AURORA: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adult Subjects With Nonalcoholic Steatohepatitis
Phase: PHASE3
Conditions: Nonalcoholic Steatohepatitis
Sponsor: Tobira Therapeutics, Inc.

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Title Page
Title:
AURORA: A Phase 3, Multicenter, Randomized, 
Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Cenicriviroc for the Treatment of Liver 
Fibrosis in Adult Subjects with Nonalcoholic Steatohepatitis 
Protocol Number:
3152-301-002
Amendment Number: 
4
Product:
Cenicriviroc mesylate (CVC)
Phase of Study:
3
Sponsor Name and:
Tobira Therapeutics, Inc., a subsidiary of Allergan plc
Legal Registered Address
701 Gateway Blvd, Suite 300
South San Francisco, CA 94080
United States of America
Allergan Limited, 
Marlow International, The Parkway, 
Marlow, Buckinghamshire SL7, 1YL
EudraCT Number:
2016-004566-26
Emergency Telephone Number
Refer to the study contacts page
SAE Reporting Fax Number/Email:
Business Unit 
/Legacy 
Organization
Email
Phone
Fax
Allergan
Not applicable
Approval Date: 25 April 2019

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Protocol Amendment Summary of Changes 
DOCUMENT HISTORY
Document
Date
Amendment 4
25 Apr 2019
Amendment 3
10 Apr 2018
Amendment 2
29 Jun 2017
Amendment 1
04 May 2017
Original Protocol
05 Dec 2016
The purpose of Global Protocol Amendment 4 is to provide additional clarification and 
updates to the previous Global Protocol Amendment 3 (dated 10 Apr 2018, details provided 
in Section 12.19). These changes will not impact the safety assessment of CVC or alter the 
risk-benefit ratio for study subjects.
The following is a summary of content-oriented changes that were made. Strikethrough text 
denotes text removed and bolded text denotes added text. Additional administrative edits 
were also made, but not specifically noted (eg, corrected spelling, punctuation, grammar, 
abbreviation, and style errors) including global edits required for consistency.
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.

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Protocol Section(s)
Summary of Changes
Rationale for Changes
General 

All instances of 8 weeks changed to 3 months

All instances of 180 days changed to 6 months
In response to request from the sites to 
increase duration of 8 weeks for timing of 
Screening visit to facilitate enrollment. All 
instances of “weeks” has been changed to 
“months” for clarification and consistency 
with current practice.
Cover page and Section 1 
Emergency Contacts

Updated emergency contact and SAE reporting information

Added address for Allergan international office in Marlow

Added “Allergan Global Patient Safety and Epidemiology” under 
SAE/Pregnancy/AEoSI Reporting
To align with current Allergan template
Section 1 Emergency Contacts
Updated information for Syneos Medical Monitoring Team
Updated to reflect change in CRO to 
Syneos
Section 4 Synopsis

All relevant changes made below in subsequent sections in the body have
been carried up to the synopsis

Increase in number of sites from 425 up to 600
To align with the body of the protocol
To increase the number of subjects who 
will be randomized
Section 5.3 Clinical Studies 
with CVC

Updated exposure data
To reflect current information
Section 5.3.2 Phase 1 PK 
Study in Subjects with Hepatic 
Impairment

Added details regarding patient population for 652-1-121

Added details regarding Study 3152-102-002

To provide additional clarity

To provided updated information 
regarding 3152-102-002, now 
completed
Section 5.3.3 Phase 2b Study 
in Subjects with NASH and 
Liver Fibrosis 
Updated results for year 2 CENTAUR based on final CSR
To reflect final results for CENTAUR as 
provided in the final CSR
Section 5.4 Study Rationale, 
Section 7.1 Overall Study 
Design and Plan, Section 8 
Study Population
Re-worded for clarification and added details regarding newly randomized 
Stage 3 subjects in Part 2
For clarification

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Protocol Section(s)
Summary of Changes
Rationale for Changes
Section 6 Objectives, 
Section 6.1 Part 1

Redefined primary efficacy objective and endpoint for Part 1:
Primary Objective (Part 1): Demonstrate the superiority of CVC compared 
to placebo on liver histology at Month 12 relative to the Screening biopsy 
in adult subjects with a liver biopsy diagnosis of NASH and Stage 2 or 3 
liver fibrosis (by NASH CRN system) as confirmed by an independent 
central pathologist. 
Primary Efficacy Endpoint: Proportion of subjects with improvement in 
fibrosis by at least 1 stage (NASH CRN system) AND no worsening of 
steatohepatitis (no worsening of lobular inflammation or hepatocellular 
ballooning grade). 

Reorganized secondary efficacy objectives for Part 2 (Section 6.2) by 
moving 5th and 6th bullet up. There was no change in text.
Section 7.1 Overall Study 
Design and Plan

Re-worded for clarification and to add details regarding newly 
randomized Stage 3 subjects in Part 2:
Part 2 of the study will focus on assessing the effect of CVC on clinical 
outcomes (Section 7.1.2) and will include approximately 2000 subjects, of 
which up to 1200 subjects will have been randomized in Part 1. In Part 2, 
approximately 800 subjects will be newly enrolled and randomized 2:1 to 
receive CVC or placebo. 
The study population will include the following:
•
Part 1: adult subjects with a liver biopsy diagnosis of NASH and 
Stage 2 or 3 liver fibrosis (by NASH CRN system) as confirmed by an 
independent central pathologist
•
Part 2: subjects who continue on from Part 1 as well as newly 
randomized adult subjects with a liver biopsy diagnosis of NASH and 
Stage 2 or 3 liver fibrosis (by NASH CRN system) 
Section 7.1 Overall Study 
Design and Plan

Added a statement clarifying subsequent study visits

Revised Figure 1, and revised footnote a, g, and h

Added text regarding source of liver fibrosis

Added description of PRO assessment via electronic tablet

Added description of the subjects to be newly enrolled and randomized to 
Part 2

Table 4 was edited to reflect these are subjects in Part 2 and instructions 
For clarification

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Protocol Section(s)
Summary of Changes
Rationale for Changes
were clarified
Section 8.1 Number of 
Subjects
Added details regarding patient population Part 2
Section 8.2 Inclusion Criteria
Added details in IC #4 regarding newly randomized Stage 3 subjects in 
Part 2
For clarification
Section 8.3 Exclusion Criteria

Added “at Screening” for EC #12-16

Defined stable weight in EC #18

EC#23: Added additional details regarding immunomodulating agents, 
vaccines, and steroids

EC#24: Added exception for subjects in stable therapy with GLP-1 
receptor agonists for more than 6 months

EC#25: Added details regarding disallowed medication use and washout 
period 
For clarification
Section 9.1 Treatments 
Administered
Added details regarding newly randomized Stage 3 subjects in Part 2
Section 9.2 Study Drug; 
Section 9.2.8 Part 2
Re-worded for clarification and to add details regarding newly randomized 
Stage 3 subjects in Part 2
Section 9.4 Blinding
Clarify that individual subject treatment assignments will not be provided to 
sites, subjects, or study staff/sponsor until analysis of Part 2
For clarification
Section 9.5 Prior, 
Concomitant, and Subsequent 
Therapy

Added details regarding disallowed medication use and washout period

Added details regarding disallowed antidiabetic agents

Added clarification on Fentanyl use
For clarification and update
Section 10.1 Part 1 and Part 2: 
Screening (Month 2; Visit 1)
Text added to allow retest for subjects who do not meet laboratory eligibility 
criteria during the Screening period
To clarify retest requirements for subjects 
who do not meet laboratory eligibility 
criteria during the Screening period

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Protocol Section(s)
Summary of Changes
Rationale for Changes
Section 10.6 Part 2: 
On-Treatment Evaluations 
Post Biopsy
Add details regarding newly randomized subjects in Part 2
To align with changes made above 
regarding patient population in Part 2
Section 11.2 Assessment of 
Efficacy

Add details regarding newly randomized subjects in Part 1 and 2 

Serum hepatic fibrosis indices: Added text clarifying process to be 
implemented
To align with changes made above 
regarding patient population in Part 2
Section 11.3.2.2 Clinically 
Significant Laboratory 
Abnormalities
Clarified resolution of abnormal values
For clarification
Section 11.3.3 Vital Signs
Added exception to obtaining vital signs at the Early Discontinuation visit
For clarification
Section 11.3.6.4
Revision made in table to correct typo for “≤5 × baseline”
Correction of typo in previous amendment
Section 14.4 Subject 
Confidentiality
Added text relevant to EU requirement: ...European Union Data Protection 
Directive 95/46/EC).
To align with current guidelines
Section 15.2.3 Study 
Monitoring and Access to 
Added text regarding role and responsibilities of the study monitor
For clarification

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Protocol Section(s)
Summary of Changes
Rationale for Changes
Source Documents
Section 20.1 Schedule of 
Assessments

Added confirmation of inclusion/exclusion criteria to Screening Visit

Revised footnote “a” to clarify rescreening and eligibility

Revised footnote “c” to clarify calculation of visit window

Added footnote “dd”: Prior use of and outcomes associated with diet and 
exercise, prior use of and outcomes associated with NAFLD or NASH 
treatment
For clarification
Section 20.3 Information on 
Contraception Effectiveness

Text was revised to address concerns from specific country health 
authorities but which the sponsor determined could be applicable to all 
countries 
To address health authority concerns
Section 20.4 Disallowed 
Medications

Added information for BCRP substrates and disallowed medications due 
to possible confounding effect on efficacy
For clarification
Section 20.5

Added text to table titles clarifying enrolled and randomized subjects 
under Part 2
To align with changes made above 
regarding patient population in Part 2

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1.
EMERGENCY CONTACTS
In emergency situations, the investigator should contact the contract research organization 
(CRO) medical monitor, indicated below:
Syneos Medical Monitoring Team
Email:
Fax: 
Back-up Fax:
Serious Adverse Event/Pregnancy/Adverse Events of Special Interest Reporting
Allergan Global Patient Safety and Epidemiology
Email:
Fax: 
Back-up Fax:

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2.
TABLE OF CONTENTS
Protocol Amendment Summary of Changes .........................................................................2
1.
EMERGENCY CONTACTS...........................................................................................8
2.
TABLE OF CONTENTS .................................................................................................9
2.1.
List of In-Text Tables ................................................................................................12
2.2.
List of In-Text Figures...............................................................................................12
3.
LIST OF ABBREVIATIONS ........................................................................................13
4.
SYNOPSIS.......................................................................................................................17
5.
INTRODUCTION ..........................................................................................................35
5.1.
Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis ....................35
5.2.
CVC Mechanism of Action .......................................................................................35
5.3.
Clinical Studies with CVC.........................................................................................36
Phase 1 Pharmacokinetic Studies in Healthy Subjects.....................................36
5.3.1.
Phase 1 Pharmacokinetic Study in Subjects with Hepatic Impairment .........37
5.3.2.
Phase 2b Study in Subjects with NASH and Liver Fibrosis ............................38
5.3.3.
5.4.
Study Rationale..........................................................................................................41
5.5.
Dose Rationale............................................................................................................41
6.
STUDY OBJECTIVES ..................................................................................................42
6.1.
Part 1...........................................................................................................................42
6.2.
Part 2...........................................................................................................................43
7.
INVESTIGATIONAL PLAN ........................................................................................46
7.1.
Overall Study Design and Plan.................................................................................46
Part 1.....................................................................................................................48
7.1.1.
Part 2.....................................................................................................................50
7.1.2.
8.
STUDY POPULATION .................................................................................................53
8.1
Number of Subjects....................................................................................................54
8.1.
Inclusion Criteria: Part 1 and Part 2 .......................................................................54
8.2.
Exclusion Criteria: Part 1 and Part 2 ......................................................................55
9.
TREATMENTS ..............................................................................................................58
9.1.
Treatments Administered .........................................................................................58
9.2.
Study Drug..................................................................................................................58
Investigational Product .......................................................................................58
9.2.1.
Packaging and Labeling ......................................................................................59
9.2.2.
Storage ..................................................................................................................59
9.2.3.
Study Drug Dispensing and Collection ..............................................................59
9.2.4.
Investigational Product Accountability .............................................................59
9.2.5.
Randomization .....................................................................................................60
9.2.6.
Part 1.....................................................................................................................60
9.2.7.
Part 2.....................................................................................................................61
9.2.8.
9.3.
Study Drug Administration ......................................................................................61
9.4.
Blinding.......................................................................................................................61
9.5.
Prior, Concomitant and Subsequent Therapy ........................................................62
9.6.
Additional Restrictions and Precautions .................................................................65
9.7.
Treatment Adherence................................................................................................65

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10. STUDY PROCEDURES ................................................................................................65
10.1.
Part 1 and Part 2: Screening (Month -3; Visit 1)....................................................65
11. STUDY ASSESSMENTS ...............................................................................................92
11.1.
Demographic and Other Pretreatment Assessments: Part 1 and/or Part 2 .........92
11.2.
Assessments of Efficacy .............................................................................................92
11.3.
Assessments of Safety ................................................................................................96
Adverse Events and Serious Adverse Events ....................................................96
11.3.1.
Laboratory Assessments....................................................................................103
11.3.2.
Vital Signs...........................................................................................................104
11.3.3.
Electrocardiogram .............................................................................................104
11.3.4.
Physical Examination ........................................................................................104
11.3.5.
Toxicity Management ........................................................................................105
11.3.6.
11.4.
Assessments of Pharmacokinetics ..........................................................................114
11.6.
Assessments of Drug Accountability and Medication Adherence.......................114
11.7.
Pharmacogenetic Sampling.....................................................................................115
12. STATISTICS.................................................................................................................116
12.1.
General Considerations...........................................................................................116
Analysis Sets .......................................................................................................116
12.1.1.

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Data and Safety Monitoring Board..................................................................118
12.1.2.
Adjudication Committee ...................................................................................118
12.1.3.
Handling of Missing Data..................................................................................118
12.1.4.
Multiple Comparisons .......................................................................................119
12.1.5.
12.2.
Subject Disposition, Demographics, and Treatment Adherence.........................119
12.3.
Efficacy......................................................................................................................120
Efficacy Endpoints.............................................................................................120
12.3.1.
Methods of Analysis for Efficacy Endpoints ...................................................123
12.3.2.
12.4.
Safety.........................................................................................................................126
Safety Endpoints (Part 1 and Part 2) ...............................................................126
12.4.1.
Methods of Analysis for Safety Endpoints (Part 1 and Part 2) .....................126
12.4.2.
12.5.
Population Pharmacokinetics .................................................................................128
Population Pharmacokinetic Endpoints ..........................................................128
12.5.1.
Methods of Analysis for Population Pharmacokinetic Endpoints ................128
12.5.2.
12.8.
Sample Size and Power............................................................................................129
Part 1...................................................................................................................129
12.8.1.
Part 2...................................................................................................................130
12.8.2.
13. QUALITY CONTROL AND QUALITY ASSURANCE..........................................130
13.1.
Sponsor Audits .........................................................................................................130
13.2.
Inspection by Regulatory Authorities ....................................................................130
14. ETHICS AND PROTECTION OF HUMAN SUBJECTS .......................................131
14.1.
Compliance Statement.............................................................................................131
14.2.
Institutional Review Board/Independent Ethics Committee ...............................131
14.3.
Informed Consent ....................................................................................................132
14.4.
Subject Confidentiality............................................................................................132
14.5.
Study Conduct..........................................................................................................133
14.6.
Study Discontinuation .............................................................................................133
15. DATA HANDLING AND RECORD KEEPING.......................................................133
15.1.
Data Management Responsibilities ........................................................................133
15.2.
Data Handling and Record Keeping ......................................................................133
Data Collection and Retrieval...........................................................................133
15.2.1.
Records Retention..............................................................................................134
15.2.2.
Study Monitoring and Access to Source Documents ......................................134
15.2.3.
16. PUBLICATION POLICY............................................................................................135
17. REFERENCES .............................................................................................................137
18. SPONSOR’S SIGNATURE PAGE .............................................................................140
19. INVESTIGATOR’S SIGNATURE PAGE.................................................................141
20. APPENDICES...............................................................................................................142
20.1.
Schedule of Assessments..........................................................................................143

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20.2.
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE)...........................................................................................................154
20.3.
Information on Contraception Effectiveness.........................................................156
20.4.
Disallowed Medications...........................................................................................158
20.5.
Clinical Laboratory Tests........................................................................................163
2.1.
List of In-Text Tables
Table 7–1
Treatment Arms: Part 1...................................................................................48
Table 7–2
Treatment Arms in Part 2................................................................................51
Table 9–1
Treatment Arms: Part 1 and Part 2................................................................58
Table 9–2
Treatment Arms: Part 1...................................................................................61
Table 9–3
Treatment Arms: Part 2...................................................................................61
Table 9-4
Antidiabetic Medications .................................................................................64
2.2.
List of In-Text Figures
Figure 1
Study Design Schematic ...................................................................................47

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3.
LIST OF ABBREVIATIONS
Abbreviation
Definition 
A1AT
alpha-1-antitrypsin
ADL
activities of daily living
ADR
adverse drug reaction
AE
adverse event
AESI
adverse event(s) of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANA
antinuclear antibody
ANCOVA
analysis of covariance
APRI
aspartate aminotransferase to platelet count ratio index
AST
aspartate aminotransferase
AUC0-tau
area under the concentration-time curve up to the last measurable concentration
BCRP
breast cancer resistance protein
BMI
body mass index
CCL
chemokine (C-C motif) ligand 
CCR
C-C chemokine receptor 
CI
confidence interval
CLDQ-NAFLD
Chronic Liver Disease Questionnaire for NAFLD
Cmax
maximum plasma concentration
CMH
Cochran-Mantel-Haenszel 
Cmin
minimum plasma concentration
CPK
creatine phosphokinase
CRN
Clinical Research Network
CRO
contract research organization
CVC
cenicriviroc mesylate
CYP
cytochrome P450
DCIS
ductal carcinoma in situ
DILI
drug-induced liver injury
DPP-4
dipeptidyl peptidase 4
DSMB
Data and Safety Monitoring Board
DSUR
Development Safety Update Report

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CONFIDENTIAL
Abbreviation
Definition 
ECG
electrocardiogram
ECmin50
Cmin associated with half-maximal response
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EU
European Union
FDA
Food and Drug Administration
FIB-4
noninvasive hepatic fibrosis index score combining standard biochemical 
values (platelets, ALT, AST) and age
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide 1
GPP2
Good Publications Practice for Communicating Company Sponsored Medical 
Research
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAb
HBsAg
hepatitis B surface antibody
hepatitis B surface antigen
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
HDPE
high-density polyethylene
HDL
high-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
hs-CRP
high-sensitivity C-reactive protein
ICF
informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IL
interleukin
INR
international normalized ratio

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Abbreviation
Definition 
IRB
Institutional Review Board
ITT
intent-to-treat
IxRS
interactive response system
LC1
liver cytosol type 1
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LKM1
liver/kidney microsome type 1
MCP-1
monocyte chemotactic protein-1
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MELD
Model for end stage liver disease
MIP
macrophage inflammatory protein
mITT
modified intent-to-treat
NAFLD
nonalcoholic fatty liver disease
NAS
NAFLD activity score
NASH
nonalcoholic steatohepatitis
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NFS
NAFLD fibrosis score
OR
odds ratio
P-gp
P-glycoprotein
PD
pharmacodynamics(s)
PK
pharmacokinetic(s)
PK/PD
pharmacokinetic/pharmacodynamic
PP
per protocol
PPI
proton pump inhibitor
PR
time between the start of the P wave to the start of the QRS complex (ECG)
QD
once daily
QT
time between the start of the Q wave and the end of the T wave (ECG)
QTc
QT interval corrected for heart rate
QTcB
Bazett's corrected QT interval
QTcF
Fridericia's corrected QT interval
RANTES
regulated on activation normal T-cell expressed and secreted

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Abbreviation
Definition 
RNA
ribonucleic acid
SAE
serious adverse event
SAR
suspected adverse reaction
SGLT2
sodium–glucose cotransporter 2
SMA
sDILI
smooth muscle antibodies
suspected drug-induced liver injury
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
T2DM
type 2 diabetes mellitus
TE
transient elastography
TEAE
treatment-emergent adverse event
tmax
time to maximum plasma concentration
TZD
thiazolidinedione
ULN
upper limit of normal
US(A)
United States (of America)
VLDL
very low-density lipoprotein
WHO
World Health Organization

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4.
SYNOPSIS
Title
AURORA: A Phase 3, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
Cenicriviroc for the Treatment of Liver Fibrosis in Adult Subjects with 
Nonalcoholic Steatohepatitis
Clinical Phase
3
Indication
Treatment of liver fibrosis in adult subjects with nonalcoholic 
steatohepatitis (NASH)
Objectives
Part 1
Primary Objective (Part 1): Demonstrate the superiority of cenicriviroc 
(CVC) compared to placebo on liver histology at Month 12 relative to 
the Screening biopsy in adult subjects with a liver biopsy diagnosis of 
NASH and Stage 2 or 3 liver fibrosis (by NASH CRN system) as 
confirmed by an independent central pathologist 

Primary Efficacy Endpoint: Proportion of subjects with 
improvement in fibrosis by at least 1 stage (NASH CRN system) 
AND no worsening of steatohepatitis (no worsening of lobular 
inflammation or hepatocellular ballooning grade).
Key Secondary Objective (Part 1):

Evaluate the effect of CVC compared to placebo on liver histology 
at Month 12 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis of at least 2 stages (NASH 
CRN system) AND no worsening of steatohepatitis (no worsening 
of lobular inflammation or hepatocellular ballooning grade)
Secondary Objectives (Part 1):

Evaluate the effect of CVC compared to placebo on liver histology 
at Month 12 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis by at least 1 stage (NASH 
CRN system), regardless of effect on steatohepatitis

Evaluate the effect of CVC compared to placebo on liver histology 
at Month 12 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis by at least 2 stages (NASH 
CRN system), regardless of effect on steatohepatitis

Evaluate the safety and tolerability of CVC for the treatment of 
liver fibrosis in adult subjects with NASH
Objectives
Part 2
Primary Objective (Part 2):

Demonstrate the superiority of CVC compared to placebo on the 
composite endpoint of histopathologic progression to cirrhosis 
(defined by NASH CRN Fibrosis Stage 4), liver-related clinical 
outcomes, and all-cause mortality, as measured by the time to first 
occurrence of any of the listed adjudicated events (clinical 
outcomes composite endpoint) – (all subjects)

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Secondary Objectives (Part 2):

Evaluate the effect of CVC compared to placebo on liver histology 
at Month 12 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis by at least 1 stage (NASH 
CRN system) AND no worsening of steatohepatitis (no worsening 
of lobular inflammation or hepatocellular ballooning grade) –
(subjects newly randomized in Part 2)

Evaluate the effect of CVC compared to placebo on liver histology 
at Month 12 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis by at least 1 stage (NASH 
CRN system), regardless of effect on steatohepatitis – (subjects 
newly randomized in Part 2) 

Evaluate the effect of CVC compared to placebo on liver histology 
at Month 60 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis by at least 1 stage (NASH 
CRN system) AND no worsening of steatohepatitis (no worsening 
of lobular inflammation or hepatocellular ballooning grade) – (all 
subjects)

Evaluate the effect of CVC compared to placebo on liver histology 
at Month 60 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis by at least 1 stage (NASH 
CRN system), regardless of effect on steatohepatitis – (all subjects)

Evaluate the effect of CVC compared to placebo on liver histology 
at Month 12 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis by at least 2 stages (NASH 
CRN system) AND no worsening of steatohepatitis (no worsening 
of lobular inflammation or hepatocellular ballooning grade) – (for 
subjects newly randomized in Part 2)

Evaluate the effect of CVC compared to placebo on liver histology 
at Month 12 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis by at least 2 stages (NASH 
CRN system) regardless of effect on steatohepatitis – (for subjects 
newly randomized in Part 2)
Evaluate the effect of CVC compared to placebo on liver histology 
at Month 60 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis by at least 2 stages (NASH 
CRN system) AND no worsening of steatohepatitis (no worsening 
of lobular inflammation or hepatocellular ballooning grade) – (all 
subjects)
Evaluate the effect of CVC compared to placebo on liver histology 
at Month 60 relative to the Screening biopsy for the proportion of 
subjects with improvement in fibrosis by at least 2 stages (NASH 
CRN system), regardless of effect on steatohepatitis – (all subjects)

Evaluate the safety and tolerability of CVC for the treatment of 
liver fibrosis in adult subjects with NASH – (all subjects)

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Study Design
Overall
This is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled study of CVC for the treatment of Stage 2 or 3 liver 
fibrosis in adult subjects with NASH. The study will be conducted in 
2 parts: Part 1 (surrogate endpoint) and Part 2 (clinical outcomes) as 
described below. 
A Data and Safety Monitoring Board (DSMB) will be formed to review 
ongoing data from Part 1 and Part 2 of this study.
The study will be terminated when adjudicated events have been 
accrued in 367 unique subjects overall. All subjects who complete the 
study or are terminated from the study early due to an adjudicated 
clinical endpoint or due to any other reason, will have an End of Study 
visit at that time and will return to the clinic for a Follow-up visit 30 
days after the last dose of study drug.
Subjects who permanently discontinue study drug, for any reason, 
before the planned end of study are encouraged to complete all 
subsequent study visits for assessment of clinical outcomes (at the 
discretion of the investigator, subjects who permanently discontinue 
study drug may be followed every 6 months unless otherwise specified 
by the protocol).
Subjects who undergo early termination from the study will return to the 
clinic within 48 hours for an early discontinuation visit and will return 
to the clinic for a Follow-up visit 30 days after the last dose of study 
drug.  
Survival data will be collected for all study subjects at the end of the 
study.
Study Design
Part 1
Part 1 will assess the effect of CVC on the surrogate endpoint at 
Month 12 in approximately 1200 subjects with a liver biopsy diagnosis 
of NASH and Stage 2 or 3 liver fibrosis (by NASH CRN system) as 
confirmed by an independent central pathologist. Subjects will be 
randomized 2:1 to receive CVC or placebo and will receive the same 
treatment for the duration of the study. 
At Baseline (Day 1), eligible subjects will be assigned to the treatment 
arms using permuted block randomization and presence or absence of 
documented type 2 diabetes mellitus (T2DM) (yes or no). Eligible 
subjects will be randomized 2:1 to one of the following 2 treatment arms
and will receive the same treatment for the duration of the study:
Arm
N
Treatment 
A
800
CVC 150 mg, once daily
B
400
Placebo, once daily
All subjects will undergo safety assessments at the Baseline visit and at 
Months 1, 3, 6, 9, and 12.    
The liver biopsy, used to evaluate the efficacy endpoints, must be 
performed within ± 2 weeks of the Month 12 visit (Visit 7).
Subjects who remain in Part 1 at Month 12 will continue to be evaluated 

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in Part 2 of the study and will continue the same treatment through the 
end of Part 2. Individual subject treatment assignments will not be 
revealed until the completion of Part 2 of the study. 
Study Design
Part 2
Part 2 of the study will focus on assessing the effect of CVC on clinical 
outcomes in approximately 2000 subjects, including up to 1200 subjects 
with a liver biopsy diagnosis of NASH and Stage 2 or 3 liver fibrosis 
(by NASH CRN system) previously randomized in Part 1 and an 
additional 800 adult subjects with a liver biopsy diagnosis of NASH and 
Stage 3 liver fibrosis (by NASH CRN system) newly randomized 2:1 to 
receive CVC or placebo in Part 2.
Subjects who enter Part 2 from Part 1 of the study will have study visits 
every 3 months until Part 2 is completed. Study drug will be dispensed 
and adverse events (AEs), concomitant medications, and adherence to 
study drug will be reviewed at every visit (every 3 months). Safety 
laboratory assessments will be performed every 6 months through the 
end of the study.
At Baseline (Day 1), eligible subjects who newly enroll in Part 2 of the 
study will be assigned to the treatment arms using permuted block 
randomization, and presence or absence of documented T2DM (yes or 
no). Newly enrolled subjects will be randomized 2:1 to one of the 
following 2 treatment arms to achieve a total of approximately 2000 
randomized subjects in the study (of which up to 1200 subjects will 
have been randomized in Part 1 and 800 in Part 2.
Arm
Newly 
Randomized 
Subjects in Part 
2
N
Total Subjects 
(Randomized in Part 1 
or Part 2)
N
Treatment 
A
534
1334
CVC 150 
mg, once 
daily
B
266
666
Placebo, 
once daily
Newly enrolled subjects in Part 2 will undergo safety laboratory 
assessments at Months 1, 6, and 12 and every 6 months thereafter 
through the end of the study. Beginning at Month 3, AEs, concomitant 
medications, and adherence will be reviewed every 3 months through 
the end of the study.  
Newly enrolled subjects in Part 2 will undergo a liver biopsy at 
Screening for assessment of eligibility and a further liver biopsy at 
Month 12 (within ± 2 weeks). 
Newly enrolled subjects will undergo a liver biopsy at Screening for 
assessment of eligibility and performed at Month 12 visit (within ± 2 
weeks). All subjects (newly randomized subjects with a liver biopsy 
diagnosis of NASH and Stage 3 liver fibrosis [by NASH CRN system] 
and those who continue from Part 1) will undergo a liver biopsy at 

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Month 60 (within ± 2 weeks) after the first dose of study drug.
Treatment Duration 
Estimated to be 60 months for subjects participating in the study. Actual 
treatment duration will vary depending on the time to accrue adjudicated 
events in 367 unique subjects in the CVC and placebo arms combined. 
Number of Subjects
Part 1: Approximately 1200 subjects will be included in Part 1:

Treatment Arm A (CVC 150 mg, once daily): approximately 
800 subjects or 

Treatment Arm B (placebo, once daily): approximately 400 
subjects). 
Subjects who remain in Part 1 at Month 12 will continue to be evaluated 
in Part 2 of the study and will continue the same treatment through the 
end of Part 2.
Part 2: Approximately 2000 subjects will be included in Part 2,, 
including up to1200 from Part 1 and approximately 800 newly 
randomized in Part 2. Approximately 60% or more of subjects with 
Stage 3 fibrosis will be enrolled in the study overall.

Treatment Arm A (CVC 150 mg, once daily): approximately 1334 
subjects of which approximately 534 are newly enrolled 

Treatment Arm B (placebo, once daily): approximately 666 subjects 
of which approximately 266 subjects are newly enrolled
Number of Study 
Centers
A total of 2000 subjects will be enrolled in the study at up to 600 centers 
in North, Central, and South America; Europe; and Asia Pacific region. 
It is expected that at least 30% of subjects will be randomized in the 
United States (US). and at least 30% of subjects will be randomized in 
the EU. 
Target Population 
Part 1: Adult subjects with liver biopsy diagnosis of NASH and Stage 2 
or 3 liver fibrosis (by NASH CRN system) –Part 2: Subjects newly 
enrolled and randomized in Part 2 will include adult subjects with a liver 
biopsy diagnosis of NASH and Stage 3 liver fibrosis (by NASH CRN 
system).
Inclusion Criteria
1.
Male and female subjects aged between 18-75 years
2.
Ability to understand and sign a written informed consent form 
(ICF)
3.
Histological evidence of NASH based on central reading of the 
Screening liver biopsy 
 

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iv. Subjects must have been metabolically stable since the 
biopsy (no significant weight loss [≥7% of body weight], 
no major deterioration of glycemic control, and no 
introduction of new or investigational drugs for the 
treatment of T2DM)
4.
Subjects included in Part1 must have histopathological evidence of 
Stage 2 or 3 liver fibrosis per the NASH CRN System based on 
central reading of the Screening biopsy slides. Subjects newly 
randomized in Part 2 must have histological evidence of Stage 3 
liver fibrosis per the NASH CRN System, based on central reading 
of the Screening period biopsy slides. Historical biopsy can be used, 
provided the criteria listed on Item 3a above are fulfilled.
5.
Females of childbearing potential and males participating in the 
study must agree to use at least 2 approved methods of 
contraception throughout the duration of the study and for 30 days 
after stopping study drug. Females who are postmenopausal must 
have documentation of cessation of menses for ≥12 months 
without an alternative medical cause. Follicle-stimulating hormone 
(FSH) level in the postmenopausal range (≥30 mU/mL at
Screening) 
 
 
 
 
Exclusion Criteria 
1.
Inability to undergo a liver biopsy safely
2.
Hepatitis B surface antigen (HBsAg) positive
3.
Hepatitis C antibody (HCVAb) positive 
 
4.
Human immunodeficiency virus (HIV)-1 or HIV-2 infection
5.
Prior or planned liver transplantation
6.
Other known causes of chronic liver disease

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7.
History or presence of cirrhosis (NASH CRN Fibrosis Stage 4)
and/or hepatic decompensation including ascites, hepatic 
encephalopathy or variceal bleeding
8.
Alcohol consumption greater than 21 units/week for males or 
14 units/week for females 
 
 
9.
Aspartate aminotransferase (AST) > 5 × upper limit of normal 
(ULN) at Screening
10. Alanine aminotransferase (ALT) > 5 × ULN at Screening
11. Hemoglobin A1c (HbA1c) > 9% at Screening 
12. Serum albumin < 3.5 g/dL at Screening
13. Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2
according to the Modification of Diet in Renal Disease (MDRD) 
equation at Screening
14. Platelet count < 100,000/mm3 at Screening
15. Total bilirubin > 1.3 mg/dL (subjects with hyperbilirubinemia 
associated with documented Gilbert’s syndrome may be eligible
upon review by the medical monitor) at Screening
16. International normalized ratio (INR) > 1.3 at Screening
17. Model for end stage liver disease (MELD) score > 12
18. Weight reduction, defined as ≥7% of body weight, through bariatric 
surgery in the past 5 years or bariatric surgery planned during the 
conduct of the study (including gastric banding and sleeve surgery)
19.
 
history of malignancy within the past 5 years or ongoing 
malignancy other than: basal cell carcinoma, resected noninvasive 
cutaneous squamous cell carcinoma,
 
20. Active, serious infections that require parenteral therapy (antibiotic 
or antifungal) within 30 days prior to Screening visit
21. Clinically significant cardiovascular or cerebrovascular disease 
within the past 3 months

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22. Females who are pregnant or breastfeeding
23. Current or anticipated treatment with radiation therapy, cytotoxic 
chemotherapeutic agents and immune-modulating agents (such as 
interleukins and interferons)
24. Receiving a glucagon-like peptide 1 (GLP-1) receptor agonist, a 
dipeptidyl peptidase 4 (DPP-4) inhibitor, a sodium–glucose 
cotransporter 2 (SGLT2) and/or SGLT1 inhibitor, or a 
thiazolidinedione (TZD), for less than 6 months prior to the 
Screening period liver biopsy. Subjects on a stable therapy with a 
GLP-1 receptor agonist, DPP-4 inhibitor, SGLT1 and/or SGLT2
inhibitor, or a TZD for at least 6 months prior to the Screening liver 
biopsy may be considered eligible. (Important Note: if a historical 
biopsy is to be used, subjects need to be on stable therapy for at 
least 6 months prior to the day historical liver biopsy was 
performed).
Test Article 
CVC 150-mg tablet
Dosage and 
Administration 
CVC 150 mg administered orally once daily with food
Placebo 
Matching placebo 
Dosage and 
Administration 
Matching placebo administered orally once daily with food 

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Study Procedures/ 
Frequency
During Part 1 and Part 2, a Screening visit is to occur within 3 months 
before the Baseline visit. In Part 2, the Screening visit will only be 
required for newly enrolled subjects. The Screening visit will not be 
required for subjects continuing their previously assigned blinded 
treatment from Part 1. As part of Screening, assessment of serum 
laboratory tests (hematology and chemistry panels), serum hepatic 
fibrosis indices including FIB-4, APRI, and NFS, and evaluation of liver 
stiffness via transient elastography (TE) or liver imaging (performed no 
more than 6 months prior to the first day of Screening at sites where 
available) will be performed to aid in identifying subjects with clinically 
significant liver fibrosis prior to proceeding with a new liver biopsy. 
A historical liver biopsy obtained no more than 6 months prior to the 
first day of Screening that meets protocol-required specifications will be 
evaluated for all subjects as part of Screening to confirm histologic 
evidence of NASH and Fibrosis Stages 2 or 3.
Subjects meeting all other eligibility criteria and with suspicion of 
significant liver fibrosis (through clinical evaluation, hepatic fibrosis 
indices, and/or liver stiffness assessment [performed no more than 
6 months prior to the first day of Screening]) will undergo a liver biopsy 
during the Screening period; randomized subjects will undergo, a 
second post-treatment liver biopsy at the Month 12 visit (± 2 weeks). 
Newly enrolled subjects will undergo a liver biopsy at Screening for 
assessment of eligibility and a second post-treatment liver biopsy will be 
collected within ± 2 weeks of the Month 12 visit. All subjects (newly 
randomized subjects with a liver biopsy diagnosis of NASH and Stage 3 
liver fibrosis [by NASH CRN system] and those who continue from Part 
1) will undergo a liver biopsy at Month 60 (within ± 2 weeks) after the 
first dose of study drug. 
Fasting metabolic parameters will be measured at Baseline, at Months 3, 
6, and 12 in Part 1 and at Baseline for newly randomized subjects and 
every 6 months through the end of study for all subjects. 
Samples for biomarkers of systemic inflammation will be collected at 
Baseline, at Months 3, 6, and 12 in Part 1, and at Baseline for newly 
randomized subjects in Part 2, and every 6 months through the end of 
the study for all subjects. 
At selected sites where available, non-invasive assessment of liver 
fibrosis by TE will be performed at Baseline (if not performed at 
Screening), at Months 6 and 12 in Part 1, and annually in Part 2. 
Pharmacokinetic samples for CVC will be collected at Months 3, 6, 
and 12 in Part 1.
Weight, waist circumference, and hip circumference will be performed 
at Screening, Baseline, at Months 3, 6, and 12 in Part 1, and every 
6 months in Part 2. Height will be performed at Screening. 
Physical examinations, vital signs, and laboratory analyses (serum 
chemistries and hematology) will be performed at Screening, Baseline, 
Months 1, 6 and 12 for subjects who are newly randomized in Part 2, 
and every 6 months thereafter through the end of the study for all 

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subjects.
Electrocardiograms (ECG) will be performed at Baseline and annually 
for all study subjects. Clinical outcomes, AEs, and concomitant 
medications will be assessed at each visit.
An ultrasound exam to screen for HCC and presence of ascites will be 
performed at Month 60.
Efficacy Evaluation
Part 1
Primary Efficacy Endpoint (Part 1):

Proportion of subjects with improvement in fibrosis by at least 
1 stage (NASH CRN system) AND no worsening of steatohepatitis 
(no worsening of lobular inflammation or hepatocellular 
ballooning grade) on liver histology at Month 12 relative to the 
Screening biopsy
Key Secondary Efficacy Endpoint (Part 1):
Proportion of subjects with improvement in fibrosis by at least 
2 stages (NASH CRN system) AND no worsening of 
steatohepatitis (no worsening of lobular inflammation or 
hepatocellular ballooning grade) on liver histology at Month 12 
relative to the screening biopsy
Secondary Efficacy Endpoints (Part 1):

Proportion of subjects with improvement in fibrosis by at least 
1 stage (NASH CRN system), regardless of effect on 
steatohepatitis, at Month 12 relative to the Screening biopsy 

Proportion of subjects with improvement in fibrosis by at least 
2 stages (NASH CRN system), regardless of effect on 
steatohepatitis, at Month 12 relative to the screening biopsy
Efficacy Evaluation
Part 2
Primary Efficacy Endpoint (Part 2):

Time to first occurrence of any of the following adjudicated 
events (all subjects):
o
Death (all cause)
o
Histopathologic progression to cirrhosis (defined by 
NASH CRN Fibrosis Stage 4)
o
Liver transplant
o
MELD score ≥15
o
Ascites (requiring intervention, ie, large volume 
paracentesis ≥1L or initiation of a diuretic)

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o
Hospitalization (as defined by a stay of ≥ 24 hours) for 
onset of: variceal bleed, hepatic encephalopathy 
(defined by a West Haven Stage of ≥2), spontaneous 
bacterial peritonitis (confirmed by diagnostic 
paracentesis with positive ascitic fluid bacterial culture)
Each component of this endpoint will be considered by the 
independent adjudication committee, and only events confirmed by 
the committee will be included in the primary analysis.
If any of the above events occur in Part 1, they will be included in 
this primary efficacy endpoint for Part 2.
Secondary Efficacy Endpoints (Part 2):

Proportion of subjects with improvement in fibrosis by at least 
1 stage (NASH CRN system) AND no worsening of 
steatohepatitis (no worsening of lobular inflammation or 
hepatocellular ballooning grade) on liver biopsy at Month 12 
relative to the Screening biopsy – (subjects newly randomized 
in Part 2)

Proportion of subjects with improvement in fibrosis by at least 
1 stage (NASH CRN system), regardless of effect on 
steatohepatitis, on liver biopsy at Month 12 relative to the 
Screening biopsy – (subjects newly randomized in Part 2) 

Proportion of subjects with improvement in fibrosis by at least 
2 stages (NASH CRN system) AND no worsening of 
steatohepatitis (no worsening of lobular inflammation or 
hepatocellular ballooning grade) on liver biopsy at Month 12 
relative to the screening biopsy – (subjects newly randomized 
in Part 2) 

Proportion of subjects with improvement in fibrosis by at least 
2 stages (NASH CRN system) regardless of effect on 
steatohepatitis on liver biopsy at Month 12 relative to the 
screening biopsy – (subjects newly randomized in Part 2)

Proportion of subjects with improvement in fibrosis by at least 
1 stage (NASH CRN system) AND no worsening of 
steatohepatitis (no worsening of lobular inflammation or 
hepatocellular ballooning grade) on liver biopsy at Month 60 
relative to the Screening biopsy – (all subjects)

Proportion of subjects with improvement in fibrosis by at least 
1 stage (NASH CRN system), regardless of effect on 
steatohepatitis, on liver biopsy at Month 60 relative to the 
Screening biopsy – (all subjects) 

Proportion of subjects with improvement in fibrosis by at least 
2 stages (NASH CRN system) AND no worsening of 
steatohepatitis (no worsening of lobular inflammation or 
hepatocellular ballooning grade) on liver biopsy at Month 60 
relative to the screening biopsy – (all subjects) 

Proportion of subjects with improvement in fibrosis by at least 

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2 stages (NASH CRN system), regardless of effect on 
steatohepatitis on liver biopsy at Month 60 relative to the 
screening biopsy – (all subjects)
Safety Evaluation
Safety endpoints (Part 1 and Part 2):

Clinically evident adverse events, including major adverse 
cardiovascular events (MACE) and new-onset T2DM

Clinical laboratory tests (hematology, chemistry, and fasting 
metabolic parameters) 

Physical examination

Vital signs

12 lead ECG
Pharmacokinetic 
Evaluation
Part 1

Characterization of the population PK of CVC and possible 
metabolites in subjects with NASH

Evaluation of covariates that impact the PK of CVC and possible 
metabolites (age, sex, weight, race, ethnicity, fibrosis stage, etc.)
Statistical Analysis
Analysis Sets
Intent-to-treat (ITT) analysis set: All subjects randomly assigned to a 
treatment group will be included in ITT analysis set. Subjects will be 
included with the randomly assigned treatment, if they receive treatment 
other than that to which they are randomly assigned. This will be a 
supportive analysis set for selected efficacy analyses. Subjects with 

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missing Screening biopsy data should not be randomized in the study, 
hence will not be included in the ITT analysis set, should such subjects 
exist.
Modified intent-to-treat (mITT) analysis set: All subjects in the ITT 
analysis set who receive at least one dose of study drug will be included 
in the mITT analysis set. Subjects will be included with the randomly 
assigned treatment, if they receive treatment other than that to which 
they are randomly assigned. This will be the primary analysis set for the 
efficacy analyses.
Month 12 per protocol (PP1) analysis set: All subjects randomly 
assigned to a treatment group who have an evaluable biopsy at 
Screening and another after at least 6 months but before 15 months of 
follow-up, receive at least 6 months of assigned study drug and have no 
significant protocol deviations that potentially influence the primary 
efficacy assessment will be included in the PP1 analysis set. This will be 
a supportive analysis set for selected efficacy analyses of Part 1 and Part 
2. 
Month 60 per protocol (PP2) analysis set: All subjects randomly 
assigned to a treatment group who have an evaluable biopsy at 
Screening, have no significant protocol deviations that potentially 
influence the primary efficacy assessment, and either:

Have an adjudicated event that is a component of the primary 
composite endpoint within 24 months after randomization 
OR 

Have at least 24 months of follow-up for clinical events AND
one of the following:
o
Have an adjudicated event that is a component of the 
primary composite endpoint within 6 months of last intake 
of study drug
OR
o
Have a biopsy at least 24 months after randomization and 
within 6 months of last intake of study drug. 
This will be a supportive analysis set for selected efficacy analyses of 
Part 2. 
Safety analysis set: All subjects randomly assigned to a treatment 
group who receive at least one dose of study drug will be included in the 
safety analysis set. Subjects will be included with the treatment group 
according to treatment actually received, if they receive treatment other 
than that to which they are randomly assigned. Subjects who
inadvertently receive both treatments will be included with the CVC 
group. This will be the primary analysis set for the safety analyses.
Pharmacokinetic analysis set: All subjects who are randomized and 
receive at least one dose of study drug and have at least one post-dose 
PK sample will be included in the PK analysis set.
Efficacy
Part 1
The significance level of both 0.00125 (2-sided) and 0.05 (2-sided) will 
be applied to hypothesis testing in this study, with the former to 

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manifest strong evidence from a single confirmatory study and the latter 
for study success. 
To manifest strong evidence from a single confirmatory study, the 
familywise type I error rate (between the surrogate endpoint and the 
clinical outcome endpoint) will be controlled at the 0.00125 level by 
initial assignment of 0.0012 to the surrogate endpoint and 0.00005 to the 
clinical outcome endpoint, and the clinical outcome endpoint will be 
tested at 0.00125 level if the test of surrogate endpoint is successful. The 
testing procedure will be the same for study success, except the 
familywise type I error rate will be controlled at the 0.05 level instead of 
0.00125 level, in which an initial alpha level of 0.048 to the surrogate 
endpoint and of 0.002 to the clinical outcome endpoint will be allocated.
The primary analysis of Part 1 will occur when approximately 
1200 randomized subjects have been followed for at least 12 months. 
Subjects who will contribute to the primary analysis of Part 1 will be 
identified before unblinding of any subjects for Part 1 analysis. 
Individual subjects’ treatment group assignments will not be 
disseminated to the sites until the end of Part 2 to allow for continued 
blinded assessment during Part 2.
For the primary efficacy analysis in Part 1, using the mITT analysis set, 
any available liver biopsy after baseline will be used as the Month 12
biopsy, no matter when it was obtained relative to the first dose of study 
drug. Subjects who do not have an evaluable liver biopsy at both 
Screening and Month 12 will be included in the analyses as non-
responders. Subjects with multiple liver biopsies will have the evaluable 
biopsy closest to the Month 12 visit included in the analysis.
The proportion of subjects who meet the primary efficacy endpoint in 
Part 1, and each component, will be summarized by treatment group. 
Two-sided 95% confidence intervals (CI) for the proportion who meet 
the primary efficacy endpoint, calculated using Wilson’s method for CI, 
will also be reported.
Part 1 testing hierarchy includes 2 tests, one for the primary endpoint 
and the other for the key secondary endpoint. Within Part 1 testing, the 
key secondary endpoint is to be tested only when the primary endpoint 
result is significant.  
Analysis of the primary and the key secondary endpoints of Part 1 will 
use the Cochran-Mantel-Haenszel (CMH) test, stratified by 
randomization strata (fibrosis stage [2 vs 3] and presence or absence of 
T2DM at Baseline, for a total of 4 strata), to compare the rates in the 
2 randomized treatment arms. 
Sensitivity analyses for the primary efficacy endpoint will also be 
performed. Subgroup analyses using the CMH test will be reported for 
selected subgroups.
Analysis of other secondary efficacy endpoints of Part 1 will use similar 
methods to the primary endpoint analysis. Results for the mITT and PP1 
analysis sets will be reported for secondary efficacy endpoints. Binary 
endpoints will be analyzed with the CMH procedure, stratified by 
randomization strata. Continuous endpoints will be analyzed with 

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analysis of covariance, with randomization strata included as covariates.
Efficacy
Part 2
Part 2 of this study will include all subjects randomized to this study. 
The primary analysis for Part 2 will occur when adjudicated events have 
been accrued in 367 unique subjects overall (regardless of treatment 
assignment). Because many events may be observed from the Month 60 
liver biopsy and given that all reported events will need to undergo 
independent adjudication prior to being included or excluded from the 
analysis, it is possible that more than or fewer than 367 events will be 
included in the analysis. All subjects and events in the database at the 
time of Part 2 database lock and unblinding, and only those events, will 
be included in the primary analysis of Part 2. If multiple events are 
observed in a single subject, only the first observed event will be used in 
the analysis.
For the primary efficacy analysis in Part 2 using the mITT analysis set, 
any available liver biopsy after baseline will be used for assessment of 
components of the clinical endpoint that require a biopsy, no matter 
when obtained. Subjects who do not have an evaluable liver biopsy at 
both Screening and postbaseline will be included in the analyses as 
having an event only if they meet a component that does not require a 
biopsy; otherwise they will be included as not having an event and 
censored at the last visit. Subjects with multiple liver biopsies will be 
included as an event if any (one or more) biopsy meets the definition of 
the primary endpoint, as determined by the adjudication committee.
The proportion of subjects who meet the primary efficacy endpoint in 
Part 2, and each component, will be summarized by treatment group. 
Two-sided 95% CIs for the proportion who meet the primary efficacy 
endpoint, calculated using Wilson’s method for CI, will also be 
reported. Additionally, Kaplan-Meier product-limit estimates will be 
presented as graphs to show the event rates over time and a table will 
present Kaplan-Meier estimates for the probability of an event at 
specific time intervals. Subjects will be censored for analysis at the last 
recorded study visit.
Analysis of the primary endpoint of Part 2 will use the logrank test, 
stratified by randomization strata (fibrosis stage [2 vs 3] and presence or 
absence of T2DM at Baseline, for a total of 4 strata), to compare the 
rates in the 2 randomized treatment arms. The p-value for the test of no 
difference between treatment arms (hazard ratio = 1) will be presented 
as well as the hazard ratio from a proportional hazards model (CVC 
divided by placebo) and corresponding 95% CI. 
Analysis of secondary efficacy endpoints of Part 2 will use similar 
methods to the primary endpoint analysis in Part 2. The primary 
endpoint in Part 1, improvement in fibrosis by at least one stage and no 
worsening of steatohepatitis at Month 12, will be reported for subjects 
not in the Part 1 analysis (subjects newly randomized in Part 2), and for 
all subjects in the study (Month 12 results from Part 1 and Part 2 
combined). Results for the mITT and PP2 analysis sets will be reported 

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for the secondary endpoints in Part 2. Binary endpoints will be analyzed 
with the CMH procedure, stratified by randomization strata. Continuous 
endpoints will be analyzed with analysis of covariance, with 
randomization strata included as covariates. Time to event endpoints 
will be analyzed with the stratified logrank test, stratified by 
randomization strata.
Safety 
No statistical hypotheses are pre-specified for safety endpoints. 
Analyses will be primarily descriptive, with any p-values post-hoc and 
any comparative conclusions requiring confirmation.
Any event reported on the electronic case report form (eCRF) that 
occurs or worsens on or after the initiation of study drug and through 30 
days after the last intake of study drug is defined as treatment-emergent. 
Any event reported on the eCRF that occurs or worsens after last intake 
of study drug + 30 days is defined as subsequent. AEs will be 
categorized by the Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term and system-organ classification. The 
occurrence of treatment-emergent adverse events (TEAEs) will be 
summarized by treatment group for the safety analysis set using 
MedDRA preferred terms, system organ classifications, and severity. 
All AEs (including nontreatment-emergent events) recorded on the 
eCRF will be listed for individual subjects showing both verbatim and 
preferred terms. The number of subjects with at least one TEAE, at least 
one severe TEAE, at least one serious TEAE, at least one TEAE judged 
by the investigator to be related to study drug, and with a TEAE leading 
to death will be summarized by treatment group. Summaries of TEAEs 
will also be presented by subgroups of age, sex, race, and ethnicity.
Descriptive summaries of clinical laboratory results will be presented by 
study visit. Laboratory abnormalities will be graded according to 
National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 4.03. The number and percentage of 
subjects experiencing treatment-emergent graded toxicities will be 
summarized by treatment group and severity grade. Change from 
baseline in laboratory tests will be summarized for each treatment 
group.
Any abnormal findings in the physical examination or vital signs that 
are considered clinically significant in the opinion of the investigator 
will be recorded as AEs or be captured as medical history, if already 
present at Screening. Descriptive summaries of vital signs will be
presented by study visit. Descriptive summaries of quantitative changes 
in vital signs will be presented by treatment group and study visit. 
Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria. Subjects exhibiting 
Grade 3 or 4 PR or QT interval corrected for heart rate (QTc) interval 
will be summarized. Abnormalities in Fridericia's corrected QT interval 
(QTcF) interval, Bazett's corrected QT interval (QTcB) interval, QRS, 
PR, and heart rate (HR) will be will be summarized.

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Prior, concomitant, and subsequent (taken more than 30 days after 
permanent discontinuation of study drug) medications will be mapped to 
a World Health Organization (WHO) preferred term and drug 
classification. The number and percent of subjects taking prior, 
concomitant, and subsequent medications will be summarized by 
treatment group using preferred terms and drug classifications. 
Pharmacokinetics
A population PK analysis of CVC will be performed by using pre-dose 
and post-dose PK samples collected at steady state throughout Part 1 of 
the study. Population PK modeling of measured plasma CVC 
concentrations will be conducted using nonlinear mixed effects 
modeling. An analysis of subject covariates will be conducted.
Sample Size
Part 1
The sample size for the primary endpoint of Part 1 is based on the 
primary binary endpoint at the end of Month 12 comparing treatment 
with CVC versus placebo. The planned sample size of 1200 subjects 
(800 in treatment Arm A and 400 in treatment Arm B) for Part 1 of this 
study is expected to provide 84% power to demonstrate strong evidence 
with a single study (2-sided alpha level of 0.0012), assuming a 
15% response rate for the placebo arm and a 25% response rate for CVC 
according to the results from the Phase 2b Study 652-2-203 
(CENTAUR). 
The planned 800 subjects in treatment Arm A and 400 subjects in 
treatment Arm B is expected to provide 97% power to demonstrate 
strong evidence with a single study (2-sided alpha level of 0.0012) in 
the key secondary endpoint, assuming a 2.2% response rate for the 
placebo arm and an 8.6% response rate for CVC according to the results 
from the Phase 2b Study 652-2-203 (CENTAUR). 
PASS 8.0 was used to calculate the sample size.
These response rates reflect the primary analysis, in which subjects 
missing the post-baseline liver biopsy will be included as non-
responders. The anticipated proportion of subjects with missing Month 
12 liver biopsies, as a result of either premature subject discontinuation 
or non-evaluable liver biopsy results (ie, biopsy sample deemed 
inadequate for evaluation of efficacy endpoints by an independent 
central pathologist), is estimated to be 15% of subjects at Month 12, 
compared to approximately 13% of missing post-treatment liver 
biopsies in the Phase 2b study.

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Sample Size
Part 2
The sample size for the primary endpoint analysis in Part 2 is based on 
the estimated event-free survival rate of 80% for the placebo group and 
detection of a hazard ratio of 0.62 by the anticipated end of the study at 
Month 60 (corresponding to a median event-free survival time of 
approximately 15 years for placebo and 25 years for CVC). A total of 
2000 subjects (2:1 randomization ratio between CVC and placebo) 
enrolled approximately uniformly over 2 years for an overall study 
duration of approximately 8 years (2 years of accrual period plus 
5 to 6 years of follow-up) will lead to about 367 events, after accounting 
for an overall dropout rate of 20%. With these events, there will be 85% 
power to demonstrate strong evidence of superiority of CVC over 
placebo (at a 2-sided 0.00125 significance level, for a single registration 
study), and 99% power to test the superiority of CVC over placebo (at 
the 2-sided test 0.05 significance level for a registration study). 
EAST 6.4 was used for the calculation.

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5.
INTRODUCTION
Cenicriviroc mesylate (CVC) is a novel, once-daily, orally active and potent inhibitor of 
ligand binding to C-C chemokine receptor (CCR) type 2 (CCR2) and type 5 (CCR5), 
currently in clinical development for the treatment of liver fibrosis in adult subjects with 
nonalcoholic steatohepatitis (NASH).
5.1.
Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis
Nonalcoholic fatty liver disease (NAFLD) is a common, often “silent”, liver disease 
associated with obesity related disorders, such as type-2 diabetes mellitus (T2DM) and the 
metabolic syndrome, occurring in people who consume little or no alcohol and is 
characterized by the accumulation of fat in the liver with no other apparent causes.1-11 At the 
beginning of the NAFLD spectrum is simple or bland steatosis, which is characterized by a 
build-up of fat within the liver. Liver steatosis without inflammation is usually described as 
benign or non-progressive. NASH is usually described as a severe form of NAFLD where 
steatosis is complicated by liver-cell injury and inflammation, with or without fibrosis. The 
rising prevalence of obesity-related disorders has contributed to a rapid increase in the 
prevalence of NASH. Approximately 10% to 20% of subjects with NAFLD will progress to 
NASH.12 Due to the growing epidemic of obesity and diabetes worldwide, NASH is 
projected to become the most common cause of advanced liver disease and the most common 
indication for liver transplantation.13-16 The burden of NASH, combined with a lack of any 
approved therapeutic interventions, represents an unmet medical need.
5.2.
CVC Mechanism of Action
In vitro data with CVC have demonstrated that it blocks the binding of C-C motif chemokine 
ligand 2 (CCL)2 (also known as monocyte chemotactic protein 1 [MCP-1]) to CCR2, and 
also blocks the binding of CCR5 ligands, CCL3 (also known as macrophage inflammatory 
protein [MIP]-1), CCL4 (also known as MIP-1) and CCL5 (also known as regulated on 
activation normal T-cell expressed and secreted [RANTES]), to CCR5. Ex vivo experiments 
showed that nanomolar concentrations of CVC achieved 98% receptor occupancy of CCR2 
on human monocytes and ~90% receptor occupancy for CCR5 on human CD4+ and CD8+ 
T-cells. Additionally, CVC was an efficient inhibitor of monocyte and human lymphocyte 
(primarily T-cells) migration in vitro. 
The mechanism of action of CVC, as an anti-inflammatory and anti-fibrotic agent, supports 
its use in liver diseases, such as liver fibrosis associated with NASH. CVC treatment 
decreases the recruitment and migration of CCR2-expressing monocytes to the site of liver 
injury, mainly via CCR2 antagonism, thereby reducing the infiltration of pro-inflammatory, 
monocyte-derived macrophages into the liver.17,18 In addition, CCR5 antagonism by CVC is 
expected to impair the migration, activation and proliferation of collagen-producing 
activated hepatic stellate cells and myofibroblasts, therefore reducing fibrogenesis.19,20

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5.3.
Clinical Studies with CVC
Overall, as of January 2019, approximately 1579 subjects have been exposed to CVC in 
completed and ongoing clinical studies (January 2018 Development Safety Update Report 
[DSUR] cutoff).
Phase 1 Pharmacokinetic Studies in Healthy Subjects
5.3.1.
Initial human pharmacokinetic (PK) data for CVC was obtained in 2003 when the molecule 
was being developed by Takeda Pharmaceutical. The first 2 Phase 1 studies of CVC 
(Study 2080/16 [RCP-001] and Study 001 [01-03-TL-652-001]) established CVC’s 
bioavailability in humans and demonstrated that CVC was not excreted in urine, that plasma 
drug exposure was nearly dose proportional up to single doses of 400 mg, and that M-II and 
M-I were the major and minor metabolites, respectively, in humans. More importantly, the 
studies established rapid attainment of clinically significant drug levels, with a time to 
maximum plasma concentration (tmax) of 3 to 6 hours, and the possibility of once-daily
dosing with a half-life (t1/2) of 34 to 42 hours.
Tobira conducted its first clinical study with CVC tablet formulation at doses up to 800 mg in 
2008 (Study 652-1-101) and confirmed that CVC was readily absorbed with median tmax 
occurring about 3 to 6 hours post-dose across the dose levels. CVC was eliminated from 
plasma with a mean t1/2 of approximately 30 to 40 hours across the wide dose range studied, 
suggesting linear elimination kinetics. Evaluation of single oral dose administration of the 
Phase 3 formulation of CVC 150 mg in Study 3152-101-002 suggested that food increases 
exposure of CVC by 5.2-fold with a mean t1/2 of approximately 40 hours.
CVC was well tolerated in all of the single-dose studies, with no clinically important findings 
with respect to vital signs, electrocardiogram (ECG) findings, physical examinations, or 
laboratory tests for any subject. A few subjects had mild, usually isolated elevations in 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) while on CVC.
Study 102 (652-1-102) was the first multiple-dose study in humans. This randomized, 
double-blind, placebo-controlled, multiple-dose study was conducted in cohorts of 12 healthy 
adult male and female subjects. In Part 2 of Study 102, CVC at doses of 25 to 200 mg once 
daily was readily and well absorbed following single (Day 1) or repeated (Day 10) doses 
with a high-fat meal, achieving peak plasma concentrations about 3 to 6 hours post-dose. The 
mean t1/2 of CVC following repeated doses was similar to that after a single dose, averaging 
approximately 35 to 40 hours across dose regimens, indicating that the elimination kinetics of 
CVC were unchanged following repeated doses.
In Study 102, 2 subjects experienced adverse events (AEs) that resulted in discontinuation of 
study drug: Grade 4 AST/ALT in 1 subject, and a Grade 2 AST elevation and an elevated 
lactate dehydrogenase (LDH) in the other subject.
The safety, tolerability, and PK of the Phase 3 formulation following once daily escalating 
doses of CVC (450 and 900 mg) and combination with a single dose of 100 mg ritonavir 

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were evaluated in Study 3152-107-002. Steady state levels of CVC, M-1, and M-II 
metabolites were achieved with once daily dosing of 450 or 900 mg CVC with a high-fat 
meal for 7 days. Comparison of PK parameters suggested dose-proportional increase in Cmax
and AUC0-of CVC and M-1 metabolite, while M-II exposure increased less than 
proportionally. Coadministration of CVC with a single dose of 100 mg ritonavir resulted in 
increased CVC Cmax and AUC0-by 33.5% and 20.4%, respectively. Overall, multiple-dose 
administration of 450 and 900 mg CVC with a high-fat meal and coadministration with 
single dose of ritonavir 100 mg was safe and well tolerated.
The PK, safety, and tolerability of CVC were assessed in several drug-drug interaction 
studies. In clinical studies, potent cytochrome P450 (CYP)3A4 inhibitors such as ritonavir, 
darunavir/ritonavir combination, and atazanavir/ritonavir combination increased the exposure 
of CVC by 3.55-fold, 3.13-fold, and 3.89-fold, respectively. The exposure of midazolam, a 
substrate of CYP3A4, is increased by 1.84-fold when co-administered with 150 mg CVC. 
CVC increased the exposure of rosuvastatin (breast cancer resistance protein [BCRP]
substrate) by 3.52-fold, atorvastatin and simvastatin (CYP3A4 substrates) by 1.37-fold and 
2.48-fold, respectively. However, no significant increase in the exposure of digoxin 
(P-glycoprotein [P-gp] substrate) and caffeine (CYP1A2 substrate) was observed 
(Study 652-124). 
Based on clinical data as well as in vitro drug interaction studies, potent CYP3A4 inhibitors 
could significantly increase CVC exposure. Since CYP2C8 is identified to contribute to 
metabolism of CVC, potent CYP2C8 inhibitors may increase exposure of CVC. CVC was
identified as a P-gp substrate in vitro; however, based on currently available exposure-safety 
CVC data (Study 3152-107-002), co-administration of CVC with P-gp inhibitors is not 
expected to result in any clinically meaningful increase in CVC exposure. CVC can be co-
administered with P-gp substrates such as digoxin. Caution is recommended while co-
administering substrates of CYP3A4 with narrow therapeutic index (eg, midazolam). It is 
also recommended not to exceed the suggested maximum daily dose of rosuvastatin (BCRP 
substrate) and other statins (atorvastatin, lovastatin, pravastatin and simvastatin). The 
detailed list of disallowed medications and the list of medications that are allowed but with 
specific restrictions are provided in Appendix 20.4.
Phase 1 Pharmacokinetic Study in Subjects with Hepatic Impairment
5.3.2.
A Phase 1 open-label study (Study 121 [652-1-121]) in subjects with differing levels of 
hepatic impairment was conducted. This study was designed to evaluate the PK, safety, and 
tolerability of CVC in subjects with mild and moderate hepatic impairment (Child Pugh class 
A and B) compared to subjects with normal hepatic function. CVC exposures were not 
increased in subjects with mild hepatic impairment relative to matched healthy control 
subjects. CVC exposures were increased in subjects with moderate hepatic impairment 
relative to matched healthy control subjects. On Day 14, subjects with moderate hepatic 
impairment had CVC exposures approximately 29% (maximum plasma concentration [Cmax]) 
to 55% (area under the concentration-time curve up to the last measurable concentration 
[AUC0-tau]) higher compared to healthy matched controls. In subjects with hepatic 
impairment, a longer half-life was observed compared to healthy control subjects with 

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normal hepatic function (Day 14, t1/2 geometric mean: 37.6 hours [moderate] and 29.7 hours 
[mild] versus 22.4 hours [matched healthy controls, moderate] and 22.0 hours [matched 
healthy controls, mild]). Based on the magnitude of these observed differences in exposure in 
subjects with mild or moderate hepatic impairment, it is unlikely that a CVC dose adjustment 
will be required. In another study, the effect of severe hepatic impairment on PK of CVC and 
its metabolites was evaluated following single dose administration (Study 3152-102-002).
While the Cmax of CVC decreased by 26.39%, the AUC0-t and AUC0-∞increased by 39.67% 
and 77.75%, respectively.
In Study 121, CVC showed a favorable safety profile with few treatment-related AEs and 
with only 1 AE (mild vomiting; mild hepatic impairment subject) leading to treatment 
discontinuation. Two subjects (both with long-standing history of hepatitis C and liver 
cirrhosis) experienced Grade 3 (5.1 to 10.0 × upper limit of normal [ULN]) or Grade 4 
(> 10.0 × ULN) elevations in liver transaminases during the study; however, these returned 
to their prior grade of abnormality, and both subjects completed the 14-day dosing period and 
all study visits with no further sequelae. Both of these subjects had bilirubin levels within 
normal limits.
Phase 2b Study in Subjects with NASH and Liver Fibrosis   
5.3.3.
The Phase 2b study (CENTAUR; Study 652-2-203) was a randomized, double-blind, 
placebo-controlled, multinational, 2-year study. The study was designed to determine the 
efficacy and safety of CVC for the treatment of NASH in adult subjects with liver fibrosis. 
The study population included subjects with a nonalcoholic fatty liver disease activity score 
(NAS) ≥ 4 and liver fibrosis Stage 1 to 3 based on the NASH Clinical Research Network 
(CRN) criteria who were at increased risk of disease progression due to the presence of 
T2DM, body mass index (BMI) > 25 kg/m2 and meeting at least 1 of the criteria for 
metabolic syndrome, or bridging fibrosis (NASH CRN Stage 3) and/or definite NASH 
(NAS ≥ 5). Subjects were randomized in a 2:1:1 ratio to receive 1 of 3 treatments as follows: 

CVC 150 mg once daily for 2 years (Arm A; CVC/CVC group)

Placebo once daily for 1 year followed by CVC 150 mg once daily for an additional 
1 year (Arm B; placebo/CVC group)

Placebo once daily for 2 years (Arm C; placebo/placebo group) 
Fibrosis stage, NASH status, and NAS were assessed in serial liver biopsies read by an 
independent central pathologist at baseline, Year 1, and Year 2. The independent central 
pathologist remained blinded to individual subject treatment assignment throughout the 
conduct of the study.
A total of 289 subjects (intent-to-treat [ITT] population) were randomized into the 
CENTAUR study.21 Overall, 39 of 289 subjects (13.5%) withdrew early during Year 1 
(Treatment Period 1), with the most commonly reported reasons for early discontinuation 
during Year 1 being due to AEs and withdrawal of consent. A total of 250 subjects (86.5%) 
completed Year 1, and 242 subjects (83.7%) entered Year 2 (Treatment Period 2). During 

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Year 2, 16 subjects (5.5%) withdrew early, with the most commonly reported reason for 
early discontinuation during Year 2 being due to AEs, which were more commonly reported 
in the CVC/CVC group (3.4%, 5 subjects) compared with the placebo/CVC group (1.4%, 1 
subject) and the placebo/placebo group (0 subjects).
Overall, 47.4% (137/289) of subjects were male and 52.6% (152/289) were female. Most 
subjects were white (86.5% [250/289]) and not Hispanic or Latino (82.4% [238/289]). The 
mean age at screening was 54.1 years. Except for documented evidence of T2DM, the 
treatment groups were well balanced with respect to demographics and baseline 
characteristics. A higher percentage of subjects in the CVC/CVC group (58.6%) and 
placebo/CVC group (52.8%) than in the placebo/placebo group (40.3%) had documented 
evidence of T2DM.
Results
Although the primary endpoint of the CENTAUR study was not met, this study demonstrated 
that treatment with CVC resulted in a clinically meaningful antifibrotic benefit in participants 
with NASH. Twice as many participants treated with CVC 150 mg once daily, compared 
with placebo, achieved the key secondary outcome of improvement in fibrosis by ≥1 stage 
and no worsening of steatohepatitis at Year 1.  
The CENTAUR Year 2 analysis results confirm the antifibrotic effect of CVC observed at 
Year 1, as reflected in several analyses performed using 2 independent subgroups (ie, Year 1 
placebo nonresponders subgroup, in the placebo/CVC group versus placebo/placebo group 
over Year 1 to Year 2; and pooled participants treated with CVC for 1 year in the CVC/CVC 
and placebo/CVC groups versus the placebo/placebo group). The antifibrotic benefit 
associated with CVC treatment compared with placebo was most evident in the following 
clinical endpoints:

Improvement in fibrosis by ≥ 1 stage and no worsening of steatohepatitis at Year 1

Improvement in fibrosis by ≥ 2 stages and no worsening of steatohepatitis, with 
greater treatment effects observed at Years 1 and 2 

Improvement in fibrosis by ≥ 1 stage regardless of effect on steatohepatitis 
The majority of CVC-treated participants achieving at least a 1-stage improvement in fibrosis 
at Year 1 maintained the antifibrotic effect at Year 2. Furthermore, the greatest antifibrotic 
effect and durability of response was observed in NASH patients with advanced disease (eg, 
Stage 3 fibrosis at baseline). 
Overall, the safety profile of CVC (150 mg QD) was comparable to that in participants 
treated with placebo and was well tolerated over 2 years. The types, severity, and frequency 
of TEAEs reported after 2 years of CVC treatment was consistent with those reported after 1 
year of treatment. The overall incidence of TEAEs during the study was similar across the 
treatment groups (≥ 95.0% of participants in each group). No deaths occurred during the 
study. The frequency and types of TEAEs reported were comparable between treatment 
groups during Year 1 and Year 2. The incidence of treatment-emergent Grade 3 or 4 
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total, 3.3% (4/121) subjects in CVC/CVC group (Arm A), 3.3% (2/61) subjects in the 
placebo/CVC group (Arm B), and 3.3% (2/60) subjects in the placebo/placebo group 
(Arm C) met any protocol-defined biochemical criterion for suspected DILI. Hepatobiliary 
disorders during Treatment Period 2 were reported in 5/242 (2.1%) subjects overall. Of note, 
among the subjects who met the criteria for suspected DILI during Year 1, 2 hepatobiliary 
adverse events of “autoimmune hepatitis” were reported during Year 1 (1 subject in CVC 
Arm A group [Grade 3] and 1 subject in the Placebo Arm C [Grade 3]), and these subjects 
did not continue treatment during Year 2. One additional subject in the CVC group (Arm A) 
had a postbaseline liver biopsy “suggestive of autoimmune hepatitis or a drug hepatoxicity 
mimicking autoimmune hepatitis,” which was performed in the context of treatment 
emergent Grade 3 elevations in liver transaminases.
In conclusion, CVC treatment over 2 years resulted in a clinically meaningful, durable 
antifibrotic benefit and was generally well tolerated. Given that severity of fibrosis stage has 
been shown to be the only histological feature independently associated with clinical 
outcomes over the long term, these results provide additional evidence of CVC as a safe and 
efficacious pharmacologic treatment for liver fibrosis in adults with NASH. For further 
details, please refer to the most current CVC Investigator Brochure.
Pharmacokinetics/Pharmacodynamics
Findings from the pharmacokinetic/pharmacodynamic (PK/PD) analyses of CENTAUR were 
consistent with those of previous studies, which served as the basis for selection of the CVC 
dose of 150 mg evaluated in this study: 

Increases in CCL2 levels and decreases in fibrinogen levels were both found to be 
related to increases in CVC drug exposures, although most participants had attained a 
level of exposure where no additional changes in the biomarker would be expected

Neither exposures nor changes in CCL2 levels could be linked to improvement in 
fibrosis and no worsening of steatohepatitis. 
Results from a drug interaction study (Study 652-123) have shown that administration of a 
proton pump inhibitor (PPI) 90 minutes prior to CVC, dosed at 150 mg, resulted in 
significantly decreased CVC concentrations. In the CENTAUR study, PPIs were allowed 
with specific dosing instructions (ie, dosing of PPIs at least 2 hours after CVC 150 mg daily 
dose) and were used in 44% of all subjects. Although fewer subjects achieved an ECmin50 of 
40 ng/mL when using PPIs (84.5%) compared to those who did not (94.3%), a similar 
proportion of subjects in both groups achieved the key efficacy endpoint of improvement in 
fibrosis by at least 1 stage and no worsening of steatohepatitis: 21.0% for PPI users versus 
25.0% for nonusers, respectively (mITT). Therefore, the dose of 150 mg appears sufficient 
when managing co-administration of CVC with commonly used concomitant medications, 
such as PPIs.
Taken together, along with the lack of apparent exposure-response for efficacy in this study, 
the main findings from the PK/PD analyses further support that the CVC 150 mg dose was 

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able to maximize CCR2/CCR5 blockade in most subjects and support its evaluation in the 
Phase 3 program. 
5.4.
Study Rationale
The clinically important results from the Phase 2b CENTAUR study are robust and suggest 
that CVC treatment may be disease modifying in adult patients with liver fibrosis as a result 
of NASH. This is particularly relevant when considering the comprehensive and clinically 
evidence which demonstrates that liver fibrosis, regardless of other histological components 
of steatohepatitis, is the only histologic feature independently associated with all-cause 
mortality and liver-related outcomes in patients with NAFLD.22 Cenicriviroc appears to be 
safe with no notable differences observed in previous clinical studies in incidence of 
treatment-emergent AEs and laboratory abnormalities, including liver transaminase 
elevations, which were generally similar between treatment groups. 
The AURORA study (Protocol 3152-301-002) will be conducted to confirm the efficacy and 
safety of CVC for the treatment of liver fibrosis in adult subjects with NASH.
The study will be conducted in 2 parts:

Part 1: Evaluate the surrogate endpoint of improvement in fibrosis of at least 1 stage 
(nonalcoholic steatohepatitis clinical research network [NASH CRN]) and no 
worsening of steatohepatitis at Month 12 in subjects with Stage 2 and 3 liver fibrosis. 

Part 2: Determine the long-term clinical outcomes composed of histopathologic
progression to cirrhosis (defined by NASH CRN Fibrosis Stage 4), liver-related 
clinical outcomes, and all-cause mortality in subjects from Part 1 who have 
continued into Part 2 and additional newly randomized subjects with a liver biopsy
diagnosis of NASH and Stage 3 liver fibrosis enrolled in Part 2.
5.5.
Dose Rationale
A dose of CVC 150 mg will be evaluated for the treatment of liver fibrosis in adult subjects 
with NASH in the Phase 3 development program.
This dose was evaluated in the CENTAUR study (652-2-203) and selected based on the 
clinical activity, PK, pharmacodynamics (PD), and safety data from prior studies (652-1-110, 
652-1-111, 652-120, 652-1-121, 652-1-122, 652-123, 652-124, 652-2-202, and 652-2-201), 
which together support:

Evidence of meaningful clinical efficacy of CVC 150 mg in subjects with NASH and 
liver fibrosis in the CENTAUR study (Study 652-2-203)

Evidence that CVC 150 mg is safe and well tolerated subjects with NASH and liver 
fibrosis in the CENTAUR study (Study 652-2-203)

CVC dose of 150 mg provides an expectation of effective primary pharmacology 
(ie, CCR2 and CCR5 antagonism) 

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
Evidence of improvement in systemic inflammation biomarkers support underlying 
CVC pharmacology
6.
STUDY OBJECTIVES
6.1.
Part 1
Primary Objective (Part 1):

Demonstrate the superiority of CVC compared to placebo on liver histology at 
Month 12 relative to the Screening biopsy in adult subjects with a liver biopsy 
diagnosis of NASH and Stage 2 or 3 liver fibrosis (by NASH CRN system) as 
confirmed by an independent central pathologist, by assessing the following 
composite primary endpoint:
o
Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH 
CRN system) AND no worsening of steatohepatitis (no worsening of lobular 
inflammation or hepatocellular ballooning grade)
Key Secondary Objective (Part 1):

Evaluate the effect of CVC compared to placebo on liver histology at Month 12 
relative to the Screening biopsy for the proportion of subjects with improvement 
in fibrosis of at least 2 stages (NASH CRN system) AND no worsening of 
steatohepatitis (no worsening of lobular inflammation or hepatocellular 
ballooning grade)
Secondary Objectives (Part 1):

Evaluate the effect of CVC compared to placebo on liver histology at Month 12 
relative to the Screening biopsy for the proportion of subjects with improvement 
in fibrosis by at least 1 stage (NASH CRN system), regardless of effect on 
steatohepatitis

Evaluate the effect of CVC compared to placebo on liver histology at Month 12 
relative to the Screening biopsy for the proportion of subjects with improvement 
in fibrosis by at least 2 stages (NASH CRN system), regardless of effect on 
steatohepatitis

Evaluate the safety and tolerability of CVC for the treatment of liver fibrosis in 
adult subjects with NASH

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6.2.
Part 2
Primary Objective (Part 2):

Demonstrate the superiority of CVC compared to placebo on the composite endpoint 
of histopathologic progression to cirrhosis (defined by NASH CRN Fibrosis Stage 4), 
liver-related clinical outcomes, and all-cause mortality, as measured by the time to 
first occurrence of any of the listed adjudicated events (clinical outcomes composite 
endpoint) – (all subjects)
Secondary Objectives (Part 2):

Evaluate the effect of CVC compared to placebo on liver histology at Month 12 
relative to the Screening biopsy for the proportion of subjects with improvement in 
fibrosis by at least 1 stage (NASH CRN system) AND no worsening of steatohepatitis 
(no worsening of lobular inflammation or hepatocellular ballooning grade) – (subjects 
newly randomized in Part 2)

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
Evaluate the effect of CVC compared to placebo on liver histology at Month 12 
relative to the Screening biopsy for the proportion of subjects with improvement in 
fibrosis by at least 1 stage (NASH CRN system), regardless of effect on 
steatohepatitis – (subjects newly randomized in Part 2)

Evaluate the effect of CVC compared to placebo on liver histology at Month 60 
relative to the Screening biopsy for the proportion of subjects with improvement in 
fibrosis by at least 1 stage (NASH CRN system) AND no worsening of steatohepatitis 
(no worsening of lobular inflammation or hepatocellular ballooning grade) – (all 
subjects)

Evaluate the effect of CVC compared to placebo on liver histology at Month 60 
relative to the Screening biopsy for the proportion of subjects with improvement in 
fibrosis by at least 1 stage (NASH CRN system), regardless of effect on 
steatohepatitis – (all subjects)

Evaluate the effect of CVC compared to placebo on liver histology at Month 12 
relative to the screening biopsy for the proportion of subjects with improvement in 
fibrosis by at least 2 stages (NASH CRN system) AND no worsening of 
steatohepatitis (no worsening of lobular inflammation or hepatocellular ballooning 
grade) – (for subjects newly randomized in Part 2)

Evaluate the effect of CVC compared to placebo on liver histology at Month 12 
relative to the screening biopsy for the proportion of subjects with improvement in 
fibrosis by at least 2 stages (NASH CRN system) regardless of effect on 
steatohepatitis – (for subjects newly randomized in Part 2)

Evaluate the effect of CVC compared to placebo on liver histology at Month 60 
relative to the screening biopsy for the proportion of subjects with improvement in 
fibrosis by at least 2 stages (NASH CRN system) AND no worsening of 
steatohepatitis (no worsening of lobular inflammation or hepatocellular ballooning 
grade) – (all subjects)

Evaluate the effect of CVC compared to placebo on liver histology at Month 60 
relative to the screening biopsy for the proportion of subjects with improvement in 
fibrosis by at least 2 stages (NASH CRN system), regardless of effect on 
steatohepatitis – (all subjects)

Evaluate the safety and tolerability of CVC for the treatment of liver fibrosis in adult 
subjects with NASH – (all subjects)

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7.
INVESTIGATIONAL PLAN
7.1.
Overall Study Design and Plan
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of CVC 
for the treatment of Stage 2 or 3 liver fibrosis in adult subjects with NASH. The study will be 
conducted in 2 parts: Part 1 (surrogate endpoint) and Part 2 (clinical outcomes). 
Part 1 will assess the effect of CVC on the surrogate endpoint at Month 12 (Section 7.1.1) in
approximately 1200 subjects with a liver biopsy diagnosis of NASH and Stage 2 or 3 liver 
fibrosis (by NASH CRN system) as confirmed by an independent central pathologist. 
Subjects will be randomized 2:1 to receive CVC or placebo and will receive the same 
treatment for the duration of the study. 
Part 2 of the study will focus on assessing the effect of CVC on clinical outcomes in 
approximately 2000 subjects, including up to 1200 subjects with a liver biopsy diagnosis of 
NASH and Stage 2 or 3 liver fibrosis (by NASH CRN system) previously randomized in 
Part 1 and an additional 800 adult subjects with a liver biopsy diagnosis of NASH and 
Stage 3 liver fibrosis (by NASH CRN system) newly randomized 2:1 to receive CVC or 
placebo in Part 2 (Section 7.1.2).
A Data and Safety Monitoring board (DSMB) will be formed to review ongoing data from 
Part 1 and Part 2 of this study.
The study will be terminated when adjudicated events have been accrued in 367 unique 
subjects overall. All subjects who complete the study or are terminated from the study early 
due to an adjudicated clinical endpoint or due to any other reason, will have an End of Study 
visit at that time and will return to the clinic for a Follow-up visit 30 days after the last dose 
of study drug.
Subjects who permanently discontinue study drug, for any reason, before the planned end of 
study, are encouraged to keep participation in the study and complete all subsequent study 
visits (without treatment) for assessment of clinical outcomes (at the discretion of the 
investigator, subjects who permanently discontinue study drug may be followed every 
6 months unless otherwise specified by the protocol).
Subjects who undergo early termination from the study drug will return to the clinic within 
48 hours for an Early Discontinuation visit and will return to the clinic for a Follow-up visit 
30 days after the last dose of study drug.
Survival data will be collected for all study subjects at the end of the study.
Subjects who progress to cirrhosis or reach a liver-related clinical outcome, which must be 
adjudicated by an independent adjudication committee, will complete the study and return to 
the clinic for a Follow-up visit 30 days after the last dose of study drug (Visit 98). After 
completion of the Follow-up visit (Visit 98), these subjects will become eligible for 
open-label access to CVC in a separate study (Clinical Study Protocol 3152-201-002).

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The study design is illustrated in Figure 1 and described briefly in Section 7.1.1 (Part 1) and 
Section 7.1.2 (Part 2). Study procedures are summarized across all study visits within the 
Schedule of Assessments for Part 1 (Table 20–1) and Part 2 (Table 20–2). Except for the End 
of Treatment and Follow-up visits, all subsequent visits are based on the Baseline visit date.
Figure 1
Study Design Schematic
Subjects Randomized in Part 1 and Continuing to Part 2
SCR
Part 1 
(Baseline to Month 12)
Part 2 
(Month 12 to the End of Study)a
EOSb
FU
Screeningc
Month -3
Baseline 
Day 1
Months 1, 3,
6, 9
Month 12
Every 3 months Month 60
Every 3 months 
End of 
Study
30-day 
Follow-
up
Screening 
Biopsyd,e,f
Month 12 
Biopsyg
Month 60 
Biopsyh
Treatment Arm A
CVC 150 mg, QD
Rx
2:1
Treatment Arm B 
Placebo, QD
Subjects Newly Randomized in Part 2
SCR
Part 2 
(Baseline to the End of Study)a
EOSb
FU
Screeningc
Month -3
Baseline 
Day 1
Months 1, 3, 
6, 9
Month 12
Every 3 months 
Month 60
Every 3 months 
End of 
Study
30-day 
Follow-
up
Screening 
Biopsyd,e,f
Month 12 
Biopsyg
Month 60 
Biopsyh
Treatment Arm A
CVC 150 mg, QD
Rx
2:1
Treatment Arm B 
Placebo, QD
AE = adverse event; CVC = cenicriviroc mesylate; EOS = End of Study; FU = Follow-up; QD = once daily; 
Rx = randomization; SCR = Screening
a
The duration of treatment is estimated to be 60 months for subjects participating in the study. Actual treatment duration 
will vary depending on the time to accrue adjudicated events in 367 unique subjects in the CVC and placebo arms 
combined.

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b
The study will be terminated when adjudicated events have been accrued in 367 unique subjects overall. All subjects 
will have an End of Study visit at that time and will return to the clinic for a Follow-up visit 30 days after the last dose 
of study drug.
c
Subjects who do not meet any of the laboratory eligibility criteria during the Screening period will be allowed to retest 
twice, with at least 1-week interval between the date of the first failed test and the date of subsequent test. However, if a 
subject fails to meet eligibility criteria upon these 2 retest opportunities, he or she will remain ineligible for the study.
Subjects who continue from Part 1 to Part 2 will not require a Screening visit in Part 2.
d
Screening laboratory tests, Screening serum hepatic fibrosis indices and evaluation of liver stiffness performed no more 
than 6 months prior to the first day of Screening will aid in identifying subjects with clinically significant liver fibrosis 
prior to proceeding with a new liver biopsy.
e
A historical biopsy, obtained no more than 6 months prior to the first day of Screening, may be used if the criteria 
detailed in inclusion criterion 3a (Section 8.2) are met.
f
Screening biopsy result is required before Baseline visit can be conducted and before subject can be randomized.
g
The Month 12 biopsy will be collected within ± 2 weeks of the Month 12 visit.
h
The Month 60 biopsy will be collected within ± 2 weeks of the Month 60 visit.
Part 1
7.1.1.
Part 1 of the study will include approximately 1200 adult subjects with a liver biopsy 
diagnosis of NASH and Stage 2 or 3 liver fibrosis (by NASH CRN system). 
In Part 1, eligible subjects will be randomized 2:1 to receive CVC or placebo, once daily for 
12 months in order to assess the effect of CVC on the surrogate endpoint at Month 12. 
At Baseline (Day 1), eligible subjects will be assigned to the treatment arms using permuted 
block randomization stratified by NASH CRN Fibrosis stage (2 or 3) and presence or 
absence of documented T2DM (yes or no). Eligible subjects will be randomized 2:1 to one of 
the following 2 treatment arms and will receive the same treatment for the duration of the 
study:
Table 7–1
Treatment Arms: Part 1
Arm
N
Treatment 
A
800
CVC 150 mg, once daily
B
400
Placebo, once daily
CVC and placebo will be administered as double-blinded study drug. Study drug (CVC or 
placebo) must be taken once daily with food.
All subjects will undergo safety assessments at the Baseline visit and Months 1, 3, 6, 9, 
and 12.  
The liver biopsy, used to evaluate the efficacy endpoints, must be performed within 
± 2 weeks of the Month 12 visit (Visit 7).
Subjects who permanently discontinue study drug before planned end of study are 
encouraged to complete all subsequent study visits and participate (without treatment) in 
Part 2 of the study for assessment of clinical outcomes (at the discretion of the investigator, 

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subjects who permanently discontinue study drug may be followed every 6 months unless 
otherwise specified by the protocol). Subjects who undergo early termination from the study 
will return to the clinic within 48 hours for an Early Discontinuation visit and will return to 
the clinic for a Follow-up visit 30 days after the last dose of study drug.
Survival data will be collected for all study subjects at the end of the study.
Subjects who progress to cirrhosis or reach a liver-related clinical outcome, which must be 
adjudicated by an independent adjudication committee, will complete the study and return to 
the clinic for a Follow-up visit 30 days after the last dose of study drug (Visit 98). After 
completion of the Follow-up visit (Visit 98), subjects will become eligible for open-label 
access to CVC in a separate study (Clinical Study Protocol 3152-201-002).
Key Assessments
During Part 1 of the study:

A Screening visit is to occur within3 months before the Baseline visit. The 
informed consent form for Study 3152-301-002 (Parts 1 and 2) and patient 
education materials about NASH, liver fibrosis, liver biopsy procedures, and 
study retention tools will be reviewed at the Screening visit.

As part of Screening, assessment of serum laboratory tests (hematology and 
chemistry panels), serum hepatic fibrosis indices (non-invasive hepatic fibrosis 
index score combining standard biochemical values, platelets, ALT, AST, and age 
[FIB-4]; AST to platelet count ratio index [APRI]; and NAFLD fibrosis score 
[NFS]) and evaluation of liver stiffness via transient elastography (TE) or liver 
imaging (performed no more than 6 months prior to the first day of Screening at 
sites where available) will aid in identifying subjects with clinically significant
liver fibrosis prior to proceeding with a new liver biopsy. 

A historical liver biopsy, obtained no more than 6 months prior to the first day of 
Screening, that meets protocol-required specifications, or a new liver biopsy will 
be evaluated by an independent central pathologist for all subjects as part of 
Screening to confirm histologic evidence of NASH and fibrosis Stages 2 or 3.

Subjects meeting all other eligibility criteria and with suspicion of significant 
liver fibrosis (through clinical evaluation, hepatic fibrosis indices, and/or liver 
stiffness assessment [performed no more than 6 months prior to the first day of 
Screening]) will undergo a new liver biopsy during the Screening period. In 
randomized subjects, a second post-treatment liver biopsy will be collected at the 
Month 12 visit (± 2 weeks).

Fasting metabolic parameters, including lipid panel (triglycerides, total 
cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], very 
low-density lipoprotein [VLDL]), glucose, insulin and hemoglobin A1c (HbA1c), 
will be measured at Baseline and at Months 3, 6, and 12.

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
Samples for biomarkers of systemic inflammation, including interleukin (IL)-1β, 
IL-6, high-sensitivity C-reactive protein (hs-CRP), and fibrinogen will be 
collected at Baseline and at Months 3, 6, and 12. 

Samples of non-invasive serum hepatic fibrosis indices (FIB-4, APRI, NFS), ELF 
Score, and PRO-C3 will be collected at Months 6 and 12.

At selected sites where available, non-invasive assessment of liver fibrosis by TE 
will be performed at Baseline (if not performed at Screening), and at Months 6 
and 12. 

Pharmacokinetic samples for CVC will be collected at Months 3, 6, and 12 (pre-
dose and at least 1-hour post-dose) (see Section 11.7)

Weight, waist circumference, and hip circumference will be performed at 
Screening, Baseline and at Months 3, 6, and 12. Height will be performed at 
Screening.

Physical examination, vital signs, and laboratory analyses (serum chemistry and 
hematology) will be performed at each visit. Serum immunoglobulin G (IgG), 
antinuclear antibody (ANA), anti-smooth muscle antibodies (SMA), 
anti-liver/kidney microsome type 1 (LKM1) and anti-liver cytosol type 1 (LC1) 
antibodies will be evaluated at Baseline. Electrocardiograms will be performed at 
Baseline and at Month 12.  

Adverse events and concomitant medications will be assessed at each visit.
Part 2
7.1.2.
Part 2 of the study will focus on assessing the effect of CVC on clinical outcomes in 
approximately 2000 subjects, including up to 1200 subjects with a liver biopsy diagnosis of 
NASH and Stage 2 or 3 liver fibrosis (by NASH CRN system) previously randomized in Part 
1 and an additional 800 adult subjects with a liver biopsy diagnosis of NASH and Stage 3 
liver fibrosis (by NASH CRN system) newly randomized 2:1 to receive CVC or placebo in 
Part 2.
Subjects who remain in Part 1 at Month 12 will continue to be evaluated in Part 2 of the 
study and will continue the same treatment through the end of Part 2. Individual subject 
treatment assignments will not be revealed until the completion of Part 2 of the study.

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Subjects who enter Part 2 from Part 1 of the study will have study visits every 3 months until 
Part 2 is completed. Study drug will be dispensed and AEs, concomitant medications, and 
adherence to study drug will be reviewed at every visit (every 3 months). Safety laboratory 
assessments will be performed every 6 months through the end of the study.
Subjects who are newly randomized in Part 2 of the study will complete the following visits: 
At Baseline (Day 1) eligible subjects will be randomized to treatment using permuted block 
randomization, and presence or absence of documented T2DM (yes or no). Newly enrolled 
subjects will be randomized 2:1 to one of the following 2 treatment arms to achieve a total of 
approximately 2000 randomized subjects in study (of which up to 1200 subjects will have 
been randomized in Part 1 and 800 in Part 2):
Table 7–2
Treatment Arms in Part 2
Arm
Randomized
Subjects in Part 2
N
Total Subjects (Randomized 
in Part 1 or Part 2)
N
Treatment 
A
534
1334
CVC 150 mg, once daily
B
266
666
Placebo, once daily
Study drug will be administered as double-blinded treatment and must be taken once daily 
with food.
Newly enrolled subjects in Part 2 will undergo safety laboratory assessments at Months 1, 6, 
and 12 and every 6 months thereafter through the end of the study. Beginning at Month 3, 
AEs, concomitant medications, and adherence will be reviewed every 3 months through the 
end of the study.  
Newly enrolled subjects will undergo a liver biopsy at Screening for assessment of eligibility 
and a second post-treatment liver biopsy will be collected within ± 2 weeks of the Month 12 
visit. All subjects (newly randomized subjects with a liver biopsy diagnosis of NASH and 
Stage 3 liver fibrosis [by NASH CRN system] and those who continue from Part 1) will 
undergo a liver biopsy at Month 60 (within ± 2 weeks) after the first dose of study drug.
Subjects who permanently discontinue study drug before planned end of study are 
encouraged to complete all subsequent study visits and participate (without treatment) in 
Part 2 of the study for assessment of clinical outcomes (at the discretion of the investigator, 
subjects who permanently discontinue study drug may be followed every 6 months unless 
otherwise specified by the protocol). 
Subjects who undergo early termination from the study will return to the clinic within 
48 hours for an Early Discontinuation visit and will return to the clinic for a Follow-up visit 
30 days after the last dose of study drug.  
Survival data will be collected for all study subjects at the end of the study.

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Subjects who progress to cirrhosis or reach a liver-related clinical outcome, which must be 
adjudicated by an independent adjudication committee, will complete the study and return to 
the clinic for a Follow-up visit 30 days after the last dose of study drug (Visit 98). After 
completion of the Follow-up visit (Visit 98), these subjects will become eligible for open-
label access to CVC in a separate study (Clinical Study Protocol 3152-201-002). 
Key Assessments
During Part 2 of the study

Screening will only be required for newly enrolled subjects and will not be 
required for subjects continuing their previously assigned blinded treatment from 
Part 1. A Screening visit is to occur within 3 months before the Baseline visit for 
any new subjects to be enrolled in Part 2. The informed consent and patient 
education materials about NASH, liver fibrosis, liver biopsy procedures, and 
study retention tools will be reviewed at the Screening visit for newly enrolled 
subjects.

As part of Screening, assessment of serum laboratory tests (hematology and 
chemistry panels), serum hepatic fibrosis indices (including FIB-4, APRI, and 
NFS) and evaluation of liver stiffness via TE or liver imaging (performed no more 
than 6 months prior to the first day of Screening at sites where available) should
be performed to aid in identifying subjects with clinically significant liver fibrosis 
prior to proceeding with a new liver biopsy. 

A historical liver biopsy, obtained no more than 6 months prior to the first day of 
Screening, that meets protocol-required specifications or a new liver biopsy will 
be evaluated for all subjects as part of Screening to confirm histologic evidence of 
NASH and fibrosis Stages 2 or 3.

Subjects newly enrolled in Part 2 meeting all other eligibility criteria and with 
suspicion of significant liver fibrosis (through clinical evaluation, hepatic fibrosis 
indices, and/or liver stiffness assessment [performed no more than 6 months prior 
to the first day of Screening]) will undergo a new liver biopsy during the 
Screening period. Newly randomized subjects in Part 2 will undergo a further 
liver biopsy at Month 12 (within ± 2 weeks). A liver biopsy will be performed at 
the Month 60 visit (± 2 weeks) for all subjects.

Fasting metabolic parameters, including lipid panel (triglycerides, total 
cholesterol, HDL, LDL, VLDL), glucose, insulin, and HbA1c, will be measured 
at Baseline for newly randomized subjects and every 6 months through the end of 
study for all subjects.

Samples for biomarkers of systemic inflammation, including IL-1β, IL-6, hs-CRP, 
and fibrinogen, will be collected at Baseline for newly randomized subjects and 
every 6 months through the end of the study for all subjects. 

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
Samples for non-invasive serum hepatic fibrosis indices (FIB-4, APRI, NFS), 
Liver Stiffness, ELF Score, and PRO-C3 every 12 months for all subjects

At selected sites where available, non-invasive assessment of liver fibrosis by TE 
will be performed at Baseline (if not performed at Screening) for newly 
randomized subjects and annually through the end of the study for all subjects.

Weight, waist circumference, and hip circumference will be performed at 
Screening and Baseline for newly randomized subjects and every 6 months 
through the end of the study for all subjects.  Height will be performed at 
Screening.

Physical examinations, vital signs, and laboratory analyses (serum chemistries 
and hematology) will be performed at Screening, Baseline, Months 1, 6 and 12 for 
subjects who are newly randomized in Part 2, and every 6 months thereafter 
through the end of the study for all subjects. Serum IgG, ANA, anti-SMA, and 
anti LKM 1 and anti-LC1 antibodies will be evaluated at Baseline for subjects 
newly randomized in Part 2. Electrocardiograms will be performed at Baseline for 
newly randomized subjects and annually through the end of the study for all 
subjects.

Clinical outcomes, AEs and concomitant medications will be assessed at each 
study visit.  

An ultrasound exam to screen for hepatocellular carcinoma (HCC) and presence
of ascites will be performed at Month 60.
8.
STUDY POPULATION
A total of 2000 subjects will be enrolled in the study at up to 600 centers in North, Central, 
and South America; Europe; and Asia Pacific region. It is expected that at least 30% of 
subjects will be randomized in the United States (US). 

Part 1: Adult subjects with liver biopsy diagnosis of NASH and Stage 2 or 3 liver 
fibrosis (by NASH CRN system)

Part 2: Subjects who remain in Part 1 at Month 12 will continue the same treatment 
through the end of Part 2. Subjects newly enrolled and randomized in Part 2 will 
include adult subjects with a liver biopsy diagnosis of NASH and Stage 3 liver 
fibrosis (by NASH CRN system).

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8.1.
Number of Subjects 
Part 1:
Part 1: Approximately 1200 subjects will be included in Part 1. They will be randomized 2:1 
to the following treatment arms:

Treatment Arm A (CVC 150 mg, once daily): approximately 800 subjects  

Treatment Arm B (placebo, once daily): approximately 400 subjects. 
Subjects who remain in Part 1 at Month 12 will continue to be evaluated in Part 2 of the 
study and will continue the same treatment through the end of Part 2.
Part 2: Approximately 2000 subjects (including up to 1200 subjects who continue from Part 1 
to Part 2) will be included in Part 2. Approximately 60% or more of subjects with Stage 3 
fibrosis will be enrolled in the study overall. 

Treatment Arm A (CVC 150 mg, once daily): approximately 1334 subjects, of which 
approximately 534 are newly enrolled 

Treatment Arm B (placebo, once daily): approximately 666 subjects, of which 
approximately 266 subjects are newly enrolled
8.2.
Inclusion Criteria: Part 1 and Part 2
For a subject to be eligible for participation in Part 1 or Part 2 of this study, all of the 
following criteria must apply.
1. Male and female subjects aged between 18 to 75 years
2. Ability to understand and sign a written informed consent form (ICF)
3. Histological evidence of NASH based on central reading of the Screening biopsy slides
a.
Historical biopsy may be substituted for Screening period biopsy to determine 
eligibility if the following are met:
i.
Historical biopsy was obtained no more than 6 months prior to the first 
day of screening
ii.
Hepatic tissue is available for central histologic evaluation
iii.
No new therapeutic intervention for NASH was made during the 6-month 
period (eg, obeticholic acid, vitamin E > 400 IU/day, pioglitazone, 
liraglutide, loss of ≥ 7% of body weight, bariatric surgery including gastric 
banding, investigational NASH agents)
iv.
Subjects must have been metabolically stable since the biopsy (no 
significant weight loss [≥ 7% of body weight], no major deterioration of 

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glycemic control, and no introduction of new or investigational drugs for 
the treatment of T2DM)
4. Subjects included in Part1 must have histopathological evidence of Stage 2 or 3 liver 
fibrosis per the NASH CRN System based on central reading of the Screening biopsy 
slides. Subjects newly randomized in Part 2 must have histological evidence of Stage 3 
liver fibrosis per the NASH CRN System, based on central reading of the Screening 
period biopsy slides. Historical biopsy can be used, provided the criteria listed on Item 3a 
above are fulfilled.
5. Females of childbearing potential and males participating in the study must agree to 
use at least 2 approved methods of contraception throughout the duration of the study and 
for 30 days after stopping study drug. Females who are postmenopausal must have 
documentation of cessation of menses for ≥ 12 months without an alternative medical 
cause. Follicle-stimulating hormone (FSH) level in the postmenopausal range 
(≥30 mU/mL at Screening) may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormone replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
a.
Females on HRT and whose menopausal status is in doubt will be required to use 
the contraception methods in Appendix 20.3 if they wish to continue their HRT 
during the study. Otherwise, they must temporarily discontinue HRT to enable 
confirmation of postmenopausal status before study enrollment.
8.3.
Exclusion Criteria: Part 1 and Part 2
A subject will not be eligible for participation in Part 1 and/or Part 2 of this study if any of 
the following criteria apply.
1. Inability to undergo a liver biopsy
2. Hepatitis B surface antigen (HBsAg) positive
3. Hepatitis C antibody (HCVAb) positive with the following 2 exceptions: 
4. Human immunodeficiency virus (HIV)-1 or HIV-2 infection
5. Prior or planned liver transplantation

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6. Other known causes of chronic liver disease, such as the following:
7. History or presence of cirrhosis (NASH CRN Fibrosis Stage 4) and/or hepatic 
decompensation including ascites, hepatic encephalopathy, or variceal bleeding
8. Alcohol consumption greater than 21 units/week for males or 14 units/week for females 
9. AST > 5 × ULN at Screening
10. ALT > 5 × ULN at Screening
11. HbA1c > 9% at Screening
12. Serum albumin < 3.5 g/dL at Screening
13. Estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease (MDRD) equation at Screening
14. Platelet count < 100,000/mm3 at Screening
15. Total bilirubin > 1.3 mg/dL at Screening (subjects with hyperbilirubinemia associated 
with documented Gilbert’s syndrome may be eligible upon review by the medical 
monitor)
16. International normalized ratio (INR) > 1.3 at Screening
17. Model of end stage liver disease (MELD) score > 12
18. Weight reduction, defined as ≥7% of body weight, through bariatric surgery in the past 5 
years or bariatric surgery planned during the conduct of the study (including gastric 
banding and sleeve surgery)
19.
history of malignancy within the past 5 years or 
ongoing malignancy other than: basal cell carcinoma, resected noninvasive cutaneous 
squamous cell carcinoma

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20. Active, serious infections that require parenteral therapy (antibiotic or antifungal) within 
30 days prior to Screening visit
21. Clinically significant cardiovascular or cerebrovascular disease within the past 3 months, 
22. Females who are pregnant or breastfeeding
23. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic 
agents and immunomodulating agents (eg, interleukins, interferons, cyclosporine, 
tacrolimus) except for vaccines or short-term corticosteroids.
24. Receiving a glucagon-like peptide 1 (GLP-1) receptor agonist, a dipeptidyl peptidase 4 
(DPP-4) inhibitor, a sodium–glucose cotransporter 2 (SGLT2) and/or SGLT1 inhibitor, or 
a thiazolidinedione (TZD) for less than 6 months prior to the Screening period liver 
biopsy. Subjects on a stable therapy with a GLP-1 receptor agonist, DPP-4 inhibitor, 
SGLT1 and/or SGLT2 inhibitor, or a TZD for at least 6 months prior to the Screening 
liver biopsy may be considered eligible. (Important Note: if a historical biopsy is to be 
used, subjects need to be on stable therapy for at least 6 months prior to the day 
historical liver biopsy was performed).

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assigned to placebo in such trials may be eligible immediately following completion of 
their participation in the previous trial)
29. Participation in any other clinical trial at Screening without approval from the sponsor
30. Any other clinically significant disorders or prior therapy that, in the opinion of the 
investigator, would make the subject unsuitable for the study or unable to comply with 
the dosing and protocol requirements
9.
TREATMENTS
9.1.
Treatments Administered
At Baseline in Part 1 or Part 2 (newly randomized subjects), eligible subjects will be 
randomized 2:1 to one of 2 treatment arms: 
Table 9–1
Treatment Arms: Part 1 and Part 2
Arm
Part 1
N
Part 2 
Newly 
Randomized 
Subjects
N
Part 2 
Total Subjects (Randomized in 
Part 1 or Part 2)
N
Treatment 
A
800
534
1334
CVC 150 mg, once daily
B
400
266
666
Placebo, one daily
Subjects who remain in Part 1 of the study at Month 12 will continue their previously 
assigned blinded treatment from Part 1 into Part 2 and will continue to be evaluated in Part 2. 
In addition, new eligible subjects will be enrolled into Part 2 and randomized after the 
enrollment for Part 1 is completed. This will result in a total of approximately 2000 subjects 
in Part 2 (including up to 1200 subjects who were randomized in Part 1); approximately 1334 
subjects treated with CVC and 666 subjects treated with placebo.
In Parts 1 and 2, CVC and placebo will be administered as double-blinded study drug. Study 
drug (CVC or placebo) must be taken once daily with food.
9.2.
Study Drug
Investigational Product
9.2.1.
Chemical Name:
(S)-8-[4-(2-Butoxyethoxy)phenyl]-1-isobutyl-N-(4-{[(1-propyl-
1H-imidazol-5-yl)methyl]sulfinyl}phenyl)-1,2,3,4-tetrahydro-1-
benzazocine-5-carboxamide monomethane sulfonate 
Generic Name:
Cenicriviroc mesylate
Abbreviated Name:
CVC
Laboratory Designation:
TBR-652
Trade Name:
Not applicable

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The CVC drug product is formulated with fumaric acid (160 mg) and other excipients, 
including microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate, and Opadry® II yellow (film coating).
The CVC drug product is provided as 150-mg yellow-coated, immediate release tablets for 
oral administration. 
The matching placebo tablet contains tartrazine E 102 (10 mg), as a component of 39 mg of 
the dye FD&C Yellow/Tartrazine Aluminum Lake. 
WARNING: Tartrazine may cause allergic reactions.
Packaging and Labeling
9.2.2.
The study drug, CVC and matching placebo, will be packaged in high-density polyethylene 
(HDPE) bottles containing 30 tablets per bottle with desiccant and induction sealed. The site 
pharmacist, investigator, or designee will dispense study drugs. When dispensed, supplies 
will contain sufficient drug to cover the visit window period.
All labels for CVC and placebo will meet all applicable requirements of the United States 
(US) Food and Drug Administration (FDA) and Annex 13 of Good Manufacturing Practices 
and/or all local regulations, as applicable.
Storage
9.2.3.
All study drug should be stored at controlled room temperature (refer to the packaging or 
study/pharmacy manual). CVC tablets will continue to be monitored for stability at ICH 
recommended storage conditions. Detailed storage and handling information is provided in 
the Pharmacy Manual.
Study Drug Dispensing and Collection
9.2.4.
Study drug (CVC or placebo) will be supplied in a bottle containing 30 tablets of medication 
for each subject, which is sufficient for 30 days dosing. At scheduled visits where visits are 
scheduled more than 1 month apart, multiple bottles will be supplied to ensure drug supply 
until the next scheduled visit. 
Study drug will be assigned by interactive response system (IxRS) to study sites/subjects. 
Subjects will be instructed that 1 tablet of study drug must be taken once daily with food. 
Unused medication and empty medication bottles will be collected from each subject at each 
scheduled study visit, beginning with the Month 1 visit in Part 1 or Part 2.
Investigational Product Accountability
9.2.5.
Responsibility for drug accountability at the study site rests with the investigator; however, 
the investigator may assign some of the drug accountability duties to an appropriate 
pharmacist or designee. Inventory and accountability records must be maintained and must 

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be readily available for inspection by the study monitor and are open to inspection at any 
time by any applicable regulatory authorities.
The investigator or designee will be expected to collect and retain all used, unused, and 
partially used containers of study drug. The investigator or designee must maintain records 
that document the following:

Study drug delivery to the study site

Inventory at the site

Storage conditions

Use by each subject, including tablet counts from each supply dispensed

Return of study drugs to the investigator or designee.
These records should include dates, quantities, batch/serial numbers (if available), and the 
unique code numbers (if available) assigned to the study drug and study subjects.
The study drug must be used only in accordance with the protocol. The investigator will also 
maintain records adequately documenting that the subjects were provided the study drug 
specified.
Completed accountability records will be archived by the site. All used and unused bottles 
are to be sent back to the originating depot for destruction in accordance with the 
protocol-specific monitoring plan. Guidance and information regarding the final disposition 
of all study drug are provided in the Pharmacy manual.
Guidance and information regarding the final disposition of unused study drug are provided 
in the Pharmacy Manual.
Randomization
9.2.6.
Randomization will be accomplished via IxRS.
Part 1
9.2.7.
In Part 1, at Baseline (Day 1), following Screening evaluations, eligible subjects will be 
assigned to the treatment arms using permuted block randomization stratified by NASH CRN 
Fibrosis Stage (2 or 3) and presence or absence of documented T2DM (yes or no). Eligible 
subjects will be randomized 2:1 to receive the following double-blind treatment:

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Table 9–2
Treatment Arms: Part 1
Arm
N
Treatment 
A
800
CVC 150 mg, once daily
B
400
Placebo, one daily
Subjects who remain in Part 1 at Month 12 will continue the same treatment through the end 
of Part 2, and individual subject treatment assignments will not be revealed until the 
completion of Part 2 of the study.
Part 2
9.2.8.
In Part 2, at Baseline (Day 1), following Screening evaluations, eligible subjects with a liver 
biopsy diagnosis of NASH and Stage 3 liver fibrosis (by NASH CRN system) who are newly 
randomized in Part 2 of the study will be assigned to the treatment arms using permuted 
block randomization, and presence or absence of documented T2DM (yes or no). Newly 
enrolled, eligible subjects will be randomized 2:1 to receive the following double-blind 
treatment:
Table 9–3
Treatment Arms: Part 2
Arm
Newly Randomized 
Subjects 
N
Total Subjects (Randomized in 
Part 1 or Part 2)
N
Treatment 
A
534
1334
CVC 150 mg, once daily
B
266
666
Placebo, one daily
9.3.
Study Drug Administration
Subjects will take 1 tablet of study drug daily for approximately 6 to 8 years of treatment. 
Subjects will be instructed to take their medication (CVC or placebo) with food. 
If a subject has missed a dose of study drug and is still within 12 hours of the time it is 
usually taken, the subject should take a dose of the missed drug as soon as possible, with 
food. The subject may then continue the usual dosing schedule. If the subject has missed a 
dose of study drug more than 12 hours after the time it is usually taken, the subject should 
not take the missed dose and should resume the usual dosing at the next scheduled time. The 
subject should not take a double dose to make up for a missed dose or take more than 1 tablet 
within 12 hours.
9.4.
Blinding
Subjects, investigators, and all site personnel will be blinded to CVC and placebo individual 
treatment assignment until all subjects have completed Part 2 and the database has been 
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allow for analysis of Part 1 data only. Individual subject treatment assignments will not be 
provided to sites, subjects, study staff, or sponsor staff involved in the conduct of the study 
until analysis of Part 2, except in case of emergency unblinding described below. 
Blinding of the oral investigational product will be accomplished by the sponsor providing 
CVC and matching placebo. Packaging for active and placebo product will be identical with 
the exception of a unique bottle identification number on the label. 
Emergency Unblinding: In emergency situations, the investigator may need to break the 
blind if he/she finds it is in the best interest of the study subject. In the event that immediate 
knowledge of the treatment received (CVC versus placebo) is necessary for the management of 
the subject, the investigator may request unblinded treatment information using IxRS. The 
medical monitor should be notified promptly about the unblinding. (See Section 11.3.1.9 for 
unblinding procedures). 
9.5.
Prior, Concomitant and Subsequent Therapy
A prior medication is defined as a (nonstudy) medication taken at any time during 30 days 
before first study drug intake and stopped before the date of first dose of study drug. Any 
prior medication received within 30 days before the first dose of study drug will be recorded 
in the electronic case report form (eCRF). 
Disallowed medication in use prior to enrollment will be required to be discontinued. (Note: 
subjects receiving allowed concomitant medications need to be on stable therapy for at least 
30 days prior to the Baseline visit. Subjects receiving drugs with potential interaction with 
CVC, must respect a washout period of 14 days or 5 half-lives, whichever is longer, before 
CVC is started). For medications that are disallowed due to potential confounding effect on 
efficacy, a washout period of at least 6 months must be observed prior to the Screening liver 
biopsy. A list of disallowed medication is provided in Section 20.4. All medications (or 
treatments) other than study drug taken or received by the subject at any time during the 
study from first intake of study drug through the 30-day Follow-up visit after last study drug 
intake (or final visit, for subjects who do not complete a Follow-up visit) will be considered 
concomitant medications (or treatments). This includes medications ongoing at the time of 
first study drug intake and medications started after first study drug intake. A new 
concomitant medication will be a (nonstudy) medication started or for which the dose 
increased between first study drug intake through the 30-day Follow-up visit after last study 
drug intake (or final visit, for subjects who do not complete a Follow-up visit). All 
concomitant medications other than study drug, taken or received at any time during the 
study from first intake of study drug through to the 30-day Follow-up visit, will be recorded 
in the eCRF. 
A subsequent medication is defined as a (nonstudy) medication taken after the date of the 
30-day Follow-up visit (or 30 days after last intake of study drug, if no 30-day Follow-up 
visit occurs). Any subsequent medication taken after the 30-day Follow-up visit (or 30 days 
after last intake of study drug, if no 30-day Follow-up visit occurs) will be recorded in the 
eCRF.

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Subjects will be allowed to continue their usual standard-of-care medications that are not 
specifically disallowed by the protocol. 
The detailed list of disallowed medications and the list of medications that are allowed but 
with specific restrictions are provided in Appendix 20.4. 
The following classes of medications are disallowed at any time during Part 1 and Part 2, 
from Screening through the 30-day Follow-up visit, if applicable:

Potent CYP3A4 inhibitors and CYP3A4 inducers will be excluded 

Potent CYP2C8 inhibitors will be excluded

Drugs with narrow therapeutic windows that are sensitive CYP3A4 substrates will 
be excluded (ie, drugs which should not be co-administered with weak CYP3A4 
inhibitors such as CVC)

Medications that may have confounding effects on the efficacy of CVC
The disallowed concomitant medications commonly administered to patients with NASH are 
provided in Appendix 20.4.
Should subjects have a need to initiate treatment with any disallowed concomitant 
medication, the medical monitor must be consulted prior to initiation of the new medication. 
In instances where a disallowed medication is initiated prior to discussion with the medical 
monitor, the investigator must notify the sponsor or designee as soon as he/she is aware of 
the use of the excluded medication to discuss the subject's continued participation in the 
study.
The following medications are allowed but should be used with caution as CVC (a weak 
CYP3A4 inhibitor and BCRP inhibitor) may increase exposure of these CYP3A4 and BCRP 
substrates or these medications may affect the absorption of CVC. If used, these medications 
should be used at the doses recommended in Appendix 20.4. Clinical monitoring and dose 
titration are recommended to achieve the desired clinical response. 

Lipid Lowering Agents: Atorvastatin, simvastatin, pravastatin, lovastatin (CYP3A4 
substrates), and rosuvastatin (BCRP substrate) at recommended doses per 
Appendix 20.4

Pitavastatin use is allowed without dose restriction.

Intravenous midazolam use is allowed for sedation on the day of the liver biopsy or 
for surgical outpatient procedures; however, if given for biopsies performed at 
Month 12 and Month 60, or for any procedure requiring this medication after intake 
of study drug, the first dose should be reduced by 50% of the recommended dose and 
titrated according to the desired clinical response. 

Intravenous alfentanil or fentanyl may be used on the day of the Screening liver 
biopsy. These drugs are allowed with restrictions for biopsies performed at Month 12 
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drug. Fentanyl is to be administered under medical supervision and all precautions 
should be in place, including availability of antidote, to prevent complication from its 
use. It is recommended that the initial dose be decreased by 50% and titrated to the 
desired effect. 

Intravenous propofol use is allowed without dose restriction.

When required, acid-reducing agents should be administered at least 2 hours after the 
CVC dose to ensure that adequate CVC concentrations are maintained. When 
possible, use of an H2 receptor antagonist (except cimetidine) or antacids is preferred 
over a PPI. It is recommended to start with the lowest dose of these agents and titrate 
according to clinical response. See section 5.3.1 for further details.

If H2 receptor antagonists (eg, famotidine or ranitidine) are used, these should 
preferably be given from 2 to 12 hours after administration of study drug at a dose 
that does not exceed doses comparable to famotidine 40 mg daily.  

If antacids (eg, aluminum hydroxide, calcium carbonate, magnesium carbonate, 
magnesium hydroxide, or bismuth subsalicylate) are used, these should preferably 
be given at least 4 hours after administration of study drug due to their immediate 
effect in increasing gastric pH. 

If PPIs (eg, omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole, 
or dexlansoprazole) must be utilized, these should preferably be given 
approximately 3 hours after administration of study drug at a dose that does not 
exceed doses comparable to omeprazole 20 mg daily. Due to the prolonged 
acid-reducing effect of PPIs (~16 – 24 hours), it is advised to follow these dosing 
recommendations to reduce their potential impact on CVC absorption at 
subsequent dosing. 
Antidiabetic Medications
9.5.1.

The benefits of intensive glycemic control on microvascular and neuropathic 
complications are well established for both type 1 and type 2 diabetes. The choice of 
therapies must be individualized based on attributes of the subject and the 
medications themselves (AACE/ACE Comprehensive diabetes management 
algorithm, 2015). For subjects participating in this study, the use of certain 
medications should be carefully considered, due to potential for confounding effects 
of the efficacy endpoint. If antidiabetic agents are used, the following ranking of 
medication is suggested (Table 9-4) in order to minimize the potential impact on the 
study efficacy assessments.

Additional recommendations are provided in the ADA – Standards of Medical Care 
in Diabetes.
Table 9-4
Antidiabetic Medications
Rank
Medication
Route
Weight Change
Notes

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CONFIDENTIAL
1
Metformin
PO
Neutral
2
Sulfonylureas (2nd 
generation)
PO
Gain
3
DPP-4 Inhibitors
PO
Neutral
4
SGLT1/2
PO
Loss
Discuss with medical monitor prior
to introduction.
Potential benefit in CVD
5
GLP-1 Agonists
SQ
Loss
Discuss with medical monitor prior 
to introduction.
Potential benefit in CVD
6
Thiazolidinediones
PO
Gain
Pioglitazone disallowed per 
protocol
9.6.
Additional Restrictions and Precautions
Subjects should refrain from alcohol consumption and strenuous physical activity (eg, weight 
lifting, strenuous yard work, intensive exercise workouts) for 48 hours prior to study visits 
and laboratory evaluations.
9.7.
Treatment Adherence
Subjects will bring all of their study-supplied bottles of study drug to every clinic visit, and 
clinic staff will assess adherence based on the number of remaining tablets less any overage 
provided to cover the visit window. Subjects who miss doses must be counseled on the 
importance of adhering to their daily dosing schedule. 
10.
STUDY PROCEDURES
Study procedures are summarized across all study visits within the Schedule of Assessments 
for Part 1 (Table 20–1) and Part 2 (Table 20–2). 
10.1.
Part 1 and Part 2: Screening (Month -3; Visit 1)
Prior to any clinical procedures and evaluations, written signed informed consent must be 
obtained. In Part 1 and Part 2, a Screening visit is to occur within 3 months before the 
Baseline visit (see Section 10.2). 
Subjects who do not meet all eligibility criteria at Screening will be allowed to rescreen 
twice. However, if a subject fails to meet eligibility criteria upon rescreening, he or she will 
remain ineligible for the study.
Subjects who do not meet any of the laboratory eligibility criteria during the Screening 
period will be allowed to retest twice, with at least 1-week interval between the date of the 
first failed test and the date of subsequent test. However, if a subject fails to meet eligibility 

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CONFIDENTIAL
criteria upon these 2 retest opportunities, he or she will remain ineligible for the study. In 
Part 2, the Screening visit will only be required for newly enrolled subjects. The Screening 
visit will not be required for subjects continuing their previously assigned blinded treatment 
from Part 1.
Approval Date: 16-Apr-2021 14:55:03 (GMT)

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11.
STUDY ASSESSMENTS 
11.1.
Demographic and Other Pretreatment Assessments: Part 1 and/or Part 2
After written informed consent is obtained, demographic data and a complete medical and 
medication history will be collected at the Screening visit. A complete physical examination, 
including measurements of height and body weight will be performed. Medical history will 
be updated until the first dose of study drug. All AEs will be recorded from the time of 
informed consent and throughout the study, regardless of apparent causality from use of the 
study drug. Medications taken before the first dose of study drug will be recorded as prior 
medications.
11.2.
Assessments of Efficacy
In Part 1, subjects meeting all eligibility criteria and with suspicion of significant liver 
fibrosis (through clinical, hepatic fibrosis indices, and/or liver stiffness assessment) will have 
a liver biopsy read by an independent central pathologist during the Screening period. In 
randomized subjects, a second post-treatment liver biopsy will be collected within ± 2 weeks 
of the Month 12 visit.
In Part 2, newly enrolled subjects will undergo a liver biopsy at Screening for assessment of 
eligibility and a second post-treatment liver biopsy will be collected within ± 2 weeks of the 

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Month 12 visit. All subjects (newly randomized subjects with a liver biopsy diagnosis of 
NASH and Stage 3 liver fibrosis (by NASH CRN system) and those who continue from 
Part 1) will undergo a liver biopsy at Month 60 (within ± 2 weeks) after first dose of study 
drug.
At the end of study, if a subject has received study drug for at least 6 months and has not had 
the Month 60 biopsy, then a biopsy should be taken within 30 days of the end of study, if 
feasible.
Liver biopsies will be performed per standard of care (eg, taking into account the subject’s 
health status, coagulation profile, and use of concomitant medications). Subjects who 
discontinue study drug are encouraged to continue with all other evaluations as scheduled in 
this protocol, including biopsies and other invasive procedures at the scheduled visits. If a 
subject discontinues study participation early and has received study drug for at least 
6 months in Part 1 or Part 2, then a biopsy should be taken within 30 days of discontinuation, 
if feasible. All liver biopsies will be evaluated by an independent central pathologist; 
whenever possible, the same pathologist will evaluate all biopsies from an individual subject.
The independent central pathologists will be blinded to individual treatment assignment.
Liver biopsy at Screening and Months 12 and 60 will be used to determine improvement in 
histologic fibrosis stage (NASH CRN – the system used to assess the primary efficacy 
endpoint – and Ishak systems).
NASH CRN Staging System
The NASH CRN adopted the staging system validated by Kleiner.28 The authors evaluated a 
scoring system comprising 14 histological features that addressed the full spectrum of lesions 
of NAFLD. Five features were evaluated semi-quantitatively (steatosis [0-3], location [0-3], 
lobular inflammation [0-3], hepatocellular ballooning [0-2], and fibrosis stage [0-4]) and 
9 additional features were recorded as present or absent. As a result of this evaluation, the 
NASH CRN staging system for evaluating histological changes after therapeutic intervention 
trials adopted a defined and validated semi-quantitative scoring system, NAS, based on the 
unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. The 
system is simple and requires only routine histochemical stains (hematoxylin and eosin and 
Masson trichrome stains). This strong scoring system and NAS for NAFLD and NASH was 
shown to have reasonable inter-rater reproducibility in both adults and children with any 
degree of NAFLD. A NAS of > 5 correlated with a diagnosis of NASH, and biopsies with 
scores of < 3 were diagnosed as not NASH. The primary purpose of the NAS is to assess 
overall histological change; it is not intended that numeric values replace the pathologist’s 
diagnostic determination of steatohepatitis.

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The evaluation of fibrosis stage associated with NASH will be based on the NASH CRN 
Fibrosis Staging System, as follows:28
Fibrosis
Stage
None
0
Perisinusoidal or periportal
1
Mild, zone 3, perisinusoidal
1A
Moderate, zone 3, perisinusoidal
1B
Portal/periportal
1C
Perisinusoidal and portal/periportal
2
Bridging fibrosis
3
Cirrhosis
4
Ishak Staging System
The morphological features that are important in undertaking grading and staging in chronic 
hepatitis are described by Ishak.29 The Ishak fibrosis stage will be based on the following 
scoring system:29
Architectural Changes, Fibrosis and Cirrhosis
Score
No fibrosis 
0
Fibrous expansion of some portal areas, with or without short fibrous septa 
1
Fibrous expansion of most portal areas, with or without short fibrous septa 
2
Fibrous expansion of most portal areas with occasional portal to portal (P-
P) bridging 
3
Fibrous expansion of portal areas with marked bridging [portal to portal 
(P-P) as well as portal to central (P-C)]
4
Marked bridging (P-P and/or P-C) with occasional nodules (incomplete 
cirrhosis) 
5
Cirrhosis, probable or definite
6
Serum hepatic fibrosis indices
Serum hepatic fibrosis indices (including FIB-4, APRI, and NFS) will be determined at 
Screening, Baseline, and Months 6 and 12 in Part 1, and at Screening, Baseline, Months 6 
and 12, and every 12 months thereafter in Part 2.
APRI is calculated using the formula:30
APRI = (AST level [/ULN] / platelet counts [109/L]) 100

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An APRI index of ≤ 0.50 indicates the absence of significant fibrosis and an index of 
> 1.50 indicates the presence of significant fibrosis.
NFS is a validated simple scoring system consisting of routinely measured and readily 
available clinical and laboratory data to categorize NAFLD patients with and without 
advanced fibrosis:32
NFS = -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG/diabetes (yes = 1, 
no = 0) + 0.99 × AST/ALT ratio – 0.013 × platelet (×109/L) – 0.66 × albumin (g/dL).FIB-4 
is a noninvasive hepatic fibrosis index score combining standard biochemical values, 
platelets, ALT, AST, and age that is calculated using the formula:31
FIB-4 = (Age [years] AST [U/L]) / (platelets [109/L] (ALT [U/L])1/2)
A FIB-4 index of < 1.45 indicates no or moderate fibrosis and an index of > 3.25 indicates 
extensive fibrosis/cirrhosis.
The Enhanced Liver Fibrosis (ELF™) Test is a blood test that provides an ELF Score that 
delivers information on liver fibrosis severity and will be assessed in this study. The ELF 
Score is determined by combining in an algorithm, quantitative measurements of by-products 
of the fibrotic process (hyaluronic acid [HA]), amino-terminal propeptide of type III 
procollagen [PIIINP]), tissue inhibitor of metalloproteinase 1 [TIMP-1]).
The ELF Score will be determined at Baseline, Month 6, Month 12, and every 12 months 
thereafter. 
The authors analyzed routine demographic, clinical, and laboratory variables to predict 
presence or absence of advanced fibrosis. Age, hyperglycemia, BMI, platelet count, serum 
albumin, and AST/ALT ratio were found to be independent indicators of advanced liver 
fibrosis, so these 6 variables were included in the NFS scoring system. A low cut-off score 
of -1.455 indicates the absence of advanced fibrosis and a high cut-off score of 0.676 
indicates the presence of advanced fibrosis.
At sites where available, liver stiffness will be assessed in fasting subjects by ultrasound TE 
at Baseline (if not performed within 6 months prior to the first day of Screening), at Months 6 
and 12 in Part 1, and annually in Part 2. The Screening value (if performed by TE) will be
used as the Baseline value. The visit window will be ± 2 weeks for all on-treatment TE 
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11.3.
Assessments of Safety
AEs will be assessed at each visit.
Adverse Events and Serious Adverse Events
11.3.1.
11.3.1.1.
Definitions
11.3.1.1.1.
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
11.3.1.1.2.
Treatment-Emergent Adverse Events
An event will be considered a TEAE if:

The event began on or after the date of the first dose of study drug; or  

An exacerbation of a chronic or intermittent pre-existing condition, including either 
an increase in frequency and/or intensity of the condition on or after the date of the 
first dose of study drug
An AE that occurs more than 30 days after the last dose of study drug will not be counted as 
a TEAE.
11.3.1.1.3.
Adverse Drug Reaction
An adverse drug reaction (ADR) is defined as any adverse event caused by the use of a 
pharmaceutical product. Adverse reactions are a subset of all suspected adverse reactions for 
which there is reason to conclude that the pharmaceutical product caused the event.
11.3.1.1.4.
Suspected Adverse Reaction 
Suspected adverse reaction (SAR) means any adverse event for which there is a reasonable 
possibility that the study drug caused the adverse event. “Reasonable possibility” means 
there is evidence to suggest a causal relationship between the study drug and adverse event. 
A suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means an adverse event caused by a study drug.
11.3.1.1.5.
Unexpected Adverse Event or Reaction
An adverse event or suspected adverse drug reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent with the 
risk information described in the general investigational plan. 

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11.3.1.1.6.
Events Related to Disease Under Study
Worsening of a pre-existing illness other than the disease under study will be assessed as an 
AE. If such an AE meets the definition of an SAE (see Section 11.3.1.1.10), it must be 
reported as such (see Section 11.3.1.5).
11.3.1.1.7.
Clinically Significant Laboratory Abnormalities
Any laboratory abnormalities deemed clinically significant by the investigator must be 
reported as an AE. A clinically significant abnormality is a confirmed abnormality (by repeat 
testing) that is changed sufficiently from Baseline so that in the judgment of the investigator 
a change in management is warranted. This alteration may include: monitoring the laboratory 
test further, initiating other diagnostic tests or procedures, changing ongoing treatment, or 
administering new treatment. See Section 11.3.6 for details regarding the management and 
monitoring of laboratory abnormalities of interest. See Section 11.3.1.2 for details regarding 
recording of adverse events.
11.3.1.1.8.
Surgical Procedures
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions 
that require surgery. The condition for which the surgery is required may be an AE, if it 
occurs or is detected during the study period. Planned surgical measures permitted by the 
clinical study protocol and the condition(s) leading to these measures are not AEs, if the 
condition(s) was (were) known before the start of the study drug. In the latter case, the 
condition should be reported as medical history.
11.3.1.1.9.
Overdose
An overdose is defined as a subject’s report of taking more than 1 tablet of study drug (ie, 
more than 1 tablet per day of blinded CVC or placebo). Overdose per se will not be reported 
as an AE or SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. For reporting 
purposes, overdose will be considered an SAE only if any of the seriousness criteria are met 
(see definition in Section 11.3.1.1.10).
11.3.1.1.10.
Serious Adverse Event or Serious Adverse Reaction
An AE or suspected adverse reaction is considered serious if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:

Death

Life-threatening AE
o
An AE or suspected AE is considered life-threatening if, in the view of either 
the investigator or sponsor, its occurrence places the patient or subject at 

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immediate risk of death. It does not include an AE or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death.

Inpatient hospitalization (ie, admission, overnight stay) or prolongation of existing 
hospitalization

Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions

Congenital anomaly/birth defect

Important medical events
o
An important medical event is one that, when based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above in the definition of an 
SAE. (Examples of such events include allergic bronchospasm requiring 
intensive treatment at an emergency room or at home, blood dyscrasias, 
convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse.)
11.3.1.1.11.
Adverse Events of Special Interest
An adverse event of special interest (AESI) (serious or non-serious) is one of scientific and 
medical concern specific to the sponsor’s study drug/device or program, which warrants 
ongoing monitoring and rapid communication by the investigator to the sponsor. Such an 
event might warrant further investigation in order to characterize and to understand it.
Elevations in biochemistry that are associated with liver injury have been identified as
potentially important risks and are considered AESI for the study drug in this protocol. If 
subjects meet biochemical criteria for suspected DILI, as defined in Section 11.3.6.4, the 
event should be reported to Global Patient Safety and Epidemiology (GPSE) within 24 hours 
on the AESI form (see Section 1). In addition, the AESI form should be completed and sent 
to GPSE within 24 hours of permanent study drug discontinuation for confirmed ALP, ALT, 
AST, and/or bilirubin elevations. AESI will be adjudicated by a hepatologist with expertise 
in DILI and reviewed by the DSMB.
11.3.1.2.
Adverse Event and Clinically Significant Laboratory Abnormality Recording
Treatment-emergent adverse events and laboratory test abnormalities considered to be 
clinically significant should be recorded as AEs in the eCRF. 
The AE or clinically significant laboratory abnormality should be reported in standard 
medical terminology. If known, the diagnosis of the underlying illness or disorder should be 
recorded, rather than its individual symptoms. If a definitive diagnosis is not possible, the 
individual symptoms and signs should be recorded.

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If the laboratory abnormalities are part of a clinical constellation of signs and/or symptoms 
that comprise a medical diagnosis, then the terminology for that medical diagnosis should be 
used in the AE record. 
AEs and clinically significant laboratory abnormalities that are reported as AEs fall into the 
categories of “non-serious” and “serious.” From the time of informed consent and throughout 
the study, all AEs and clinically significant laboratory abnormalities must be recorded in the 
eCRF, regardless of apparent causality from use of the study drug. 
The following information should be captured for all AEs and clinically significant 
laboratory abnormalities: date of onset and end date or outcome (eg, ongoing), severity of the 
event, seriousness of the event, investigator’s opinion of the relationship to investigational 
product (CVC), action taken with regard to any of the study drugs and treatment required for 
the AE, cause of the event (if known), and information regarding the resolution/outcome.
AEs classified as serious must be recorded on the appropriate SAE reporting tool and 
reported to the sponsor using expeditious handling to comply with regulatory requirements 
(see Section 11.3.1.5).
11.3.1.3.
Adverse Event Classification
The intensity of an AE or clinically significant laboratory abnormality will be graded 
according to the scale below in addition to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Table for Grading the 
Severity of Adult Adverse Events (see Appendix 20.2). The clinical significance of the AE is 
determined by the investigator. The investigator is encouraged to consult with the medical 
monitor. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 
with unique clinical descriptions of severity for each AE based on this general guideline.

Grade 1 (Mild): Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated

Grade 2 (Moderate): Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)

Grade 3 (Severe): Medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL

Grade 4 (Life-Threatening): Life-threatening consequences; urgent intervention 
indicated

Grade 5 (Death): Death related to AE
When the intensity of an AE or clinically significant laboratory abnormality changes over 
time for a reporting period (eg, between visits), each change in intensity will be reported as 
an AE until the event resolves. For example, 2 separate AEs will be reported if a subject 

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experiences Grade 1 diarrhea for 3 days, meeting the definition of an AE, and then after 
3 days the event increases to a Grade 3 intensity that lasts for 2 days and then resolves. The 
Grade 1 event will be reported as an AE with a start date equal to the day the event met the 
AE definition and a stop date equal to the day that the event increased in intensity from 
Grade 1 to Grade 3. The Grade 3 event will also be reported as an AE with the start date 
equal to the day the event changed in intensity from Grade 1 to Grade 3 and a stop date on 
the day that the event changed intensity again or resolved. For analysis purposes, this will be 
considered one AE for this subject and the maximum intensity will be recorded.
The relationship or association of the AE to a study drug (CVC or placebo) should be 
assessed using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the 
investigational medicinal product. For SAEs, an alternative causality must be 
provided (eg, pre-existing condition, underlying disease, intercurrent illness, or 
concomitant medication)

Yes: A temporal relationship exists between the AE onset and administration of the 
investigational medicinal product that cannot be readily explained by the subject’s 
clinical state or concomitant therapies. Furthermore, the AE appears with some 
degree of certainty to be related, based on the known therapeutic and pharmacologic 
actions or AE profile of the study drug. In case of cessation or reduction of the dose, 
the AE abates or resolves and reappears upon re-challenge. 
It should be emphasized that ineffective treatment should not be considered as causally 
related in the context of adverse event reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or liver 
biopsy) should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study 
procedure

Yes: The adverse event occurred as a result of protocol-mandated procedures such as 
venipuncture or liver biopsy
11.3.1.4.
Adverse Event Coding
AE verbatim terms provided by the investigator will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), Version 16.0 or later.
11.3.1.5.
Reporting of Serious Adverse Events
The sponsor is required to expedite to regulatory authorities reports of SAEs, serious ADRs, 
or suspected unexpected serious adverse reactions (SUSARs) in line with relevant legislation 
or regulations, including the applicable US FDA Code of Federal Regulations, the European 
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regulations. Expectedness of SAEs will be determined by the sponsor using reference safety 
information specified in the Investigator Brochure. 
Any SAE, serious ADR or SUSAR that occurs during the study from the time of signing the 
ICF to within 30 days following discontinuation of study drug, regardless of relationship to 
the study drug, must be reported within 24 hours to the contact below: 
Send completed Safety Report Forms to Global Patient Safety and Epidemiology, 
Allergan plc (see Section 1)
The required SAE information must be completed on the SAE Form. The sponsor may 
request additional information from the investigator to ensure the timely completion of 
accurate safety reports. For questions on SAE reporting, please contact the medical monitor
(see Section 1 for contact information).
A copy of the submitted SAE form must be retained on file by the investigator. The 
investigator must submit the SAE to the IRB/IEC according to local requirements and retain 
documentation of these submissions in the site study file.
The investigator must take all therapeutic measures necessary for resolution of the SAE. Any 
medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE Form.
If the investigator detects an SAE in a study subject after the end of the period of 
observation, and considers the event possibly related to prior study drug, he/she should 
contact the medical monitor to determine how the event should be documented and reported.
In case of emergency, contact the medical monitor (see Section 1 for contact information).
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB/IEC as soon as is practical, of serious events in writing 
where this is required by local regulatory authorities, and in accordance with the local 
institutional policy.
In accordance with the European Union (EU) Clinical Trials Directive (2001/20/EC), the 
sponsor or specified designee will notify worldwide regulatory authorities and the relevant 
Ethics Committees in concerned Member States of applicable SUSARs as individual 
notifications or through a periodic line listing.
11.3.1.6.
Follow-up of AEs and SAEs
AEs (including SAEs) will be collected from the time of informed consent, throughout the 
treatment period, until 30 days after the last dose of study drug is administered.
All subjects who have AEs, whether considered associated with the use of the investigational 
product or not, must be monitored to determine the outcome. The clinical course of the AE 
will be followed up according to accepted standards of medical practice, even after the end of 
the period of observation, until a satisfactory explanation is found, or the investigator 

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considers it medically justifiable to terminate follow-up. Should the AE result in death, a full 
pathologist’s report should be supplied if and when available. In Parts 1 and 2, a plasma 
sample for PK should be collected, preferably within 24 to 48 hours of last intake of 
study drug, in any subject who develops an adverse event of hepatic injury or 
decompensation or if early treatment discontinuation was due to an AE. The date and 
time of the PK draw and the last dose of study drug must be recorded in the eCRF.
11.3.1.7.
Pregnancy
If a female subject becomes pregnant during the study, the subject must be instructed to 
discontinue study drug and inform the investigator immediately. The investigator should 
report all pregnancies occurring in a subject or partner of a subject participating in the study 
that occur up to 3 months following the last dose of study drug to Allergan Global Patient 
Safety and Epidemiology within 24 hours of becoming aware of the pregnancy. The 
investigator should counsel the subject regarding the possible effects of prior study drug 
exposure on the fetus and the need to inform the study site of the outcome of the pregnancy.
Any pregnancy complication or elective termination of a pregnancy for medical reasons will 
be recorded as an AE or a SAE. Elective abortion procedures, without complications, should 
not be considered as AEs.
All reports of congenital abnormalities/birth defects and spontaneous abortions/miscarriages 
should be reported as an SAE for this study. Furthermore, any SAE occurring as an adverse 
pregnancy outcome post study must be reported to Allergan Global Patient Safety and 
Epidemiology.
11.3.1.8.
Special Situation Reports
Special situation reports include reports of medication error, abuse, misuse, or overdose, and 
reports of adverse reactions associated with product complaints. 

Medication error is any preventable event that can cause or lead to inappropriate 
medication use or patient harm while the medication is in the control of a healthcare 
professional, patient, or consumer. The administration or consumption of the 
unassigned treatment and administration of an expired product are always reportable 
as medication errors. Cases of subjects missing doses of investigational product are 
not considered reportable as medication error.

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
Abuse is defined as persistent, sporadic or intentional excessive use of a medicinal 
product by a patient accompanied by harmful, physical, and/or psychological effects. 

Misuse is defined as any use of a medicinal product in a way that is not in accordance 
with the protocol instructions or the local prescribing information and may be 
accompanied by harmful physical and/or psychological effects. 

An overdose refers to the administration of a quantity of a medicinal product given 
per administration or cumulatively (accidentally or intentionally), which is above the 
maximum recommended dose according to the authorized product information 
(protocol). Clinical judgment should always be applied. In cases of a discrepancy in 
drug accountability, overdose will be established only when it is clear that the subject 
has taken the excess dose(s) or the investigator has reason to suspect that the subject 
has taken the additional dose(s). 

Product complaint is defined as any written or verbal report arising from potential 
deviations in the manufacture, packaging or distribution of the product. 
All clinical sequelae in relation to these special situation reports will be reported as AEs or 
SAEs (using the criteria for AEs and SAEs as described in Section 11.3.1) at the same time 
using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management and outcome will be reported, when available. 
11.3.1.9.
Unblinding of Study Drug
Emergency Unblinding: In emergency situations, the investigator may need to break the 
blind if he/she finds it is in the best interest of the study subject.  In the event that immediate 
knowledge of the treatment received (CVC versus placebo) is necessary for the management of 
the subject, the investigator may request unblinded treatment information using IxRS. The 
medical monitor should be notified promptly about the unblinding.
The event, the date, the time, the person who made the request, and the reason for unblinding 
will be recorded in the source documents. The identity and study responsibility of the 
individual(s) who were made aware of the unblinded treatment assignment must also be 
documented.
It is mandatory that research staff who were involved in the unblinding and who had access 
to the unblinded treatment assignment maintain the confidentiality of this information. 
Subjects who are prematurely unblinded should return for an Early Discontinuation and 
follow-up visit.
Laboratory Assessments
11.3.2.
11.3.2.1.
Measurement of Laboratory Assessments
A central laboratory will perform clinical safety laboratory tests. Urine pregnancy tests will 
be performed at the site using a dipstick method. Central laboratory values for INR that are 
> 1.5 should be repeated in the local laboratory and the central laboratory. 

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A complete list of all laboratory tests is provided in Appendix 20.5.
Refer to the manual provided by the sponsor for details on the laboratories for this study and 
for country-specific laboratory requirements.
Samples for hematology and serum chemistry will be prepared using standard procedures. 
Refer to the laboratory manual provided by the sponsor for further details and specifications 
for sample handling, processing, and shipment. 
11.3.2.2.
Clinically Significant Laboratory Abnormalities
Any laboratory test showing abnormal results (including those recorded as AEs) that are 
believed to be possibly/probably related to study drug treatment will be repeated weekly (or 
as often as deemed prudent by the investigator) until the abnormality is resolved (if baseline 
was within normal range), returns to Baseline range (if baseline was abnormal), or is 
otherwise explained. Whenever possible, the etiology of the abnormal findings will be 
documented on the eCRF. See Section 11.3.1.1.7 for a definition of clinically significant 
laboratory abnormality.
Vital Signs 
11.3.3.
Vital sign measurements (systolic and diastolic blood pressure, temperature, pulse rate, and 
respiration rate) will be taken at each visit. For subjects who discontinue study drug early, 
vital signs will be measured at the Early Discontinuation visit within 48 hours of stopping 
study drug unless the subject remains on study post-treatment termination. Vital signs will be 
performed with the subject in the sitting position after 5 minutes of rest and before any blood 
draws.
Electrocardiogram
11.3.4.
A 12-lead ECG will be taken at Baseline and at Month 12 in Part 1, and at Baseline and 
annually throughout the study in Part 2. ECGs will be performed with the subject in the 
supine position after 5 minutes of rest and before any blood draws.
Physical Examination
11.3.5.
A complete physical examination will be performed at the Screening visit and the 
Baseline/Day 1 visit in Part 1 and Part 2. A symptom-directed physical examination will be 
performed, as needed, at all On-treatment Visits, at the Early Discontinuation visit within 
48 hours of stopping study drug, and at the Follow-up visit. The complete physical 
examination will include (but not limited to) the following organ or body system 
assessments: skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular; abdomen 
(liver and spleen); extremities; lymph nodes; and a brief neurological exam. Abbreviated 
symptom-directed physical examinations will target signs and symptoms; any abnormal 
findings that are reported as AEs will be recorded in the eCRF.

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Toxicity Management
11.3.6.
Clinical events and clinically significant laboratory abnormalities will be graded according 
NCI CTCAE version 4.03 (Appendix 20.2).
11.3.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator and manage according to local 
practice.
11.3.6.2.
Grade 3 Laboratory Abnormality or Clinical Event
For detailed management of subjects with ALT, AST, alkaline phosphatase (ALP), or 
bilirubin elevations, see Section 11.3.6.4.
For Grade 3 laboratory abnormalities, a confirmatory measurement should be obtained within 
48 to 72 hours after the laboratory results become available. 

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to resume the normal study visit schedule must be agreed upon between the investigator and 
the medical monitor. 
11.3.6.3.
Grade 4 Laboratory Abnormality or Clinical Event
For detailed management of subjects with ALT, AST, ALP, or bilirubin elevations, see 
Section 11.3.6.4.
For Grade 4 laboratory abnormalities, a confirmatory measurement should be obtained within 
48 to 72 hours after the laboratory results become available. 

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11.4.
Assessments of Pharmacokinetics
In Part 1, all subjects who have consented to PK assessment will hold their daily dose on the 
day of clinic visits on Months 3, 6, and 12. Subjects will bring their study drug bottle to the 
clinic and take one dose of the study drug under witnessed dosing. One predose plasma 
sample will be collected and one sample will be collected between 1 to 2 hours after dosing
(actual sample collection time and dosing time will be recorded) for population PK analysis 
at Months 3 and 12 in Part 1. If the subject takes the daily dose before the predose sample is 
collected, 2 PK samples will be drawn at least 1 hour apart instead and actual sample 
collection time will be recorded in addition to the dosing time.
Also, in all subjects who have consented to PK assessment, one sample will be collected 
between 2 to 6 hours after dosing (sample collection time and actual dosing time will be 
recorded) for population PK analysis at Month 6 in Part 1.
For all subjects enrolled in the study, at the Early Discontinuation visit (if applicable) in 
Parts 1 and 2, a PK sample should be collected, preferably within 24 to 48 hours of last 
intake of study drug, for any subjects who discontinue treatment due to an AE. The date and 
time of the PK draw and the last dose of study drug must be recorded in the eCRF.
Refer to the laboratory manual for further details and specifications for sample handling, 
processing, and shipment.
11.6.
Assessments of Drug Accountability and Medication Adherence
Drug accountability through the assessment of tablet counts will be performed by clinic staff 
at each on-treatment evaluation visit. 
Subjects will be instructed to bring back their bottles of study drug (used and unused) with 
them to every site visit. The investigator, or designee, will count all returned study drug to 
assess and estimate adherence. Subjects will receive sufficient number of study drug bottles 
and be reminded to take study drug once daily with food.
If the study drug adherence drops below 80% at any given time during the Treatment Period, 
the investigator, or designee, should discuss adherence with subject and counsel the subject 
appropriately. Nonadherence includes missed doses in addition to taking the wrong dose. The 
investigator must encourage adherence with the study drug and with the study procedures at 
all times. 

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11.7.
Pharmacogenetic Sampling
Pharmacogenetic sampling is to be conducted only at study centers where the IRB has 
approved the pharmacogenetic portion of the study. Participation in the pharmacogenetics 
portion of the study is optional and will require a separate ICF. 
A subject who initially consents can withdraw that consent at any time and have his or her 
pharmacogenetic sample destroyed, including any by-products of the sample whenever 
possible. If a subject withdraws consent, their physical sample will be destroyed and no new 
health information identifying the subject will be gathered after that date. However, once the 
genetic data is anonymized and placed into the pharmacogenetic biorepository database, the 
information cannot be withdrawn.

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12.
STATISTICS
12.1.
General Considerations
Continuous data will be described with sample size, mean, standard deviation, median, 
minimum and maximum. Categorical data will be described with counts and percentages in 
each category. Two-sided p-values for all hypothesis tests will be reported and will be 
interpreted in accordance with the multiple comparisons procedure described in 
Section 12.1.5.
Subjects will be enrolled in 2 parts, Part 1 and Part 2. Only subjects randomized for Part 1 
will contribute to the Part 1 analyses, and all randomized subjects will contribute to the Part 2 
analyses. Subjects randomized for Part 1 will be determined at time of enrollment: when a 
sufficient number has been randomized for the Part 1 analysis, subsequent subjects will be 
randomized only for the Part 2 analysis. When subjects who contribute to Part 1 have 
completed their 12-month biopsy (or have been followed for a sufficient time to confirm that 
such a biopsy will not be obtained), the Part 1 analysis will commence. The Part 1 analysis 
will summarize subject disposition, protocol deviations, study drug exposure, concomitant 
medications, demographics and baseline characteristics, and safety for 2 sets of subjects: 
those who were randomized for Part 1 efficacy, including data up to the Month 12 visit, and 
all subjects randomized, including all available data in the database at the time of database 
lock. At the completion of the entire study, analyses will be provided for all subjects whether 
randomized for Part 1 or for Part 2 only, including all available data in the database.
The significance level of both 0.00125 (2-sided) and 0.05 (2-sided) will be applied for 
hypothesis testing, with the former to manifest strong evidence from a single confirmatory
study and the latter for study success. 
Analysis Sets
12.1.1.
The following sets of subjects will be analyzed to evaluate the effect of CVC compared to 
placebo in subjects with NASH:
Intent-to-treat (ITT) analysis set: All subjects randomly assigned to a treatment group will 
be included in ITT analysis set. Subjects will be included with the randomly assigned 
treatment, if they receive treatment other than that to which they are randomly assigned. This 
will be a supportive analysis set for selected efficacy analyses. Subjects with missing 
Screening biopsy data should not be randomized in the study, hence will not be included in 
the ITT analysis set, should such subjects exist.
Modified intent-to-treat (mITT) analysis set: All subjects in the ITT analysis set who 
receive at least one dose of study drug will be included in the mITT analysis set. Subjects 
will be included with the randomly assigned treatment, if they receive treatment other than 
that to which they are randomly assigned. This will be the primary analysis set for the 
efficacy analyses.

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Month 12 per protocol (PP1) analysis set: All subjects randomly assigned to a treatment 
group who have an evaluable biopsy at Screening and another after at least 6 months but 
before 15 months of follow-up, receive at least 6 months of assigned study drug and have no 
significant protocol deviations that potentially influence the primary efficacy assessment will 
be included in the PP1 analysis set. This will be a supportive analysis set for selected efficacy 
analyses of Part 1 and Part 2. Subjects will be included with the randomly assigned 
treatment; this will also be the treatment subjects actually received since subjects who 
receive treatment other than that to which they are randomly assigned will be excluded from 
PP1. The list of significant protocol deviations will be reviewed by the study team on an 
ongoing basis and the set of subjects excluded from the PP1analysis set will be identified 
prior to locking and unblinding the study database.
Month 60 per protocol (PP2) analysis set: All subjects randomly assigned to a treatment 
group who have an evaluable biopsy at Screening, have no significant protocol deviations 
that potentially influence the primary efficacy assessment, and either:

Have an adjudicated event that is a component of the primary composite endpoint 
within 24 months after randomization 
OR

Have at least 24 months of follow-up for clinical events AND one of the following:
o
Have an adjudicated event that is a component of the primary composite 
endpoint within 6 months of last intake of study drug,  
OR
o
Have a biopsy at least 24 months after randomization and within 6 months of 
last intake of study drug, 
This will be a supportive analysis set for selected efficacy analyses of Part 2. Subjects will be 
included with the randomly assigned treatment; this will also be the treatment subjects 
actually received since subjects who receive treatment other than that to which they are 
randomly assigned will be excluded from PP2. The list of significant protocol deviations will 
be reviewed by the study team on an ongoing basis and the set of subjects excluded from the 
PP2 analysis set will be identified prior to locking and unblinding the study database.
Safety analysis set: All subjects randomly assigned to a treatment group who receive at least 
one dose of study drug will be included in the safety analysis set. Subjects will be included 
with the treatment group according to treatment actually received, if they receive treatment 
other than that to which they are randomly assigned. Subjects who inadvertently receive both 
treatments will be included with the CVC group. This will be the primary analysis set for the 
safety analyses.

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Pharmacokinetic analysis set: All subjects who are randomized and receive at least one 
dose of study drug and have at least one post-dose PK sample will be included in the PK 
analysis set.
Data and Safety Monitoring Board
12.1.2.
An independent DSMB will be formed to review ongoing data from this study. The DSMB 
will be composed of members who have medical expertise in liver disease and at least one 
statistician. The DSMB will be empowered to recommend changes to the protocol to ensure 
the safety of subjects in the study, but will not be empowered to recommend stopping or 
changing the study due to accumulating efficacy data, other than at the planned futility 
analysis in Part 2 of the study.
Safety data will be reviewed by the DSMB. The first review will occur after the first subject 
has been followed for at least 6 months. Subsequent reviews will be at least quarterly, at a 
schedule agreed by the sponsor and the members of the board per the DSMB charter. This 
data review will not result in any adjustments to alpha because there will not be a chance to 
stop the study early for a conclusion of efficacy.
For Part 2 of the study, one unblinded assessment of futility will be considered by the 
DSMB. This will occur after the last randomized subject has been followed for at least 
2 years and at least half of the expected events have been observed. If the conditional power 
exceeds 5%, the study will continue. The study will be stopped only for a conclusion of 
futility. This data review will not result in any adjustments to alpha because there will not be 
a chance to stop the study early for a conclusion of efficacy.
No investigator or subject will be unblinded to support DSMB review. No one involved in 
data review or subject care will be unblinded.
Adjudication Committee
12.1.3.
An independent adjudication committee will be formed to review all events that would 
potentially be components of the primary composite endpoint for the study. Only events 
confirmed by the adjudication committee will be included in the analysis of the primary 
endpoint of Part 2; the time to onset will be determined as the date on which the event 
occurred according to the adjudication committee.
Handling of Missing Data
12.1.4.
Data will be analyzed as recorded. Results will be used in the analysis as obtained, without 
regard for any visit windows. Subjects with missing baseline biopsy data should not be 
randomized in the study; in the unlikely event that any such subject is incorrectly randomized
into the study, the subject will be excluded from analyses (including ITT) due to lack of data 
for stratification. Such subjects will be listed.
For the primary efficacy analysis in Part 1 using the mITT analysis set, any available liver 
biopsy after randomization will be used for the Month 12 biopsy, no matter when it was

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obtained relative to the first dose of study drug. Subjects with multiple liver biopsies will 
have the evaluable biopsy closest to the Month 12 visit included in the analysis. Subjects who 
do not have an evaluable liver biopsy at both Screening and Month 12 will be included in the 
analyses as non-responders. Summaries of subjects who do and who do not have evaluable 
liver biopsies at Month 12 will be provided to assess whether demographics, baseline data or 
safety data are predictive of missingness. Sensitivity analyses for the primary efficacy 
endpoint will be performed, accounting for both missing at random and missing not at 
random scenarios.
For the primary efficacy analysis in Part 2 using the mITT analysis set, any available liver 
biopsy after baseline will be used for assessment of components of the clinical endpoint that 
require a biopsy, no matter when obtained.  Subjects with multiple liver biopsies will be 
included as an event if any (one or more) biopsy meets the definition of the primary 
endpoint, as determined by the adjudication committee. Subjects who do not have an 
evaluable liver biopsy at both Screening and postbaseline will be included in the analysis as 
nonevents for any components of the primary endpoint requiring biopsies but may be 
included as events if they meet criteria for another component of the primary endpoint. 
Subjects with partial follow-up data will be included as an event if they meet the criteria for 
any component of the primary efficacy endpoint, and as a nonevent if they do not meet the 
criteria for any component. A sensitivity analysis assuming data are missing not at random 
will be reported.33 An additional sensitivity analysis imputing an event at the time of
censoring will also be reported, although it is anticipated that this analysis will not be 
informative unless many subjects discontinue due to unobserved NASH progression, which 
cannot be known.
Multiple Comparisons
12.1.5.
Alpha splitting will be applied for multiplicity adjustment. 
12.2.
Subject Disposition, Demographics, and Treatment Adherence
Subject disposition will be presented for all subjects. The number of subjects who were 
screened, randomized, started study drug, completed the study, discontinued study drug
early, and discontinued from the study early will be provided for Part 1 and for Part 2. The 
reasons for early discontinuation of study drug and of study will be presented for each part.
Demographic data (age, gender, ethnicity and race) and baseline characteristics will be listed 
and summarized by randomized treatment group and overall for the ITT Analysis Set.
Adherence to planned study drug dosing will be estimated by drug accountability. 

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12.3.
Efficacy
Efficacy Endpoints
12.3.1.
12.3.1.1.
Part 1
Primary Efficacy Endpoint (Part 1)

Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN 
system) AND no worsening of steatohepatitis (no worsening of lobular inflammation 
or hepatocellular ballooning grade) on liver histology at Month 12 relative to the 
Screening biopsy
Key Secondary Efficacy Endpoint (Part 1)

Proportion of subjects with improvement in fibrosis by at least 2 stages (NASH CRN 
system) AND no worsening of steatohepatitis (no worsening of lobular inflammation 
or hepatocellular ballooning grade) on liver histology at Month 12 relative to the 
screening biopsy
Secondary Efficacy Endpoints (Part 1)

Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN 
system), regardless of effect on steatohepatitis, at Month 12 relative to the Screening 
biopsy

Proportion of subjects with improvement in fibrosis by at least 2 stages (NASH CRN 
system), regardless of effect on steatohepatitis, at Month 12 relative to the Screening 
biopsy

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
Change from baseline to Month 12 in ELF.
12.3.1.2.
Part 2
Primary Efficacy Endpoint (Part 2)

Time to first occurrence of any of the following adjudicated events:
o
Death (all cause)
o
Histopathologic progression to cirrhosis (defined by NASH CRN Fibrosis 
Stage 4)
o
Liver transplant
o
MELD score ≥15
o
Ascites (requiring intervention, ie, large volume paracentesis ≥1L or initiation 
of a diuretic)
o
Hospitalization (as defined by a stay of ≥ 24 hours) for onset of: variceal 
bleed, hepatic encephalopathy (defined by a West Haven Stage of ≥2), 
spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis with 
positive ascitic fluid bacterial culture)
Each component of this endpoint will be considered by the independent adjudication 
committee, and only events confirmed by the committee will be included in the 
primary analysis.
If any of the above events occur in Part 1, they will be included in this primary 
efficacy endpoint for Part 2.
Secondary Efficacy Endpoints (Part 2)

Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN 
system) AND no worsening of steatohepatitis (no worsening of lobular inflammation 
or hepatocellular ballooning grade) on liver biopsy at Month 12 relative to the 
Screening biopsy – (subjects newly randomized in Part 2)

Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN 
system), regardless of effect on steatohepatitis, on liver biopsy at Month 12 relative to 
the Screening biopsy – (subjects newly randomized in Part 2)

Proportion of subjects with improvement in fibrosis by at least 2 stages (NASH CRN 
system) AND no worsening of steatohepatitis (no worsening of lobular inflammation 
or hepatocellular ballooning grade) on liver biopsy at Month 12 relative to the 
screening biopsy – (subjects newly randomized in Part 2)

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
Proportion of subjects with improvement in fibrosis by at least 2 stages (NASH CRN 
system) regardless of effect on steatohepatitis on liver biopsy at Month 12 relative to 
the screening biopsy – (subjects newly randomized in Part 2)

Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN 
system) AND no worsening of steatohepatitis (no worsening of lobular inflammation 
or hepatocellular ballooning grade) on liver biopsy at Month 60 relative to the 
Screening biopsy – (all subjects)

Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN 
system), regardless of effect on steatohepatitis, on liver biopsy at Month 60 relative to 
the Screening biopsy – (all subjects)

Proportion of subjects with improvement in fibrosis by at least 2 stages (NASH CRN 
system) AND no worsening of steatohepatitis (no worsening of lobular inflammation 
or hepatocellular ballooning grade) on liver biopsy at Month 60 relative to the 
screening biopsy – (all subjects)

Proportion of subjects with improvement in fibrosis by at least 2 stages (NASH CRN 
system), regardless of effect on steatohepatitis on liver biopsy at Month 60 relative to 
the screening biopsy – (all subjects)

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
Proportion of subjects with improvement in fibrosis by at least 1 stage (Ishak system), 
regardless of effect on steatohepatitis, on liver biopsy at Month 12 relative to the 
Screening biopsy – (subjects newly randomized in Part 2)

Proportion of subjects with complete resolution of steatohepatitis (defined as 
histopathologic interpretation of no fatty liver disease or simple or isolated steatosis 
with no steatohepatitis) AND no worsening of liver fibrosis (defined as progression of 
NASH CRN fibrosis stage) at Month 60 relative to the Screening biopsy – (all 
subjects)

Proportion of subjects with improvement in fibrosis by at least 1 stage (Ishak system), 
regardless of effect on steatohepatitis, on liver biopsy at Month 60 relative to the 
Screening biopsy – (all subjects)

Proportion of subjects with histopathologic progression to cirrhosis (defined by NASH 
CRN Fibrosis Stage 4) at Month 60– (all subjects)

Change from baseline in noninvasive assessments of liver fibrosis (including FIB-4, 
APRI, NFS, ELF and liver stiffness through TE) over time – (all subjects)
Methods of Analysis for Efficacy Endpoints
12.3.2.
12.3.2.1.
Part 1
The primary analysis of Part 1 will occur when approximately 1200 randomized subjects 
have been followed for at least 12 months. Subjects who will contribute to the primary 
analysis of Part 1 will be identified before unblinding of any subjects for Part 1 analysis; 
subjects who will not contribute to the primary analysis of Part 1 will be identified by date of 
randomization and will be determined before randomization.  Individual subjects’ treatment 
group assignments will not be disseminated to the sites until the end of Part 2 to allow for 
continued blinded assessment during Part 2.
For the primary efficacy analysis in Part 1, using the mITT analysis set, any available liver 
biopsy after baseline will be used as the Month 12 biopsy, no matter when it was obtained 
relative to the first dose of study drug. Subjects who do not have an evaluable liver biopsy at 
both Screening and Month 12 will be included in the analyses as nonresponders. Subjects 
with multiple liver biopsies will have the evaluable biopsy closest to the Month 12 visit 
included in the analysis.
The proportion of subjects who meet the primary efficacy endpoint in Part 1, and each 
component, will be summarized by treatment group. Two-sided 95% confidence intervals for 
the proportion who meet the primary efficacy endpoint, calculated using Wilson’s method for 
CI, will also be reported.
Part 1 testing hierarchy includes 2 tests, one for the primary endpoint and the other for the 
key secondary endpoint. The key secondary endpoint is tested only when the primary 
endpoint result is significant. The surrogate endpoint will be tested at 0.0012 (2-sided) level 

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12.3.2.2.
Part 2
The primary analysis for Part 2 will occur when adjudicated events have been accrued in 
367 unique subjects across Part 1 and Part 2. Because many events may be observed from the 
Month 60 liver biopsy, and given that all reported events will need to undergo independent 
adjudication prior to being included or excluded from the analysis, it is possible that more 
than or fewer than 367 events will be included in the analysis. All subjects and events in the 

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database at the time of Part 2 database lock and unblinding, and only those events, will be 
included in the primary analysis of Part 2. If multiple events are observed in a single subject, 
only the first observed event will be used in the analysis.
For the primary efficacy analysis in Part 2 using the mITT analysis set, any available liver 
biopsy after baseline will be used for assessment of components of the clinical endpoint that 
require a biopsy, no matter when obtained. Subjects who do not have an evaluable liver 
biopsy at both Screening and postbaseline will be included in the analyses as having an event 
only if they meet a component that does not require a biopsy; otherwise they will be included 
as not having an event and censored at the last visit. Subjects with multiple liver biopsies will 
be included as an event if any (one or more) biopsy meets the definition of the primary 
endpoint, as determined by the adjudication committee.
The proportion of subjects who meet the primary efficacy endpoint in Part 2, and each 
component, will be summarized by treatment group. Two-sided 95% CIs for the proportion 
who meet the primary efficacy endpoint, calculated using Wilson’s method for CI, will also 
be reported. Time-to-event analyses will be performed using the Kaplan-Meier product-limit 
method with tabular and graphical presentation for the cumulative probability of event rate 
by treatment group. Subjects will be censored for analysis at the last recorded study visit.
Analysis of the primary endpoint of Part 2 will use the logrank test, stratified by 
randomization strata (fibrosis stage [2 vs 3] and presence or absence of T2DM at Baseline, 
for a total of 4 strata), to compare the rates in the 2 randomized treatment arms. If multiple 
adjudicated events are observed in a single subject, only the first observed event will be used 
in the analysis. The analysis will use the mITT analysis set, with supportive analyses reported 
for the ITT and PP2 analysis sets. Subjects who do not have an adjudicated event will be 
censored for analysis at the last recorded study visit. The p-value for the test of no difference 
between treatment arms (hazard ratio=1) will be presented as well as the hazard ratio from a 
proportional hazards model (CVC divided by placebo) and corresponding 95% CI. To 
manifest strong evidence from a single confirmatory study, the hypothesis test of clinical 
endpoint will be performed at a significance level of 0.00125 (2-sided) if the test of the 
surrogate endpoint is successful and 0.00005 (2-sided) otherwise. For study success, the 
hypothesis test of clinical endpoint will be performed at a significance level of 0.05 (2-sided) 
if the test of the surrogate endpoint is successful and 0.002 (2-sided) otherwise.
Analysis of secondary efficacy endpoints of Part 2 will use similar methods to the primary 
endpoint analysis in Part 2. The primary endpoint in Part 1, improvement in fibrosis by at 
least one stage and no worsening of steatohepatitis at Month 12, will be reported for subjects 
not in the Part 1 analysis (subjects newly randomized in Part 2), and for all subjects in the 
study (Month 12 results from Part 1 and Part 2 combined).  Results for the mITT and PP2 
analysis sets will be reported for the secondary endpoints in Part 2. Binary endpoints will be 
analyzed with the CMH procedure, stratified by randomization strata. Continuous endpoints 
will be analyzed with analysis of covariance, with randomization strata included as 
covariates. Time to event endpoints will be analyzed with the stratified logrank test, stratified 
by randomization strata.

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12.4.
Safety 
Safety Endpoints (Part 1 and Part 2)
12.4.1.

Clinical adverse events, including major adverse cardiovascular events (MACE) and 
new-onset T2DM

Clinical laboratory tests (hematology, chemistry, and fasting metabolic parameters) 

Physical examination

Vital signs

12 lead ECG
Methods of Analysis for Safety Endpoints (Part 1 and Part 2)
12.4.2.
No statistical hypotheses are prespecified for safety endpoints. Analyses will be primarily 
descriptive, with any p-values post-hoc and any comparative conclusions requiring 
confirmation.
12.4.2.1.
Adverse Events
AEs will be categorized by the Medical Dictionary for Regulatory Activities (MedDRA)
preferred term and system-organ classification. The occurrence of TEAEs will be 
summarized using MedDRA preferred terms, system organ classifications, and severity (see 
Sections 11.3.1.3 and 11.3.1.4). The occurrence of TEAEs will be summarized by treatment 
group for the safety analysis set using MedDRA preferred terms, system organ 
classifications, and severity.
All AEs (including nontreatment-emergent events) recorded on the eCRF will be listed for 
individual subjects showing both verbatim and preferred terms. The number of subjects with 
at least one TEAE, at least one severe TEAE, at least one serious TEAE, at least one TEAE 
judged by the investigator to be related to study drug, and with a TEAE leading to death will 

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be summarized by treatment group. Summaries TEAEs will also be presented by subgroups 
of age, sex, and race.
12.4.2.2.
Clinical Laboratory Tests
Descriptive summaries of clinical laboratory results will be presented by study visit. The 
Baseline assessment will be the last value before randomization for each laboratory 
parameter. The change from baseline to each postbaseline assessment will be derived for 
each of the continuous laboratory parameters. Laboratory abnormalities will be graded 
according to NCI CTCAE version 4.03 (see Appendix 20.2). The number and percentage of 
subjects experiencing treatment-emergent graded toxicities will be summarized by treatment 
group and severity grade. Change from baseline in laboratory tests will be summarized for 
each treatment group.
12.4.2.3.
Physical Examination and Vital Signs
Any abnormal findings that are considered clinically significant in the opinion of the 
investigator will be recorded as AEs or be captured as medical history, if already present at 
Screening.
Descriptive summaries of vital signs will be presented by study visit. A baseline value will be 
derived for each parameter as the last value prior to randomization. A change from baseline 
to each of the postbaseline assessments will be derived. Descriptive summaries of 
quantitative changes in vital signs will be presented by treatment group and study visit. 
12.4.2.4.
Electrocardiograms
Any abnormal findings that are considered clinically significant in the opinion of the 
investigator will be recorded as AEs or be captured as medical history, if already present at 
Screening.
ECG results will be reviewed for clinically notable abnormalities according to predefined 
criteria. Subjects exhibiting Grade 3 or 4 PR or QT interval corrected for heart rate (QTc) 
interval will be summarized. Abnormalities in Fridericia's corrected QT interval (QTcF) 
interval, Bazett's corrected QT interval (QTcB) interval, QRS, PR, and heart rate (HR) will 
be summarized.
12.4.2.5.
Prior and Concomitant Medications
A prior medication is defined as a (nonstudy) medication taken at any time during 30 days
before first study drug intake and stopped before the date of first dose of study drug.
Concomitant medications are those taken at any time during the study from first intake of 
study drug through the 30-day Follow-up visit after last study drug intake (or final visit, for 
subjects who do not complete a Follow-up visit). This includes medications ongoing at the 
time of first study drug intake and medications started after first study drug intake. A new 
concomitant medication will be a (nonstudy) medication started or for which the dose 

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increased between first study drug intake through the 30-day Follow-up visit after last study 
drug intake (or final visit, for subjects who do not complete a Follow-up visit).
A subsequent medication is defined as a (nonstudy) medication started after the date of the 
30-day Follow-up visit after last study drug intake (or 30 days after last intake of study drug, 
if no 30-day Follow-up visit occurs).
Prior, concomitant, and subsequent medications will be coded based on the World Health 
Organization (WHO) preferred term and drug classification. The number and percent of 
subjects taking prior, concomitant and subsequent medications will be summarized by 
treatment group using preferred terms and drug classifications for the Safety Analysis Set. In 
addition, a summary of the number and percent of subjects taking new concomitant 
medications by treatment group will be presented.
12.5.
Population Pharmacokinetics
Population Pharmacokinetic Endpoints
12.5.1.

Characterization of the population PK of CVC and possible metabolites in subjects 
with NASH

Evaluation of covariates that impact the PK of CVC and possible metabolites (age, 
sex, weight, race, ethnicity, fibrosis stage, etc.)
Methods of Analysis for Population Pharmacokinetic Endpoints
12.5.2.
A population PK analysis of CVC will be performed by using predose and post-dose PK 
samples collected at steady state throughout Part 1 of the study. Population PK modeling of 
measured plasma CVC concentrations will be conducted using nonlinear mixed effects 
modeling. An analysis of subject covariates will be conducted.

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12.8.
Sample Size and Power
Part 1
12.8.1.
The sample size for the primary endpoint of Part 1 is based on the primary binary endpoint at 
the end of Month 12 comparing treatment with CVC versus placebo. The planned sample 
size of 1200 subjects (800 in treatment Arm A and 400 in treatment Arm B) for Part 1 of this 
study is expected to provide 84% power to demonstrate strong evidence with a single study 
(2-sided alpha level of 0.0012), assuming a 15% response rate for the placebo arm and a 25% 
response rate for CVC according to the results from the Phase 2b Study 652-2-203
(CENTAUR).
The planned 800 subjects in treatment Arm A and 400 subjects in treatment Arm B is 
expected to provide 97% power to demonstrate strong evidence with a single study (2-sided 
alpha level of 0.0012) in the key secondary endpoint, assuming a 2.2% response rate for the 
placebo arm and an 8.6% response rate for CVC according to the results from the Phase 2b 
Study 652-2-203 (CENTAUR). 

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PASS 8.0 was used to calculate the sample size.
These response rates reflect the primary analysis, in which subjects missing the postbaseline 
liver biopsy will be included as nonresponders. The anticipated proportion of subjects with 
missing Month 12 liver biopsies, as a result of either premature subject discontinuation or 
nonevaluable liver biopsy results (ie, biopsy sample deemed inadequate for evaluation of 
efficacy endpoints by an independent central pathologist), is estimated to be 15% of subjects 
at Month 12, compared to approximately 13% of missing post-treatment liver biopsies in the 
Phase 2b study. 
Part 2
12.8.2.
The sample size for the primary endpoint analysis in Part 2 is based on the estimated 
event-free survival rate of 80% for the placebo group and detection of a hazard ratio of 0.62 
by the end of the study (corresponding to a median event-free survival time of approximately 
15 years for placebo and 25 years for CVC). A total of 2000 subjects (2:1 randomization 
ratio between CVC and placebo) enrolled approximately uniformly over 2 years for an 
overall study duration of approximately 8 years (2 years of accrual period plus 5 to 6 years of 
follow-up) will lead to about 367 events, after accounting for an overall dropout rate of 20%.  
With these events, there will be 85% power to demonstrate strong evidence of superiority of 
CVC over placebo (at a 2-sided 0.00125 significance level, for a single registration study), 
and 99% power to test the superiority of CVC over placebo (at the 2-sided test 0.05 
significance level for a registration study). EAST 6.4 is used for the calculation.
13.
QUALITY CONTROL AND QUALITY ASSURANCE
13.1.
Sponsor Audits
During the study, individuals from the sponsor’s quality assurance department and/or their 
authorized representative may visit the investigator’s site to conduct an audit of the study. 
The purpose of this visit will be to determine the investigator’s adherence to the protocol, 
applicable regulations, and the sponsor’s procedures, in addition to assessing the accuracy of 
the study data. Prior to initiating this audit, the investigator will be contacted by the sponsor 
to arrange a convenient time for this visit. The investigator and staff are expected to 
cooperate with the auditors and allow access to all subject records supporting the eCRFs and 
other study-related documents.
13.2.
Inspection by Regulatory Authorities
At some point during the investigational product’s development program, a regulatory 
authority may visit the investigator to conduct an inspection of the study and the site. The 
investigator and staff are expected to cooperate with the inspectors and allow access to all 
source documents supporting the eCRFs and other study-related documents. The investigator 
must immediately notify the sponsor when contacted by any regulatory authority for 
purposes of conducting an inspection.

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14.
ETHICS AND PROTECTION OF HUMAN SUBJECTS
14.1.
Compliance Statement
The investigator agrees to conduct the study in compliance with the protocol, ICH E6 Good 
Clinical Practice (GCP) guidelines, and all local and national regulations.
The investigator must adhere to the protocol as described in this document and agree that 
deviations to the protocol, with the exception of medical emergencies, must be discussed and 
approved by the sponsor prior to seeking approval from the IRB/IEC. The investigator is 
responsible for enrolling subjects who have met the protocol inclusion and exclusion criteria 
or must have obtained prior documented approval from the sponsor prior to enrollment in the 
study. The IRB/IEC that granted original approval, or the IRB/IEC currently responsible for 
overseeing the conduct of the study, must be notified of all changes in and deviations from 
the protocol that may increase risk to the subject, and/or that may adversely affect the rights 
of the subject or validity of the investigation. The investigator must send a copy of the 
approval letter from the IRB/IEC to the sponsor or contract research organization (CRO) and 
retain the original in the site study regulatory file.
14.2.
Institutional Review Board/Independent Ethics Committee
It is the responsibility of the investigator to assure that all aspects of the ethics review are 
conducted in accordance with the Declaration of Helsinki (October 2013) as described in the 
ICH E6: GCP, and/or local laws, whichever provides the greatest level of protection for the 
study participants. The protocol and any information supplied to the subject to obtain 
informed consent, including written ICF(s), subject recruitment procedures 
(eg, advertisements), and written information to be provided to subjects (information 
leaflets), must be reviewed and approved by a qualified IRB/IEC prior to enrollment of 
participants in the study. Prior to initiation of the study, the sponsor must receive 
documentation of the IRB/IEC approval, which specifically identifies the study/protocol, and 
a list of the committee members.
Amendments to the protocol and revisions to the informed consent must also be submitted to 
and, if required, approved by the IRB/IEC.
Investigators must submit progress reports to the IRB/IEC in accordance with the IRB/IEC 
requirements. Annual re-approval of the study must be obtained. Copies of progress reports 
and annual re-approvals must be sent to the sponsor.
When the sponsor provides the investigator with a safety report, the investigator must 
promptly forward a copy to the IRB/IEC.
After completion or termination of the study, the investigator must submit a final report to 
the IRB/IEC and to the sponsor.
The investigator, as part of the records retention requirements for the study, must maintain 
documentation of all submissions, correspondence, and approvals to and from the IRB/IEC.

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The investigator is responsible for conducting the study in accordance with the protocol, all 
applicable laws, regulations, and GCP according to ICH guidelines.
14.3.
Informed Consent
Preparation of the consent form is the responsibility of the investigator and the sponsor or 
designee and must include all elements required by the ICH, GCP, and applicable regulatory 
requirements, and must adhere to GCP and to the ethical principles that have their origin in 
the Declaration of Helsinki.
A template will be provided by the sponsor or designee. The sponsor or designee must 
review and approve all changes to site-specific ICFs.
The consent form must include a statement that the sponsor or designee and regulatory 
authorities have direct access to subject records. Prior to the beginning of the study, the 
investigator must have the IRB/IEC’s written approval/favorable opinion of the written ICF 
and any other information to be provided to the subjects.
Before being enrolled in the clinical study, subjects must consent to participate after the 
nature, scope, and possible consequences of the study have been explained in a form 
understandable to them.
An informed consent document that includes both information about the study and the 
consent form will be prepared and given to the subject. This document will contain all the 
elements required by the ICH E6 Guideline for Good Clinical Practice and any additional 
elements required by local regulations. The document must be in a language understandable 
to the subject and must specify who informed the subject. Where required by local law, the 
person who informs the subject must be a physician.
A copy of the signed consent document must be given to the subject. The original signed 
consent document will be retained by the investigator.
The investigator will not undertake any measures specifically required only for the clinical 
study until valid consent has been obtained.
The investigator must inform the subject’s primary physician about the subject’s 
participation in the trial if the subject has a primary physician and if the subject agrees to the 
primary physician being informed.
14.4.
Subject Confidentiality
Applicable data privacy laws and regulations must be adhered to. The investigator and the 
sponsor are responsible for ensuring that sensitive information is handled in accordance with 
local requirements (eg, Health Insurance Portability and Accountability Act [HIPAA] and the 
European Union Data Protection Directive 95/46/EC). Appropriate consent and 
authorizations for use and disclosure and/or transfer (if applicable) of protected information 
must be obtained.

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Subject names will not be supplied to the sponsor. Only the subject number will be recorded 
in the eCRF, and if the subject name appears on any other document (eg, laboratory report), 
it must be obliterated on the copy of the document to be supplied to the sponsor. Study 
findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be informed that representatives of the sponsor, IRB/IEC, or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence 
and in accordance with local data protection laws.
14.5.
Study Conduct
The study will be conducted in compliance with the Declaration of Helsinki (October 2013) 
and the ICH E6 Guideline for GCP. All national, state, and local laws of the pertinent 
regulatory authorities will be followed.
If it is necessary to amend either the protocol or the ICF, the investigator will be responsible 
for ensuring that the IRB/IEC reviews and approves the amended documents. Amended ICFs 
must be obtained and used for obtaining consent from new subjects.
14.6.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study, according to 
the terms specified in the study contract. The investigator is to notify the IRB/IEC in writing 
of the study’s completion or early termination, and send a copy of the notification to the 
sponsor or CRO and retain one copy for the site study regulatory file.
15.
DATA HANDLING AND RECORD KEEPING
15.1.
Data Management Responsibilities
All eCRF data will be entered into a validated database. Laboratory data will be imported to 
the database electronically.
All data entry, verification, and validation will be performed in accordance with the current 
standard operating procedures of the sponsor or its designee. The database will be authorized 
for lock once no data queries are outstanding, all study data are considered clean, and all 
defined procedures completed.
15.2.
Data Handling and Record Keeping
Data Collection and Retrieval
15.2.1.
The investigative site will be provided with eCRFs in which to record all the protocol-
specified data for each subject in this study. Entries made in the eCRF must be verifiable 
against source documents, or in certain circumstances as directed by the sponsor, entries will 
have been directly entered into the eCRF; in such cases, the entry in the eCRF will be 
considered as the source data. Data reported in the eCRF that are derived from source 

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documents should be consistent with the source documents or the discrepancies should be 
explained.
The investigator will be responsible for reviewing all data and eCRF entries and will sign and 
date the designated pages in each subject’s eCRF, verifying that the information is true and 
correct.
Queries generated by Data Management will be sent to the study site for resolution. The 
investigator is responsible for the review and approval of all responses to eCRF queries.
Records Retention
15.2.2.
The investigator must ensure that all records pertaining to the conduct of the clinical study, 
ICFs, drug accountability records, source documents, and other study documentation are 
adequately maintained for a period of 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.
The investigator must not destroy any records associated with the study without receiving 
approval from the sponsor. The investigator must notify the sponsor in the event of 
accidental loss or destruction of any study records. If the investigator leaves the institution 
where the study was conducted, the sponsor must be contacted to arrange alternative record 
storage options.
Whenever possible, an original recording of an observation must be retained as the source 
document. However, a photocopy of a record is acceptable provided it is legible and is a 
verified copy of the original document.
All eCRF data entered by the site (including audit trail), as well as computer hardware and 
software (for accessing the data), will be maintained or made available at the site in 
compliance with applicable record retention regulations. The sponsor will retain the original 
eCRF data and audit trail.
Study Monitoring and Access to Source Documents
15.2.3.
Qualified representatives of the sponsor or its designees (“study monitors”) will monitor the 
study according to a predetermined monitoring plan. Monitoring visits provide the sponsor 
with the opportunities to do the following:

Evaluate the progress of the study

Verify the accuracy and completeness of eCRFs

Assure that all protocol requirements, applicable laws and/or regulations, and 
investigator’s obligations are being fulfilled

Resolve any inconsistencies in the study records

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The investigator must allow the study monitors to periodically review, at mutually 
convenient times during the study and after the study has been completed, all eCRFs and 
office, hospital, and laboratory records supporting the participation of each subject in the 
study. The eCRFs and other documentation supporting the study must be kept up-to-date by 
the investigator and the research staff at the investigative site. These study materials (written 
notes and electronic medical records, if used) must be available for review by the study 
monitor, and/or other qualified representatives of the sponsor, at each monitoring visit.
The study monitor will periodically monitor the progress of the study by conducting on-site 
visits. The study monitor will review data remotely, possibly warranting more frequent 
communication and/or site visits with the investigator and the study site staff. Protocol 
deviations will also be identified and recorded. The study monitor will create action items in 
order to ensure that each issue identified during a monitoring visit is appropriately 
documented, reported, and resolved in a timely manner.
16.
PUBLICATION POLICY
Neither the institute nor the principal investigator shall have the right to publish or present 
any materials made available or generated through the study except as specified herein.  
The institute and the principal investigator shall be free to publish or present site-specific 
results of the project subject to the following conditions:
a. In the case of a study conducted at multiple institutions or study sites, institute and 
principal investigator agree that they will not submit a publication or make any 
presentation prior to the initial publication of the joint, multi-center results of the 
study, which shall be coordinated by sponsor
b. Institute and principal investigator agree that any authorized publication or 
presentation shall not reveal any of the sponsor’s information without the expressed 
written consent of the sponsor
c. Institute and principal investigator shall send sponsor a copy of any such proposed 
publication for sponsor’s review and comment ninety (90) days prior to submission 
for publication and shall not disclose to any third party prior to such submission any 
data, results, discoveries, or inventions arising from the clinical research study 
regardless of a determination of the ownership of rights to such material
d. Institute and principal investigator, upon sponsor’s request, shall delete any of 
sponsor’s information in the proposed publications; and shall not include raw data in 
such publications, except in the case of any information or data to the extent 
necessary to present the analysis in a manner consistent with generally accepted 
scientific and academic standards 
e. Institute and principal investigator, upon sponsor’s request, shall delay submission for 
any publication or presentation while the sponsor files applications for patents or 
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Any publication or presentation, including summaries or abstracts will appropriately 
reference the support received from the sponsor for the conduct of the Project. The parties 
agree that any authorized publication or presentation shall comply with applicable guidelines 
set forth by International Committee of Medical Journal Editors (ICMJE) and Good 
Publications Practice for Communicating Company Sponsored Medical Research (GPP2).  
Institute agrees that pursuant to any authorized publication or presentation, authors must 
disclose in their manuscripts, journal submissions, and elsewhere as appropriate or required, 
any potential conflicts of interest, including their financial or personal relationship with 
sponsor, and the names of any individuals who have provided editorial support for any 
manuscript or other publication.
Sponsor shall have the right to identify Institute as the site at which the study was conducted 
and to identify those individuals responsible for conducting the study, including principal 
investigator, and to provide any other information as necessary to post the study on 
www.clinicaltrials.gov or any other applicable public registries as required by applicable 
laws and regulations.

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17.
REFERENCES
1.
Sheth SG, Chopra S. Natural history and management of nonalcoholic fatty liver 
disease in adults, UpToDate; 2014; http://www.uptodate.com/contents/natural-history-
and-management-of-nonalcoholic-fatty-liver-disease-in-adults
2.
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The 
diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by 
the American Association for the Study of Liver Diseases, American College of 
Gastroenterology, and the American Gastroenterological Association. Hepatology 
2012;55:2005-23.
3.
McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic 
fatty liver disease. Clin Liver Dis 2004;8(3):521–33.
4.
Loomba R, Sirlin CB, Schwimmer JB, Lavine JE. Advances in pediatric nonalcoholic 
fatty liver disease. Hepatology 2009;50(4):1282–93.
5.
Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment of 
nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2012;10(8):837–58.
6.
Schwenger KJ, Allard JP. Clinical approaches to non-alcoholic fatty liver disease. 
World J Gastroenterol 2014;20(7):1712–23.
7.
Koo SH. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic 
steatosis. Clin Mol Hepatol 2013;19(3):210–5.
8.
Attar BM, Van Thiel DH. Current concepts and management approaches in 
nonalcoholic fatty liver disease. ScientificWorld Journal 2013;2013:481893
9.
Basaranoglu M, Basaranoglu G, Sentürk H. From fatty liver to fibrosis: a tale of 
"second hit". World J Gastroenterol 2013;19(8):1158–65.
10.
Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new 
insights. Science 2011;332(6037):1519–23.
11.
Matteoni CA, Younossi ZA, Gramlich T, et al. Nonalcoholic fatty liver disease: A 
spectrum of clinical and pathological severity. Gastroenterology 1999;116(6):1413–
1419
12.
World Gastroenterology Organisation Global Guidelines. Nonalcoholic Fatty liver 
Disease and Nonalcoholic Steatohepatitis. June 2012. 
http://www.worldgastroenterology.org/assets/export/userfiles/2012_NASH%20and%20
NAFLD_Final_long.pdf
13.
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and 
natural history of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis in 
adults. Aliment Pharmacol Ther 2011;34:274-85.

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14.
Charlton MR, Burns JM, Pederson RA, Watt KD, Heimbach JK, Dierkhising RA. 
Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the 
United States. Gastroenterology 2011;141:1249-53.
15.
Vatche G. Agopian et al. Liver Transplantation for Nonalcoholic Steatohepatitis. Ann 
Surg 2012; 256(4); 624-633.
16.
McCullough AJ. Epidemiology of the metabolic syndrome in the USA. J Dig Dis. 
2011;12:333-40.
17.
Mossanen JC, Krenkel O, Ergen C, Govaere O, Liepelt A, Puengel T, et al. Chemokine 
(C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-
induced acute liver injury. Hepatology 2016; 64(5):1667-82.
18.
Puengel T, Krenkel O, Mossanen J, Longerich T, E. Lefebvre E, Trautwein C, et al. 
The dual CCR2/CCR5 antagonist cenicriviroc ameliorates steatohepatitis and fibrosis in 
vivo by inhibiting the infiltration of inflammatory monocytes into injured liver. J 
Hepatol 64, s159-s182. 2016.
19.
Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology 
2014;147(3):577-94.
20.
Schwabe RF, Bataller R, Brenner DA. Human hepatic stellate cells express CCR5 and 
RANTES to induce proliferation and migration. Am J Physiol Gastrointest Liver 
Physiol. 2003;285:G949-58.
21.
Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of 
cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 
2018;67(5):1754-1767.
22.
Angulo P, Kleiner DE, Dam-Larsen S, Adam LA, Bjornsson ES, 
Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is 
associated with long-term outcomes of patients with nonalcoholic fatty liver disease. 
Gastroenterology 2015;149:389-397.
23.
Kamath PS, Kim WR, Advanced Liver Disease Study Group. The model for end-stage 
liver disease (MELD). Hepatology. 2007;45:797-805.
24.
OPTN Jan 2016 policy change. Available at: 
https://optn.transplant.hrsa.gov/media/1575/policynotice_20151101.pdf. Accessed on 
13 March 2018.
25.
WHO Obesity and Overweight Fact Sheet. February 2018. Available at: 
http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed on 13 March 2018.
26.
WHO Global Recommendations on Physical Activity for Health. 2010. Available at: 
http://apps.who.int/iris/bitstream/10665/44399/1/9789241599979_eng.pdf. Accessed on 
13 March 2018.

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27.
FDA Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. July 2009. Available at 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf
28.
Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. 
Design and validation of a histological scoring system for nonalcoholic fatty liver 
disease. Hepatology 2005;41:1313-21.
29.
Ishak K, Baptista A, Bianchi L, Callea F, De Grootes J, Gudat F, et al. Histological 
grading and staging of chronic hepatitis. J Hepatol. 1995;22:696-9.
30.
Wai C-T, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et 
al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in 
patients with chronic hepatitis C. Hepatology 2003;38:518-26.
31.
Vallet-Prichard A, Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-Venier V, et al. 
FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison 
with liver biopsy and FibroTest. Hepatology 2007;46:32-36
32.
Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The 
NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients 
with NAFLD. Hepatology 2007;45:846-54.
33.
Zhao Y, Herring AH, Zhou H, Ali MW, Koch GG. A multiple imputation method for 
sensitivity analyses of time-to-event data with possibly informative censoring. Journal 
Biopharmaceutical Statistics. 2014; 24:229-253.
34.
Trussell J. Contraceptive failure in the United States. Contraception 2004;70:89-96.
35.
Clinical Trial Facilitation Group Recommendations Related to Contraception and 
Pregnancy Testing in Clinical Trials – Version 15 September 2014

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18.
SPONSOR’S SIGNATURE PAGE
Protocol Number:  
3152-301-002
Protocol Title:
AURORA: A Phase 3, Multicenter, Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Cenicriviroc for the Treatment of Liver Fibrosis in 
Adult Subjects with Nonalcoholic Steatohepatitis
Amendment Number:
Date: 29 April 2019
4
I have reviewed and approved the attached version, cited above, of 3152-301-002 
Amendment 4.

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19.
INVESTIGATOR’S SIGNATURE PAGE
Protocol Number:  
3152-301-002
Protocol Title:
AURORA: A Phase 3, Multicenter, Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Cenicriviroc for the Treatment of Liver Fibrosis in 
Adult Subjects with Nonalcoholic Steatohepatitis
Amendment Number:
Date: 
4
I have reviewed and approved the attached version, cited above, of 3152-301-002 
Amendment 4.
Principal Investigator Name (Print)
                            Signature
Date                                                                              Site Number

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20.
APPENDICES

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20.1.
Schedule of Assessments
Table 20–1
Schedule of Assessments: Part 1

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Table 20–2
Schedule of Assessments: Part 2 

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20.2.
National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) 
Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010)
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
Quick Reference
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) is a descriptive terminology which can be utilized for adverse event (AE) reporting. 
A grading (severity) scale is provided for each AE term.
Components and Organization
System Organ Class
System Organ Class (SOC), the highest level of the MedDRA hierarchy, is identified by 
anatomical or physiological system, etiology, or purpose (eg, SOC investigations for 
laboratory test results). CTCAE terms are grouped by MedDRA Primary SOCs. Within each 
SOC, AEs are listed and accompanied by descriptions of severity (grade). 
CTCAE Terms
An adverse event is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure that may or may not be considered related to the medical treatment or procedure. 
An AE is a term that is a unique representation of a specific event used for medical 
documentation and scientific analyses. Each CTCAE v4.0 term is a MedDRA lowest level 
term (LLT).
Definitions
A brief definition is provided to clarify the meaning of each AE term.

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Grades
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline:
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*.
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**.
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE.
ADL = activities of daily living
A semi-colon indicates ‘or’ within the description of the grade.
A single dash (-) indicates a grade is not available.
Not all grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than 
5 options for grade selection.
Grade 5 (Death) is not appropriate for some AEs and therefore is not an option.
Activities of Daily Living (ADL)
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.

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20.3.
Information on Contraception Effectiveness
For Female Study Subjects of Child-Bearing Potential and For Male Study Subjects with 
Female Partners:
The following methods have been determined to achieve a failure rate < 1% per year, when 
used consistently and correctly, are considered highly effective birth control methods and are 
permitted under this protocol:

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20.4.
Disallowed Medications
Caution should always be exercised when administering concomitant medications based on 
the individual medication profile and clinical risk-benefit assessment. 
The subject must not take the following disallowed medications at any time during the study, 
from Screening through the 30-day Follow-up visit.
Disallowed Medications
Medicinal Product 
Class (WHO 
preferred term and 
drug classification)
Examples of CYP3A4 
Substrates with 
Narrow Therapeutic 
Index
Examples of 
Strong/Moder
ate CYP 3A4 
Inducers
Examples of Strong 
CYP3A4 Inhibitors
Examples of 
Strong 
CYP2C8 
Inhibitors
Antibacterials
rifampin, 
nafcillin 
clarithromycin, 
erythromycin, 
telithromycin 
Anticonvulsants
carbamazepin, 
phenytoin 
Antidepressants
nefazodone 
Antifungals
voriconazole, 
itraconazole, 
ketoconazole, 
posaconazole
Antihistamines
astemizole 
Antipsychotics
pimozide
Antivirals
efavirenz, 
etravirine
boceprevir,
dasabuvir/ 
ombitasvir/paritaprevir
/ritonavir,
indinavir, 
lopinavir/ritonavir, 
nelfinavir, 
ombitasvir/paritaprevir
/ritonavir, ritonavir, 
saquinavir, telaprevir 
Ergot Alkaloids
dihydroergotamine, 
ergonovine, 
ergotamine, 
methylergonovine 
Immunosuppressants
cyclosporine, 
tacrolimus
Lipid-lowering 
agents
gemfibrozil

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Disallowed Medications
Medicinal Product 
Class (WHO 
preferred term and 
drug classification)
Examples of CYP3A4 
Substrates with 
Narrow Therapeutic 
Index
Examples of 
Strong/Moder
ate CYP 3A4 
Inducers
Examples of Strong 
CYP3A4 Inhibitors
Examples of 
Strong 
CYP2C8 
Inhibitors
Opioids
fentanyl, alfentanil 
Exception: fentanyl or
alfentanil use is 
allowed for sedation on 
the day of Screening 
liver biopsy. However, 
for liver biopsies 
conducted at Months 12 
and 60 or for any 
procedure after intake 
of study drug.
Fentanyl is to be 
administered under 
medical supervision 
and all precautions 
should be in place, 
including availability of 
antidote, to prevent 
complication from its 
use. It is recommended 
that the initial dose be 
decreased by 50% and 
titrated to the desired 
effect. 
Sedative/hypnotics
midazolam, triazolam 
Exception: Midazolam 
use is allowed for 
sedation on the day of 
liver biopsy or for 
surgical outpatient 
procedures; however, 
for liver biopsies 
conducted at Months 12 
and 60 or for any
procedure after intake 
of study drug, the first 
dose should be 
decreased by 50% of 
the recommended dose 
and titrated according 
to the desired clinical 
response.
Other
cisapride

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Disallowed Medications— BCRP Substrates
WHO preferred term and drug 
classification
Example of BCRP Substrates
Anti-inflammatory drugs
sulfasalazine 
Antimetabolite drugs
methotrexate 
Antivirals
glecaprevir/pibrentasvir

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Disallowed Medications Due to Possible Confounding Effect on Efficacy
WHO preferred term and drug 
classification
Example of drugs/components that may have a 
confounding effect on efficacy
Antidiabetics
pioglitazone
Fruits, vegetables, other foods, vitamins 
and supplements
high-dose (ie, > 400 IU/day) vitamin E 
Other
obeticholic acid

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The following medications, if used, should be used with caution as CVC (mild CYP3A4 
inhibitor and BCRP inhibitor) may increase exposure of these CYP3A4 and BCRP substrates 
or these medications may affect the exposure of CVC. If used, these medications should be 
used at the lowest possible dose and for the shortest duration possible considering individual 
subject risk-benefit considerations. Clinical monitoring and dose titration are recommended 
to achieve the desired clinical response. Other medications of a similar class should be 
considered if possible. Consult the individual medication prescribing information for 
additional guidance.
Medicinal Product Class
Drugs that are Allowed but Must be Taken with Precaution During 
Intake of Study Drug (Mechanism)
Acid-reducing agents 
(H2 receptor antagonists, 
antacids, proton-pump 
inhibitors [PPIs])
Acid-reducing agents should be administered at least 2 hours after the CVC 
dose to ensure that adequate CVC concentrations are maintained. When 
possible, use of an H2 receptor antagonist (except cimetidine) or antacids is 
preferred over a proton pump inhibitor (PPI).  It is recommended to start 
with the lowest dose of these agents and titrate according to clinical 
response.  
H2 receptor antagonists (eg, famotidine or ranitidine) should preferably be 
given from 2 to 12 hours after administration of study drug at a dose that 
does not exceed doses comparable to famotidine 40 mg daily.   
Antacids (eg, aluminum hydroxide, calcium carbonate, magnesium 
carbonate, magnesium hydroxide, or bismuth subsalicylate) should 
preferably be given at least 4 hours after administration of study drug due to 
their immediate effect in increasing gastric pH.  
PPIs (eg, omeprazole, lansoprazole, esomeprazole, pantoprazole, 
rabeprazole, or dexlansoprazole) should preferably be given approximately 3 
hours after administration of study drug at a dose that does not exceed doses 
comparable to omeprazole 20 mg daily. Due to the prolonged acid-reducing 
effect of PPIs (~16 – 24 hours), it is advised to follow these dosing 
recommendations to reduce their potential impact on CVC absorption at 
subsequent dosing
Lipid-lowering agents
atorvastatin, simvastatin, lovastatin, (CYP3A4 substrates); pravastatin
(CYP3A4 substrate, weak CYP2C8 inhibitor); rosuvastatin (BCRP substrate)
The maximum recommended daily doses are as follows: 
atorvastatin 40 mg, simvastatin 20 mg, lovastatin 40 mg, pravastatin 40 mg, 
and rosuvastatin 20 mg; pitavastatin use is allowed without dose restriction
The medical monitor must be consulted prior to use of higher doses of statins 
than those recommended above.
PDE5 enzyme inhibitors
sildenafil, tadalafil, vardenafil (CYP3A4 substrates)
The recommended starting doses for these medications are as follows:
sildenafil 25 mg, tadalafil 2.5 mg, vardenafil 2.5 mg
Source: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m093664.htm

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20.5.
Clinical Laboratory Tests 

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©2016. Center for Outcomes Research in Liver Disease, Washington DC

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