divided by 365.25 days/year.   
Strategies for management of pruritus (≤ Grade 2 Severity) include: 
•
Interruption of investigational product
•
Decreased dose frequency of investigational product
•
Any medication initiated for pruritus
−
bile acid sequestrants
−
antihistamines
−
corticosteroids
−
other (e.g., naltrexone/naloxone, rifampin/rifampicin)
•
None of these strategies (no management).
•
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)
received, adjustments to investigational product dosing frequency or amount,
mandatory investigational product interruption, and/or holiday.  The time between
each event and its preceding one will be presented per subject.
10.4.2. 
Hepatic Safety Analysis  
Hepatic disorders are different and separate from primary efficacy endpoint of hepatic clinical 
outcomes and 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; and pregnancy-related hepatic disorders.  
Summaries will include overall summary of hepatic disorder TEAEs, summary of the incidence 
of hepatic disorder TEAEs, related TEAEs, TEAEs with CTCAE Grade 3 or higher, TEAEs 


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leading to treatment discontinuation, TEAEs leading to study discontinuation, SAEs, TEAEs 
leading to death. 
In order to explore the relationship between hepatic disorders and OCA, the following time-to 
event analyses will be performed: 
•
EAIR of custom hepatic queries for PTs “Acute hepatic failure” (hepatic failure) and
“Ammonia increased” (hepatic injury)
•
Incidence of hepatic TEAEs by PT, and baseline fibrosis status
•
Incidence of hepatic SAEs by PT, and baseline fibrosis status
Potential drug induced liver injury (DILI) Triggers: Potential cases of DILI in Study 747-303 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). 
Summary tables for identified cases will present frequencies of triggers by treatment group as 
well as highest causality and severity association. 
Additional DILI analyses will include the following: 
•
EAIR of DILI cases adjudicated for ALL cases of hepatic injury by severity and
treatment arms
•
EAIR of DILI cases adjudicated as ≥ possible causality and severity injury by
treatment arms
•
Incidence of potential DILI by baseline weight (<85kg, 85-100 kg, and >100 kg)
•
Incidence of potential DILI by baseline BMI (<30 kg/m2, ≥30 kg/m2 to <35 kg/m2,
≥35 kg/m2)
•
Incidence of potential DILI by use of known hepatotoxic medications prior to the
event
•
Incidence of potential DILI by baseline fibrosis using histology based on original
eligibility baseline fibrosis stage.
•
Time to onset of first occurrence of adjudicated DILI (Possible, Prob, Highly Likely
causality AND ≥ Moderate severity)
•
Time to onset of first occurrence of adjudicated DILI (Possible/Prob/Highly Likely
causality AND Mild severity)
•
Time to onset of first occurrence of adjudicated DILI (Unlikely causality AND >/=
Moderate severity)
•
Time to onset of first occurrence of adjudicated DILI (Unlikely causality AND Mild
severity)


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10.4.3. 
Dyslipidemia 
Dyslipidemia adverse events are defined as events included in the dyslipidemia SMQ.  Analyses 
to be performed specifically for dyslipidemia events include: 
•
Incidence of dyslipidemia TEAEs by PT and presence of dyslipidemia medical
history (yes, no)
•
Incidence of dyslipidemia SAEs by PT and presence of dyslipidemia medical history
(yes, no)
•
Incidence of dyslipidemia TEAEs by PT and statin use at baseline (no concomitant
use, prior and concomitant use, new concomitant use)
•
Incidence of dyslipidemia SAEs by PT and statin use at baseline (no concomitant use,
prior and concomitant use, new concomitant use)
•
Incidence of LDL increase ≥15%
•
Incidence of sustained LDL increase ≥15% (defined as present for 2 or more
consecutive visits)
•
Incidence of dyslipidemia TEAEs preceding any Gallbladder disease and Related
Complications TEAE
•
KM plot for time to onset of first dyslipidemia TEAE
•
Incidence of LDL >100, >130, >190 post baseline (BL) by treatment group.
•
Incidence of LDL increase ≥15%
10.4.4. 
Gallbladder Disease and Related Complications 
TEAEs of Gallbladder Disease and Related Complications, including cholelithiasis and 
cholecystitis, are defined as events included in the Gallbladder Related Disorders narrow SMQ 
and Gallstone Related Disorders narrow SMQ, with additional PTs 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, and Perforation bile duct. 
Specific analyses for gallbladder/gallstone associated events will include: 
•
Incidence of Gallbladder disease and Related Complications TEAEs by PT and
baseline BMI (<30 kg/m2, ≥30 to <35 kg/m2, ≥35 kg/m2)
•
Incidence of Gallbladder and Related Complications TEAEs by PT and body weight
quartiles
•
Incidence of Gallbladder disease and Related Complications TEAEs by PT and
baseline diabetes status (defined as history of diabetes mellitus at baseline or on
antidiabetic medications at baseline with indication of diabetes mellitus or baseline
HbA1c ≥6.5%)
•
Incidence of Gallbladder disease and Related Complications TEAEs by PT and
presence of Gallbladder disease and Related Complications medical history.


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•
Number and percentage of subjects who underwent a cholecystectomy
•
Number and percentage of subjects who underwent a cholecystectomy on or
subsequent to adverse event onset day
•
KM plot for time to onset of first Gallbladder disease and Related Complications
TEAE
•
KM plot for time to onset of cholecystectomy.
•
KM plot for time to onset of cholecystectomy on or subsequent to
gallstone/gallbladder related event onset day
10.4.5. 
Pancreatitis 
Treatment-emergent adverse events of pancreatitis, defined by Acute Pancreatitis narrow SMQ, 
will be summarized as follows: 
•
Incidence of pancreatitis TEAEs, by PT and presence of Gallbladder disease and
Related Complications medical history (yes, no)
•
Incidence of pancreatitis TEAEs, by PT and presence of Pancreatitis (acute or
chronic) medical history (yes, no)
•
Incidence of pancreatitis TEAEs by PT and presence of Gallbladder disease and
Related Complications TEAE (occurring before or simultaneous to Pancreatitis
TEAE)
•
Incidence of pancreatitis TEAEs by glucagon-like peptide-1 (GLP-1) agonist use
(never used, baseline use, initiated during study, baseline use or initiated during
study); Note: GLP-1 use initiated during study will only be counted if initiated prior
to onset of first pancreatitis TEAE.
•
Incidence of pancreatitis TEAEs by shift from baseline to worst post-baseline
triglycerides >1000 mg/dL.  Note: Only the worst post-baseline triglycerides
measurement recorded prior to onset of first pancreatitis TEAE is utilized.
•
KM plot for time to onset of first pancreatitis TEAE
•
KM plot of pancreatitis cases with on treatment gallbladder Disease or related
complications (occurring before or simultaneous to Pancreatitis)
10.4.6. 
Renal Injury 
Treatment-emergent renal injury is broadly defined as events included in the Acute Renal Failure 
SMQ, Chronic Kidney Disease SMQ, Proteinuria SMQ, Renovascular disorders SMQ and 
Tubulointerstitial disease SMQ.  Analyses to be performed specifically for renal events include: 
•
Incidence of renal TEAEs by PT and presence of renal medical history (yes, no)
•
Incidence of renal SAEs by PT and presence of renal medical history (yes, no)
•
Incidence of renal TEAEs in subjects with >50% increase in serum creatinine from
baseline


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•
Incidence of renal TEAEs by worst change from baseline eGFR (≥25% reduction
from baseline – yes, no); Note: Only the worst post-baseline eGFR measurement
recorded prior to onset of first renal TEAE is utilized.
•
EAIR specifically for PTs in the broad SMQ “acute renal failure”
•
Listing and narratives will be provided for any subjects who had:
−
≥2x increase in serum creatinine compared to baseline
−
≥50% decrease in eGFR compared to baseline
−
TEAE of “Nephrolithiasis” (search based on that specific MedDRA PT)
In addition of assessing kidney injury during the trial, the following analyses will be performed, 
per FDA feedback, to identify a potential kidney injury, using the PT terms as noted in 
Appendix C. 
•
To assess severity of acute kidney injury (AKI) the following will be provided:
−
Proportion of subjects with TEAE by PT (as noted in Appendix C, Table C1
[List 1]) including risk differences and 95% CIs (using Cochran-Mantel-Haenszel
[CMH] method)
−
Proportion of subjects with TEAE by PT (as noted in Appendix C, Table C2
[List 2]) including risk differences and 95% CIs (using CMH method)
•
Proportion of subjects who had an action taken due to AKI adverse events including
risk differences and 95% CIs (using CMH method)
•
Incidence of eGFR decrease ≥25% and ≥50 % from baseline by chronic kidney
disease (CKD) stage at baseline based on the standard eGFR categories as defined in
Table 7 (Section 10.5.6).
•
A listing of subjects who discontinue treatment because of renal dysfunction and their
associated last renal lab values while on treatment will be provided by treatment and
eGFR decrease.
10.4.7. 
Urolithiases 
Treatment-emergent urolithiases is defined as events included in the high-level group term 
Urolithiases (SOC Renal and Urinary Disorders).  Analyses to be performed specifically for 
urolithiasis events include: 
•
incidence of urolithiases TEAEs in subjects with >50% increase in serum creatinine
from baseline prior to urolithiases.
10.4.8. 
Hyperglycaemia/New Onset Diabetes Mellitus 
Hyperglycemia is defined as adverse events included in the hyperglycaemia/new onset diabetes 
mellitus narrow SMQ.  Analyses to be performed specifically for hyperglycemia/diabetes events 
include: 


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•
Incidence of Hyperglycaemia/new onset diabetes mellitus TEAEs and SAEs by PT
and baseline diabetes status (history of diabetes mellitus at baseline or on anti-
diabetic medications at baseline with indication for diabetes mellitus or baseline
HbA1c ≥6.5%).
•
Incidence of Hyperglycaemia/new onset diabetes mellitus SAEs by PT and baseline
diabetes status (history of diabetes mellitus at baseline or on anti-diabetic medications
at baseline with indication for diabetes mellitus or baseline HbA1c ≥6.5%).
•
KM plot for time to onset of first Hyperglycaemia/new onset diabetes mellitus TEAE
by baseline diabetes status
•
Incidence of initiation of antidiabetic medication in any non-diabetes mellitus subject
(no history of diabetes at baseline or not already on medication or HbA1c <6.5% at
baseline).
•
Incidence of antidiabetic agent intensification (defined as addition of another oral
agent/ injectable antidiabetic agent / or insulin) post-baseline in subjects with history
of diabetes mellitus or medication for diabetes mellitus at baseline.
•
Incidence of treatment emergent HbA1c ≥6.5% by treatment group and time to event
post-baseline of HbA1c ≥6.5% by treatment group will be presented.
10.4.9. 
Cardiovascular Risk 
10.4.9.1. Adjudicated Cardiovascular Events 
Adjudicated cardiovascular events, including Major Adverse Cardiovascular Events (MACE) 
(defined as death, myocardial infarction, and stroke) and other related events including 
hospitalization for unstable angina, revascularization procedures, hospitalization for congestive 
heart failure, transient ischemic attack, and additional events related to adverse cardiovascular 
outcomes, will be included in the CEC Charter for adjudication.  The adjudication of these 
events will be handled separately from the adjudication of events for assessment of the primary 
clinical composite outcome endpoint in this study.  
Summaries of adjudicated cardiovascular events including 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 and ITT Population. 
The time-to-event endpoints include: 
•
Time from randomization to the first confirmed occurrence of cardiovascular death,
nonfatal myocardial infarction, nonfatal stroke
•
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)


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•
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 hospitalization for clinically
significant arrhythmias
•
Time from randomization to the first occurrence of hospitalization for peripheral
revascularization procedures
In addition, subjects with any adjudicated cardiovascular event will be presented by the 
following lipid subgroups: 
•
Total Cholesterol (TCHOL): Mean and median TCHOL values by visit after first
dose of investigational product.
•
HDL:  Mean and median HDL values by visit values after first dose of investigational
product
•
LDL:  Mean and median LDL values by visit after first dose of investigational
product
•
LDL/HDL: Mean and median LDL/HDL values by visit after first dose of
investigational product
•
Apolipoprotein B: Mean and Median apolipoprotein B values by visit after first dose
of investigation product
Subgroup analysis by prior CV disease, by CV risk factors (eg, FRS), by baseline type 2 diabetes 
mellitus (T2DM) status will be performed.  
Additional analyses for all adjudicated CV events will include: 
•
EAIR of CV cases adjudicated for ALL cases of CV by severity and treatment arms
•
EAIR of CV cases adjudicated as ≥ possible causality and severity by treatment arms
10.4.9.2. Cardiovascular Adverse Events 
CV adverse events are defined as events included in the Embolic and thrombotic events broad 
SMQ, Ischemic heart disease broad SMQ, or Central nervous system vascular disorders narrow 
SMQ. 
Analyses to be performed specifically for CV events include: 


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•
Incidence of CV TEAEs by SOC and PT
•
Incidence of CV TEAEs by PT and presence of CV medical history (yes, no)
•
Incidence of CV SAEs by PT and presence of CV medical history (yes, no)
•
Incidence of CV SAEs by PT and baseline LDL quartiles
•
Incidence of CV SAEs by PT and LDL increase >15% from baseline
•
Incidence of CV SAEs by PT and baseline HDL quartiles
10.4.9.4. Serum Chemistry Lipids 
Summary statistics will be presented for total cholesterol, LDL, HDL, very low density 
lipoprotein (VLDL), and triglycerides by visit, as well as worst and last postbaseline value.  Plots 
will also be created for these parameters showing mean values over time.  Summary tables will 
be repeated for the following subgroups: 
•
Baseline LDL quartiles (Reference categories: <100 mg/dL; 101-103 mg/dL; 131-159
mg/dL; >160 mg/dL)
•
Baseline HDL quartiles
Additionally, shift tables from baseline to each post-baseline visit will be presented for HDL and 
LDL, using the normal and abnormal cutoffs below: 
•
LDL: normal (<100 mg/dL) and abnormal (≥100 mg/dL)
•
HDL: normal (≥40 mg/dL in men, or ≥50 mg/dL in women) and abnormal (<40
mg/dL in men or <50 mg/dL in women)
10.5. 
Clinical Laboratory Evaluations 
Laboratory parameters will be summarized in both conventional units and the standard 
international (SI) system of units.  Analysis of efficacy-related liver biochemistry endpoints is 
specified in Section 6.4.6.3. 
The submitted datasets will also include results from local lab evaluations and these values will 
be flagged in the ADLB dataset with the flag variable LOCALFL=”Y”.  Dataset with 
conventional units will be labelled using standardized names (e.g. ADLB) and the one with SI 
units will be labelled by adding “SI” to the file name (e.g. ADLBSI). 
All clinical laboratory data will be presented in by-subject data listings. 


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10.5.1. 
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.  The 
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. 
10.5.2. 
Shifts in CTCAE Toxicity Grade 
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. 
10.5.3. 
Urine Chemistry and Urinalysis 
Quantitative urine chemistry and urinalysis results by treatment group using descriptive statistics 
at baseline and at each on-study 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.   
10.5.4. 
Liver Laboratory Criteria for Monitoring for Suspected Hepatic Injury or 
Decompensation 
The evaluation of hepatic safety will include the following laboratory parameters: ALT, AST, 
and ALP, GGT, total bilirubin, direct bilirubin, albumin, INR of prothrombin time, and platelets. 
Summary statistics will be presented by visit, including change from baseline and percent change 
from baseline.  In addition, mean values of ALT, AST, ALP, GGT, total bilirubin, direct 
bilirubin, and albumin will be plotted over time.  
Summaries will be repeated by baseline fibrosis stage. 
In addition, the hepatic safety parameters noted above will be utilized to present analyses of 
worst post-baseline elevations.  EAIR will be presented for each of the following 
parameters/criteria at any post-baseline visit: 
•
ALT (≥ULN, ≥3x ULN, ≥5x ULN, ≥10x ULN, ≥20x ULN, or an increase of 250 U/L
from baseline)
•
AST (≥ULN, ≥3x ULN, ≥5x ULN, ≥10x ULN, ≥20x ULN, or an increase of 250 U/L
from baseline)
•
ALP (≥2x ULN, ≥3x ULN, or an increase of 150 U/L from baseline)


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•
Total Bilirubin (≥2x ULN, ≥5x ULN, ≥8x ULN, or an increase of 2 mg/dL from
baseline)
•
Direct Bilirubin (≥2x ULN, ≥5x ULN, or an increase of 1 mg/dL from baseline)
•
GGT (≥2x ULN)
•
INR (≥1.5x ULN, ≥3x ULN, ≥5x ULN
Evaluation of drug-induced serious hepatotoxicity (eDISH) will be conducted to visually 
compare maximum ALT and total bilirubin values at any post-baseline visit.  For subjects with 
baseline ALT or total bilirubin levels 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 ALP and total bilirubin.  Plots 
based on multiples of elevations above the baseline value will use 2×BL for ALP and 2×BL for 
total bilirubin. 
The summary table as well as visual plots will be based on central lab data.  eDISH using 
maximum post-baseline ALT and total bilirubin will be repeated with central and local lab data. 
In addition, EAIR will be presented for each of the following biochemical triggers for potential 
DILI by treatment group using the worst post-baseline elevations.  For subjects with normal 
baseline liver biochemistry: 
•
(ALT ≥3x ULN or AST ≥3x ULN) and total bilirubin ≥2x ULN
•
ALT ≥5x ULN or AST ≥5x ULN
•
ALT ≥8x ULN or AST ≥8x ULN
•
(ALT ≥3x ULN or AST ≥3x ULN) and INR >1.5
•
ALP ≥2x ULN and direct bilirubin ≥2x ULN
•
GGT ≥2x ULN and direct bilirubin ≥2x ULN
For subjects with elevated BL liver biochemistry: 
•
(ALT ≥3x BL or AST ≥3x BL) and total bilirubin ≥2x BL
•
ALT ≥3x BL or AST ≥3x BL
•
ALT ≥5x BL or AST ≥5x BL
•
(ALT ≥2x BL or AST ≥2x BL) and INR >1.5
•
ALP ≥2x BL and ALP >ULN and direct bilirubin ≥2x BL and direct bilirubin >ULN
•
GGT ≥2x BL and GGT >ULN and direct bilirubin ≥2x BL and direct bilirubin >ULN
For the above summaries the following triggers will be also considered to allow identification of 
subjects in whom abnormalities were not detected using elevations relative to baseline: 


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•
Trigger 1: BL ALT + 250 U/L
•
Trigger 2: BL AST +250 U/• Trigger 3: BL ALT + 150 U/L and BL total bilirubin +
2 mg/dL
•
Trigger 4: BL AST + 150 U/L and BL direct bilirubin + 1 mg/dL
•
Trigger 5: BL AST or ALT + 150 U/L and BL total bilirubin + 2 mg/dL
•
Trigger 6: BL AST or ALT + 150 U/L and INR >1.5
•
Trigger 7: BL AST or ALT + 100 U/L and BL total bilirubin + 2 mg/dL and INR >1.5
•
Trigger 8: BL ALP + 150 U/L and BL TB + 2 mg/dL
•
Trigger 9: BL ALP + U/L and Baseline direct bilirubin + 1 mg/dL
•
Trigger 10: BL total bilirubin + 2 mg/dL
•
Trigger 11: BL direct bilirubin + 1 mg/dL
•
Trigger 12: INR >1.5 (confirmed with repeat test and not responsive to vitamin K
administration)
Any elevation ≥1.5x ULN will be categorized as a “elevated” baseline value.  For these analyses, 
the following ULN thresholds will be used: 
•
ALT – 30 U/L
•
AST – 35 U/L
•
Total Bilirubin – 1.25 mg/dL
•
Direct bilirubin – 0.3 mg/dL
•
ALP – 120 IU/L
A summary of the number (%) of subjects who met the stopping criteria provided in Table 3 of 
the protocol (see Appendix D) will be presented by treatment group and each of the criteria.  A 
listing of these subjects with the associated laboratory parameters will be presented along with 
the action taken with the study drug and flags to denote values or subjects that meet the proposed 
mitigation criteria for DILI. 
10.5.5. 
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.  
Analyses of quantitative lipoprotein analytes will be carried out using MMRM as described in 
the General Statistical Methods (Section 4).   


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Subgroup analysis by statin use (no concomitant statin use, statin use started prior to first dose of 
investigational product and statin use started after first dose of investigational product) will be 
performed.  In addition to statin use, similar subgroup analyses will be performed by use of other 
antihyperlipidemic drugs.  Only descriptive statistics will be provided.  
10.5.6. 
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, serum creatinine, and urinary albumin to creatinine ratio as specified in Table 8.  The 
summary will also be repeated for baseline CKD stage, baseline diabetes status (history of 
diabetes mellitus at baseline or on antidiabetic medications at baseline with indication for 
diabetes mellitus or baseline HbA1Cc ≥ 6.5%), and baseline fibrosis stage.  The 95% CIs for the 
difference in mean change will be also presented. 
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. 
Plots will be created to show mean laboratory (kidney function) data change from baseline over 
time for eGFR, serum creatinine, and as appropriate other markers of kidney function or injury 
such as Albumin to creatinine ratio.  An additional plot for the percent change from baseline over 
time will be created only for serum creatinine. 
Descriptive statistics for eGFR will be presented for subgroups by baseline CKD stage, baseline 
diabetes status, and baseline fibrosis stage. 
Renal safety parameters serum creatinine and eGFR will also be utilized to present analyses of 
the worst change from baseline at any post-baseline visit, including risk differences and 95% CIs 
(using CMH method).  The following change from baseline categories will be analyzed: 
•
Creatinine (≥1.5 x BL, ≥2.0 x BL, ≥3.0 x BL)
•
eGFR (≥25% decrease from BL, ≥50% decrease from BL, ≥75% decrease from BL)
A listing will be created to display subjects with any post-baseline serum creatinine value ≥2.0 x 
BL or eGFR ≥50% decrease from BL.  
A summary will also be provided based only on the last on-treatment measurements recorded for 
serum creatinine and eGFR, including risk differences and 95% CIs (using CMH method).  The 
following change from baseline categories will be analyzed: 
•
Creatinine (≥1.5 x BL, ≥2.0 x BL)
•
eGFR ((≥25% decrease from BL, ≥50% decrease from BL)
In addition, shifts from baseline to each on-study evaluation will be presented for eGFR, based 
on the standard eGFR categories as defined in Table 7. 


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Table 7: 
Stages of CKD 
CKD Stage 
Glomerular Filtration Rate (mL/min/1.73 m2) 
G1/Normal 
≥90 
G2 
60 – 89 
G3 
30 – 59 
G3a 
45-59
G3b 
30-44
G4/5 
<30 
CKD = chronic kidney disease; G = Group 
Shifts from baseline to Month 18 in urinary albumin to creatinine ratio (mg/g) will also be 
presented using the categories defined in Table 8. 
Table 8: 
Cutoffs of Albumin to Creatinine Ratio 
Category 
Albumin to Creatinine Ratio (mg/g) 
Normal 
<30 
Microalbuminuria 
30 – 300 
Macroalbuminuria 
>300
10.6. 
Pregnancies 
If any subject gets pregnant during the course of the study, a by-subject data listing will be 
provided including all data on the Pregnancy eCRF. 
10.7. 
Vital Signs 
The results, change and percentage change from Baseline to each on-study evaluation visit will 
be summarized for oral temperature, sitting heart rate, and respiratory rate.   
All vital sign data will be presented in by-subject data listings. 
10.8. 
Electrocardiograms 
The central read ECG data will be analyzed based on methodology recommended in the 
International Conference on Harmonisation (ICH) E14 guideline, The Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs.   
Baseline is defined as the mean of all available evaluations before treatment.  Descriptive 
statistics of ECG parameters (time between 2 consecutive R waves [RR], PR, QRS, QT, and QT 
interval corrected by the 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 subjects with values of >450 msec, >480 msec, and >500 msec will be presented, and 


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the number of subjects with change from baseline values of >30 msec and >60 msec will also be 
presented.   
Overall interpretation results for ECGs and the investigator interpretation results are collected as 
normal, abnormal not clinically significant (NCS), and abnormal clinically significant (CS).  
Subjects whose interpretations shift from normal to abnormal (CS or NCS) will be listed 
separately, including description of the abnormality and any associated comments. 
All ECG results will be presented in by-subject data listings. 
11.
CHANGES TO PLANNED ANALYSES
As of this date, the Month 18 IA analyses for resubmission have been conducted per FDA 
agreement following SAP addendum V2.0 (dated 25April 2022).  
The key changes for this SAP are summarized in the table below: 
Key Changes 
Rationale 
Contents 
Changed to one 
clinic outcome 
interim analysis at 
66% of information 
fraction  
One IA 66% information fraction will 
balance preserving type I error with 
obtaining a reasonable estimate of 
clinical outcomes efficacy while 
minimizing the potential for any 
increases of patient discontinuations 
as a result of availability of 
commercial OCA should the agency 
grant approval of OCA for the NASH 
indication.  
Changed to IA at 66% of 
information fraction from two 
IAs at 50% and 80% before end 
of study analysis under 
section 2.2. 
Updated Alpha spending and 
HR boundaries under 
section 3.2. 
Added Estimands 
for clinical 
composite outcomes 
for end of study 
analyses  
Per current regulatory 
agencies, the estimand 
approach following the ICH 
request for the definition of 
Estimands should be defined 
in clinical trials and the 
statistical analysis plan. 
Estimands including strategies 
to handle the intercurrent events 
are provided under 
section 2.3.2.1. 
Updated monitoring 
plan 
The monitoring of clinical 
outcome events will be used 
to set up the timeline to 
initiate and prepare for IA and 
end of study analysis per 
FDA’s comment. 
Updated Monitoring plan for IA 
and End of study analysis under 
section 6.4.1. 


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Key Changes 
Rationale 
Contents 
Included 
description of 
consensus method 
Consensus Method has been 
used to re-read the liver 
biopsies samples for 
histological endpoint 
estimates at Month 18 interim 
analysis resubmission per 
FDA agreement.  It will be 
used for subsequent 
histological analysis for 
clinical outcomes assessment.  
Description of Consensus 
Method under section 6.2.2. 
Added Safety 
Objectives to be 
assessed and 
additional AESIs 
Based on the FDA feedback 
after Month 18 interim 
analysis submission according 
to protocol version 11.0 
(Dated 04May2021) 
Added additional analyses for 
AESIs under section 10.4. 
Added additional analyses based 
on adjudicated data by Renal, 
Cardiovascular Diseases and 
Hepatic Safety Committee under 
section 10.4 
Added Analysis of 
Covid-19 impact on 
the study   
Following FDA guidance: 
Conduct of Clinical Trials of 
Medical Products During the 
COVID-19 Public Health 
Emergency 
Impact of Covid-19 on protocol 
deviations under section 5.6 
Incidence of Covid-19 infection 
under section 10.3 
Incidences of AEs before and 
after Covid-19 under section 10. 
Updated lab 
analysis 
Per FDA feedbacks, 
additional lab data analyses 
related to cardiovascular, 
renal and hepatic injuries 
from both local and central 
laboratories have been 
produced in Month 18 IA 
resubmission and will be also 
done at the end of study 
Updated Serum Chemistry 
Lipids analysis under 
section 10.4.9.4 
Updated Liver Injury related lab 
data analyses under 
section 10.5.4. 
Updated Renal injury related lab 
data analyses under 
section 10.5.6 


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12.
REFERENCES
Guidance for Industry E9: Statistical Principles for Clinical Trials. U.S. Department of Health 
and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research 
(CDER), Center for Biologics Evaluation and Research (CBER), September 1998. 
Guidance for Industry E9(R1): Statistical Principles for Clinical Trials: Addendum: Estimands 
and Sensitivity Analysis in Clinical Trials. U.S. Department of Health and Human Services, Food 
and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for 
Biologics Evaluation and Research (CBER), May 2021. 
CKD-EPI Chronic Kidney Disease Epidemiology Collaboration. Implementation of the 2021 
CKD-EPI Equations, October 2021. 
Guidance for Industry E14 The Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-antiarrhythmic Drugs, U.S. Department of Health and Human 
Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 
October 2005. 
Lan KKG, DeMets DL. Discrete sequential boundries for clinical trials. Biometrika. 
1983;70(3):659-3. 
Mayo MJ, Parkes J, Adams-Huet B, Combes B, Mills AS, Markin RS, R, Wheeler D, Contos M, 
West AB, Saldana S, Getachew Y, Butsch R, Luketic V, Peters M, Di Bisceglie A, Bass N, Lake 
J, Boyer T, Martinez E, Boyer J, Garcia-Tsao G, Barnes D, Rosenberg WM. Prediction of 
clinical outcomes in primary biliary cirrhosis by serum enhanced liver fibrosis assay. Hepatology 
2008; 48: 1549-1557. 
Reboussin DM, DeMets DL, Kim KM, Lan KK. Computations for group sequential boundaries 
using the Lan-DeMets spending function method. Control Clin Trials. 2000; 21:190-207. 
Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley & Sons; 
1987. 
Vansteelandt S, Carpenter J, Kenward M. Analysis of Incomplete Data Using Inverse Probability 
Weighting and Doubly Robust Estimators. Methodology 2010; Vol. 6(1):37–48. 


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APPENDIX A. DATA CONVENTIONS AND STANDARD 
PROGRAMMING 
DATA PRESENTATION CONVENTIONS: 
The precision of original measurements will be maintained in summaries, when possible.  
Minimum and Maximum will be presented with the same decimal places as the raw data.  
Means, medians, SEMs, and SDs will be presented with an increased level of precision, where 
means, medians, and percentiles will be presented to one more decimal place than the raw data, 
and the SEMs and SDs will be presented to two more decimal places than the raw data.  In 
general, the decimal places should not exceed 3 decimal places, unless appropriate.   
For tables where rounding is required, rounding will be done to the nearest round-off unit.  For 
example, when rounding to the nearest integer, values ≥XX.5 will be rounded up to XX + 1 
(eg, 97.5 will round up to 98), while values <XX.5 will be rounded down to XX (eg, 97.4 will 
round down to 97).  
Percentages based on frequency counts will be based on available data, and denominators will 
generally exclude missing values.  Percentages based on frequency counts will be presented as 
whole numbers (no decimal places), and values less than 1% will be presented as “<1%.”  Values 
less than 100% but that round up from 99.5% to 100% will be presented as “>99%.” 
Quantitative laboratory tests containing less than (<) and greater than (>) symbols are test results 
that are below and above quantifiable limits, respectively.  In order to retain these values for 
analysis purpose, the following imputations will be done within the analysis datasets: 
For laboratory test results that are below the quantifiable limit: 
Imputed laboratory results = (numeric portion of the result) x 0.9. 
For laboratory test results that are above the quantifiable limit: 
Imputed laboratory results = (numeric portion of the result) x 1.1. 
Date variables will be formatted as DDMMMYYYY for presentation.  Time will be formatted in 
military time as HH:MM for presentation. 
All output will be incorporated into Microsoft Word rich text format (.rtf) files, sorted, and 
labeled according to the ICH recommendations, and formatted to the appropriate page size(s). 
PROGRAMMING CONVENTIONS AND STANDARD CALCULATIONS: 
Partial and Missing Dates 
If only a partial date is available, and it is required for analysis (for example, duration or time to 
event analysis), the following general imputation rules will be applied.  More details will be 
provided below for each specific safety endpoints.  
•
Start date:
−
For missing day only – Day will be imputed as the first day of the month (ie, 1).


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−
For missing day and month – Day and month will be imputed as the first day of
the year (ie, 1 January).
−
Missing dates will not be imputed
•
Stop date:
−
For missing stop day only - Day will be imputed as the last day of the month
(ie, 28, 29, 30, or 31).
−
For missing stop day and month - Day and month will be imputed as the last day
of the year (ie, 31DEC).
−
Imputed stop dates must be on or after the start date.
Partial Date Imputation by Safety Endpoints: 
•
Diagnosis date:  Follow the general imputation rules above for start date
•
Concomitant medication Start date: Follow the general imputation rules with the
following exceptions:
−
If the partial date falls in the same month and year as the first dose date, then the
partial date will be imputed to equal the first dose date
−
If the partial date falls in the same year as the first dose date, then the partial date
will be imputed to equal the first dose date
•
Investigational Product (OCA): Consider only exposure records with non-missing
dose.
−
If start date is partial or missing, then start date = non-missing stop date of the
preceding exposure record +1 if there is a preceding record (including
interruptions and drug holiday).  If both dates are partial, choose the date in the
middle after imputing the earliest date as the first day in the month and the latest
date as the last day in the month.
−
If stop date is partial or missing, then stop date = non-missing start date of the
following exposure record -1.  If both dates are partial, choose the date in the
middle after imputing the earliest date as the first day in the month and the latest
date as the last day in the month.
−
Missing stop date in the last exposure record will be imputed by the earliest of
1. Last exposure date in the EOT/EOS CRF.
2. End of treatment visit date
3. Last visit before the end of treatment
4. End date of study discontinuation, death date or data-cutoff date


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•
Adverse Events:
−
Missing start day of the first record of AEs with the same system organ class
(SOC) and preferred term (PT):  Day will be imputed as the first day of the month
with the following exception:  if the partial date falls in the same month and year
as the first dose date, then the partial date will be imputed to equal the first dose
date.
−
Missing start day and month of the first record of AEs with the same system
organ class (SOC) and preferred term (PT): Day and month will be imputed as the
first day of the year with the following exception:  if the partial date falls in the
same year as the first dose date, then the partial date will be imputed to equal the
first dose date
−
Imputed start dates must be prior to the stop date.
−
Missing stop day only: Day will be imputed as the latest of the last day of the
month (ie, 28, 29, 30, or 31).
−
For missing stop day and month - Day and month will be imputed as the last day
of the year (ie, 31DEC).  Imputed stop dates must be on or after the start date.
Last Contact Date: 
Last contact date for time-to-event analysis is calculated as follows: 
•
Ongoing Subjects (including subjects on-treatment and subjects that discontinued
treatment but on-study):  DCO date
•
Subjects that discontinued study: The date of study discontinuation
•
Subjects lost to follow up: The latest of last assessment, last visit, and last dose date
Standard Calculations: 
Variables requiring calculation will be derived using the following formulas: 
•
Days – A duration expressed in days between one date (date1) and another later date
(date2) will be calculated using the following formulas:
duration in days = date2 – date1 + 1, where date1 ≥first dose date 
duration in days = date2 – date1, where date1 <first dose date 
•
Months – A duration expressed in months is calculated as the number of days divided
by 28 for study-related duration.
•
Years – A duration expressed in years between one date (date1) and another date
(date2) is calculated using the following formulas:
duration in years = (date2 – date1 + 1)/(# of days in the year), where date1 ≥first 
dose date 


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duration in years = (date2 – date1)/ (# of days in the year), where date1<first dose 
date 
# of days in the year= 336 is based on 12 months with 28 days per month for 
study-related duration calculations.  
# of days in the year= 365.25 for age, years since NASH  diagnosis, patient-year 
and other duration calculations that are not study-related 
•
Age – Age is calculated as the number of years from the date of birth (DOB) to the
specified date, eg, date of informed consent (DOIC).  If the month of DOIC <month
of DOB or the month of DOIC=DOB and the day of DOIC <day of DOB, then the
following formula is used:
age (years) = year of DOIC – year of DOB – 1. 
Otherwise, the following formula is used: 
age (years) = year of DOIC – year of DOB. 
If only Year is provided in DOB then use July 1 for the month and day  
•
Date of birth in Year format:  To convert the date of birth format from
Day/Month/Year to Year only, the following will be applied:
If birth date before July 1, then use year of birth= reported year -1 
If birth date after July 1, then use year of birth= reported year  
•
Height – Height entries made in inches (in) are converted to centimeters (cm) using
the following formula:
height (cm) = height (in) × 2.54 
•
Weight – Weight entries made in pounds (lb) are converted to kilograms (kg) using
the following formula:
weight (kg) = weight (lb) / 2.2046 
•
Temperature – Temperature entries in degrees Fahrenheit are converted to degrees
Celsius using the following formula:
temp (degrees Celsius) = 5 / 9 × (temp [degrees Fahrenheit] – 32) 
•
Body Mass Index (BMI) – BMI is calculated using height (cm) and weight (kg) using
the following formula:
BMI (kg/m2) = weight (kg) / ([height (cm)/100]2) 
•
Change from Baseline – Change from Baseline will be calculated as:
Change = post Baseline value – Baseline value 
•
Percentage change from Baseline – Change from Baseline will be calculated as:
Percentage change from Baseline = ([post Baseline value – Baseline value] / 
Baseline value) × 100 


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•
NAS (0-8) is derived as the sum of three components of standardized histologic
feature scoring system for liver biopsies:
NAS = steatosis score (0-3) + lobular inflammation score (0-3) + hepatocellular 
ballooning score (0-2) 
•
MELD score will be reported as an integer and is derived using the following formula
(OPTN):
Candidates who are at least 12 years old receive an initial MELD(i) score equal 
to:   
0.957 x Loge(creatinine mg/dL) + 0. 378 x Loge(bilirubin mg/dL) + 1.120 x Loge 
(INR) + 0.643 Laboratory values less than 1.0 will be set to 1.0 when calculating 
a candidate’s MELD score.  
The maximum MELD score is 40.  The MELD score derived from this calculation 
will be rounded to the tenth decimal place and then multiplied by 10.   
For candidates with an initial MELD score greater than 11, the MELD score is 
then re-calculated as follows:   
MELD = MELD(i) + 1.32*(137-Na) – [0.033*MELD(i)*(137-Na)] 
Sodium values less than 125 mmol/L will be set to 125, and values greater than 
137 mmol/L will be set to 137.  MELD Na will be rounded to the nearest integer. 
MELD Score computed from lab results for samples collected in the same visit 
date.  Any exceptional cases, prior to protocol version X, will be documented  
•
The eGFR will be calculated using the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) 2021 equation (CKD-EPI Chronic Kidney Disease
Epidemiology Collaboration 2021):
𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒(𝑚𝑚𝑚𝑚/𝑚𝑚𝑚𝑚𝑚𝑚/1.73 𝑚𝑚2) = 142 ×
൬𝑆𝑆𝑐𝑐𝑐𝑐
𝛼𝛼൰
−0.241
× 0.993𝑎𝑎𝑎𝑎𝑎𝑎× 1.012 𝑖𝑖𝑖𝑖 𝑆𝑆𝑐𝑐𝑐𝑐
≤α for female 
−
= 142 × (𝑆𝑆𝑆𝑆𝑆𝑆/𝛼𝛼)-1.200 × 0.993𝑎𝑎𝑎𝑎𝑎𝑎 × 1.012 𝑖𝑖𝑖𝑖 Scr  > 𝛼𝛼 for female
−
= 142 × (𝑆𝑆𝑆𝑆𝑆𝑆/𝛼𝛼)-0.302 × 0.993𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 Scr  <= 𝛼𝛼 for male
−
= 142 × (𝑆𝑆𝑆𝑆𝑆𝑆/𝛼𝛼)-1.200 × 0.993𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 Scr  > 𝛼𝛼 for male
Where Scr (standardized serum creatinine) = mg/dL, α = 0.7 if female and 0.9 if male, 
age = years.  


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Baseline Definition: 
−
The table below provides baseline definition for the endpoints to be analyzed.  If
the endpoint doesn’t have assessment except at Day 1 (such as PRO) then
baseline will be Day 1 value
−
High/Low/Normal will be derived for baseline values, calculated as the mean of
all pre-treatment results, based on the ULN and LLN.
−
Subjects with repeated baseline:  For the purpose of change from baseline, if the
subject has a repeated baseline after IP re-challenge, change from baseline will
based on the 1st baseline value
Baseline Definition 
Assessment 
Baseline Definition 
Serum Chemistry, Hematology and 
Coagulation 
The mean of all available evaluations prior to the first 
administration of investigational product.   
Lipoprotein 
The last fasted assessment prior to the first administration of 
investigational product   
Markers of glucose metabolism 
The last fasted assessment prior to the first administration of 
investigational product   
Cardiovascular Assessment 
The last assessment prior to the first administration of 
investigational product   
ECG 
The mean of all available evaluations prior to the first 
administration of investigational product.   
Anthropometric measures 
The mean of all available evaluations prior to the first 
administration of investigational product   
Vital signs 
The mean of all available evaluations prior to the first 
administration of investigational product   
Exploratory Biomarkers 
The mean of all available evaluations prior to the first 
administration of investigational product.   


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Pharmacodynamic Parameters 
The mean of all available evaluations prior to the first 
administration of investigational product.   
Additional Conventions: 
1. Normal reference ranges may change during the study due to assays re-validated with
new reference ranges.  For example, reference ranges used in the 747-303 study including
INR, APT, APPT, Bicarbonate have been updated during the study.
−
INR, APT, and PPT:  Changes in normal reference ranges were implemented to
reflect appropriate ranges based on collected data overtime.  The update in
reference ranges does not reflect changes in sample analysis and consequently the
same value corresponding to reference ranges should be considered the same.
The latest reference range will be used in summaries.  In listings, reference ranges
will be reported as received from ICON lab.
2. Concomitant medications:
−
Use of CMSCAT and CMCLASCD versus ATC (level 2, level 4) for
hypertensive medications and diabetic medications along with indication.
3. AEs: SMQ
-
Hepatic disorder: Hepatic Disorders SMQ, excluding the following sub-SMQs:
congenital, familial, neonatal and genetic disorders of the liver; Liver infections;
alcohol related sub SMQ as one of the excluded sub SMQ, and Pregnancy-related
hepatic disorders.
-
Cardiac events: the MedDRA Broad SMQs of embolic and thrombotic events or
Ischemic heart disease, or Central nervous system vascular disorders narrow
SMQ.
-
Renal AEs: Renal Standardized MedDRA query (SMQ): acute renal failure,
chronic kidney disease, proteinuria, renovascular disorders, or tubulointerstitial
diseases
-
Dyslipidemia: Dyslipidemia SMQ
-
Gallbladder Disease and Related Complications: Gallbladder Related Disorders
narrow SMQ and Gallstone Related disorders narrow SMQ, with additional PTs
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, and Perforation bile duct.
-
Pancreatitis: Acute Pancreatitis narrow SMQ
-
Hyperglycemia: Hyperglycaemia/new onset diabetes mellitus narrow SMQ
4. CTCAE Clarifications:
−
CTCAE for PH is based on blood test and not urine test


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−
CTCAE for glucose depends on fasting glucose test for grade 1-2 and any
available glucose test (fasting or non-fasting) for grade 3-4.
−
Lab units in CTCAE grade derivation:  Values in SI values will be used to derive
CTCAE classification


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APPENDIX C. PREFERRED TERMS TO IDENTIFY POTENTIAL 
KIDNEY INJURY 
Table C1: Preferred Terms (List 1) 
Acute kidney injury 
Acute phosphate nephropathy 
Acute prerenal failure 
Anuria 
Cardiorenal syndrome 
Continuous haemodiafiltration 
Crush syndrome 
Crystal nephropathy 
Haemolytic uremic syndrome 
Hepatorenal failure 
Nephritis 
Nephropathy toxic 
Pancreatorenal syndrome 
Postoperative renal failure 
Postrenal failure 
Prerenal failure 
Renal failure acute 
Renal injury 
Renal ischemia 
Renal tubular injury 
Renal tubular necrosis 
Traumatic anuria 
Tubulointerstitial nephritis 
Urate nephropathy 
Urine output decreased 


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Table C2:  Preferred Terms (List 2) 
Azotemia 
Blood creatinine abnormal 
Blood creatinine increased 
Blood urea increased 
Blood urea nitrogen/creatinine ratio increased 
Creatinine renal clearance abnormal 
Creatinine renal clearance decreased 
Dialysis 
Glomerular filtration rate abnormal 
Glomerular filtration rate decreased 
Haemodialysis 
Haemofiltration 
Hypercreatinemia 
Hypercreatininemia 
Metabolic nephropathy 
Neonatal anuria 
Oedema due to renal disease 
Renal disorder 
Renal failure 
Renal failure neonatal 
Renal function test abnormal 
Renal impairment 
Renal insufficiency 
Renal tubular disorder 
Renal tubular dysfunction 
Subacute kidney injury 
Urea renal clearance decreased 
Urinary tract toxicity 


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APPENDIX D. LIVER LABORATORY CRITERIA FOR MONITORING 
FOR POTENTIAL HEPATIC INJURY 
SiTns and 
Basl'linl' 
Tt·l'atment Eml't-gl'nt 
Symptoms of 
Action 
Hepatic Injury• 
ALT2:5xULN 
TB normal 
No 
• Repeat laborat01y testing
Gilbe.rt•sc: no change in BL 
including CPK within 2-4 days
TB 
Interrnpt 
ALT2:3xULN 
Yes 
• Repeat laborat01y testing
Regardless of TB or DB 
including CPK within 2-4 days
ALTNomial/Near 
• Collect PK sample within 7 days
om1alb 
Interrnpt 
ALT2:8xULN 
No 
• Repeat lahorat01y testing
Regardless of TB or DB 
including CPK within 2-4 days
• Collect PK sample within 7 days
ALT 2:3x ULNTB 2:2x ULN 
Interrnpt 
Gilbe1t•sc: DB 2:2x ULN or 
No 
• Repeat laborat01y testing
INR 
including CPK within 2-4 days
>l.5
• Collect PK sample within 7 days
ALT 2:3x BL or 2:300 U/L, 
whichever occurs first 
TBnom1al 
No 
• Repeat laborat01y testing
Gilbe1t'sc: no change from BL 
including CPK within 2-4 days
TB 
ALT 2:2x BL or 2:300 U/L, 
Interrnpt 
whichever occurs first 
Yes 
• Repeat lahorat01y testing
Regardless of TB or DB 
including CPK within 2-4 days
• Collect PK sample within 7 days
ALT Elevatedb 
ALT 2:5x BL or 2:500 U/L 
Intel'l'upt 
whichever occurs first 
No 
• Repeat laborat01y testing
Regardless of TB or DB 
including CPK within 2-4 days
• Collect PK sample within 7 days
ALT 2:2x BL or 2:300 U/L, 
Inte1Tupt 
whichever occurs first 
TB2:2xULN 
No 
• Repeat lahorat01y testing
Gilbe1t'sc: DB >2x ULN or 
including CPK within 2-4 days
INR>l.5 
• Collect PK sample within 7 days
TB (>1.5 mg/dL 
lntel'l'Upt 
exclusion criterion 
TB 2:2.0 mg/dL and DB >30% 
Yes/No 
• Repeat laborat01y testing
747-303)
ofTB 
including CPK within 2-4 days
• Collect PK sample within 7 days
Confidential and Proprietary 


Statistical Analysis Plan 
Protocol 747-303 
Baseline 
ALP:'.'SULNd 
ALP>ULNd 
Treatment Emergent 
ALP ?:_2x BL and >ULN 
ALP ?:_2x BL or >300 U/L, 
whichever occurs first 
Signs and 
Symptoms of 
Hepatic Injury" 
No 
Yes 
No 
Yes 
Action 
31Jan2023 
Page 91 
If ALP <250 UIL, then: 
• Repeat laboratory testing
including CPK within 2-4 days
If ALP ?:_250 UIL, then: 
lntel'l'Upt 
• Repeat laboratory testing
including CPK within 2-4 days
• Collect PK sample within 7 days
Interrnpt 
• Repeat laboratory testing
including CPK within 2-4 days
• Collect PK sample within 7 days
If ALP <300 U/L, then:
• Repeat laborat01y testing
including CPK within 2-4 days
If ALP ?:_300 U/L, then: 
Intel'l'upt 
• Repeat laborat01y testing
including CPK within 2-4 days
• Collect PK sample within 7 days
Intel'l'upt 
• Repeat laborat01y testing
including CPK within 2-4 days
• Collect PK sample within 7 days
ALP = alkaline phosphatase; ALT = alanine aminotransferase; BL = baseline; DB = direct bilirubin; CPK = creatine 
phosphokinase; DILI = drug-induced liver injury· INR = international nonnalized ratio; NASH = nonalcoholic 
steatohepatitis; OCA = obeticholic acid; PK = pharn1acokinetic; TB = total bilirubin; ULN = upper Ii.nut of n01mal 
• Signs and symptoms of hepatic injury include severe fatigue, nausea, vomiting, right upper quadrant pain, fever,
rash, and eosinophilia.
b Baseline ALT is defined as an average of all pre-treatment values from Screening and Day I. Elevated Baseline
defined as ALT ?:_l.5x ULN. ALT decreases are common within the first 3-6 months of treatment in NASH
subjects receiving OCA. If there is a decrease in ALT for all lab draws through the Month 6 Visit, then a new
baseline should be established for subsequent DILI detern1ination, based on the average ALT from the Month 3
and Month 6 Visits.
c A subject will be considered to have Gilbert's syndrome if it was established at baseline and documented in the 
subject's medical hist01y. 
d Baseline ALP is defined as an average of all pre-treatment values from Screening and Day I. Modest ALP 
increases ( <50%) from baseline within the first 3 months of treatment are common in NASH subjects receiving 
OCA and represent an expected phaimacodynamic effect. If there is an increase in ALP through the Month 6 
Visit, then a new baseline should be established for subsequent DILI detemiination, based on the average ALP 
from the Month 3 and Month 6 Visits. 
Confidential and Proprietary