Clinical trial NCT04048876
Conditions: Non-alcoholic Fatty Liver Disease Liver Cirrhosis
Keywords: Non-Alcoholic Steatohepatitis NASH Non-Alcoholic Fatty Liver Liver Fibrosis CC-90001
Sponsor: Celgene
Start date: 2019-08-14; Completion date: 2021-09-28
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, multinational, dose-finding study evaluating the efficacy of three treatment doses of CC-90001 compared with placebo, in Non-alcoholic Steatohepatitis (NASH) participants with Stage 2, Stage 3 liver fibrosis.

This study is designed to assess response to treatment on measures of fibrosis and other efficacy parameters. It will also assess dose response and overall safety.

Detailed description:

Arms: arm 1: CC-90001 400 mg QD arm 2: CC-90001 200 mg QD arm 3: CC-90001 100 mg QD arm 4: Placebo QD
Interventions: intervention 1: CC-90001 intervention 2: Placebo
Intervention descriptions: intervention 1: oral intervention 2: oral

Protocol documents:
Prot_SAP_001.pdf: 
Protocol for 
 
Official Title of Study 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER, 
DOSE-FINDING STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF CC-90001 IN SUBJECTS 
WITH NON-ALCOHOLIC STEATOHEPATITIS (NASH) 
AND LIVER FIBROSIS 
NCT04048876 
April 16, 2021 


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
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CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
 
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER, 
DOSE-FINDING STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF CC-90001 IN SUBJECTS 
WITH NON-ALCOHOLIC STEATOHEPATITIS (NASH) 
AND LIVER FIBROSIS
PROTOCOL NUMBER:
CC-90001-NASH-001
DATE FINAL:
DATE AMENDMENT 1 FINAL:
01 Mar 2019
23 May 2019
DATE AMENDMENT 2 FINAL:
26 Sep 2019
DATE AMENDMENT 3 FINAL:
11 Nov 2020
DATE AMENDMENT 4 FINAL:
16 Apr 2021
EudraCT NUMBER:
2018-004431-79
IND NUMBER:
138213
SPONSOR NAME/ ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Global Medical Monitor
Name:
Title:
Address: 
Phone:
E-mail:
Contact Information:
Medical Monitor for Europe
Name:
Phone:
Contact Information:
Medical Monitor for Asia-Pacific
Name:
Phone:
Note: The back-up 24-hour global emergency contact call center should only be used if 
you are not able to reach the Clinical Research Physician(s) or Medical Monitor or 
designee for emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
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CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
 
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from
Celgene representatives, the Declaration of Helsinki, International Council for 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name: _______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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PROTOCOL SUMMARY
Study Title
A Phase 2, Randomized, Double-blind, Placebo-controlled, Multicenter, Dose-finding Study 
to Evaluate the Efficacy and Safety of CC-90001 in Subjects with Non-alcoholic 
Steatohepatitis (NASH) and Liver Fibrosis
Indication
Non-alcoholic steatohepatitis (NASH)
Objectives
The effect of oral (PO) CC-90001, administered once daily (QD), compared with placebo, 
will be evaluated in subjects with NASH and Stage 2 or Stage 3 fibrosis.
Primary Objective
The primary objective of the study is to evaluate the effect of oral CC-90001, administered 
QD, compared with placebo, on liver histology in subjects with NASH and Stage 2 or 
Stage 3 fibrosis.
Secondary Objective(s)
!
To evaluate the effects of oral CC-90001, administered QD, compared with placebo, 
in subjects with NASH and Stage 2 or Stage 3 fibrosis, on:
∀
Additional liver biopsy-based endpoints 
∀
Liver biochemistry-based endpoints
∀
Metabolic parameters-based endpoints
∀
Dose response
∀
Safety and tolerability
∀
Pharmacokinetics (PK)
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Study Design
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, multinational, 
dose-finding study evaluating the efficacy of treatment with CC-90001, compared with 
placebo, in NASH subjects with Stage 2 or Stage 3 liver fibrosis. Safety, PK, 
 
 of CC-90001 compared to placebo will be evaluated.
Approximately 180 adult male and female subjects with a confirmed diagnosis of NASH and 
Stage 2 or Stage 3 fibrosis will be randomized 1:1:1 to treatment with oral CC-90001 (200 
mg QD, 60 subjects; 400 mg QD, 60 subjects) or matching placebo (60 subjects) for 52 
weeks. Prior to the implementation of Protocol Amendment 4, subjects were also 
randomized into a 100 mg QD dose group. The subjects who were previously randomized to 
the 100 mg dose group will remain in the 100 mg dose group throughout the study. It is 
expected that approximately 10-15 subjects will have been randomized to the 100 mg group 
at time of implementation of Protocol Amendment 4. Thus, a total of approximately 195
subjects will participate in the study.
Randomization will be stratified by liver fibrosis stage (Stage 2/Stage 3) and by the presence 
of Type 2 Diabetes Mellitus (DM) (yes/no). To ensure enrollment of a suitable number of 
subjects with Stage 3 fibrosis, up to 15 subjects with Stage 2 fibrosis may be enrolled per 
arm.  Randomization, treatment assignment and stratification will be managed by an 
interactive web response system (IWRS).
An independent external data monitoring committee (DMC) will be responsible for review of 
the interim analyses data and will make recommendations to the Sponsor, who will be 
responsible for final decision-making. An unblinded interim analysis will be performed after 
approximately 50% of subjects complete 52 weeks of placebo-controlled treatment phase (as 
described in the DMC Charter).
Subjects who sign informed consent form (ICF) prior to the implementation of Protocol 
Amendment 4, will have an option to participate in a double-blind active treatment phase.  
After 52 weeks of placebo-controlled treatment all placebo subjects will be re-randomized 
1:1 by IWRS to the 200 mg, or 400 mg QD dose groups at Week 54. Prior to the 
implementation of Protocol Amendment 4, subjects were also re-randomized into a 100 mg 
QD dose group. The subjects who were previously re-randomized to the 100 mg dose group 
will remain in the 100 mg dose group. Subjects who were initially randomized to active 
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treatment arms will remain in their assigned dose groups through the end of the double-blind
active treatment phase. 
Subjects who sign ICF after the implementation of Protocol Amendment 4 will receive 
treatment in a double-blind placebo-controlled treatment phase only.
All subjects who complete the study treatment phases and those subjects who discontinue 
investigational product (IP) prior to the completion of the study will participate in the 4-week 
Post-treatment Observational Follow-up Phase.
The study will be conducted in compliance with International Council for Harmonisation 
(ICH) Good Clinical Practices (GCPs).
Study Population
The study population includes adult male and female subjects, ≥18 years of age, with a 
confirmed diagnosis of NASH and Stage 2 or Stage 3 fibrosis based upon the NASH Clinical 
Research Network (CRN) Histologic Scoring System and a Nonalcoholic Fatty Liver Disease 
(NAFLD) Activity Score (NAS) of 4 or higher, with a score of at least 1 for each of the three 
components (steatosis, hepatocellular ballooning, and lobular inflammation).
Length of Study
Subjects who sign ICF prior to the implementation of Protocol Amendment 4 and elect not to 
participate in the active treatment phase, or subjects who sign ICF after the implementation 
of Protocol Amendment 4:
The study will have a total duration of up to 66 weeks.  The study will consist of an up to 
10-week Screening Phase; a 52-week Double-blind Placebo-controlled Treatment Phase; 
and a 4-week Post-Treatment Observational Follow-up Phase.
Subjects who sign ICF prior to the implementation of Protocol Amendment 4 and elect to 
participate in the active treatment phase:
The study will have a total duration of up to 116 weeks.  The study will consist of an up 
to 10-week Screening Phase; a 52-week Double-blind Placebo-controlled Treatment 
Phase; a 50-week Double-blind Active Treatment Phase; and a 4-week Post-Treatment 
Observational Follow-up Phase.
The End of Trial is defined as either the date of the last visit of the last subject to complete 
the post-treatment follow-up, or the date of receipt of the last data point from the last subject 
that is required for primary, secondary 
 analysis, as prespecified in the 
protocol, whichever is the later date.
Study Treatments
All subjects will be instructed to take 3 tablets once daily, approximately the same time of 
day (preferably in the morning), with or without food.  All IP treatment allocation will be 
handled by IWRS.
!
52-Week Double-blind Placebo-controlled Treatment Phase: 
∀
100 mg PO QD CC-90001 (for subjects who are randomized prior to 
implementation of Protocol Amendment 4)
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∀
200 mg PO QD CC-90001
∀
400 mg PO QD CC-90001
∀
Matching Placebo for 100 mg and 200 mg tablets
!
50-Week Double-blind Active Treatment Phase (only for subjects who 
participate in the active treatment phase): 
∀
100 mg PO QD CC-90001 (for subjects who are randomized or re-randomized 
prior to implementation of Protocol Amendment 4)  
∀
200 mg PO QD CC-90001
∀
400 mg PO QD CC-90001
Overview of Efficacy Assessments
!
NASH CRN histological score (liver fibrosis score and NAS)
!
Liver biochemistry
∀
Aspartate aminotransferase (AST)
∀
Alanine aminotransferase (ALT) 
∀
Gamma (γ)-glutamyl transferase (GGT)
!
Metabolic parameters
∀
Serum lipids (total cholesterol, low-density lipoprotein [LDL], high-density 
lipoprotein [HDL], and triglycerides)
!
Progression to cirrhosis (Stage 2 and Stage 3 subjects only)
 
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Overview of Key Safety Assessments
!
Adverse events 
!
Physical examination, vital signs, and weight
!
Clinical laboratory tests including serum chemistry, hematology, and urinalysis 
(including urine cytology)
!
Pregnancy testing 
!
12-lead electrocardiogram 
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!
Assessments of concurrent therapies and procedures
Statistical Methods
The estimated improvement on ≥1 fibrosis score in Stage 3 subjects of 45% for CC-90001 
group and 20% for the placebo group is based on a Phase 2 study of selonsertib, which 
reported a 23% treatment difference (43% in the selonsertib 18 mg group versus 20% in the 
simtuzumab group-a compound that was not demonstrated to be effective for NASH with a 
treatment response similar to placebo from other clinical trials) (Loomba, 2018;
Neuschwander-Tetri, 2015).
With the above assumed treatment responses for the primary endpoint between the highest 
CC-90001 dose group and the placebo, and further assuming a similar treatment effect in 
Stage 2 subjects, the sample size of 60 for the placebo, 200 mg, and 400 mg treatment group 
and an expected sample size of 10-15 for the 100 mg treatment group provides the ability to 
determine a dose response with 80% power, and 5% type I error rate. It also provides high 
sensitivity to determine a Minimum Effective Dose (MED) when a range of response rates 
and clinically significant effects are assumed.
The efficacy analyses will be performed using the Full Analysis Set (FAS), defined as all 
subjects who are randomized and received at least one dose of IP.  The treatment comparison 
will be made between each of the CC-90001 treatment groups and placebo. No adjustment 
for multiple comparisons will be made. 
The binary efficacy endpoints will be summarized using counts and percentages. The 
treatment comparisons will be performed using the Cochran–Mantel–Haenszel (CMH) test 
adjusting for the stratification factors as appropriate. Missing values due to early termination 
will be imputed using data collected at the early termination visit if available; otherwise 
missing values will be imputed using the non-responder imputation (NRI) method. 
The continuous efficacy endpoints will be summarized using mean, standard deviation (SD), 
median, minimum, maximum, and number of observations analyzed. The treatment 
comparisons will be performed using a mixed model of repeated measures (MMRM) as the 
primary analysis method and an analysis of covariance (ANCOVA) model as sensitivity 
analysis method for all continuous secondary efficacy endpoints. 
 
 
 
The safety analyses for the 52-week placebo-controlled treatment phase will be performed 
using descriptive statistics based on the safety population, defined as all subjects who are 
randomized and receive at least one dose of IP. The safety analyses will also be performed 
for the CC-90001 exposure period for subjects who receive at least one dose of CC-90001, 
which will include safety data during the placebo-controlled treatment phase and active 
treatment phase.
An unblinded interim analysis will be performed after approximately 50% of subjects
complete 52 weeks of treatment (as described in the DMC Charter).
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................19
1.1.
Disease Background ...............................................................................................19
1.2.
Compound Background ..........................................................................................19
1.3.
Rationale ................................................................................................................27
1.3.1.
Study Rationale and Purpose ..................................................................................27
1.3.2.
Rationale for the Study Design ...............................................................................28
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................28
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................30
3.
OVERALL STUDY DESIGN ................................................................................35
3.1.
Study Design ..........................................................................................................35
3.2.
Study Duration for Subjects....................................................................................38
3.2.1.
Early Termination Visit ..........................................................................................38
3.2.2.
Lost to Follow-up ...................................................................................................38
3.3.
End of Trial ............................................................................................................38
4.
STUDY POPULATION.........................................................................................40
4.1.
Number of Subjects ................................................................................................40
4.2.
Inclusion Criteria....................................................................................................40
4.3.
Exclusion Criteria...................................................................................................42
5.
TABLE OF EVENTS.............................................................................................46
6.
PROCEDURES......................................................................................................53
6.1.
Screening Phase......................................................................................................53
6.2.
Treatment Period ....................................................................................................55
6.2.1.
Unscheduled Visits.................................................................................................57
6.3.
Early Termination...................................................................................................57
6.4.
Post-treatment Observational Follow-up Phase .......................................................58
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6.5.
Safety Assessments.................................................................................................58
6.5.1.
Physical Examination .............................................................................................58
6.5.2.
Electrocardiogram ..................................................................................................59
6.5.3.
Clinical Laboratory Assessments ............................................................................59
6.5.4.
Action Plan for Monitoring Potential Hepatotoxicity ..............................................60
6.6.
Efficacy Assessment...............................................................................................61
6.6.1.
Histological Scoring System for NAFLD................................................................61
6.8.
Biomarkers
.............................................63
7.
DESCRIPTION OF STUDY TREATMENTS........................................................66
7.1.
Description of Investigational Product(s)................................................................66
7.2.
Treatment Administration and Schedule .................................................................66
7.2.1.
Overdose ................................................................................................................66
7.2.2.
Dose Interruptions ..................................................................................................67
7.3.
Method of Treatment Assignment...........................................................................67
7.4.
Packaging and Labeling..........................................................................................68
7.5.
Investigational Product Accountability and Disposal ..............................................68
7.6.
Investigational Product Compliance........................................................................68
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................70
8.1.
Permitted Concomitant Medications and Procedures...............................................70
8.2.
Prohibited Concomitant Medications and Procedures..............................................71
8.3.
Required Concomitant Medications and Procedures................................................72
9.
STATISTICAL CONSIDERATIONS ....................................................................73
9.1.
Overview................................................................................................................73
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9.2.
Study Population Definitions ..................................................................................73
9.3.
Sample Size and Power Considerations...................................................................73
9.4.
Background and Demographic Characteristics........................................................75
9.5.
Subject Disposition.................................................................................................75
9.6.
Efficacy Analysis....................................................................................................75
9.6.1.
Efficacy Evaluation for the Placebo-controlled Phase (Weeks 0 to 52)....................75
9.6.1.1.
Primary Efficacy Endpoint......................................................................................75
9.6.1.2.
Secondary Efficacy Endpoints ................................................................................76
9.6.1.4.
Dose-Response modelling.......................................................................................77
9.6.1.5.
Subgroup Analysis..................................................................................................77
9.7.
Safety Analysis.......................................................................................................77
9.8.
Interim Analysis .....................................................................................................78
9.9.
Other Topics...........................................................................................................78
9.9.1.
Pharmacokinetic Analysis.......................................................................................78
9.9.2.
Internal Safety Management Team..........................................................................78
9.9.3.
External Data Monitoring Committee .....................................................................79
10.
ADVERSE EVENTS..............................................................................................80
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................80
10.2.
Evaluation of Adverse Events.................................................................................80
10.2.1.
Seriousness.............................................................................................................80
10.2.2.
Severity/Intensity....................................................................................................82
10.2.3.
Causality ................................................................................................................82
10.2.4.
Duration .................................................................................................................83
10.2.5.
Action Taken..........................................................................................................83
10.2.6.
Outcome.................................................................................................................83
10.3.
Abnormal Laboratory Values..................................................................................83
10.4.
Pregnancy...............................................................................................................83
10.4.1.
Females of Childbearing Potential ..........................................................................84
10.4.2.
Male Subjects.........................................................................................................84
10.5.
Reporting of Serious Adverse Events......................................................................84
10.5.1.
Safety Queries ........................................................................................................85
10.6.
Expedited Reporting of Adverse Events..................................................................85
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11.
DISCONTINUATIONS .........................................................................................87
11.1.
Individual Subject Stopping Criteria and Criteria for Review of Clinical Data 
by the DMC............................................................................................................87
11.1.1.
Individual Subject Stopping Criteria .......................................................................87
11.1.2.
Criteria for Review of Clinical Data by the DMC ...................................................87
11.2.
Treatment Discontinuation......................................................................................87
11.3.
Study Discontinuation ............................................................................................88
12.
EMERGENCY PROCEDURES.............................................................................89
12.1.
Emergency Contact.................................................................................................89
12.2.
Emergency Identification of Investigational Products .............................................89
13.
REGULATORY CONSIDERATIONS...................................................................90
13.1.
Good Clinical Practice............................................................................................90
13.2.
Investigator Responsibilities ...................................................................................90
13.3.
Subject Information and Informed Consent.............................................................91
13.4.
Confidentiality........................................................................................................91
13.5.
Protocol Amendments.............................................................................................91
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................91
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................92
13.8.
Termination of the Study ........................................................................................92
14.
DATA HANDLING AND RECORDKEEPING.....................................................93
14.1.
Data/Documents.....................................................................................................93
14.2.
Data Management...................................................................................................93
14.3.
Record Retention....................................................................................................93
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................95
15.1.
Study Monitoring and Source Data Verification......................................................95
15.2.
Audits and Inspections............................................................................................95
15.3.
Product Quality Complaint .....................................................................................95
16.
PUBLICATIONS ...................................................................................................97
17.
REFERENCES.......................................................................................................98
18.
APPENDICES......................................................................................................101
APPENDIX A.
TABLE OF ABBREVIATIONS..................................................................102
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APPENDIX C.
HEPATOTOXICITY MONITORING CRITERIA FOR 
INTERRUPTION AND DISCONTINUATION OF INVESTIGATIONAL 
PRODUCT BASED ON LIVER FUNCTION TEST ABNORMALITIES............108
APPENDIX D.
HEPATITIS EXCLUSION CRITERIA .......................................................110
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LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................30
Table 2:
Study Endpoints .....................................................................................................31
Table 3:
Table of Events.......................................................................................................46
Table 5:
Probability of Each Dose to Be Considered the MED for Various Response 
Scenarios and Delta ................................................................................................74
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................36
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1.
INTRODUCTION 
1.1.
Disease Background 
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the 
world, with a global prevalence estimated to be 24% (Younossi, 2018).  When steatosis is 
accompanied by evidence of liver cell injury and cell death, as well as inflammation, it is 
considered to be nonalcoholic steatohepatitis (NASH).  More advanced stages of NASH are 
accompanied by fibrosis (Diehl, 2017).  NASH occurs in approximately 20% of cases of 
NAFLD and is projected to increase to 27% of NAFLD cases in the US by 2030 (Estes, 
2018).  Approximately 20% of NASH patients will progress to cirrhosis, with potential 
complications of portal hypertension and hepatocellular carcinoma (Diehl, 2017).  The stage 
of fibrosis is the most important determinant of mortality in patients with advanced NASH 
(Hagström, 2017). Patients with NASH and intermediate fibrosis (Stage 2) or advanced 
fibrosis (ie, Stage 3 and Stage 4 fibrosis) are at a higher risk for liver-related complications 
and mortality over a relatively short time scale (Sanyal, 2015, Hagström, 2017).
Dietary changes and lifestyle modifications are considered first-line interventions for patients 
with NASH.  Treatments are primarily directed towards improving the metabolic parameters 
that contribute to disease pathogenesis, such as weight loss and exercise, reducing insulin 
resistance, and improving diabetic control.  Pharmacological options for NASH are outlined 
in clinical practice guidance or guidelines (European Association for the Study of the Liver 
[EASL], 2016; Chalasani, 2018). While no firm recommendations are offered, both 
pioglitazone and vitamin E are suggested treatment options.  Treatment with vitamin E or
pioglitazone leads to improvement or trends in improvement, respectively, in NASH and 
both agents are associated with benefits on steatosis and reduction in serum alanine and 
aspartate aminotransferase levels (Sanyal, 2010).  Weight gain is the most common side 
effect associated with pioglitazone and accelerated bone loss has been reported in women 
(Chalasani, 2018).  Other treatment options that can be considered in individual patients are 
bariatric surgery, which can lead to improvement or resolution of NASH, and liver 
transplantation in patients with NASH and end-stage liver disease (EASL, 2016; Chalasani, 
2018).  NASH is now the most rapidly growing indication for liver transplantation in the 
United States (Parikh, 2017).  Especially in light of the increasing prevalence of NASH, there 
is an urgent unmet medical need for specific treatments, with a focus on developing 
treatments that can decrease the progression of NASH and prevent or reverse fibrosis that 
accompanies NASH.
1.2.
Compound Background 
CC-90001 (also known as CC0491359) is a potent and selective inhibitor of c-Jun N-terminal 
kinase (JNK)
  
 
 
 
 
 
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1.3.
Rationale
1.3.1.
Study Rationale and Purpose
NASH patients who have liver fibrosis comprise the group of patients with both a higher
unmet need and potentially reversible disease, given the liver’s capacity for regeneration.
Data from pre-clinical models 
 
 support that CC-90001 is potentially effective in patients with NASH 
and fibrosis. In addition, results from a Phase 2 study of selonsertib, which targets apoptosis 
signal-regulating kinase 1 (ASK1), provides preliminary evidence that treatment with an anti-
inflammatory/anti-fibrotic agent may result in benefits on fibrosis in patients with NASH
(Loomba, 2018).  Since ASK1 is upstream of the JNK pathway (Win, 2018), CC-90001 as 
JNK inhibitor may also be an effective treatment in patients with NASH and advanced 
fibrosis.
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The purpose of this study is to evaluate the efficacy and safety of CC-90001 in NASH 
subjects with either Stage 2 or Stage 3 fibrosis.  It is expected that the results from this study 
will demonstrate a treatment-related difference in the proportion of Stage 2 or Stage 3
subjects who achieve a ≥1 stage improvement in liver fibrosis score at Week 52.  
1.3.2.
Rationale for the Study Design
CC-90001-NASH-001 is a Phase 2, double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy and safety of CC-90001 in subjects with NASH and liver fibrosis.
Efficacy evaluation will be based on liver biopsy-based endpoints 
 
.  
Liver biopsy is widely considered as the “gold standard” for assessing fibrosis in NASH and 
has been validated in a large cohort of NASH patients (Kleiner, 2005).  The primary efficacy 
endpoint will be the proportion of Stage 2 or Stage 3 subjects who achieve a ≥ 1 stage 
improvement in liver fibrosis score. The primary efficacy endpoint will be evaluated at 
Week 52 to allow slowly reversible subjects the opportunity to demonstrate a treatment 
benefit.  Other liver biopsy-based endpoints, such as Non-alcoholic Fatty Liver Disease 
Activity Score (NAS) for evaluation of steatohepatitis and combination assessment of liver
fibrosis score and steatohepatitis will be assessed as key secondary efficacy evaluations.
Laboratory evaluations, AEs, vital signs, electrocardiograms (ECGs), pregnancy tests and 
physical examinations will be monitored during the study to evaluate safety.
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
The efficacy and safety of 100 mg, 200 mg and 400 mg PO QD doses of CC-90001 will be 
evaluated in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the effect of oral CC-90001, administered once daily
(QD), compared with placebo, on liver histology in subjects with nonalcoholic steatohepatitis (NASH)
and Stage 2 or Stage 3 fibrosis.
Secondary Objective(s)
The secondary objectives are:
!
To evaluate the effects of oral CC-90001, administered QD, compared with placebo, in subjects 
with NASH and Stage 2 or Stage 3 fibrosis, on:
-
Additional liver biopsy-based endpoints
-
Liver biochemistry-based endpoints
-
Metabolic parameters-based endpoints
-
Dose response
-
Safety and tolerability
-
Pharmacokinetics (PK)
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Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary
Liver fibrosis 
score
Proportion of subjects who achieve a ≥1 
stage improvement in liver fibrosis using 
the nonalcoholic steatohepatitis (NASH)
clinical research network (CRN) 
Histological Scoring System 
Week 52
Secondary
Combined 
assessment of 
liver fibrosis 
score and 
steatohepatitis
Proportion of subjects who achieve a ≥1 
stage improvement in liver fibrosis and no 
worsening of steatohepatitis (no 
worsening of lobular inflammation or 
hepatocellular ballooning score) 
Week 52
Nonalcoholic 
fatty liver disease 
(NAFLD) activity 
score (NAS)
Proportion of subjects with an 
improvement of ≥2 points in the total 
NAS in more than one category of 
steatosis, lobular inflammation, and 
hepatocellular ballooning, and no 
worsening of liver fibrosis 
Week 52
Resolution of 
NASH
Proportion of subjects who demonstrate 
absence of ballooning, and lobular 
inflammation score of 0 or 1
Week 52
Resolution of 
NASH without 
worsening of 
liver fibrosis
Proportion of subjects who demonstrate 
absence of ballooning, and lobular 
inflammation score of 0 or 1 and no 
worsening of liver fibrosis 
Week 52 
Progression to 
cirrhosis
Proportion of subjects who progress to 
cirrhosis 
Week 52
Liver 
biochemistry
Change from Baseline in serum aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT) and γ-glutamyl 
transferase (GGT) 
through Week 52
Metabolic 
parameters
Change from Baseline in total cholesterol, 
low density cholesterol (LDL) high 
density cholesterol (HDL), and 
triglycerides 
through Week 52
Dose response
Dose-related changes in the primary and 
secondary endpoints 
through Week 24 
(secondary endpoints); 
through Week 52 
(primary and secondary 
endpoints)
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Table 2:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Secondary
Safety
Type, frequency, severity, and 
relationship of adverse events (AEs) to 
CC-90001; Laboratory, 12-lead 
electrocardiogram (ECG), physical 
examination or other changes and 
tolerability 
through End of Study
Pharmacokinetics 
(PK)
Maximum plasma concentration of drug 
(Cmax), area under the plasma 
concentration time-curve (AUC), time to 
peak (maximum) plasma concentration 
(Tmax), terminal half-life (t1/2), apparent 
total body clearance of the drug (CL/F), 
apparent volume of distribution (Vz/F), 
and accumulation index of CC-90001 
Day 1 and Week 4
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3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter, multinational, 
dose-finding study evaluating the efficacy of treatment with CC-90001, compared with 
placebo, in NASH subjects with Stage 2 or Stage 3 fibrosis. Safety, PK, 
 
 of CC-90001 compared to placebo will be evaluated.
This study is designed to assess response to treatment on measures of fibrosis (liver biopsy, 
), 
 liver biochemistry, and other efficacy 
parameters. It will also assess dose response and overall safety.
Subjects who sign ICF prior to the implementation of Protocol Amendment 4 and elect not to 
participate in the active treatment phase, or subjects who sign ICF after the implementation 
of Protocol Amendment 4 (Figure 1):
!
Screening Phase: up to 10 weeks
!
Double-blind Placebo-controlled Treatment Phase: 52 weeks
!
Post-treatment Observational Follow-up Phase: 4 weeks
Subjects who sign ICF prior to the implementation of Protocol Amendment 4 and elect to 
participate in the active treatment phase (Figure 1):
!
Screening Phase: up to 10 weeks
!
Double-blind Placebo-controlled Treatment Phase: 52 weeks
!
Double-blind Active Treatment Phase: 50 weeks 
!
Post-treatment Observational Follow-up Phase: 4 weeks
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Figure 1:
Overall Study Design
After the implementation of Protocol Amendment 4:
Note: The subjects who were previously randomized to the 100 mg dose group will remain in the 100 mg dose group 
throughout the study. It is expected that approximately 10-15 subjects will have been randomized to the 100 mg group at 
time of implementation of Protocol Amendment 4.
Prior to the implementation of Protocol Amendment 4:
EOF = end of follow-up; EOT = end of treatment; PO = oral; QD = once daily.
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Approximately 180 adult male and female subjects with a confirmed diagnosis of NASH and 
Stage 2 or Stage 3 fibrosis based upon the NASH Clinical Research Network (CRN)
Histologic Scoring System and a NAS of 4 or higher, with a score of at least 1 for each of the 
three components (steatosis, hepatocellular ballooning, and lobular inflammation), will be 
randomized 1:1:1 to treatment with oral CC-90001 (200 mg QD, 60 subjects; 400 mg QD, 60
subjects) or matching placebo (60 subjects) for 52 weeks. Prior to the implementation of 
Protocol Amendment 4, subjects were also randomized into a 100 mg QD dose group. The 
subjects who were previously randomized to the 100 mg dose group will remain in the 100 
mg dose group throughout the study. It is expected that approximately 10-15 subjects will 
have been randomized to the 100 mg group at time of implementation of Protocol 
Amendment 4. Thus, a total of approximately 195 subjects will participate in the study.
Randomization will be stratified by liver fibrosis stage (Stage 2/Stage 3) and by the presence 
of Type 2 Diabetes Mellitus (DM) (yes/no). Approximately 60 subjects with Stage 2 or Stage 
3 fibrosis will be enrolled per treatment arm. To ensure enrollment of a suitable number of 
subjects with Stage 3 fibrosis, up to 15 subjects with Stage 2 fibrosis may be enrolled per 
arm. Randomization to one stratum will be halted once the enrollment target is achieved for 
that stratum.  Randomization, treatment assignment and stratification will be managed by an 
interactive web response system (IWRS).
An independent external data monitoring committee (DMC) will be responsible for review of 
the interim analyses data and will make recommendations to the Sponsor, who will be 
responsible for final decision-making. An unblinded interim analysis will be performed after 
approximately 50% of subjects complete 52 weeks of the placebo-controlled treatment phase
(as described in the DMC Charter).  The DMC will review the totality of the available data to 
determine the following options: 
!
Continue the study as planned
!
Terminate the study for futility
!
Stop enrolling a treatment arm due to futility if not fully enrolled at interim analysis
Subjects who sign informed consent form (ICF) prior to the implementation of Protocol 
Amendment 4 will have an option to participate in a double-blind active treatment phase.  
After 52 weeks of placebo-controlled treatment all placebo subjects will be re-randomized 
1:1 by IWRS to the 200 mg QD or 400 mg QD dose groups at Week 54. Prior to the 
implementation of Protocol Amendment 4, subjects were also re-randomized into a 100 mg 
QD dose group. The subjects who were previously re-randomized to the 100 mg dose group 
will remain in the 100 mg dose group. Subjects who were initially randomized to active 
treatment arms will remain in their assigned dose groups through the end of the active 
treatment phase.
Subjects who sign ICF after the implementation of Protocol Amendment 4 will receive 
treatment in a double-blind placebo-controlled treatment phase only.  
Subjects will have regularly scheduled visits to assess efficacy, safety, tolerability, 
 
 PK 
; refer to Table 3, Table of Events.
All subjects who discontinue prematurely from the study at any time will be required to enter 
the 4-week Post-treatment Observational Follow-up Phase.
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The study will be conducted in compliance with the International Council for Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
3.2.
Study Duration for Subjects 
Subjects who sign ICF prior to the implementation of Protocol Amendment 4 and elect not to 
participate in the active treatment phase, or subjects who sign ICF after the implementation 
of Protocol Amendment 4:
Subjects will participate for a maximum of 66 weeks in this study, which includes an up 
to 10-week Screening Phase; a 52-week Double-blind Placebo-controlled Treatment 
Phase; and a 4-week Post-treatment Observational Follow-up Phase.
Subjects who sign ICF prior to the implementation of Protocol Amendment 4 and elect to 
participate in the active treatment phase:
Subjects will participate for a maximum of 116 weeks in this study, which includes an up 
to 10-week Screening Phase; a 52-week Double-blind Placebo-controlled Treatment 
Phase; a 50-week Double-blind Active Treatment Phase; and a 4-week Post-treatment 
Observational Follow-up Phase.
3.2.1.
Early Termination Visit
The Early Termination (ET) Visit is based on the subject’s withdrawal from the study prior
to the Week 102 Visit for subjects who participate in the active treatment phase or prior to the 
Week 52 Visit for subjects who do not participate in the active treatment phase. In addition,
the Investigator may discontinue the subject from the study at any time based on his/her 
assessment of clinical efficacy and/or safety. The decision to discontinue a subject remains 
the responsibility of the treating physician and will not be delayed or refused by the sponsor. 
When a subject withdraws or is discontinued from the study treatment, every effort should be
made to complete as many safety and efficacy assessments as reasonably appropriate.  Refer 
to the Table of Events (Table 3) for the assessments to be performed at the ET Visit.  The ET 
Visit should be scheduled as soon as possible after the decision is made to permanently 
discontinue study treatment.
3.2.2.
Lost to Follow-up
Subjects will be considered lost to follow-up when they fail to attend study visits without 
stating an intention to withdraw from the study.  The Investigator should show due diligence 
by documenting in the source documents the steps taken to contact the subject through 
multiple telephone calls and/or emails and one registered letter.  After all reasonable attempts 
have been made to contact the subject, the subject should be recorded as “lost to follow-up” 
in the electronic case report form (eCRF).
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete 
the post-treatment follow-up, or the date of receipt of the last data point from the last subject 
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that is required for primary, secondary 
 analysis, as prespecified in the 
protocol, whichever is the later date.
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4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 195 subjects with NASH and Stage 2 or Stage 3 liver fibrosis will be 
randomized worldwide.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is male or female ≥ 18 years of age at the time of signing the informed 
consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
3. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
4. Diagnosis of NASH with presence of Stage 2 or Stage 3 fibrosis based upon central 
reading of the NASH CRN Histologic Scoring System and a NAFLD Activity Score 
(NAS) of 4 or higher, with a score of at least 1 for each of the three components 
(steatosis scored 0 to 3, ballooning degeneration scored 0 to 2, and lobular 
inflammation scored 0 to 3) within 6 months prior to Screening or at Screening. 
5. If histopathological specimens are submitted from a historical liver biopsy, the 
subject could not be on a therapy specifically for the treatment of NASH after liver 
biopsy and the subject’s weight must have been documented to be stable since the 
liver biopsy (ie, within 5% if the liver biopsy was obtained 4 to 6 months prior to 
Screening or within 2.5% if the liver biopsy was obtained less than 4 months prior to 
Screening).
6. If receiving any of the following agents, the doses must have been stable for 3 months 
prior to Screening and the subject must agree to maintain stable doses during the 
course of the study, unless required to adjust doses due to safety reasons: 
ursodeoxycholic acid, fibric acid derivatives (fibrates) (eg, gemfibrozil), metformin, 
sodium-glucose co-transporter 2 (SGLT2) inhibitors (eg, canagliflozin), dipeptidyl 
peptidase-4 inhibitors (‘gliptins’) (such as sitagliptin), glucagon peptide-1 (GLP-1)
agonists (eg, liraglutide), anti-obesity medications (eg, orlistat, lorcaserin, liraglutide, 
phentermine-topiramate, or naltrexone-bupropion). Note: If historical liver biopsy is 
submitted, the doses of above medications must have been stable for 3 months prior 
to biopsy and stable doses should be maintained through screening and during the 
course of the study.  If SGLT2 inhibitors, GLP-1 agonists and anti-obesity 
medications have been recently discontinued, the treatment must have been stopped 
for at least 3 months prior to Screening or historical biopsy used for Screening 
assessment.
7. If receiving thiazolidinediones (eg, pioglitazone) or vitamin E, the doses must have 
been stable for 3 months prior to Screening and the subject must agree to maintain 
stable doses during the course of the study.  Note: If historical liver biopsy is 
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submitted the doses of above medications must have been stable for 3 months prior to 
biopsy and stable doses should be maintained through screening and during the 
course of the study. If thiazolidinediones (eg, pioglitazone) or vitamin E have been 
recently discontinued, the treatment must have been stopped for at least 3 months
prior to Screening or historical biopsy used for Screening assessment.
8. Females of childbearing potential (FCBP) 1must:
a.
Have two negative pregnancy tests as verified by the Investigator prior to 
starting investigational product (IP). She must agree to ongoing pregnancy 
testing during the course of the study, and after end of study treatment. This 
applies even if the subject practices true abstinence* from heterosexual 
contact.
b. Either commit to true abstinence* from heterosexual contact (which 
must be reviewed on a monthly basis and source documented) or 
agree to use two forms of effective birth control (one of which is 
highly effective) at the same time, and be able to comply with, 
effective contraception without interruption, 28 days prior to starting 
IP, during the study therapy (including dose interruptions), and for 28 
days after discontinuation of IP.  
Approved options for birth control are:
!
Any one of the following highly effective methods: Hormonal 
contraception (for example, birth control pills, intravaginal ring, 
transdermal patch, injection, implant); intrauterine device (IUD); tubal 
ligation (tying your tubes); or a partner with a vasectomy.  
Note: Certain drugs may reduce the effectiveness of hormonal 
contraceptives during and up to one month after discontinuation of 
these concomitant therapies.  
!
Any effective method, for example, condoms.
9. Male subjects must:
Practice true abstinence* (which must be reviewed on a monthly basis) or agree to 
use a latex condom or nonlatex condom not made out of natural (animal) membrane
(eg, polyurethane) during sexual contact with a pregnant female or a female of 
childbearing potential while participating in the study, during dose interruptions and 
for at least 28 days following IP discontinuation, even if he has undergone a 
successful vasectomy.  
*True abstinence is acceptable when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception).
                                               
1 A female of childbearing potential is a sexually mature female who 1) has not undergone a hysterectomy (the surgical removal 
of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been postmenopausal for at least 
24 consecutive months (that is, has had menses at any time during the preceding 24 consecutive months).
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4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has any significant medical condition, laboratory abnormality (other than 
NASH related dyscrasias), or psychiatric illness that would confound the ability to 
interpret data, prevent the subject from participating or place the subject at 
unacceptable risk if he/she were to participate in the study.
2. History or evidence of decompensated liver disease, including clinical ascites, hepatic 
encephalopathy, or variceal bleeding.
3. Hepatitis and fibrosis more likely related to etiologies other than NASH such as, but 
not limited to, alcoholic steatohepatitis, autoimmune hepatitis, hepatitis B virus 
(HBV) infection, hepatitis C virus (HCV) infection, primary biliary cirrhosis, primary 
sclerosing cholangitis, Wilson's disease, alpha-1-antitrypsin deficiency, 
hemochromatosis or iron overload, and drug-induced liver disease.
4. Hemoglobin A1c (HbA1c) ≥9.5% at Screening.
5. Subject has evidence of worsening liver function based on two measurements of 
AST, ALT, alkaline phosphatase (ALP) and total bilirubin (TBL) during Screening 
period (refer to Section 6.1).
6. Subject has a QTcF > 450 msec.
7. Subject has a history of liver transplantation or subject is likely to have liver 
transplantation during the study.
8. Current or history of recreational drug abuse or significant alcohol consumption for a 
period of more than 3 consecutive months within 1 year prior to screening.  
Significant alcohol consumption is defined as more than 14 oz (420 mL) per week in 
females and more than 21 oz (630 mL) per week in males, on average (1 oz/30 mL of 
alcohol is present in one 12 oz/360 mL beer, one 4 oz/120 mL glass of wine, or a 1.5
oz/45 mL measure of 40% proof alcohol).
9. Subject has urine ethyl glucuronide (EtG) > 500 ng/mL at Screening.
10. Use of any drugs that are known to cause hepatotoxicity, such as, but not limited to, 
acetaminophen (paracetamol) at dosages of > 3 grams/day and niacin at dosages of > 
2 grams/day within 2 weeks of randomization.
11. Receiving immunomodulator agents (eg, tumor necrosis factor [TNF] inhibitors), or 
cytokine inhibitors (eg, tofacitinib) within 3 months of Screening.
12. History of recurrent bacterial, viral, fungal, mycobacterial or other infections 
(including, but not limited to, atypical mycobacterial disease and herpes zoster), or 
any major episode of infection requiring either hospitalization or treatment with IV or 
oral antibiotics within 4 weeks of the Screening Visit and at any time during the 
Screening Phase, up through the first dose of IP. Additionally, in the case of prior 
SARS-CoV-2 infection, symptoms must have completely resolved and based on 
investigator assessment in consultation with the clinical trial physician, there are no 
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sequelae that would place the participant at a higher risk of receiving investigational
treatment.
13. History of active or latent tuberculosis (TB), unless there is medical record 
documentation of successful completion of a standard course of treatment considered 
appropriate, based on local prevalence of multi-drug resistant TB and consistent with 
World Health Organization guideline
Note: If a subject has adequate documentation of successful treatment for either 
latent or active TB, the QuantiFERON-TB Gold test is not needed.  Instead, a chest 
radiograph, obtained within the 12 weeks prior to Screening, without changes 
suggestive of active TB infection as determined by a qualified radiologist, will be 
sufficient to permit further participation in the study for these subjects.  
Documentation of adequate treatment for TB must be obtained prior to 
randomization.
14. Subject has had a household contact with a person with active TB and subject did not 
receive appropriate and documented prophylaxis for TB
Note: Household contact is a person who shared the same enclosed living space as 
the index case for one or more nights or for frequent or extended daytime periods 
during the 3 months before the start of current treatment.
15. History or positive screen for human immunodeficiency virus (HIV) infection or 
congenital or HIV-unrelated acquired immunodeficiencies (eg, common variable 
immunodeficiency [CVID]).
16. History or positive screen for hepatitis B (See Appendix D) and/or hepatitis C.
Note: A subject who is hepatitis C antibody (HCV Ab) positive must be excluded 
unless the subject has a history of HCV and sustained viral response (undetectable 
HCV ribonucleic acid [RNA]) for at least 2 years prior to Screening and have a
negative HCV RNA at Screening.
17. History of cardiac valve replacement requiring chronic anticoagulation therapy
18. History of inflammatory bowel disease (IBD).
19. History of bleeding peptic ulcer or bleeding diverticular disease within the last 5 
years.
20. Subjects with Type 1 DM.
21. History of malignancy within the last 5 years (exceptions: excised and cured 
basal/squamous cell skin carcinomas or cervical carcinoma in situ).
Approved
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Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
44
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
25. Pregnancy or lactation.
26. Subject has a known hypersensitivity to CC-90001 or any ingredient in the 
investigational product (IP).
27. Concurrent treatment with another IP, including through participation in an 
interventional trial for COVID-19. Prospective subjects may not participate in a 
concurrent IP study or have received an IP within 5 drug half-lives prior to screening. 
28. Prior use of approved agents for treatment of NASH within 6 months prior to 
Screening or historical biopsy used for Screening.
29. Subject has a history of bariatric surgery (eg, gastroplasty, roux-en-Y gastric bypass) 
within 5 years prior to Screening or subject is likely to have bariatric surgery during 
the study.
30. Evidence of the following abnormal laboratory values at Screening:
!
Serum ALT ≥ 5 X upper limit of normal (ULN) 
!
Serum AST ≥ 5 X ULN
!
Serum ALP ≥ 2 X ULN
!
Serum TBL ≥1.3 mg/dL, unless subject has a documented diagnosis of 
Gilbert’s syndrome. Subjects with Gilbert’s syndrome must have total 
bilirubin of ≤ 5× ULN, with direct bilirubin ≤ULN and no clinical or 
laboratory evidence of hemolysis
!
Serum albumin < 3.5 g/dL
!
Alpha-fetoprotein ≥200 ng/mL (Note: Alpha-fetoprotein > 20 ng/mL 
should be discussed with Sponsor to review the evaluation of 
Hepatocellular Cancer [HCC])
!
Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2
!
Hemoglobin < 10 g/dL
!
Platelet count < 140,000/mm3
!
INR > 1.2
31. Subjects who have received live attenuated SARS-CoV-2 vaccine within 1 month 
prior to Screening or anticipate the need to be vaccinated with live attenuated vaccine 
during the study. Further, for subjects who received an investigational COVID-19 
vaccine as part of a clinical trial prior to the Screening, enrollment must be delayed 
until the biologic impact of the vaccine is stabilized, as determined by discussion 
between the Investigator and the Clinical Trial Physician. 
Approved
11.0
v
Approved
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v


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
45
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
Subjects who have received a vaccine approved for Emergency Use Authorization 
may be considered for inclusion, after discussion with the Medical Monitor.
Approved
11.0
v
Approved
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v


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
46
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
5.
TABLE OF EVENTS
Table 3:
Table of Events
Year 1 - For all subjects
Screening 
Phase
Double-Blind, Placebo-controlled Treatment Phase
Early 
Termination
Post-Treatment 
Observational 
Follow-up Phase
Visit Number
Screening
2
Baseline
3
4-9
Every 4 weeks
10-13
Every 6 weeks
14
15
ETa
28
Week
-10 to 0
0
1
± 3 
days
4, 8d, 12, 
16d, 20, 24
± 3 days
30, 36, 
42, 48
± 3 days
52
± 3 days
53f
4 Weeks 
After Last Dose
(± 3 days)
STUDY ENTRY AND GENERAL ASSESSMENTS
Main Informed Consent
X
-
-
-
-
-
-
-
-
Inclusion/Exclusion Criteria
X
X
-
-
-
-
-
-
-
Demographics
X
-
-
-
-
-
-
-
-
Complete Medical History
X
-
-
-
-
-
-
-
-
FibroScanb
X
-
-
-
-
-
-
-
-
Prior/ Concomitant Medication 
Evaluation
Continuous starting after the informed consent form is signed through 28 days after end of treatment
Prior/Concomitant Procedures 
Evaluation
Continuous starting after the informed consent form is signed through 28 days after end of treatment
Hemoglobin A1c
X
-
-
-
-
-
-
-
-
Urine EtG Test
X
-
-
Week 24
-
X
-
-
-
Approved
11.0
v
Approved
1.0
v


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
47
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
Table 3:
Table of Events (Continued)
Year 1 - For all subjects
Screening 
Phase
Double-Blind, Placebo-controlled Treatment Phase
Early 
Termination
Post-Treatment 
Observational 
Follow-up Phase
Visit Number
Screening
2
Baseline
3
4-9
Every 4 weeks
10-13
Every 6 weeks
14
15
ETa
28
Week
-10 to 0
0
1
± 3 
days
4, 8d, 12, 
16d, 20, 24
± 3 days
30, 36, 
42, 48
± 3 days
52
± 3 days
53f
4 Weeks 
After Last Dose
(± 3 days)
Postmenopausal testing: estradiol 
and follicle-stimulating hormone (for 
women 50-55 years with 
undocumented status)
X
-
-
-
-
-
-
-
-
α-fetoprotein
X
-
-
-
-
-
-
-
-
QuantiFERON® -TB Gold Testc, 
Hepatitis B & C and HIV Tests
X
-
-
-
-
-
-
-
-
SAFETY ASSESSMENTS
Adverse Event Evaluation
Continuous starting after the informed consent form is signed through 28 days after end of treatment.
Complete Physical Examination
X
-
-
-
-
X
-
X
X
Targeted Physical Examination
-
X
X
X
X
-
X
-
-
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
Height
X
-
-
-
-
-
-
-
-
12-Lead ECG 
X
-
-
Weeks
4, 12, 24
-
X
-
X
X
Hematology Panel
X
X
X
X
X
X
X
X
X
Chemistry Panel
X
X
X
X
X
X
X
X
X
PT and INR
X
X
X
X
X
X
-
X
X
Approved
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Approved
1.0
v


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
48
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
Table 3:
Table of Events (Continued)
Year 1 - For all subjects
Screening 
Phase
Double-Blind, Placebo-controlled Treatment Phase
Early 
Termination
Post-Treatment 
Observational 
Follow-up Phase
Visit Number
Screening
2
Baseline
3
4-9
Every 4 weeks
10-13
Every 6 weeks
14
15
ETa
28
Week
-10 to 0
0
1
± 3 
days
4, 8d, 12, 
16d, 20, 24
± 3 days
30, 36, 
42, 48
± 3 days
52
± 3 
days
53f
4 Weeks 
After Last Dose
(± 3 days)
Urinalysis
X
X
-
X
Week 36
X
-
X
X
Urine cytology
X
-
-
Weeks 12, 24
-
X
-
X
X
FOBT
X
-
-
Weeks 12, 24
Weeks 36, 48
-
-
X
X
Serum β-hCG
X
X
-
X
X
X
-
X
X
Urine β-hCG
-
Xe
-
Weeks 8, 16
-
-
-
-
-
Pregnancy counseling for FCBP
X
X
X
X
X
X
X
X
X
EFFICACY ASSESSMENTS
Liver biopsy/histologyf
Xf
-
-
-
-
-
Xf
Xf
-
Approved
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Approved
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EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
49
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
Table 3:
Table of Events (Continued)
Year 1 - For all subjects
Screening 
Phase
Double-Blind, Placebo-controlled Treatment Phase
Early 
Termination
Post-Treatment 
Observational 
Follow-up Phase
Visit Number
Screening
2
Baseline
3
4-9
Every 4 weeks
10-13
Every 6 weeks
14
15
ETa
28
Week
-10 to 0
0
1
± 3 
days
4, 8d, 12, 
16d, 20, 24
± 3 days
30, 36, 
42, 48
± 3 days
52
± 3 
days
53f
4 Weeks 
After Last Dose
(± 3 days)
PHARMACOKINETIC
 ASSESSMENTS
Blood sample for metabolic tests 
-
X
-
Week 24
-
X
-
X
-
INVESTIGATIONAL PRODUCT (IP)
Dispense IP
-
Xj
X
X
X
-
-
-
-
Return and Count IP
-
-
X
X
X
X
-
X
-
Approved
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v
Approved
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v


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
50
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
Table 3:
Table of Events (Continued)
Year 2 - For subjects who participate in the active treatment phase:
Double-Blind, Active Treatment / Extension Phase
Early 
Termination
Post-Treatment Observational 
Follow-up Phase
Visit Number
16
17-22
Every 4 weeks
23-26
Every 6 weeks
27
EOT
ETa
28
Week
54 f
55, 58, 62, 66, 70, 74
± 3 days
78, 84, 90, 96
± 3 days
102
± 3 days
4 Weeks 
After Last Dose
(± 3 days)
SAFETY ASSESSMENTS
Prior/ Concomitant Medication Evaluation
Continuous starting after the informed consent form is signed through 28 days after end of treatment
Prior/Concomitant Procedures Evaluation
Continuous starting after the informed consent form is signed through 28 days after end of treatment
Adverse Event Evaluation
Continuous starting after the informed consent form is signed through 28 days after end of treatment.
Complete Physical Examination
-
-
-
X
X
X
Targeted Physical Examination
X
X
X
-
-
-
Vital Signs and Weight
X
X
X
X
X
X
12-Lead ECG 
-
Weeks 58, 66, 74
Week 84
X
X
X
Hematology Panel
-
X
X
X
X
X
Chemistry Panel
-
X
X
X
X
X
PT and INR
-
X
X
X
X
X
Urinalysis
-
X
Week 84
X
X
X
Urine cytology
-
Weeks 66, 74
-
X
X
X
FOBT
-
Weeks 62, 74
Weeks 84, 96
X
X
X
Serum β-hCG
X
X (except Week 55)
X
X
X
X
Pregnancy counseling for FCBP
X
X
X
X
X
X
Approved
11.0
v
Approved
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EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
51
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
Table 3:
Table of Events (Continued)
Year 2 - For subjects who participate in the active treatment phase:
Double-Blind, Active Treatment / Extension Phase
Early 
Termination
Post-Treatment Observational 
Follow-up Phase
Visit Number
16
17-22
Every 4 weeks
23-26
Every 6 
weeks
27
EOT
ETa
28
Week
54f
55, 58, 62, 66, 70, 74
± 3 days
78, 84, 90, 96
± 3 days
102
± 3 days
4 Weeks 
After Last Dose
(± 3 days)
PHARMACOKINETIC
 ASSESSMENTS
Blood sample for metabolic tests 
-
-
-
X
X
-
INVESTIGATIONAL PRODUCT (IP)
Dispense IP
X
X
X
-
-
-
Return and Count IP
-
X
X
X
X
-
Approved
11.0
v
Approved
1.0
v


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
52
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
Abbreviations: β- hCG = beta human chorionic gonadotropin; 
 ECG = 
electrocardiogram; 
 EtG = ethyl glucuronide; EOT = end of treatment; ET = Early Termination Visit; FCBP = females of child 
bearing potential; FOBT = fecal occult blood test; HCC =  hepatocellular cancer; HIV = human immunodeficiency virus; 
 INR = international 
normalized ratio; IP = investigational product;
 
PT = prothrombin time; 
 TB = tuberculosis.
a Subjects who discontinue the study prior to the Week 52 Visit (subjects who do not participate in the active treatment phase) or the Week 102 Visit (subjects 
who participate in the active treatment phase) will have an ET Visit. Subjects who discontinue the study prior to the Week 52 will undergo all of the 
assessments required at the Week 52 Visit and Subjects who discontinue the study after the Week 52 and prior to Week 102 Visit will undergo all of the 
assessments required at the Week 102 Visit.
b FibroScan can be used to determine eligibility for liver biopsy.
c If a subject has adequate documentation of successful treatment for either latent or active TB, the QuantiFERON-TB Gold test is not needed.  Instead, a chest 
radiograph, obtained within the 12 weeks prior to Screening, without changes suggestive of active TB infection as determined by a qualified radiologist, will be 
sufficient to permit further participation in the study for these subjects.  Documentation of adequate treatment for TB must be obtained prior to randomization.
d Visit 5 Week 8 and Visit 7 Week 16 will be remote visits. Central laboratory tests, target physical examination, vital sign and weight will not be performed 
during these remote visits. However, if laboratory tests and/or physical examination is needed based on the Investigator’s clinical judgement, an unscheduled 
visit should be performed at the investigational site. Urine pregnancy test kits will be provided to the subjects at Visit 4 Week 4 and Visit 6 Week 12. At Visit 
5 Week 8 and Visit 7 Week 16 subjects will perform urine β-hCG test at home. IP will be dispensed at Visit 4/Week 4 and Visit 6/Week 12 for these 2 visits.
e Urine pregnancy test will be performed to assess subject eligibility prior to the first administration of IP if a serum pregnancy test was not obtained within 72 
hours prior to dosing (negative results required for IP administration).
f Subjects who do not have a historical biopsy will undergo a liver biopsy procedure for study eligibility. The independent histopathologists will review the liver 
biopsy specimens to assess whether the subject meets the histological inclusion criteria. Screening liver biopsy will serve as the Baseline assessment. Subjects 
who discontinue after Week 20 and before Week 52 will undergo a liver biopsy procedure at ET Visit. IP should be stopped 7-10 days prior to Week 53 or ET 
Visit biopsy and restarted 7 days after biopsy at Week 54 if subjects participate in the active treatment phase.
j First dose of IP should be administered at the investigative site.
Approved
11.0
v
Approved
1.0
v


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
53
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
6.
PROCEDURES
Any questions regarding the protocol should be directed to the Celgene Medical Monitor or 
designee. 
6.1.
Screening Phase
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 10 weeks prior to the first dose of IP (study 
randomization) unless noted otherwise below. 
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
Safety laboratory analyses and all assessments will be performed centrally. Screening laboratory 
values must demonstrate subject eligibility, but may be repeated within the screening window, if 
necessary.
During screening, the following will be performed as specified in Table 3, Table of Events, after 
informed consent has been obtained:
!
Inclusion/exclusion criteria: Subjects must meet all inclusion criteria (Section 4.2) 
and must not have any of the conditions specified in the exclusion criteria 
(Section 4.3) to qualify for participation in the study.  The subject’s source documents 
must support his/her qualifications for the study.
!
Demographics: Including age, sex, and race and ethnicity-if allowed by local 
regulations
!
Disease history: Including specific information regarding diagnosis, staging, 
histology
!
Complete medical history: All relevant medical conditions diagnosed/ occurring prior 
to screening should also be included.
!
Prior procedures: Including any prior procedures 
!
Prior and concomitant medication evaluation: Including all medications (prescription 
and nonprescription, including vitamins) taken by the subject up to 30 days prior to 
the Screening Visit should be recorded, including the stop dates for medications 
prohibited in the study.  All medications taken by the subject at any time during the 
study must also be recorded.  Other key medications and therapies at any time, such 
as previous treatment for tuberculosis or relevant diseases, should also be recorded.
!
Complete physical examination (Section 6.5.1)
!
Vital Signs, height and weight:  Vital signs, including seated blood pressure, body 
temperature, and heart rate will be taken.  Height and weight (to be done in street 
clothes, no shoes) will also be measured and recorded.
!
12-lead electrocardiogram (ECG) (Section 6.5.2)
Approved
11.0
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Approved
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EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
54
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
!
Clinical laboratory evaluations:  Clinical laboratory evaluations will be performed by 
a central laboratory to include the following laboratory assessments below. Subject 
eligibility and clinical laboratory criteria are provided in Section 4.2.  One laboratory 
re-test is allowed after obtaining Medical Monitor approval if the result is 
exclusionary during the Screening Period. In subjects with abnormal screening ALP 
or TBL, another measurement should be obtained at least 4 weeks apart. In subjects 
with screening AST or ALT, greater than 3 X ULN, another measurement should be 
obtained at least 4 weeks apart. The subject will be eligible for the study if elevated 
screening AST, ALT, ALP or TBL values do not increase more than 20%. Subjects 
with evidence of worsening liver function at baseline are not eligible for the study.  In 
subjects with abnormal screening ALP or TBL or screening AST or ALT, greater 
than 3 X ULN, baseline values should be established by at least two measurements of 
AST, ALT, ALP or TBL obtained at least 4 weeks apart.  Details pertaining to the 
central laboratory assessments and panels are included in Section 6.5.3.
∀
Hematology panel
∀
Chemistry panel 
∀
Coagulation tests
∀
Urinalysis and urine cytology
∀
QuantiFERON-TB GOLD (Refer to Section 6.5.3)
∀
Hepatitis B and C tests
∀
Human immunodeficiency virus (HIV) test
∀
Pregnancy test (Serum β-hCG)
∀
Postmenopausal tests
∀
Urine EtG test
∀
α-fetoprotein
∀
Fecal occult blood test (FOBT)
!
Hemoglobin A1c
!
Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted 
!
Vibration controlled transient elastography (VCTE)/ FibroScan:  Subjects who do not 
have pathological specimens from a prior liver biopsy obtained within 6 months of 
Screening and available for central reading are suggested to have results from non-
invasive tests available to help determine eligibility for liver biopsy during Screening. 
In most subjects, these tests are Fibrosis-4 (FIB-4) and VCTE by FibroScan®.  
Availability of FIB-4 and VCTE, or other tests 
 obtained within 3 
months of Screening may be acceptable.  Other subjects may undergo sequential FIB-
4 determination and VCTE by FibroScan during Screening to help assess the 
likelihood of having Stage 2 or Stage 3 fibrosis based on Investigator’s clinical 
judgement.
Approved
11.0
v
Approved
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v


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
55
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
Vibration controlled transient elastography should be performed with the subjects in a 
fasting condition for 2 hours before the procedure, lying in supine position with 
normal breathing, and with the right arm in maximum abduction to allow optimal 
exposure of the right lateral abdomen. 
!
Liver biopsy (Section 6.6.1)
Screening liver biopsy will be performed in subjects who do not have pathological 
specimens from a prior liver biopsy obtained within 6 months of Screening and 
available for central reading.
!
Adverse Event:  Adverse event assessment begins when the subject signs the 
informed consent form and is assessed continuously throughout the study, until 28 
days following the last dose of IP.  Refer to Section 10 for details pertaining to AEs.
6.2.
Treatment Period
The subject will begin treatment upon confirmation of eligibility. For all subsequent visits, an 
administrative window of ± 3 days is permitted except Visit 15/Week 53 and Visit 16/Week 54
(for the subjects who participate in the active treatment phase).  Visit 15/Week 53 should be 
performed 7 to 10 days after Visit 14/Week 52 and Visit 16/Week 54 (for the subjects who 
participate in the active treatment phase) should be performed 7 to 10 days after Visit 15/Week 
53. Scheduling of Visits 3 to 14 is based on Visit 2/Week 0 (randomization date) and scheduling 
of Visits 17 to 27 (for the subjects who participate in the active treatment phase) is based on Visit 
16/Week 54 (re-randomization date).  
 
  
Visit 5 Week 8 and Visit 7 Week 16 will be remote visits. Assessments performed at these visits 
have been specified in the Table of Events, Table 3
The following evaluations will be performed at the frequency specified in the Table of Events,
Table 3. The evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified.  
!
Adverse event evaluation (continuously)
!
Concomitant medications evaluation (continuously)
!
Concomitant procedures evaluation (continuously)
!
Counseling about pregnancy precautions and the potential risks of fetal exposure
!
Complete physical examination (Section 6.5.1)
!
Targeted physical examination (Section 6.5.1)
!
Vital signs and weight (Section 6.1)
Approved
11.0
v
Approved
1.0
v


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
56
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
!
12-lead ECG (Section 6.5.2)
!
Clinical Laboratory Evaluations (Section 6.5.3):  
∀
Hematology panel
∀
Coagulation tests
∀
Chemistry panel 
∀
Urinalysis and urine cytology
∀
Serum pregnancy test 
∀
Urine pregnancy test at Visit 5 Week 8 and Visit 7 Week 16
∀
Urine EtG test
∀
Fecal occult blood test (FOBT)
!
Efficacy assessment (Section 6.6):
∀
Liver biopsy/histology
!
Investigational product (IP) dispensation:  The Principal Investigator, Sub-
investigator, or Study Coordinator should make an effort to witness subjects taking 
their first dose and record the date and time in the source document record. Subjects 
are instructed to take 3 tablets of IP QD, approximately the same time of day
(preferably in the morning), with or without food.  Visit 5/Week 8 and Visit 7/Week 
16 will be remote visits and IP will be dispensed at Visit 4/Week 4 and Visit 6/Week 
12 for these 2 visits. 
!
Investigational product (IP) return (all used and unused blister cards) and IP 
compliance assessment (Section 7.6)
Approved
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EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
57
CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
6.2.1.
Unscheduled Visits
Unscheduled visits, if needed, may occur at any time, in particular for safety reasons (or efficacy 
reasons) as deemed necessary by the Investigator or site staff, or for any reason that the subject 
must return to study center as it pertains to the study (eg, to pick up additional or replacement 
IP).  The Unscheduled Visit eCRF will be made available to the site staff, in order to record the 
necessary unscheduled assessments and/or procedures.
6.3.
Early Termination 
An early termination (ET) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made. 
The following evaluations will be performed as specified in the Table of Events, Table 3:
!
Adverse event evaluation 
!
Concomitant medications evaluation 
!
Concomitant procedures evaluation 
!
Counseling about pregnancy precautions and the potential risks of fetal exposure
!
Complete physical examination (Section 6.5.1) 
!
Vital signs and weight (Section 6.1)
!
12-lead ECG (Section 6.5.2) 
!
Clinical Laboratory Evaluations (Section 6.5.3):
∀
Hematology panel 
∀
Coagulation tests 
∀
Chemistry panel 
∀
Urinalysis and urine cytology
∀
Serum pregnancy test 
∀
Fecal occult blood test (FOBT)
!
Efficacy assessment (Section 6.6):
∀
Liver biopsy/histology
Approved
11.0
v
Approved
1.0
v


EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
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!
Investigational product (IP) return (all used and unused blister cards) and IP 
compliance assessment (Section 7.6)
6.4.
Post-treatment Observational Follow-up Phase
All subjects will be followed for 28 days after the last dose of IP for AE reporting, as well as 
SAEs made known to the Investigator at any time thereafter that are suspected of being related to 
IP, as described in Section 10.1.  
!
Adverse event evaluation 
!
Concomitant medications evaluation 
!
Concomitant procedures evaluation 
!
Counseling about pregnancy precautions and the potential risks of fetal exposure
!
Complete physical examination (Section 6.5.1)
!
Vital signs and weight (Section 6.1)
!
12-lead ECG (Section 6.5.2)
!
Clinical Laboratory Evaluations (Section 6.5.3):  
∀
Hematology panel 
∀
Coagulation tests 
∀
Chemistry panel 
∀
Urinalysis and urine cytology
∀
Serum pregnancy test 
∀
Fecal occult blood test (FOBT)
6.5.
Safety Assessments
6.5.1.
Physical Examination
Complete physical examinations will include evaluation of the skin, nasal cavities, eyes, ears, 
respiratory, cardiovascular, abdominal, neurological, lymphatic, and musculoskeletal systems.  
Gynecological, urogenital, and rectal examinations will not be performed unless needed.  
A targeted physical examination includes evaluation of the respiratory, cardiovascular, 
abdominal systems. Gynecological, urogenital and rectal examinations will not be done unless 
needed.
Results of the physical examination will be recorded only in the source documents.  Clinically 
significant abnormal findings (with the exception of the disease under study [NASH]) identified 
prior to first dose of IP will be recorded on the eCRF as medical history; clinically significant 
findings after the first dose of IP will be recorded as AEs.
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6.5.2.
Electrocardiogram
Subjects will have a 12-lead electrocardiogram (ECG) at the frequency specified in Table 3.  The 
investigator or designee will use his/her own ECG equipment. The same ECG equipment should 
be used throughout the entire study.  A standard 12-lead ECG (reporting PR interval, QRS, QT 
and corrected QT [QTc] intervals) will be performed by the Investigator or qualified designee.
For safety evaluation of the subject’s ECG, the Investigator should utilize the QT correction 
method (Fridericia). ECGs will be performed after the subject has been in the supine or near 
supine position for at least 10 minutes.
An ECG tracing from each prespecified visit will be reviewed by the Investigator or medically-
qualified designee and any abnormal results will be classified as clinically significant (CS) or not 
clinically significant (NCS) for real-time safety monitoring. Any CS abnormal ECG result 
should be reported as an AE and followed to resolution (ie, until it returns to baseline, stabilizes, 
or becomes NCS as judged by the Investigator or medically-qualified designee).
6.5.3.
Clinical Laboratory Assessments
Clinical laboratory evaluations will be performed by a central laboratory to include the following 
laboratory assessments performed at the frequency specified in Table 3. Clinical laboratory 
evaluations are required to be fasting at Baseline Visit, Week 24 Visit, and Week 52 Visit/ Week 
102 Visit (as applicable) or at the Early Termination Visit if subjects discontinue from the study 
prior Week 52 Visit/ Week 102 Visit (as applicable). “Abnormal, clinically significant” results 
should be recorded in the Medical History eCRF if found prior to first dose of IP, or in the AE 
eCRF if found after the first dose of IP.  
!
Hematology Panel: including complete blood count (CBC) with differential, including 
red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, white blood cell 
(WBC) count (with differential), neutrophil count (percent and absolute), and platelet 
count.
!
Coagulation tests: including prothrombin time (PT) and INR.
!
Chemistry Panel: including total protein, albumin, calcium, phosphorous, glucose, lipid 
panel (total cholesterol, HDL, LDL, and triglycerides), uric acid, TBL, ALP, AST/ serum 
glutamic oxaloacetic transaminase (SGOT), ALT/ serum glutamic pyruvic transaminase
(SGPT), sodium, potassium, chloride, carbon dioxide, blood urea nitrogen (BUN), 
creatinine, and lactic dehydrogenase (LDH).
!
Urinalysis: including dipstick urinalysis (specific gravity, pH, glucose, ketones, protein, 
blood, bilirubin, leukocyte esterase, nitrite, and urobilinogen). Microscopic urinalysis 
(epithelial cells, RBC, WBC, and casts) will be performed only if the dipstick urinalysis 
is abnormal.
In addition to the routine urinalysis, urine cytology will be done for the detection of 
abnormal cells. The urine cytology specimen will be evaluated by a pathologist at the 
central laboratory.
!
Mycobacterium tuberculosis (TB) testing:  Testing will be done at the Screening Visit via 
QuantiFERON®-TB Gold.  
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Note: A positive QuantiFERONTB Gold test or 2 successive indeterminate 
QuantiFERON-TB Gold tests will disqualify the subject from further participation in the 
study.
Note: If a subject has adequate documentation of successful treatment for either latent or 
active TB, the QuantiFERON-TB Gold test is not needed.  Instead, a chest radiograph, 
obtained within the 12 weeks prior to Screening, without changes suggestive of active TB 
infection as determined by a qualified radiologist, will be sufficient to permit further 
participation in the study for these subjects.  Documentation of adequate treatment for 
TB must be obtained prior to randomization.
!
Hepatitis B and hepatitis C testing: testing will be performed at Screening. The hepatitis 
screen includes testing for hepatitis B surface antigen (HBsAg) and antibody, hepatitis B 
core antibodies (IgG/IgM), and hepatitis C antibodies (HCV Ab). A positive result for 
one or more hepatitis B tests will disqualify the subject from further participation in the 
study (See Appendix D). A subject who is HCV Ab positive must be excluded unless the 
subject has a history of HCV and sustained viral response (undetectable HCV RNA) for 
at least 2 years prior to Screening or historical biopsy including negative HCV RNA at 
Screening. The Investigator should refer the subject to his/her general practitioner or 
other appropriate healthcare provider for further follow-up. 
Note: Subjects who received hepatitis B vaccination and who test positive for hepatitis B 
surface antibody and negative for both hepatitis B surface antigen and hepatitis B core 
antibody are not excluded from the study.
!
Human immunodeficiency virus test: testing will be performed at Screening. 
!
Hemoglobin A1c: test will be performed at Screening.
!
Pregnancy test is required for all female subjects of childbearing potential.  Serum beta 
human chorionic gonadotropin (β-hCG) pregnancy test will be performed. 
Urine pregnancy test will be performed to assess subject eligibility within 72 hours prior 
to the first administration of IP, if the initial serum pregnancy test did not already occur 
within 72 hours of dosing (negative results required for IP administration).
!
Postmenopausal test: Estradiol and follicle-stimulating hormone (FSH) levels are 
required for all females 50 to 55 years of age who do not have documentation confirming 
their postmenopausal status.  Postmenopausal test will be performed at Screening.
!
Urine EtG test: Test will be performed as indicated in Table 3.
!
Fecal occult blood test (FOBT): test will be performed as indicated in Table 3.
6.5.4.
Action Plan for Monitoring Potential Hepatotoxicity
The evaluation of liver safety signals in clinical trials that enroll individuals with pre-existing 
liver disease presents special challenges.  Refer to Appendix C for the specific guidelines for 
monitoring and interrupting and discontinuing subjects based upon elevations in the liver 
function tests after treatment with IP.  
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Treatment arm safety stopping rules will be finalized in consultation with members of the DMC 
based on the:
∀
Marked elevations of aminotransferases to 5 times, 10 times, or 20 times the 
baseline values in the active treatment and not observed or less frequent in the 
placebo group.
∀
One or more Hy’s law cases, as defined by the following preliminary parameters, 
based on Guidance for Industry Drug-induced Liver Injury: Premarketing Clinical 
Evaluation; (FDA, 2009) and modified as suggested by criteria to account for 
patients with pre-existing liver injury (Parks, 2013).
6.6.
Efficacy Assessment
6.6.1.
Histological Scoring System for NAFLD
Liver biopsy has been widely considered as the “gold standard” for assessing fibrosis in NASH 
and has been validated in a large cohort of NASH patients (Kleiner, 2005). Liver biopsy will be 
performed during Screening period and Week 53 visit as described in Table 3, Table of Events. 
Subjects who discontinue after Week 20 and before Week 52 will undergo a liver biopsy 
procedure at ET Visit.  Investigational product should be stopped 7 to 10 days prior to biopsy 
and restarted 7 days after biopsy.  Refer to operational manual for the biopsy collection.
Screening liver biopsy will be performed in subjects who do not have pathological specimens 
from a prior liver biopsy obtained within 6 months of Screening and available for central 
reading.  
The historical biopsy within 6 months of Screening and liver biopsy collected during the study 
will be assessed in a blinded fashion by a central pathologist with extensive experience in 
assessing treatment response in NASH clinical trials.  
Biopsy specimens will be graded according to NASH CRN Histologic Scoring System. The 
scoring system comprised: steatosis (on a scale of 0 to 3), lobular inflammation (on a scale of 0 
to 2), hepatocellular ballooning (on a scale of 0 to 2), and fibrosis (on a scale of 0 to 4) (Kleiner, 
2005).
Liver fibrosis stage ranges from Stage 0 to Stage 4.  Stage 0 is defined as none; Stage 1 is 
defined as perisinusoidal / periportal fibrosis; focally or extensively present; Stage 2 is defined as 
perisinusoidal/pericellular fibrosis with focal or extensive periportal fibrosis; Stage 3 is 
perisinusoidal/pericellular fibrosis and portal fibrosis with focal or extensive bridging fibrosis; 
Stage 4 is defined as cirrhosis (Brunt, 1999).  Improvement in liver fibrosis, defined as a 
reduction of ≥1 stage, will be assessed according the NASH CRN Histologic Scoring System.
Non-alcoholic fatty liver disease activity score (NAS) includes the features of injury that are 
potentially reversible in the short term. The score is defined as steatosis (0 to 3), lobular 
inflammation (0 to 3) and hepatocellular ballooning (0 to 2) with a total score ranging from 0 to 
8 and the higher scores indicating increasing disease activity. 
 
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6.8.
Biomarkers
 
6.8.1.
Biomarkers
!
Metabolic parameters
-
Serum lipids (total cholesterol, LDL, HDL, and triglycerides)
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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
CC-90001, film-coated 100 mg and 200 mg tablets and placebo tablets matching the appearance 
of 100 mg and 200 mg tablets, will be supplied by the Sponsor and will be labeled appropriately 
as IP for this study.
All CC-90001 IP will be packaged in a double-blinded fashion and dispensed to subjects in the 
form of blister cards.  All placebo tablets will be identical in appearance to active study IP.  The 
dosing schedule is described in Section 7.2.
7.2.
Treatment Administration and Schedule
Subjects are instructed to take 3 tablets once daily, approximately the same time of day
(preferably in the morning), with or without food.  
!
52-Week Double-blind Placebo-controlled Treatment Phase: Baseline (Visit 2) to
Week 52 (Visit 14): 
Subject will receive 3 tablets once daily as follows:
-
CC-90001 100 mg (one 100 mg tablet), and placebo (two 200 mg placebo tablets)
(only for subjects who are randomized prior to implementation of Protocol 
Amendment 4) 
-
CC-90001 200 mg (one 200 mg tablet), and placebo (one 100 mg placebo tablet
and one 200 mg placebo tablet)
-
CC-90001 400 mg (two 200 mg tablets), and placebo (one 100 mg placebo)
-
Placebo (one 100 mg placebo tablet and two 200 mg placebo tablets)
!
50-Week Double-blind Active Treatment Phase (for subjects who participate in the 
active treatment phase):
During the 50-week double-blind active/extension treatment phase subjects who were 
initially randomized to active treatment arms will remain in their assigned dose groups. 
Subjects who were initially randomized to placebo arm will 200 mg QD or 400 mg QD.
The subjects who were previously re-randomized to the 100 mg dose group prior to 
implementation of Protocol Amendment 4 will remain in the 100 mg dose group.  
Blinded IP will be packaged in accordance with all required guidelines and in a manner that 
supports the study design and visit schedule defined within Section 5.
7.2.1.
Overdose
Overdose, as defined for this protocol, applies to protocol-required dosing of the IP (CC-90001) 
only.  Therefore, for a drug to be subject to the overdose definition it must be both required and 
an IP.  In this study, the only required IP is CC-90001 or placebo; hence, the overdose definition 
applies only to CC-90001 or matching placebo. Other medications (eg, concomitant medications, 
include those for treatment of AEs) are excluded from a designation of overdose.  
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Overdose for this protocol is defined as ingestion of > 3 tablets within the same calendar day, 
whether by accident or intentionally. Adverse Events associated with an overdose must be 
collected on the Adverse Events page of the eCRF for all overdosed subjects, but the overdose 
itself is not considered an AE.
Detailed information about any CC-90001 overdose in this study, regardless of whether the 
overdose was accidental or intentional, should be reported on the drug exposure eCRF page. 
7.2.2.
Dose Interruptions
This is a dose-finding study, therefore no dose reductions will be permitted. However, in the 
event a subject experiences a study drug-related adverse event, a temporary IP interruption for up 
to 4 days will be permitted at any time during the study. The Sponsor should be notified in 
advance of the dosage interruption; however, the decision to interrupt IP dosing will be based on 
the Investigator’s clinical judgment. If a subject misses 4 or more consecutive days of dosing, 
Celgene must be contacted to decide whether dosing should resume or whether the subject 
should be discontinued from the study IP and enter into the Post-treatment Observational 
Follow-up Phase.
  The subjects should interrupt IP 7 
to 10 days prior to an elective surgical procedure and restart 7 days after any surgical procedures, 
including liver biopsy.
If a dose of IP is missed, it should be taken as soon as possible on the same day, provided it 
occurs within 36 hours of the previous dose. The dose should be skipped if the timing of the 
dose occurs > 36 hours of the previous dose. Note: If the dose is missed for the entire day, the 
subject should not take an extra dose the next day or take an unscheduled dose.
7.3.
Method of Treatment Assignment
Approximately 180 adult male and female subjects with a confirmed diagnosis of NASH and 
Stage 2 or Stage 3 fibrosis will be randomized 1:1:1 to treatment with oral CC-90001 (200 mg 
QD, 60 subjects; 400 mg QD, 60 subjects) or matching placebo (60 subjects) for 52 weeks. 
Randomization will be stratified by liver fibrosis stage (Stage 2/Stage 3) and by the presence of 
Type 2 DM (yes/no). To ensure enrollment of a suitable number of subjects with Stage 3 fibrosis, 
up to 15 subjects with Stage 2 fibrosis may be enrolled per arm. Randomization, treatment 
assignment and stratification will be managed by an IWRS. Prior to the implementation of 
Protocol Amendment 4, subjects were also randomized into a 100 mg QD dose group. The 
subjects who were previously randomized to the 100 mg dose group will remain in the 100 mg 
dose group throughout the study. It is expected that approximately 10-15 subjects will have been 
randomized to the 100 mg group at time of implementation of Protocol Amendment 4. Thus, a 
total of approximately 195 subjects will participate in the study.
The DMC will be responsible for review of the interim analyses data and will make
recommendations to the Sponsor, who will be responsible for final decision-making. An 
unblinded interim analysis will be performed after approximately 50% of subjects with Stage 2 
or Stage 3 fibrosis complete 52 weeks of placebo-controlled treatment phase (as described in the 
DMC Charter).  A decision may be made to stop enrolling a treatment arm due to futility if not 
fully enrolled at interim analysis.
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Subjects who sign ICF prior to the implementation of Protocol Amendment 4, will have an 
option to participate in a double-blind active treatment phase.  At Week 54, all placebo subjects 
will be re-randomized 1:1 by IWRS to the 200 mg QD or 400 mg QD dose groups.  Prior to the 
implementation of Protocol Amendment 4, subjects were also re-randomized into a 100 mg QD 
dose group.  The subjects who were previously re-randomized to the 100 mg dose group will 
remain in the 100 mg dose group.  Subjects who were initially randomized to active treatment 
arms will remain in their assigned dose groups through the end of the double-blind active 
treatment phase.  
Subjects who sign ICF after the implementation of Protocol Amendment 4 will receive treatment 
in a double-blind placebo-controlled treatment phase only.
Designated study personnel at the investigational sites will be assigned password-protected, 
coded identification numbers, which give them authorization to access the IWRS to randomize 
subjects.  The system will present a menu of questions by which the study personnel will identify 
the subject and confirm eligibility.  When all questions have been answered, the IWRS will 
assign a randomization identification number. Confirmation of the randomization will be sent via 
fax to the investigational site, Celgene and/or its representative.
During the study visits, the pharmacy or authorized study personnel at the investigational site 
will dispense coded IP kits in accordance with the randomization number assigned by the IWRS.
7.4.
Packaging and Labeling
The label(s) for IP will include Sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
7.5.
Investigational Product Accountability and Disposal 
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for investigational product return, disposal, and/or destruction including responsibilities for the 
site versus Celgene (or designee).
7.6.
Investigational Product Compliance
The Investigator(s) or designee(s) is responsible for accounting for all study IP that is issued to 
and returned by the subject during the course of the study. Accurate recording of all study drug 
administration (including dispensing and dosing) will be made in the appropriate section of the 
subject’s case report form (CRF) and source documents. Study personnel will review the 
instructions printed on the package with the study subjects prior to dispensing the IP.  
Investigational product will be dispensed as noted in the Table of Events, Table 3.  The subjects 
will be instructed to return the IP containers, including any unused IP, to the study site at each 
visit for tablet counts and reconciliation.  Subjects will be asked whether they have taken their IP 
as instructed at each study visit.  Any problems with IP compliance will be reviewed with the 
subject.  If a subject misses 4 or more consecutive days of dosing, Celgene must be contacted to 
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decide whether dosing should resume. or whether the subject should be discontinued from the 
study, and enter into the Follow-up Period.
Gross compliance problems (eg, missing 4 or more consecutive days of dosing or taking less 
than 80% of the doses between study visits) should be discussed with Celgene.  Compliance will 
be categorized into 4 classes: < 50%, ≥ 50% to ≤ 80%, > 80% to ≤ 120%, > 120%.
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8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression. 
All medications (prescription and non-prescription), treatments, and therapies taken by the 
subject from screening throughout their entire participation in the study, including those initiated 
prior to the start of the study, must be recorded on the subject’s source document and on the 
appropriate page of the eCRF.  The dose, unit, frequency, route, indication, date the medication 
was started, and date the medication was stopped (if not ongoing) must be recorded. 
8.1.
Permitted Concomitant Medications and Procedures
!
The following drugs may be used during the trial, but doses must have been stable for 3 
months prior to Screening or historical biopsy used for Screening assessment and the 
subject agrees to maintain stable doses during the course of the study, unless required to 
adjust doses due to safety reasons: ursodeoxycholic acid, gemfibrozil, metformin, 
sodium-glucose co-transporter 2 (SGLT2) inhibitors (eg, canagliflozin), dipeptidyl 
peptidase-4 inhibitors (“gliptins”) (such as sitagliptin), glucagon peptide-1 agonists (eg, 
liraglutide), anti-obesity medications (eg, orlistat, lorcaserin, liraglutide, phentermine-
topiramate, or naltrexone-bupropion).  If SGLT2 inhibitors, GLP-1 agonists and anti-
obesity have been recently discontinued, the treatment must have been stopped for at 
least 3 months prior to Screening or historical biopsy.
!
Thiazolidinediones (eg, pioglitazone) and vitamin E are allowed during the study, but 
doses must have been stable for 3 months prior to Screening or 3 months prior to 
historical biopsy used for Screening assessment and the subject agrees to maintain stable 
doses during the course of the study. If thiazolidinediones (eg, pioglitazone) or vitamin E
have been recently discontinued, the treatment must have been stopped for at least 3 
months prior to Screening or historical biopsy.
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Exceptions may be made to initiation or changing doses of these medications if, in the opinion of 
the Investigator, a different dose of such medication(s) are needed to support best medical 
practice in the time frame of study participation AND the new dose will not interfere with 
subject safety or the interpretation of study results. In such instances, the Sponsor’s Medical 
Monitor and Investigator must concur.
8.2.
Prohibited Concomitant Medications and Procedures
The following medications cannot be administered for the specified times prior to the initiation 
of study IP and for the duration of the study.
!
Drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) for
the duration of the study
!
Vitamin E for treatment of NASH cannot be initiated after Screening.
!
Biologic agents (eg, TNF inhibitors), or cytokine inhibitors (eg, tofacitinib) within 3 
months of Screening.
!
Medications associated with hepatotoxicity risk, such as, but not limited to, 
acetaminophen > 3 grams/day and niacin > 2 grams/day while on study or within 2 weeks 
of first study dose. 
!
Use of an approved agent for treatment of NASH within 6 months prior to Screening or 
historical biopsy.
!
Use of cannabinoid products other than cannabis oils during the study
!
Use of live attenuated or investigational SARS-CoV-2 vaccine
Exceptions may be made to use of these medications if, in the opinion of the Investigator, the 
medication is needed to treat an unrelated medical condition (eg, a brief course of systemic 
corticosteroids for an asthma exacerbation) AND such medication will not interfere with subject 
safety or the interpretation of study results. In such instances, the Sponsor’s Medical Monitor and 
Investigator must concur.
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8.3.
Required Concomitant Medications and Procedures
Other than medications required for local anesthesia related to liver biopsy, there are no required 
concomitant medications.
Required procedures include liver biopsy.
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9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a Phase 2, multicenter, multinational, double-blind, randomized, placebo-controlled, 
dose-finding study evaluating the efficacy, safety, PK, 
 of treatment with
CC-90001, compared with placebo, in NASH subjects with either Stage 2, or Stage 3 fibrosis. 
The objective of the statistical analysis is to evaluate the efficacy and safety of CC-90001 versus 
placebo for 52 weeks in subjects with NASH and Stage 2, or Stage 3 fibrosis. 
The primary analysis will be performed after all subjects have completed the Placebo-controlled 
Phase (Weeks 0 to 52). The final analysis will be performed at the study completion, ie, when all 
subjects have completed the Observational Follow-up Phase. To maintain the blind at the site 
and subject level, the individual subject treatment assignments will not be revealed to the 
investigators until after the final database lock following the study completion. 
This section outlines the statistical analysis strategy and details will be documented in a separate 
Statistical Analysis Plan (SAP).
9.2.
Study Population Definitions
The Full Analysis Set (FAS) population will consist of all subjects who are randomized and 
received at least one dose of IP. Subjects will be included in the treatment group to which they 
are randomized.
The safety population will consist of all subjects who are randomized and received at least one 
dose of IP.  Subjects will be included in the treatment group corresponding to the IP they actually
receive.
The per protocol (PP) population will consist of all subjects included in the FAS population who 
receive at least one dose of IP, have both baseline and post-treatment liver fibrosis score 
evaluation, and have no important protocol deviations which may affect analyses in the Placebo-
controlled Phase. Subjects will be included in the treatment group to which they are randomized.
9.3.
Sample Size and Power Considerations
The estimated improvement on ≥1 fibrosis score in Stage 3 subjects of 45% for CC-90001 group 
and 20% for the placebo group is based on a Phase 2 study of selonsertib, which reported a 23% 
treatment difference (43% in the selonsertib 18 mg group versus 20% in the simtuzumab group-a 
compound that was not demonstrated to be effective for NASH with a treatment response similar 
to placebo from other clinical trials) (Loomba, 2018; Neuschwander-Tetri, 2015).  
With the above assumed treatment responses for the primary endpoint between the highest 
CC-90001 dose group and the placebo, and further assuming a similar treatment effect in Stage 2 
subjects, the sample size of 60 for the placebo, 200 mg, and 400 mg treatment group and an 
expected sample size of 10-15 for the 100 mg treatment group provides the ability to determine a 
dose response with 80% power, and 5% type I error rate.
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This sample size was estimated using the multiple comparison and dose-response modeling 
(MCP-Mod) procedure and considering five dose-response models (linear, log-linear, two Emax 
shapes and logistic) (Bretz, 2005; R-package “MCPMod”, version 1.0-10.1 August 5, 2017).
Determination of the minimum effective dose (MED) will follow the MCP-Mod method (Bretz, 
2005). Based on this method, a dose will be considered as MED if it satisfies the following two 
criteria: (i) the response rate of the dose is greater than that of placebo by a clinically relevant 
treatment difference (Δ), and (ii) the lower confidence bound of the response rate of that dose has 
to be greater than that of placebo. Simulations were run to assess the sensitivity to determine the 
MED with examples of Δ and 80% confidence intervals of the response rates.
Table 5:
Probability of Each Dose to Be Considered the MED for Various Response 
Scenarios and Delta
Scenarios
Response Rate
MED Probabilityc
100 mg
200 mg
400 mg
Dose (mg)
Δ=0.10
Δ=0.15
1b
0.325
(50% of 
emaxc)
0.45
0.45
100
52.80%
44.18%
200
37.06%
39.84%
400
0.44%
6.30%
MED not identified
9.70%
9.68%
2
0.2625
(25% of 
emax)
0.3875
(75% of 
emax)
0.45
100
30.38%
20.06%
200
55.86%
49.30%
400
1.54%
18.62%
MED not identified
12.22%
12.02%
3
0.25
(20% of 
emax)
0.325
(50% of 
emax)
0.45
100
17.48%
8.04%
200
62.06%
39.30%
400
4.26%
36.96%
MED not identified
16.20%
15.70%
Abbreviations: PBO = placebo; MED = minimum effective dose.
Response Rate for PBO=0.2
b Response rate at the 100 mg dose closer to response rate at the next dose than the other scenarios.
c emax is the assumed maximum effect of 45%-20%.
c With assumed sample size being 15 subjects for the 100 mg dose group and 60 subjects otherwise.
Δ clinically relevant treatment difference.
Based upon these assessments, the planned sample size provides high sensitivity to determine a 
MED when a range of response rates and clinically significant effects are assumed. Details of the 
simulations and estimations will be further elaborated in the Statistical Analysis Plan.  In 
addition to considering MED purely based on efficacy in response rates, the overall 
determination of the MED will also account for additional efficacy and safety endpoints.
Therefore, approximately 180 subjects will be randomized in a 1:1:1 ratio to receive CC-90001 
(200 mg QD, 400 mg QD) or placebo.  Randomization will be stratified by liver fibrosis stage
(Stage 2/Stage 3) and by the presence of Type 2 DM (yes/no). Approximately 60 subjects with 
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Stage 2 or Stage 3 fibrosis will be enrolled per arm. To ensure enrollment of a suitable number of 
subjects with Stage 3 fibrosis, up to 15 subjects with Stage 2 fibrosis may be enrolled per arm. 
Randomization to one stratum will be halted once the enrollment target is achieved for that 
stratum.
Subjects who have been randomized to the 100 mg QD treatment arm prior to implementation of 
Protocol Amendment 4 will be included in the study populations as appropriate. It is expected 
that randomization into the 100 mg dose group will be stopped at approximately 10-15
randomized subjects at time of implementation of Protocol Amendment 4. Thus, a total of 
approximately 195 subjects will participate in the study.
9.4.
Background and Demographic Characteristics
Subject’s age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while sex, race and other categorical variables will be provided using frequency 
tabulations.  Medical history data will be summarized using frequency tabulations by Medical 
Dictionary for Drug Regulatory Activities (MedDRA) system organ class and preferred term.
9.5.
Subject Disposition
A summary of analysis population allocation will be provided. Subject disposition (entered, 
discontinued, along with primary reason for discontinuation) will be summarized using 
frequency and percent for the Placebo-controlled Phase (Weeks 0 to 52) and the Active 
Treatment Extension Phase (Weeks 52 to 102).  A summary of subjects enrolled by site will be 
provided. Protocol deviations will be summarized using frequency tabulations.
9.6.
Efficacy Analysis
9.6.1.
Efficacy Evaluation for the Placebo-controlled Phase (Weeks 0 to 52)
For the Placebo-controlled Phase (Weeks 0 to 52), the analyses for efficacy endpoints will be 
based on the FAS. Statistical comparisons will be made between each of CC-90001 treatment 
groups versus placebo. All statistical tests will be at the two-sided 0.05 significance level and the 
corresponding p-values and 95% confidence intervals (CIs) will be reported. No adjustment for 
multiple comparisons will be made in this phase 2 study. The nominal p-values will be reported 
to give an indication of the strength of association regarding the treatment differences.
9.6.1.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects who achieve a ≥1 stage improvement 
in liver fibrosis using the NASH CRN Histological Scoring System at Week 52. It will be 
analyzed using the FAS. 
The estimand of primary interest is defined in terms of the following four attributes:
A. The population is defined through appropriate inclusion/exclusion criteria to reflect the 
targeted patient population (FAS);
B. The variable is the proportion of subjects who achieve a ≥1 stage improvement in liver 
fibrosis at Week 52. Missing values due to early termination will be imputed using data 
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collected at the early termination visit if available; otherwise missing values will be 
imputed using the non-responder imputation (NRI) method;
C. Potential intercurrent events are captured through the variable definition (B).
D. The summary measure is the difference in response proportions.
With this missing data handling approach, the estimand answers a clinically relevant question 
that compares the proportion of subjects who achieve the defined response criteria at Week 52 in 
the FAS.
The primary efficacy endpoint will be analyzed using the Cochran–Mantel–Haenszel (CMH) test 
adjusting for the stratification factors (fibrosis stage (Stage 2 /Stage 3) and by the presence of 
Type 2 DM (yes/no), at randomization) in order to compare each of CC-90001 treatment groups 
versus placebo. The two-sided p-values from the CMH test, the adjusted treatment difference in 
proportion using the weighted average of the treatment differences across the strata with the 
CMH weights, along with the associated two-sided 95% CIs using a normal approximation to the 
weighted average will be provided. A sensitivity analysis will be performed using the PP 
population. 
9.6.1.2.
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be analyzed based on the FAS. The 2-sided p-values and 
2-sided 95% CIs will be reported for treatment difference between each of the CC-90001 
treatment groups versus placebo. 
The binary endpoints will be summarized using counts and percentages, and the treatment 
comparison will be performed similarly as the primary endpoint using the CMH test. 
The continuous efficacy endpoints will be summarized using mean, standard deviation (SD), 
median, minimum, maximum, and number of observations analyzed. For all continuous efficacy 
endpoints, the treatment comparisons will be performed using a mixed model of repeated 
measures (MMRM) as the primary analysis method of the secondary efficacy endpoints. The 
MMRM will use the change from baseline as the dependent variable and will include dose, time 
on treatment, and their interaction as fixed effects covariates. The model will also include the 
stratification factors (fibrosis stage (Stage 2/ Stage 3) and presence of Type 2 DM (yes/no), at 
randomization) and corresponding baseline value as fixed effects covariates. Time will be treated 
as a categorical variable in the MMRM and will be considered as a repeated effect. All post-
baseline measurements up to Week 52 will be included in this analysis with no imputation of 
missing data other than that inherent in the MMRM. Within-group least-squares (LS) means and 
the associated standard errors (SEs) and 2-sided 95% CIs, treatment differences in LS means and 
the associated 2-sided 95% CIs and 2-sided p-values will be derived from the MMRM.
As a sensitivity analysis method for all secondary continuous efficacy endpoints an analysis of 
covariance (ANCOVA) model will be used. The ANCOVA model will use the change from 
baseline as the dependent variable, treatment group as a fixed factor, and the baseline value and 
stratification factors (fibrosis stage (Stage 2 /Stage 3) and presence of Type 2 DM (yes/no), at 
randomization) as covariates. Within-group least-squares (LS) means and the associated standard 
errors (SEs) and 2-sided 95% CIs, treatment differences in LS means and the associated 2-sided 
95% CIs and 2-sided p-values will be derived from the ANCOVA model. 
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9.6.1.4.
Dose-Response modelling
The method for dose-response modeling called MCP-Mod (Section 9.3 and Bretz, 2005) will be 
applied to the primary endpoint and select additional endpoints. It will allow for an evaluation of 
which dose-response curves are the best fit given the 52 weeks data and a potentially more 
accurate estimation of the MED. In this study, MCP-Mod delivers at least 80% power to 
ascertain a dose response with type I error rate of 5% (c.f. section 9.3). Under the scenarios 
evaluated, it has high probability to determine the MED. The details will be further elaborated in 
the Statistical Analysis Plan.
9.6.1.5.
Subgroup Analysis 
Subgroup analyses for the primary efficacy endpoint based upon baseline demographic (age, 
gender, race, etc.) or baseline disease characteristics will be provided to determine the robustness 
of the treatment effect.
9.7.
Safety Analysis
The safety analyses will be performed using the safety population, defined as all subjects who 
are randomized and receive at least one dose of investigational product. 
Safety will be assessed by clinical review of all relevant parameters including treatment 
emergent adverse events (TEAEs), laboratory tests, vital signs, and ECG; no inferential testing 
for statistical significance will be performed. Data from safety assessments will be summarized 
descriptively for the Placebo-controlled Phase (Weeks 0 to 52) by the treatment group of CC-
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90001 100 mg, 200 mg QD, 400 mg QD, and placebo; and for the CC-90001 Exposure Phase for 
subjects who receive at least one dose of CC-90001 treatment. For all safety analyses baseline 
will be relative to the first dose date following randomization at Week 0.
Adverse events will be classified using the MedDRA classification system.  All TEAEs will be 
summarized by system organ class, preferred term, severity and relationship to investigational 
product.  The TEAEs leading to death or to discontinuation from treatment and serious adverse 
events will be summarized and listed separately.
Data from other safety assessments will be summarized descriptively.  Shift tables for laboratory 
parameters showing the number of subjects with values low, normal, and high comparing with 
the normal reference ranges pre-treatment versus post treatment will be provided.
9.8.
Interim Analysis
An unblinded futility analysis will be performed after approximately 50% of subjects complete 
52 weeks of treatment.  The DMC will review the totality of the available data to determine the 
following options: 
!
Continue the study as planned
!
Terminate the study for futility
!
Stop enrolling a treatment arm due to futility if not fully enrolled at interim analysis
The details of the interim analysis will be documented in the DMC Charter.
Additional interim analyses may be conducted.
9.9.
Other Topics
9.9.2.
Internal Safety Management Team 
In addition to ongoing safety monitoring conducted by Investigators and individual study 
personnel, cumulative and interval blinded AEs, SAEs, discontinuations due to AEs, and 
abnormal laboratory findings will be reviewed internally by the Celgene Safety Management 
Team (SMT). The review will follow the Council for International Organizations for Medical 
Sciences, Working Group VI (CIOMS VI) recommendations. The SMT is comprised of lead 
representatives from multiple Celgene functions engaged in the CC-90001 development 
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program. The scope, conduct, processes, and accountabilities are specified by Celgene Standard 
Operating Procedure (SOP). 
9.9.3.
External Data Monitoring Committee
Safety monitoring will also be performed by an external, independent DMC. A DMC will be 
convened that will include physician experts with experience in treating subjects with NASH and 
a statistician, all of whom are not otherwise involved in the study conduct and for whom there is 
no identified conflict of interest. During the course of the study, the DMC will review the
unblinded safety data regularly as well as safety and efficacy data in accordance with the 
guidelines for the preplanned interim analyses.  An independent third party will prepare the 
reports of aggregate data summaries and individual subject data listings, as appropriate, to the 
DMC members for each scheduled meeting. Operational details for the DMC will be detailed in 
the DMC Charter.
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10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF. (See Section 7.2 for the definition of overdose.) Any sequela of 
an accidental or intentional overdose of an investigational product should be reported as an AE 
on the AE CRF. If the sequela of an overdose is an SAE, then the sequela must be reported on 
the AE CRF. The overdose resulting in the SAE should be identified as the cause of the event on 
the AE CRF but should not be reported as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary.  There is no known specific antidote for CC-90001 overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs, including AEs related to SARS-CoV-2 infection, during 
the study.  Assessments may include monitoring of any or all of the following parameters:  the 
subject’s clinical symptoms, laboratory, pathological, radiological or surgical findings, physical 
examination findings, or findings from other tests and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 28 days after the last dose of IP as well as those SAEs made known to the Investigator at 
any time thereafter that are suspected of being related to IP.  Adverse events and SAEs will be 
recorded on the AE page of the CRF and in the subject’s source documents.  All SAEs that occur 
after first dose of IP must be reported to Celgene Drug Safety within 24 hours of the 
Investigator’s knowledge of the event via Electronic Data Capture (EDC) system.  
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
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!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:
!
a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
!
routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.
!
hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
!
a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
!
an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 
!
emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, the AE screen of the eCRF must be completed and ticked 
‘serious’.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
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10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 5.0); 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
AEs that are not defined in the CTCAE should be evaluated for severity/intensity according to 
the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
!
Grade 5 = Death – the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
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Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or dose reduction of IP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from the study;
!
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or
!
is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.
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In the event of a pregnancy occurring in a female subject of childbearing potential or female 
partner of a male subject, Celgene will follow up with the clinical investigator each trimester of 
pregnancy and for 1 year following the birth of the infant (if applicable).  Please reference the 
pregnancy information consent (permission) forms for data collection for additional information.  
10.4.1.
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, or within at least 28 days of the subject’s last dose of IP, are considered immediately 
reportable events.  Investigational product is to be discontinued immediately and the subject 
instructed to return any unused portion of the IP to the Investigator. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety immediately by 
email, phone or facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form.  
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.
The Investigator will follow the female subject until completion of the pregnancy and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP 
should notify the Investigator, and the pregnant female partner should be advised to call their 
healthcare provider immediately.  
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of the AE page/screen of 
the eCRF, and ticked as ‘serious’ in EDC.  All SAEs that occur after first dose of IP must be 
reported to Celgene Drug Safety via EDC within 24 hours of the Investigator’s knowledge of the 
event.  This instruction pertains to initial SAE reports as well as any follow-up reports.
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) or any 
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SAE made known to the Investigator at any time thereafter that are suspected of being related to 
IP.  Serious adverse events occurring prior to treatment (after signing the ICF) will be captured
in EDC, but do not require reporting to Celgene Drug Safety.
The SAE report entered into EDC should provide a detailed description of the SAE and include a 
concise summary of hospital records and other relevant documents. If a subject died and an 
autopsy has been performed, copies of the autopsy report and the death certificate are to be 
provided to Celgene Drug Safety via EDC as soon as these become available. Any follow-up 
data should be added to the existing SAE case in EDC.  
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated through EDC.  
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to CC-90001 based on the Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 
presentation of adverse reaction reports arising from clinical trials on investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.
Celgene or its authorized representative shall notify the Investigator of the following 
information:
!
Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 14.3 for record retention 
information).
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Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Pregnancy Report Form 
Completion Guidelines.
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11.
DISCONTINUATIONS
11.1.
Individual Subject Stopping Criteria and Criteria for Review of 
Clinical Data by the DMC
11.1.1.
Individual Subject Stopping Criteria
The subject will be discontinued from the study:
-
If the subject has a positive FOBT at a study visit and a decrease of hemoglobin from 
baseline by at least 10% at that study visit or subsequent visits before next FOBT is 
performed
-
If the subject develops a Grade 3 or higher drug-related AE by CTCAE Version 5.0 
grading system
-
If the subject develops a Grade 4 or higher AE by CTCAE Version 5.0 grading 
system
-
If the subject develops decompensated liver disease such as clinically significant 
ascites, hepatic encephalopathy, or variceal bleeding
-
If the subject meets discontinuation criteria outlined in Appendix C
11.1.2.
Criteria for Review of Clinical Data by the DMC
The study enrollment will be paused, and the clinical data will be reviewed by the DMC for 
safety before proceeding with the trial: 
-
If a subject experiences a Grade 5 AE by CTCAE Version 5.0 grading system, the 
safety report(s) will be submitted to the FDA for review and discussion prior to 
dosing any subject 
-
If 2 subjects develop drug-related Grade 4 AEs by CTCAE Version 5.0 grading 
system
-
If 3 subjects develop the same drug-related Grade 3 AEs by CTCAE Version 5.0 
grading system
Treatment arms stopping criteria are described in Section 6.5.4.  
11.2.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):
!
Adverse Event
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Other (to be specified on the CRF)
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The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.3.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Screen failure
!
Adverse event
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Other (to be specified on the CRF)
The reason for study discontinuation should be recorded in the CRF and in the source 
documents.
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12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/contract 
research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
The blind must not be broken during the course of the study unless in the opinion of the 
Investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued if, in the opinion of 
the Investigator, continuing IP can negatively affect the outcome of the subject’s treatment.
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, the Investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject. 
The Investigator should ensure that the code is broken only in accordance with the protocol. The 
Investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the Investigator in the 
subject’s source documentation.
Emergency unblinding should only be performed by the Investigator through the IWRS by using 
an emergency unblinding personal identification number (PIN), and the Investigator should call 
IWRS for unblinded dose information.
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13.
REGULATORY CONSIDERATIONS
13.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International Council for 
Harmonisation (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The Investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s
study files and a copy given to the study subject.
13.4.
Confidentiality
Celgene affirms the subject’s right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene’s representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/EC approval but will be submitted to the IRB/EC for 
information purposes.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
Investigational product can only be supplied to an Investigator by Celgene or its authorized 
representative after documentation on all ethical and legal requirements for starting the study has 
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been received by Celgene or its authorized representative. This documentation must also include 
a list of the members of the IRB/EC and their occupation and qualifications. If the IRB/EC will 
not disclose the names, occupations and qualifications of the committee members, it should be 
asked to issue a statement confirming that the composition of the committee is in accordance 
with GCP. For example, the IRB General Assurance Number may be accepted as a substitute for 
this list. Formal approval by the IRB/EC should mention the protocol title, number, amendment 
number (if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc.).
In addition, the Investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment;
!
GCP noncompliance;
!
Inaccurate or incomplete data collection;
!
Falsification of records;
!
Failure to adhere to the study protocol.
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14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
14.2.
Data Management
Data will be collected and entered into the clinical database via electronic CRF per Celgene 
SOPs. This data will be electronically verified through use of programmed edit checks specified 
by the clinical team.  Discrepancies in the data will be brought to the attention of the clinical 
team, and investigational site personnel, if necessary.  Resolutions to these issues will be 
reflected in the database.  An audit trail within the system will track all changes made to the data.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:
!
Signed ICFs for all subjects;
!
Subject identification code list, screening log (if applicable), and enrollment log;
!
Record of all communications between the Investigator and the IRB/EC;
!
Composition of the IRB/EC;
!
Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);
!
List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;
!
Copies of CRFs (if paper) and of documentation of corrections for all subjects;
!
IP accountability records;
!
Record of any body fluids or tissue samples retained;
!
All other source documents (subject records, hospital records, laboratory records, 
etc.); 
!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
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The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
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15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, FDA, European Medicines 
Agency [EMA], Health Canada) and company authorized representatives.  The Investigator 
should make every effort to be available for the audits and/or inspections.  If the Investigator is 
contacted by any regulatory authority regarding an inspection, he/she should contact Celgene 
immediately.
15.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene Corporation 
after it is released for distribution.  Product Quality Complaints may reduce the usability of the 
product for its intended function or affect performance of the product and therefore pose a 
significant risk to the subject.  Examples of PQCs include (but are not limited to): mixed product, 
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mislabeling, lack of effect, seal/packaging breach, product missing/short/overage, contamination, 
suspected falsified, tampered, diverted or stolen material, and general product/packaging 
damage. If you become aware of a suspected PQC, you are obligated to report the issue 
immediately.  You can do so by emailing 
 or by contacting the 
Celgene Customer Care Center 
.
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16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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17.
REFERENCES
Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in 
dose response studies. Biometrics. 2005;61:738-48.
Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic 
steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 
1999;94(9):2467-74.
 
 
Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and 
management of nonalcoholic fatty liver disease: practice guidance from the American 
Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-57.
 
Diehl AM, Day C. Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J 
Med. 2017;377(21):2063-72.
 
European Association for the Study of the Liver [EASL], European Association for the Study of 
Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL–EASD–EASO 
Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol.
2016; 64(6):1388-402.
Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic 
fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 
2018;67(1):123-33.
 
Food and Drug Administration.  Drug-induced liver injury: premarketing clinical evaluation.  
https://www.fda.gov/downloads/Guidances/UCM174090.pdf.  July 2009.
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Hagström, H, Nasr P, Ekstedt M, Hammar U, Stål, P, Hultcrantz R, et al. Fibrosis stage but not 
NASH predicts mortality and time to development of severe liver disease in biopsy-proven 
NAFLD. J Hepatol. 2017;67(6):1265-73.
 
 
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(6):1313-21.
 
 
 
Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, et al. The ASK1 
inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. 
Hepatology. 2018. 
Mast EE, Margolis HS, Fiore AE, Brink EW, Goldstein ST, Wang SA, et al. A comprehensive 
immunization strategy to eliminate transmission of hepatitis B virus infection in the United 
States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: 
immunization of infants, children, and adolescents. MMWR Recomm Rep 2005;54(RR-
16):1-31.
 
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et 
al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic 
steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 
2015;385:956-65.
Parikh ND, Marrero WJ, Wang J, Steuer J, Tapper EB, Konerman M, et al. Projected increase in 
obesity and non-alcoholic steatohepatitis-related liver transplantation waitlist additions in the 
United States. Hepatology. 2017.
Parks D, Lin X, Painter JL, Cheng J, Hunt CM, Spraggs CF, et al. A proposed modification to 
Hy’s law and Edish criteria in oncology clinical trials using aggregated historical data. 
Pharmacoepidemiol Drug Saf. 2013 Jun;22(6):571-8.
Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, 
vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675-85.
Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. Challenges and opportunities in 
drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations 
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from an American Association for the Study of Liver Diseases-U.S. Food and Drug 
Administration joint workshop. Hepatology. 2015;61(4):1392-405.
Sanyal AJ, Harrison SA, Ratziu V, Abdelmalek MF, Diehl AM, Caldwell S, et al. The natural 
history of advanced fibrosis due to nonalcoholic steatohepatitis: Data from the simtuzumab trials. 
Hepatology 2019; 70(6):1913-27.
 
 
 
 
Win S, Than TA, Zhang J, Oo C, Min RWM, Kaplowitz N. New insights into the role and 
mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases. 
Hepatology. 2018 May;67(5):2013-24.
Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of 
NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol 
Hepatol. 2018;15(1):11-20.
 
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18.
APPENDICES
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APPENDIX A. TABLE OF ABBREVIATIONS
Abbreviation or 
Specialist Term
Explanation
ADL
Activities of daily life
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (SGPT)
ANCOVA
Analysis of covariance
ASK1
Apoptosis signal-regulating kinase 1 
AST
Aspartate aminotransferase (SGOT)
ATP
Adenosine triphosphate
AUC
Area under the curve
 
 
AUDIT
Alcohol Use Disorders Identification Test
 
β-hCG
Beta-subunit of human chorionic gonadotropin
BID
Twice daily
BUN
Blood urea nitrogen
CBC
Complete blood count
CI
Confidence interval
CIOMS
Council for International Organizations for Medical Sciences, Working Group
Cmax
Maximum plasma concentration of drug
CMH
Cochran–Mantel–Haenszel
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APPENDIX A:
TABLE OF ABBREVIATIONS (CONTINUED)
Abbreviation or 
Specialist Term
Explanation
CP
Child-Pugh
CRN
Clinical Research Network
CRF
Case report form
CS
Clinically significant
CTCAE
Common Terminology Criteria for Adverse Events
CVID
Common variable immunodeficiency
DM
Diabetes mellitus
DMC
Data monitoring committee
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EtG
Ethyl glucuronide
EOT
End of treatment
ET
Early Termination
FAS
Full Analysis Set
FCBP
Females of childbearing potential
FDA
Food and Drug Administration
FIB-4
Fibrosis-4
FOBT
Fecal occult blood test
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GD
Gestation Day
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
GLP
Good Laboratory Practice
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APPENDIX A:
TABLE OF ABBREVIATIONS (CONTINUED)
Abbreviation or 
Specialist Term
Explanation
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular cancer
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IL
Interleukin
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
ITT
Intent-to-treat
IWRS
Interactive web response system
IV
Intravenous
JNK
c-Jun N-terminal kinase
LDH
Lactic dehydrogenase
LDL
Low-density lipoprotein
LS
Least-squares
MCP-Mod
Multiple comparison and dose-response modeling
MED
Minimum effective dose
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model of repeated measures
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APPENDIX A:
TABLE OF ABBREVIATIONS (CONTINUED)
Abbreviation or 
Specialist Term
Explanation
NASH
Non-alcoholic Steatohepatitis
NAFLD
Non-alcoholic fatty liver disease
NAS
NAFLD Activity Score
NCS
Not clinically significant
NOAEL
No observed adverse effect level
NRI
Non-responder imputation
PE 
Physical examinations 
PK
Pharmacokinetics
PO 
Per os, orally
PP
Per protocol
PQC
Product Quality Complaint 
PT
Prothrombin time
QD
Quaque die, once daily
 
QTcF 
QTc calculation using Fridericia’s formula
RBC
Red blood cell count
RNA
Ribonucleic acid
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APPENDIX A:
TABLE OF ABBREVIATIONS (CONTINUED)
Abbreviation or 
Specialist Term
Explanation
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
Standard deviation
SE
Standard error
SGLT
Sodium-glucose co-transporter
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SMT
Safety Management Team
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal Half-life
TB
Tuberculosis
TBL
Total bilirubin 
TEAE
Treatment emergent adverse event
TGF- β
Transforming growth factor beta
Tmax
Time to maximum plasma concentration
TNF
Tumor necrosis factor
ULN
Upper limit of normal
 
VCTE
Vibration controlled transient elastography
Vz/F
Volume of distribution
WBC
White blood cell count
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APPENDIX C. HEPATOTOXICITY MONITORING CRITERIA FOR 
INTERRUPTION AND DISCONTINUATION OF 
INVESTIGATIONAL PRODUCT BASED ON LIVER 
FUNCTION TEST ABNORMALITIES
Laboratory Test 
Action
Normal ALT and 
AST at baseline:
(ALT or AST > 3 x ULN but ≤8 x ULN) 
and
(TBL< 2 x ULN and INR < 1.5)
Repeat ALT and AST within 48-
72 hours.
If elevations persist, evaluate other 
causea of LTFs elevation. If the 
etiology is unknown, close 
monitoring required on a weekly 
basis until ALT or AST ≤ 3 x ULN 
or meet the criteria for 
discontinuation. Subjects (whether
discontinued or not) are to be 
followed until the laboratory value 
returned to baseline.
• ALT or AST > 3 x ULN and (TBL> 2 x 
ULN or INR > 1.5)
• ALT or AST > 3 x ULN with fatigue, 
nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, and/or eosinophilia 
(> 5%)
• ALT or AST > 5 x ULN for more than 2 
weeks 
• ALT or AST > 8 x ULN
Discontinue IP and follow-up 
signs or symptoms until resolution.
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APPENDIX C: HEPATOTOXICITY MONITORING CRITERIA FOR 
INTERRUPTION AND DISCONTINUATION OF 
INVESTIGATIONAL PRODUCT BASED ON LIVER 
FUNCTION TEST ABNORMALITIES (CONTINUED)
Laboratory Test 
Action
Elevated ALT 
and/or AST at 
baseline:
ALT or AST > 2 x BLM or TBL > 1.5 x 
BLM
Repeat ALT and AST within 48-72 
hours.
If elevations persist, evaluate other causea
of AST, ALT and TBL elevation. If the 
etiology is unknown, close monitoring 
required on a weekly basis until ALT or 
AST ≤ 2 x BLM and TBL ≤ 1.5 x BLM 
or meet the criteria for discontinuation.
Subjects (whether discontinued or not) 
are to be followed until the laboratory 
value returned to baseline.
ALT or AST > 2 x BLM and (TBL > 2 x 
BLM or INR increased by > 0.2 from 
Baseline)
Discontinue IP and follow-up signs or 
symptoms until resolution.
with appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or 
tenderness, fever, and rash, with or 
without eosinophilia (> 5%) during study
Temporarily interrupt or discontinue IP 
and follow-up signs or symptoms until 
resolution.
Elevated ALT 
and/or AST at 
baseline and 
BLMb < 2 x ULN
ALT or AST > 5 x BLM
Discontinue IP and follow-up signs or 
symptoms until resolution.
Elevated ALT 
and/or AST at 
baseline and BLM 
≥ 2 x ULN but < 5 
x ULN: 
ALT or AST > 3 x BLM
Discontinue IP and follow-up signs or 
symptoms until resolution.
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BLM = 
baseline measurement(s); IP = investigational product; INR = international normalized ratio; TBL = total bilirubin; ULN = upper 
limit of normal.
a Tests for causes of increases AST or ALT include infectious (Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis E), 
acetaminophen level, toxicology screen, autoimmune (antinuclear antibodies, anti-smooth muscle antibodies, anti-liver/kidney 
microsomal antibodies type 1, immunoglobulin G [IgG]).  Additional tests and evaluations may be requested by the medical 
monitor.  Tests of function include serum albumin and prothrombin time (PT)/INR.
b In subjects with screening TBL or AST or ALT, greater than 3 X ULN, baseline values should be established by at least two 
measurements obtained at least 4 weeks apart.
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CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
APPENDIX D. HEPATITIS EXCLUSION CRITERIA
Subjects who meet any of the Hepatitis B criteria described in the table below are ineligible for 
the study.
Result
Interpretation
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
Positive
Positive
Positive
Negative
Acutely infected
HBsAg
anti-HBc
IgM anti-HBc
anti-HBs
Positive
Positive
Negative
Negative
Chronically infected
HBsAg
anti-HBc
anti-HBs
Negative
Positive
Positive
Immune due to natural infection*
HBsAg
anti-HBc
anti-HBs
Negative
Positive
Negative
Interpretation unclear; four possibilities*:
!
Resolved infection (most common)
!
False-positive anti-HBc, thus susceptible
!
“Low level” chronic infection
!
Resolving acute infection
Abbreviations: HBsAg= hepatitis B surface antigen; anti- HBc= antibody to the hepatitis B core antigen; anti- HBs= 
antibody to hepatitis B surface antigen; IgM anti-HBC= IgM antibody to hepatitis B core antigen.
* Perform hepatitis B virus (HBV) deoxyribonucleic acid (DNA):
!
If HBV DNA is detected, then participant must be excluded.
!
If HBV DNA is not detected, then the participant may be considered eligible for enrollment based on
the investigator’s judgment and after discussion with the study Medical Monitor.
Source:  Mast, 2005.
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EDMS Doc. Number: 
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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'DWH)ULGD\$SULO30(DVWHUQ'D\OLJKW7LPH
0HDQLQJ$SSURYHGQRFKDQJHVQHFHVVDU\
                                                
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EDMS Doc. Number: 
CC-90001
Summary of Changes CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
3
Protocol CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
1.
JUSTIFICATION FOR AMENDMENT
Changes included in this amendment are summarized below:
!
100 mg dose treatment arm was removed 
-
 
  The subjects who are randomized to the 100 mg dose group prior to 
implementation of Protocol Amendment 4 will stay on 100 mg QD dose 
throughout the study. 
-
Sections affected
Protocol Summary, Rationale (Section 1.3), Study objectives and Endpoints 
(Section 2), Overall Study Design (Section 3), Study Population (Section 4), 
Method of Treatment Assignment (Section 7.3), and Statistical Considerations 
(Section 9)  
!
Stage 4 population was removed 
-
The protocol was revised to focus on assessing the efficacy and safety of CC-
90001 in subjects with NASH and Stage 2 or Stage 3 liver fibrosis in this study. 
-
Sections affected
Protocol Summary, Rationale (Section 1.3), Study objectives and Endpoints 
(Section 2), Overall Study Design (Section 3), Study Population (Section 4), 
Table of Events (Section 5), Procedures (Section 6), Method of Treatment 
Assignment (Section 7.3), Statistical Considerations (Section 9), and Appendix C
!
Active Treatment/Extension Phase was removed
-
Active treatment/extension phase was removed to reduce burden for the subjects 
due to the Coronavirus Disease 2019 (COVID-19) pandemic and to shorten the 
duration of the study. Subjects who sign informed consent form (ICF) prior to the 
implementation of Protocol Amendment 4 will have an option to participate 
active treatment/extension phase.
-
Sections affected
Protocol Summary, Rationale (Section 1.3), Study objectives and Endpoints 
(Section 2), Overall Study Design (Section 3), Table of Events (Section 5), 
Procedures (Section 6), Method of Treatment Assignment (Section 7.3), and 
Statistical Considerations (Section 9)
!
Exclusion criterion #21 “Subjects has 2 positive fecal occult blood test (FOBT)
during Screening, collected at least 4 weeks apart” was removed 
-
 
 Positive FOBT may 
be caused by different cuases (such as rectal hemmorhage, ulcers, colitis, 
divertriculosis). The protocol has excluded the subjects with a history of 
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EDMS Doc. Number: 
CC-90001
Summary of Changes CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
4
Protocol CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
inflammatory bowel disease and the subjects with a history of bleeding peptic 
ulcer or bleeding diverticular disease within 5 years. Furthermore, the protocol 
also implemented FOBT at Screening and approximately every 12 weeks during 
the study and discontinuation criteria for the subject with positive FOBT in the 
study. With all these in place the occurrence of GI bleeding in the study continues 
to be well monitored to ensure safety of subjects over the course of the trial. 
-
Sections affected
Study Population (Section 4), Table of Events (Section 5), and Procedures –
Screening Phase (Section 6.1)
!
Condition of worsening liver function was changed
-
The values of alanine aminotransferase (ALT)/ aspartate aminotransferase (AST)
fluctuate over the short period of time as well as over the course of NASH 
disease. More than 20% increase of ALT or AST value in the subjects with ALT 
or AST less than 3 X upper limit of normal (ULN) may not be an evidence of 
worsening of liver function. In addition, throughout the study hepatotoxicity is 
monitored and subjects are to be discontinued if liver biochemistry abnormalities 
meet the discontinuation criteria (Appendix C).  Therefore, the protocol was 
revised that another measurement is obtained, at least 4 weeks apart, only in the 
subjects with screening ALT or AST greater than 3 X ULN. If retested ALT or 
AST increase more than 20% the subject will be excluded from study. 
-
Sections affected
Procedures – Screening Phase (Section 6.1) and Appendix C
!
Approved weight-loss medications were removed from prohibited medications
-
Exclusion criterion #12 was removed and inclusion criterion # 6 was revised to 
allow anti-obesity medications in the study if the medications have been stable for 
3 months prior to Screening or historical biopsy used for Screening.  
-
Sections affected
Study Population (Section 4) and Concomitant Medications and Procedures 
(Section 8)
!
Changed Visit 5 Week 8 and Visit 7 Week 16 to remote visit 
-
Visit 5 Week 8 and Visit 7 Week 16 were changed to remote visit to reduce 
operational complexity and the burden for the subjects.
-
Sections affected
Table of Events (Section 5) and Procedures (Section 6)
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EDMS Doc. Number: 
CC-90001
Summary of Changes CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
5
Protocol CC-90001-NASH-001 Amendment 4 Final: 16 Apr 2021
The amendment also includes other minor clarifications and corrections.
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EDMS Doc. Number: 
CC-90001
Summary of Changes CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
3
CC-90001-NASH-001 Amendment 3 Final: 11 Nov 2020
1.
JUSTIFICATION FOR AMENDMENT
The primary purpose of this amendment is to expand the study population to allow inclusion of 
subjects with Non-alcoholic Steatohepatitis (NASH) and Stage 2 fibrosis. Modifications to
inclusion/exclusion criteria were made to broaden the study population.
Changes included in this amendment are summarized below:
!
Protocol Title (Title Page and Protocol Summary)
The title was changed to “A Phase 2, Randomized, Double-blind, Placebo-controlled, 
Multicenter, Dose-finding Study to Evaluate the Efficacy and Safety of CC-90001 in 
Subjects with Non-alcoholic Steatohepatitis (NASH) and Liver Fibrosis” 
!
Therapeutic Area Head signature page
-
Name and title of therapeutic area head was changed
!
Protocol Summary, Rationale (Section 1.3), Study objectives and Endpoints (Section 2), 
Overall Study Design (Section 3), Study Population (Section 4), Method of Treatment 
Assignment (Section 7.3), Statistical Considerations (Section 9), 
 and 
Appendix C 
-
Expanded study population to allow subjects with NASH and Stage 2 fibrosis in 
the study and evaluate efficacy and safety of CC-90001 in these subjects. 
-
References to 
Appendix C were removed from Study population, 
Table of Events footnote and Procedures sections because they did not apply to 
Stage 2 fibrosis.
 Appendix C were removed as well.
!
Study Population (Section 4) Procedures (Section 6) and Concomitant Medications and 
Procedures (Section 8)
-
Inclusion criterion #6 was revised to clarify that this criterion applies to all fibric 
acid derivatives (fibrates) and to ensure that if sodium-glucose co-transporter 2 
inhibitors and glucagon peptide-1 agonists have been discontinued those 
medications must have been stopped 3 months prior to screening or historical 
biopsy. The Permitted Concomitant Medications and Procedure (Section 8.1) was 
updated accordingly.
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EDMS Doc. Number: 
CC-90001
Summary of Changes CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
4
CC-90001-NASH-001 Amendment 3 Final: 11 Nov 2020
-
Inclusion criterion #7 was revised to change stable dose of thiazolidinediones or 
vitamin E from 6 months to 3 months and to ensure that if thiazolidinediones or 
vitamin E have been discontinued those medications must have been stopped 3 
months prior to screening or historical biopsy. The Permitted Concomitant 
Medications and Procedure (Section 8.1) was updated accordingly.
-
Exclusion criterion #4 was revised to exclude subjects with HbA1C ≥9.5%.
Protocol allows for dose initiation/adjustments on of anti-diabetic medications 
during the study in order to optimize clinical care and safety risk to the subjects 
with HbA1C < 9.5% is low.
-
Exclusion criterion #5 was revised to clarify that worsening of liver function is 
based on aspartate aminotransferase, alanine aminotransferase, alkaline 
phosphatase and total bilirubin laboratory values.  
-
Exclusion criterion #7 was revised to remove bariatric surgery from this criterion
-
Exclusion criterion #10 was revised to remove the drugs historically associated 
with nonalcoholic fatty liver disease (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those 
used for hormone replacement, anabolic steroids, valproic acid, and other known 
hepatotoxins) from this criterion. The Prohibited Concomitant Medications and 
Procedure (Section 8.2) was updated accordingly.
-
Exclusion criterion #17 was revised to allow subjects with a history of hepatitis C 
virus (HCV) and sustained viral response (undetectable HCV ribonucleic acid
[RNA]) for at least 2 years prior to Screening including negative HCV RNA at 
Screening.
-
Exclusion criterion #23 was revised to allow subjects with a history of 
malignancy beyond 5 years to be enrolled in the study. 
-
Exclusion criterion # 30 was revised to “Prior use of obeticholic acid or 
participation of obeticholic acid clinical trial within 6 months prior to Screening 
or historical biopsy used for Screening”
-
Removed exclusion criterion #31
-
Added new exclusion criterion #31 to exclude subjects with history of bariatric 
surgery within 5 years prior to Screening or likely to have bariatric surgery during
the study  
-
Renumbered exclusion criteria #32 and #33 to align with the electronic case 
report form and updated criteria of serum total bilirubin.
!
Protocol Summary, Rationale (Section 1.3), Study objectives and Endpoints (Section 2), 
Study Population (Section 4), Table of Events (Section 5) and Procedures (Section 6)
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EDMS Doc. Number: 
CC-90001
Summary of Changes CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
5
CC-90001-NASH-001 Amendment 3 Final: 11 Nov 2020
 
-
Revised exclusion criterion #13 to clarify that subjects with SARS-CoV-2 
infection within 4 weeks of Screening will be excluded and symptoms must have 
completely resolved 
-
Added exclusion criterion #34 to exclude subjects who have received live 
attenuated or investigational SARS-CoV-2 vaccine within 3 months prior to the 
first dose of study treatment.
!
Clinical Laboratory Assessments (Section 6.5.3)
-
Changes were made to clarify that fasting is required for certain visits. 
!
Dose Interruptions (Section 7.2.2)
-
Revised to clarify that Investigational Product (IP) should be interrupted 7-10 
days prior to an elective surgical procedure
!
Concomitant Medications and Procedures (Section 8)
-
Use of cannabinoid products other than cannabis oils during the study was added 
to prohibited medication
-
Clarification and corrections were made to Permitted and Prohibited Concomitant 
Medications and Procedures
!
Adverse Event (Section 10)
-
Clarification was made that only Serious Adverse Events occurring after first dose 
of IP will be reported to Celgene Drug Safety
!
Appendix C: Hepatotoxicity Monitoring Criteria for Interruption and Discontinuation of 
Investigational Product Based on Liver Function Test Abnormalities
-
Clarifications were made in Appendix C
!
Appendix D: Hepatitis Exclusion Criteria  
The amendment also includes other minor clarifications and corrections.
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EDMS Doc. Number: 
CC-90001
Summary of Changes CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
3
Protocol CC-90001-NASH-001 Amendment 2 Final: 26 Sep 2019
1.
JUSTIFICATION FOR AMENDMENT
The primary purpose of this amendment is to add screening α-fetoprotein test to Table of Events
and Procedure sections for subjects with Stage 3 fibrosis and to clarify some of
inclusion/exclusion criteria.
Changes included in this amendment are summarized below:
!
Medical Monitor / Emergency Contact Information 
-
Contact information was changed to replace medical monitor’s phone numbers 
with hotline number
!
Protocol Summary and Overall Study Design (Section 3)
-
Screening period was extended to 10 weeks to allow enough time for completion 
of study procedures.
!
Study Population (Section 4)
-
Inclusion criterion #5 was updated to clarify that the historical liver biopsy in 
subjects who had been on therapy for treatment of NASH is not to be accepted.
-
Inclusion criteria #6 and #7 were updated to ensure stable doses of medications 
prior to and after historical liver biopsy is obtained, if the historical biopsy was 
going to be used for the inclusion criteria.
-
Exclusion criterion #3 was corrected.
-
Exclusion criterion #17 were updated to clarify that positive screening hepatitis 
B/C is also exclusionary for the study.
-
Exclusion criterion #31 was added to exclude subjects with history of Gilbert's 
syndrome since clinical manifestations of Gilbert's syndrome might confound the 
safety and efficacy assessments of CC-90001. 
!
Table of Events (Section 5) and Procedures (Section 6)
-
Added screening α-fetoprotein test to Table of Events and Procedures sections. 
Protocol Section 4.3.2 Exclusion Criteria for the Subjects with Stage 3 Fibrosis 
excludes subjects with a screening α-fetoprotein ≥ 200 ng/mL and α-fetoprotein > 
20 ng/mL should be discussed with Sponsor to review the evaluation of 
Hepatocellular Cancer (HCC).
-
Added ultrasound and α-fetoprotein test at Early Termination Visit to ensure HCC 
surveillance to be done for early terminated subjects with Stage 4 fibrosis.
!
Prohibited Concomitant Medications and Procedures (Section 8.2)
-
Acetaminophen dose was corrected. 
!
Individual Subject Stopping Criteria (Section 11.1.1)
-
Clarification was made on FOBT stopping criterion.
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EDMS Doc. Number: 
CC-90001
Summary of Changes CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
4
Protocol CC-90001-NASH-001 Amendment 2 Final: 26 Sep 2019
The amendment also includes other minor clarifications and corrections.
Approved
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EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
3
Protocol CC-90001-NASH-001 Amendment 1 Final: 23 May 2019
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Medical Monitor / Emergency Contact Information 
-
Contact information changed to the clinical research organization (CRO) medical 
monitor information (including Global Medical Monitor, Medical Monitor for 
Europe, and Medical Monitor for Asia-Pacific)
!
Celgene therapeutic area head signature page
-
Name of therapeutic area head was changed.
!
Exclusion Criteria for All Subjects (Section 4.3.1)
-
Revised exclusion criterion #4 to change Hemoglobin A1c ≥9.5% within 60 days 
prior to randomization to Hemoglobin A1c > 8% at screening due to recent 
consensus guidelines for the pharmacologic management of adults with Type 2 
Diabetes Mellitus (DM).
-
Revised exclusion criterion #14, and added exclusion criterion #15 to further 
clarify the eligibility of history of active or latent tuberculosis (TB) or subject 
who had a household contact with a person with active TB.
-
Added exclusion criteria #19, #20, and #21 to exclude subjects with 2 positive 
fecal occult blood tests (FOBTs), subjects with a history of bleeding peptic ulcer 
or bleeding diverticular disease within the last 5 years, and subjects with a history 
inflammatory bowel disease
 
 to exclude subjects with disorders of gastrointestinal 
(GI) bleeding.
!
Exclusion Criteria for All Subjects (Section 4.3.1) and Prohibited Concomitant 
Medications and Procedures (Section 8.2)
-
Added exclusion criterion #26 and prohibited concomitant use of warfarin within 
2 weeks prior to Screening and during study to align with inclusion and 
discontinuation criteria for subjects with liver disease and elevated international 
normalized ratio (INR).
-
Added exclusion criterion #30 and prohibited prior and concomitant use of 
obeticholic acid, which could potentially confound the evaluation of efficacy.
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EDMS Doc. Number: 
CC-90001
Protocol CC-90001-NASH-001
Celgene Corporation
Confidential and Proprietary
4
Protocol CC-90001-NASH-001 Amendment 1 Final: 23 May 2019
!
Prohibited Concomitant Medications and Procedures (Section 8.2)
-
Prohibited initiation of Vitamin E after Screening which could potentially 
confound the evaluation of efficacy.
!
Table of Events (Section 5) and Study Procedures (Section 6)
-
Added human immunodeficiency virus (HIV) test at Screening
 
 Exclusion criterion #16 (previously exclusion criterion 
#15) was modified to exclude subjects with positive Screening HIV test.
-
Added FOBTs at Screening, approximately every 12 weeks during the study, 
Early Termination Visit and Post-treatment Observational Follow-up Visit  
 to monitor for GI bleeding during the 
study.   
-
Added electrocardiograms (ECGs) at the Week 12, Week 66, and Week 84 visits 
.
!
Sample Size and Power Considerations
-
Updated Table 5 “Probability of Each Dose to Be Considered the MED for 
Various Response Scenarios and Delta” to add “No MED identified” category
!
Discontinuations (Section 11)
-
 added the following new individual 
subject stopping criteria:

A positive FOBT at a study visit and a decrease of hemoglobin from 
baseline by at least 10% at that study visit or subsequent visits.

A Grade 3 or higher drug-related AE by National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
grading system.

Grade 4 or higher AE by CTCAE Version 5.0 grading system.
-
 added and modified criteria for review 
of clinical data by the DMC:

One subject develops a Grade 5 AE by CTCAE Version 5.0 grading 
system.

Two subjects develop drug-related Grade 4 AEs by CTCAE Version 5.0
grading system.
The amendment also includes other minor clarifications and corrections.
Approved
2.0
v
Approved
1.0
v