Conditions: NASH - Nonalcoholic Steatohepatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 181
Healthy volunteers: no

Brief summary:
A Phase 2, Double-Blind (DB), Randomized, Placebo-Controlled Study Followed by an Open-Label Extension Period to Evaluate the Activity of Seladelpar in Subjects with Nonalcoholic Steatohepatitis (NASH)

OLE phase was not analyzed due to the early termination of the study

Detailed description:
Primary Objectives

1. To evaluate the effect of seladelpar on hepatic fat fraction, as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) at Week 12 in the DB phase
2. To evaluate the safety and tolerability of seladelpar in the DB and OLE phases

Secondary Objectives

1. To evaluate the effect of seladelpar on MRI- PDFF at Week 26 and Week 52 in the DB phase
2. To evaluate the effect of seladelpar on histological improvement of nonalcoholic fatty liver disease activity score (NAS) at Week 52 in the DB phase
3. To evaluate the effect of seladelpar on histological improvement of fibrosis at Week 52 in the DB phase
4. To evaluate the effect of seladelpar on metabolic biochemical markers and biochemical markers of inflammation in the DB and OLE phases

Arms:
arm 1: Subjects enrolled will receive seladelpar 10 mg, 20 mg, 50 mg or placebo daily for 52 weeks. arm 2: Subjects enrolled will receive seladelpar 10 mg, 20 mg, 50 mg or placebo daily for 52 weeks. arm 3: Subjects enrolled will receive seladelpar 10 mg, 20 mg, 50 mg or placebo daily for 52 weeks. arm 4: Subjects enrolled will receive seladelpar 10 mg, 20 mg, 50 mg or placebo daily for 52 weeks.

Interventions: intervention 1: Seladelpar intervention 2: Placebos
Intervention descriptions: intervention 1: 10 mg, 20 mg, or 50 mg intervention 2: Matching placebo Capsule

Protocol document:
Prot_002.pdf: 
CymaBay Therapeutics, Inc 
 
Protocol CB8025-21730 
 
Protocol Version 3.0, 20-DEC-2019  
CONFIDENTIAL  
Page 1 of 77 
 
PROTOCOL TITLE: 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study Followed by Open-Label Extension and Safety 
Follow-Up Phases to Evaluate the Activity of Seladelpar in 
Subjects with Nonalcoholic Steatohepatitis (NASH) 
 
PROTOCOL  
VERSION NUMBER: 
Version 3.0 
 
 
 
DATE OF PROTOCOL: 
20-DEC-2019 
 
PROTOCOL NUMBER: 
CB8025-21730 
 
STUDY PHASE: 
Phase 2 
 
SPONSOR: 
CymaBay Therapeutics, Inc. 
7575 Gateway Blvd, Suite 110 
Newark, CA 94560 
U.S.A. 
 
IND Number: 
133253 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This document contains confidential information, which should not be disclosed, copied, referred 
to, released or published without written approval from CymaBay Therapeutics, Inc. Any 
supplemental information that may be added to this document is also confidential and proprietary 
to CymaBay Therapeutics, Inc. and must be kept in confidence in the same manner as the contents 
of this document. 
 
 


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PROTOCOL CB8025-21730 
PROTOCOL TITLE: 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled 
Study Followed by Open-Label Extension and Safety Follow-
Up Phases to Evaluate the Activity of Seladelpar in Subjects 
with Nonalcoholic Steatohepatitis (NASH) 
PREVIOUS PROTOCOL 
VERSION NUMBER: 
Version 1.2 
PREVIOUS DATE OF PROTOCOL: 
26-MAR-2018
PREVIOUS PROTOCOL 
VERSION NUMBER: 
Version 2.0 
DATE OF PROTOCOL: 
13-SEP-2019
VERSION NUMBER: 
Version 3.0 
DATE OF PROTOCOL: 
20-DEC-2019
SPONSOR: 
CymaBay Therapeutics, Inc. 
7575 Gateway Blvd, Suite 110 
Newark, CA 94560 
U.S.A. 
I have read the above-mentioned Protocol dated Day/Month/Year 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good 
Clinical Practice and applicable regulatory requirements, and to inform all who assist me in the 
conduct of this study of their responsibilities and obligations. 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF TERMS AND ABBREVIATIONS .................................................................................. 8 
STUDY IDENTIFICATION .......................................................................................................... 12 
SYNOPSIS ..................................................................................................................................... 13 
1 
INTRODUCTION ..................................................................................................... 26 
1.1 
NASH ........................................................................................................................ 26 
1.2 
Seladelpar .................................................................................................................. 26 
1.2.1 
Overview ................................................................................................................... 26 
1.2.2 
Mechanism of Action ................................................................................................ 26 
1.2.3 
Seladelpar in NASH .................................................................................................. 26 
1.3 
Nonclinical Experience ............................................................................................. 27 
1.4 
Human Experience .................................................................................................... 27 
1.5 
Rationale for Dose Selection in the DB Phase .......................................................... 28 
1.6 
Rationale for Dose Selection in the OLE Phase ........................................................ 28 
1.7 
Rationale for SFU Phase ........................................................................................... 30 
2 
STUDY OBJECTIVES ............................................................................................. 31 
2.1 
Primary Objectives .................................................................................................... 31 
1.2 
Secondary Objectives ................................................................................................ 31 
2.3 
Exploratory Objectives .............................................................................................. 31 
3 
STUDY DESIGN ...................................................................................................... 32 
4 
STUDY POPULATION ........................................................................................... 34 
4.1 
DB Phase Eligibility Criteria ..................................................................................... 34 
4.2 
OLE Phase Enrollment Criteria Assessment ............................................................. 36 
4.3 
SFU Phase Enrollment Criteria Assessment ............................................................. 36 
5. 
STUDY OUTCOME MEASURES .......................................................................... 37 
5.1 
Primary Outcome Measures ...................................................................................... 37 
5.2 
Secondary Outcome Measures .................................................................................. 37 
5.3 
Exploratory Outcome Measures ................................................................................ 37 
5.4 
Safety Outcome Measures ......................................................................................... 38 
6 
STUDY MEDICATIONS ......................................................................................... 39 
6.1 
Clinical Supplies ....................................................................................................... 39 
6.1.1 
Investigational Product, Dosage, and Mode of Administration ................................ 39 


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6.1.2 
Packaging, Labeling and Shipping ............................................................................ 39 
6.1.3 
Accountability of Clinical Supplies .......................................................................... 39 
6.1.4 
Stability of Study Medication ................................................................................... 39 
6.2 
Randomization .......................................................................................................... 39 
6.2.1 
Randomization/Registration Procedure ..................................................................... 39 
6.2.2 
Emergency Unblinding ............................................................................................. 39 
6.3 
Method of Administration and Compliance .............................................................. 40 
6.4 
Concomitant Medications and Procedures ................................................................ 40 
6.4.1 
Concomitant Medications ......................................................................................... 40 
6.4.1.1 
Permitted Concomitant Medications in the DB and OLE Phases ..................... 40 
6.4.1.2 
Prohibited Concomitant Medications................................................................ 40 
6.4.2 
Concomitant Procedures ........................................................................................... 41 
7 
STUDY PROCEDURES ........................................................................................... 42 
7.1 
Study Schedule for DB Phase ................................................................................... 42 
7.1.1 
DB Screening (Week -10 to Day -1) ......................................................................... 42 
7.1.2 
DB Day 1 (Baseline) Visit ........................................................................................ 43 
7.1.3 
DB Week 4 and Week 8 Visits .................................................................................. 44 
7.1.4 
DB Week 12 Visit ..................................................................................................... 44 
7.1.5 
DB Week 19, Week 32, and Week 45 Contact ......................................................... 44 
7.1.6 
DB Week 26 Visit ..................................................................................................... 44 
7.1.7 
DB Week 39 Visit ..................................................................................................... 45 
7.1.8 
DB Week 52 End of Treatment (EOT) Visit ............................................................. 45 
7.1.9 
DB Week 56 End of Study (EOS) Visit .................................................................... 46 
7.1.10 DB Early Termination (ET) Visit .............................................................................. 46 
7.1.11 DB Unscheduled (UNS) Visit ................................................................................... 47 
7.2 
OLE Phase Study Schedule ....................................................................................... 48 
7.2.1 
OLE Day 1 Visit ........................................................................................................ 48 
7.2.2 
OLE Week 2, Week 13, Week 26, Week 39 Visit .................................................... 48 
7.2.3 
OLE Week 52 End of Treatment (EOT) or Early Termination Visits ...................... 49 
7.2.4 
OLE Week 56 End of Study (EOS) Visit .................................................................. 49 
7.2.5 
OLE Unscheduled (UNS) Visits ............................................................................... 49 
7.3 
SFU Phase Study Schedule ....................................................................................... 50 


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7.3.1 
SFU Visit ................................................................................................................... 50 
7.3.2 
SFU Unscheduled (UNS) Visits ................................................................................ 50 
7.4 
Study Assessments .................................................................................................... 50 
7.4.1 
Medical History and Physical Examination .............................................................. 50 
7.4.2 
Vital Signs and Weight/Height ................................................................................. 51 
7.4.3 
Electrocardiogram ..................................................................................................... 51 
7.4.4 
Laboratory Tests ........................................................................................................ 51 
7.4.5 
Liver Biopsy (DB AND SFU Phases Only) .............................................................. 52 
7.4.6 
Imaging Tests ............................................................................................................ 53 
7.4.6.1 
MRE Exam (DB Phase Only) ........................................................................... 53 
7.4.6.2 
MRI-PDFF Exam (DB Phase Only) ................................................................. 53 
7.4.6.3 
FibroScan® Exam (DB and SFU Phases Only) ................................................ 55 
7.4.6.4 
LMS Exam (DB Phase Only) ........................................................................... 55 
8 
ADVERSE EVENTS ................................................................................................ 56 
8.1 
General ...................................................................................................................... 56 
8.1.1 
Definition of Adverse Events (AEs) ......................................................................... 56 
8.1.2 
Definition of Serious AEs (SAEs) ............................................................................ 56 
8.1.3 
AE Severity ............................................................................................................... 56 
8.1.4 
Adverse Event Outcome ............................................................................................ 57 
8.1.5 
Relationship to Treatment ......................................................................................... 57 
8.1.6 
Action Taken with Study Medication ....................................................................... 57 
8.2 
Recording, Reporting and Follow-Up of Adverse Events ........................................ 58 
8.2.1 
SAE Reporting Process ............................................................................................. 59 
8.2.2 
Follow-up of Reported AEs ...................................................................................... 60 
8.3 
Distribution of Responsibilities ................................................................................. 60 
8.4 
Safety Monitoring Criteria, Dose Adjustment, and Withdrawal Criteria ................. 60 
8.4.1 
Drug-Induced Liver Injury (DILI) Safety Monitoring .............................................. 60 
8.4.2 
Muscle Safety Monitoring ......................................................................................... 62 
8.4.3 
Cardiac Safety Monitoring ........................................................................................ 62 
8.4.4 
Pancreatic Safety Monitoring .................................................................................... 62 
8.4.5 
Withdrawal Criteria and Replacement of Subjects ................................................... 63 
8.5 
Precautions ................................................................................................................ 63 


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8.5.1 
Pregnancy .................................................................................................................. 63 
8.6 
Study Stopping Rules ................................................................................................ 64 
9 
STUDY TERMINATION ......................................................................................... 65 
10 
DATA MANAGEMENT AND STATISTICAL ANALYSES ................................ 66 
10.1 
Data Management ..................................................................................................... 66 
10.1.1 Processing of Electronic Case Report Forms ............................................................ 66 
10.1.2 Database .................................................................................................................... 66 
10.1.3 Data Discrepancies .................................................................................................... 66 
10.2 
Statistical Analysis .................................................................................................... 66 
10.2.1 Sample Size Estimation ............................................................................................. 66 
10.2.2 Analysis Populations ................................................................................................. 66 
10.2.2.1 
Safety Population .............................................................................................. 67 
10.2.2.2 
Intent-to-Treat Population (ITT) ....................................................................... 67 
10.2.2.3 
Modified Intent-to-Treat Population (mITT) .................................................... 67 
10.2.2.4 
Modified Intent-to-Treat Population with Biopsy (mITTb) ............................. 67 
10.2.2.5 
Per-protocol population (PP) ............................................................................ 67 
10.2.3 Demographics and Baseline Characteristics ............................................................. 67 
10.2.4 Efficacy Analysis ...................................................................................................... 67 
10.2.4.1 
Primary Efficacy Analysis ................................................................................ 67 
10.2.4.1.1 Top-Line Results .......................................................................................... 68 
10.2.4.2 
Secondary Efficacy Analysis ............................................................................ 68 
10.2.5 Safety Analysis .......................................................................................................... 68 
10.2.5.1 
Adverse Events ................................................................................................. 69 
10.2.5.2 
Vital Signs ......................................................................................................... 69 
10.2.5.3 
Physical Examination ........................................................................................ 69 
10.2.5.4 
Laboratory Tests ............................................................................................... 69 
10.2.5.5 
Electrocardiograms ........................................................................................... 69 
10.2.5.6 
Concomitant Medications ................................................................................. 69 
11 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................... 70 
11.1 
Study Monitoring ...................................................................................................... 70 
11.2 
Audits and Inspections .............................................................................................. 70 
11.3 
Ethics Committees ..................................................................................................... 70 


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12 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 71 
13 
ETHICS ..................................................................................................................... 71 
13.1 
Ethics Review ............................................................................................................ 71 
13.2 
Ethical Conduct of the Study .................................................................................... 71 
13.3 
Written Informed Consent ......................................................................................... 71 
14 
RETENTION OF RECORDS ................................................................................... 72 
15 
PROTOCOL AMENDMENTS ................................................................................. 72 
16 
DISCLOSURE OF INFORMATION ....................................................................... 72 
17 
REFERENCES .......................................................................................................... 73 
APPENDIX A – ELIGIBILITY LOG (DB PHASE) ..................................................................... 74 
APPENDIX B – CLOSE OBSERVATION CRITERIA FOR DILI EVENTS ............................. 75 
APPENDIX C – NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI CTCAE) ................................................................ 76 
INVESTIGATOR’S PROTOCOL SIGNATURE PAGE .............................................................. 77 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments - Double-Blind (DB) Phase ............................................. 23 
Table 2: 
Schedule of Assessments – Open-Label Extension (OLE) Phase ............................ 24 
Table 3: 
Schedule of Assessments – Safety Follow Up Extension (SFU) Phase ................... 25 
Table 4: 
Estimated Safety Exposure Margin of Seladelpar for NASH .................................. 28 
Table 5: 
Mean Relative Changes in Hepatic Injury Biomarkers Observed from Baseline 
to Week 12 in Study CB8025-21730 ........................................................................ 29 
 
 
 


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LIST OF TERMS AND ABBREVIATIONS 
AB 
Antibody 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
APRI 
AST/Platelet Ratio Index 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
C4 
7-α-hydroxy-4-cholesten-3-one 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CK-BB 
Creatine Kinase Brain Type 
CK-MB 
Creatine Kinase Heart Type 
CK-MM 
Creatine Kinase Muscle Type 
CRO 
Clinical Research Organization 
DB 
Double-Blind 
DILI 
Drug-Induced Liver Injury 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
ELF 
Enhanced Liver Fibrosis Score 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
FAO 
Fatty Acid Oxidation 
FIB-4 
Fibrosis-4 


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FSPGR 
Fast Spoiled Gradient  
GCP 
Good Clinical Practice 
GFR 
Glomerular-Filtration Rate 
GGT 
Gamma-glutamyl Transferase 
GLP-1 
Glucagon-Like Peptide-1 
HA 
Hyaluronic Acid 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HCV AB 
Hepatitis C Antibody 
HDL-C 
High-Density Lipoprotein Cholesterol 
HIV 
Human Immunodeficiency Virus 
HoFH 
Homozygous Familial Hypercholesterolemia 
HOMA-IR 
Homeostasis Model Assessment of Insulin Resistance 
hs-CRP 
High Sensitivity C-Reactive Protein 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
ITT 
Intent-to-Treat 
IU 
International Unit 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
IXRS   
Interactive X Response Technology 
LDH 
Lactate Dehydrogenase 
LDL-C  
Low Density Lipoprotein Cholesterol  
LFC 
Liver Fat Content 
LLN 
Lower Limit of Normal 
LMS 
LiverMultiScan 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat (population) 
mITTb 
Modified Intent to Treat with Biopsy (population) 
MRE 
Magnetic Resonance Elastography 


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MRI 
Magnetic Resonance Imaging 
MRI-PDFF 
Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic Steatohepatitis 
Non-HDL 
Non-High-Density Lipoprotein Cholesterol 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
OLE 
Open-Label Extension  
PBC 
Primary Biliary Cholangitis 
PP 
Per Protocol 
PT 
Prothrombin Time 
PPAR 
Peroxisome Proliferator-Activated Receptor 
PPARα 
Peroxisome Proliferator Receptor Alpha 
PPAR- 
Peroxisome Proliferator Receptor Delta  
RBC 
Red Blood Cells 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SFU 
Safety Follow-Up 
SGLT-2 
Sodium/Glucose Co-Transporter 2 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TC 
Total Cholesterol 
TEAE 
Treatment Emergent Adverse Event 
TG 
Triglycerides 
TIMP-1 
Tissue Inhibitor of Matrix Metaloproteinases-1 
TQT  
Thorough QT 
UDCA 
Ursodeoxycholic Acid 
ULN 
Upper Limit of Normal 
UNS  
Unscheduled 
U.S.A. 
United States of America 
U.S. FDA 
United States Food and Drug Administration 


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W 
Week 
WBC 
White Blood Cells 
WHO 
World Health Organization 
WHODrug 
World Health Organization Drug Classification 
 
 




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SYNOPSIS  
Protocol 
Number 
CB8025-21730  
Title 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study Followed by 
Open-Label Extension and Safety Follow-Up Phases to Evaluate the Activity of 
Seladelpar in Subjects with Nonalcoholic Steatohepatitis (NASH) 
Study Phase 
Phase 2 
Study Design 
This is a 52-week double-blind (DB), randomized, placebo-controlled, dose-ranging 
study followed by a 52-week open-label extension (OLE). An additional Safety 
Follow-Up (SFU) phase will continue for up to 1 year after the Week 52/Early 
Termination (ET) liver biopsy in subjects with significant histologic findings. 
Number of 
Investigational 
Sites 
Up to 15 sites in the U.S.A. 
Objectives 
Primary Objectives  
1. To evaluate the effect of seladelpar on hepatic fat fraction, as assessed by 
magnetic resonance imaging-proton density fat fraction (MRI-PDFF) at Week 12 
in the DB phase 
2. To evaluate the safety and tolerability of seladelpar in the DB, OLE and SFU 
phases 
Secondary Objectives 
1. To evaluate the effect of seladelpar on MRI-PDFF at Week 26 and Week 52 in 
the DB phase 
2. To evaluate the effect of seladelpar on histological improvement of nonalcoholic 
fatty liver disease activity score (NAS) at Week 52 in the DB phase 
3. To evaluate the effect of seladelpar on histological improvement of fibrosis at 
Week 52 in the DB phase   
4. To evaluate the effect of seladelpar on metabolic biochemical markers and 
biochemical markers of inflammation in the DB and OLE phases 
Exploratory Objectives  
1. To evaluate the effect of seladelpar on biochemical markers of fibrosis in the DB 
and OLE phases  
2. To evaluate the effect of seladelpar on fibrosis and inflammation as assessed by 
magnetic resonance elastography (MRE) and LiverMultiScan (LMS) in the DB 
phase 
3. To evaluate AST/platelet ratio index (APRI) and fibrosis-4 (FIB-4) in the DB 
and OLE phases  
4. To assess markers of target engagement including 7-alpha-hydroxy-4-cholesten-
3-one (C4), serum bile acids and fatty acid oxidation (FAO) tests in the DB and 
OLE phases 


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5. To evaluate histology, biochemical markers and FibroScan® during the SFU 
phase in subjects with significant histologic findings on the Week 52/ET liver 
biopsy 
Study Outcome 
Measures 
Primary Outcome Measures 
1. Relative change in MRI-PDFF at Week 12 in the DB phase 
Adverse events (AEs) and/or treatment emergent adverse events (TEAEs), physical 
exams, vital signs, electrocardiograms (ECGs), biochemistry, hematology, and 
urinalysis as determined by investigator assessment for causality and grading by 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE), Version 4.0 in the DB, OLE and SFU phases 
Secondary Outcome Measures 
1. Absolute change in MRI-PDFF at Week 12, 26, and 52 in the DB phase 
2. Relative change in MRI-PDFF at Week 26 and 52 in the DB phase 
3. Proportion of subjects with a relative decrease in MRI-PDFF ≥ 30% at Week 12, 
26, and 52 in the DB phase 
4. Proportion of subjects with normalization of MRI-PDFF (defined as a fat fraction 
of < 5%) at Week 12, 26, and 52 in the DB phase 
5. Proportion of subjects with an absolute MRI-PDFF change > 5% at Weeks 12, 
26, and 52 in the DB phase 
6. Proportion of subjects with reversal of nonalcoholic steatohepatitis (NASH) and 
no worsening of hepatic fibrosis (centrally scored histology at Week 52) in the 
DB phase. The reversal of NASH is defined as the absence of hepatocellular 
ballooning (score of 0) and no or minimal inflammation (score of 0 or 1)  
7. Proportion of subjects with improvement by at least one stage in fibrosis without 
worsening of NASH in the DB phase 
8. Proportion of subjects with a 2-point improvement in NAS in the DB phase 
9. Percent and absolute change in alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma-glutamyl transferase (GGT) in the DB and OLE 
phases 
10. Percent and absolute change in total cholesterol (TC), high-density lipoprotein 
cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), 
non-high-density lipoprotein cholesterol (non-HDL), homeostatic model 
assessment of insulin resistance (HOMA-IR) in the DB and OLE phases 
11. Percent and absolute change in high-sensitivity C-reactive protein (Hs-CRP) and 
fibrinogen in the DB and OLE phases 
Exploratory Outcome Measures 
1. AST/platelet ratio index (APRI), FIB-4 in the DB and OLE phases 
2. Enhanced Liver Fibrosis (ELF) score and its components (hyaluronic acid, 
procollagen III N-terminal peptide, tissue inhibitor of matrix metalloproteinases) 
in the DB and OLE phases  


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3. MRE changes at Week 52 in the DB phase 
4. LMS (iron corrected T1 – cT1) changes at Week 12, 26, and 52 in the DB phase  
5. FibroScan® changes (kPa and CAP) at Week 52 and at SFU visits 
6. C4, serum bile acids and FAO tests in DB and OLE phases 
Safety Outcome Measures 
In those subjects with significant histological findings, other than NASH, in the end 
of treatment biopsy (Week 52 or Early Termination), resolution or stabilization of 
the findings at the SFU visits. 
Investigational 
Product and 
Control 
Seladelpar (and matching placebo) will be supplied as 5 mg, 10 mg, and 25 mg 
capsules. 
Study Drug 
Administration 
The study drug (seladelpar or matched placebo capsules) will be administered orally, 
once daily with or without food.  
Treatment 
Groups and 
Number of 
Subjects 
The DB phase will enroll approximately 175 subjects at the following dose levels:  
• 
Placebo (n=25) 
• 
Seladelpar 10 mg (n=50) 
• 
Seladelpar 20 mg (n=50) 
• 
Seladelpar 50 mg (n=50) 
 
The OLE phase will enroll up to approximately 175 subjects. All subjects will receive 
seladelpar 50 mg regardless of dose received during the DB phase. 
 
There is no study drug administered during the SFU Phase. 
Randomization 
and 
Stratification 
DB Phase 
Randomization: 1:2:2:2 (placebo: seladelpar 10 mg:20 mg:50 mg) 
Stratification: By diabetic status (yes/no) and fibrosis stage (F1 versus F2-3) 
OLE Phase 
No randomization or stratification criteria for the OLE phase 
SFU Phase 
No randomization or stratification criteria for the SFU phase 
Study Duration 
DB Phase 
Screening: Up to 10 weeks 
Treatment: Up to 52 weeks 
Follow-up: approximately 4 weeks 
OLE Phase:  
Treatment: Up to 52 weeks 
Follow-up: approximately 4 weeks 


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SFU Phase 
Up to 1 year from the Week 52 or ET liver biopsy   
Eligibility 
DB Inclusion Criteria 
1. 
Must be able to provide written informed consent (signed and dated) and any 
authorizations required by local law 
2. 
18 to 75 years old (inclusive) 
3. 
Histological evidence of definite NASH on a liver biopsy (obtained during the 
screening period or historical liver biopsy obtained no more than 90 days prior 
to the initial screening visit)  
4. 
NAS of 4 points or greater with a score of at least 1 point in each component 
(steatosis, lobular inflammation, and ballooning) 
5. 
Fibrosis stage 1, 2, or 3 on liver biopsy 
6. 
MRI-PDFF ≥ 10%  
7. 
Females of reproductive potential must use at least one barrier contraceptive 
and a second effective birth control method during the study and for at least 
30 days after the last dose of study drug. Male subjects who are sexually active 
with female partners of reproductive potential must use barrier contraception 
and their female partners must use a second effective birth control method 
during the study and for at least 90 days after the last dose of study drug. 
DB Exclusion Criteria 
1. 
Significant alcohol consumption, defined as more than 2 drink units per day 
(equivalent to 20 g) in women and 3 drink units per day (equivalent to 30 g) in 
men, or inability to reliably quantify alcohol intake 
2. 
Treatment with drugs associated with nonalcoholic fatty liver disease 
(NAFLD) (amiodarone, methotrexate, oral glucocorticoids at doses greater 
than 5 mg/day, tamoxifen, estrogens at doses greater than those used for 
hormone replacement or contraception, anabolic steroids (such as testosterone) 
and valproic acid for more than 4 weeks within the last 2 months prior to the 
initial screening 
3. 
Treatment with pioglitazone or high-dose vitamin E (>400 IU/day) within the 
last 2 months prior to the initial screening 
4. 
Initiation of treatment with a glucagon-like peptide-1 (GLP-1) agonist or a dose 
change within the last 2 months prior to the initial screening 
5. 
Prior or planned bariatric surgery (a prior reversed sleeve gastrectomy is 
permitted)  
6. 
Poorly controlled type 2 diabetes mellitus as defined by hemoglobin A1c 
[HbA1c]9.5% or higher or type 1 diabetes mellitus 
7. 
Diabetic patients who are taking sodium/glucose cotransporter 2 (SGLT-2) 
inhibitors must be on a stable dose within 2 months prior to the initial screening 
and throughout the study  
8. 
Significant weight loss within the last 6 months (e.g., > 10%) 
9. 
Use of any weight-loss medication for 3 months prior to and during the study 
period 
10. 
Body mass index (BMI) < 18.5 kg/m2 
11. 
Hepatic decompensation defined as the presence of any of the following:  
• 
Serum albumin less than 3.5 g/dL 
• 
International normalized ratio (INR) greater than 1.4 (unless due to 
therapeutic anticoagulants) 


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• 
Total bilirubin greater than 2 mg/dL with the exception of Gilbert syndrome 
• 
History of esophageal varices, ascites, or hepatic encephalopathy 
12. Other chronic liver diseases: 
• 
Active hepatitis B as defined by presence of hepatitis B surface antigen 
(HBsAg) 
• 
Active hepatitis C as defined by presence of hepatitis C virus antibody 
(HCV AB) plus a positive hepatitis C virus (HCV) ribonucleic acid (RNA)   
• 
History or evidence of current active autoimmune hepatitis  
• 
History or evidence of primary sclerosing cholangitis (PSC) 
• 
History or evidence of primary biliary cholangitis (PBC) 
• 
History or evidence of Wilson’s disease  
• 
History or evidence of alpha-1-antitrypsin deficiency  
• 
History or evidence of hemochromatosis 
• 
History or evidence of drug-induced liver disease, as defined exposure and 
history 
• 
Known bile duct obstruction 
• 
Suspected or proven liver cancer 
13. ALT > 200 U/L 
14. AST < 20 U/L 
15. Creatine kinase (CK) > upper limit of normal (ULN) 
16. Serum creatinine > ULN 
17. Platelet < lower limit of normal (LLN) 
18. Inability to obtain a liver biopsy 
19. History of biliary diversion 
20. Known history of human immunodeficiency virus (HIV) infection 
21. History of malignancy diagnosed or treated within 2 years 
• 
Recent localized treatment of squamous or non-invasive basal cell skin 
cancers is permitted 
• 
Cervical carcinoma in-situ is allowed if appropriately treated prior to 
Screening 
• 
Participants under active evaluation for malignancy are not eligible 
22. Active substance abuse, based on Investigator judgment, including inhaled or 
injected drugs, within 1 year prior to the initial screening 
23. Females who are pregnant or breastfeeding 
24. Patients unable to undergo MRI-PDFF due to: 
• 
Contraindication to magnetic resonance imaging (MRI) examination  
• 
Severe claustrophobia impacting ability to perform MRI during the study, 
despite mild sedation/treatment with an anxiolytic 
• 
Weight or girth exceeds the scanner capacities 
25. Treatment with any other investigational therapy or device within 30 days or 
within five half-lives, whichever is longer, prior to the initial screening 
26. Active, serious medical disease with likely life expectancy < 5 years 
27. Any other condition(s) that would compromise the safety of the subject or 
compromise study quality as judged by the Investigator 


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OLE Phase Enrollment Criteria 
Subjects must fulfill the following before allowing to start OLE dosing: 
1. Provide informed consent on or before Day 1 and prior to any OLE-related 
study procedures. 
2. Completed through the Week 52 biopsy and Week 56 lab assessments in the 
DB phase 
3. Meet the above DB phase Inclusion and Exclusion Criteria before Day 1 of 
the OLE phase, with the exception of the following: 
 
• 
AST < 20 U/L 
• 
Inability to obtain a liver biopsy (no new biopsy required for OLE) 
• 
Unable to undergo MRI-PDFF (no imaging performed in OLE) 
 
Week 56 labs from the DB phase may be used for eligibility assessment if less than 
45 days from OLE Day 1. If greater than 45 days, an Unscheduled visit must be 
performed to collect safety and eligibility labs. 
 
SFU Phase Enrollment Criteria 
 
Subjects entering the SFU phase of the study must fulfill the following criteria: 
 
1. Presence of significant histologic findings other than NASH on the Week 52 
or Early Termination liver biopsy 
2. Received seladelpar during the DB phase for at least 6 months.  
Study Design 
and Procedures 
DB Phase 
This phase of the study is designed as a dosing ranging proof-of-concept study to 
evaluate the safety and potential efficacy effects of seladelpar on hepatic fat fraction 
(MRI-PDFF). The study includes liver biopsies to confirm that subjects have 
histological evidence of NASH at screening and to evaluate histological 
improvement in NASH and fibrosis after 52 weeks of treatment.  
Approximately 175 subjects will be randomly assigned to receive placebo, seladelpar 
10 mg/day, seladelpar 20 mg/day or seladelpar 50 mg/day at a 1:2:2:2 ratio. Subjects 
will be stratified by diabetic status (yes/no) and fibrosis stage (F1 versus F2-3). Study 
drug (placebo or seladelpar) will be taken in a blinded manner orally once a day for 
a period of 52 weeks.  
The screening period will be up to 10 weeks, the blinded treatment period will be up 
to 52 weeks, and a follow-up period of 4 weeks after the last dose of study drug. 
During the treatment period, the first on-treatment visit will occur 4 weeks after 
initiation of the study drug. Subjects will then be evaluated in clinic every 4 weeks 
until Week 12. After Week 12, visits will be 6-7 weeks apart.  Subjects will also be 
contacted by phone or email at Weeks 19, 32 and 45. The amount of fat in the liver 
will be evaluated by MRI-PDFF at baseline, Weeks 12, 26, and 52. A liver biopsy 
will be performed twice during the study: at baseline and at Week 52.  
The primary efficacy analysis will be the change from baseline to Week 12 in 
MRI-PDFF. The study will continue in a blinded fashion until the Week 52 biopsy is 
collected. 


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OLE Phase 
All subjects who participate in the DB phase, complete the 52-week biopsy and the 
56-week follow-up labs, and meet the specified enrollment criteria will be offered 
participation in the OLE phase of the study. Subjects will not be required to have any 
additional liver histology, imaging or elastography assessments for enrollment or on-
treatment assessments of treatment effect. The OLE Day 1 visit may be combined 
with the Week 56 visit in the DB phase. Informed Consent may occur at Week 52 or 
Week 56 in the DB phase for subjects still active in the DB phase or any time prior 
to any OLE procedures in patients who have completed the DB phase. Eligibility 
assessment may occur on or after the Week 56 in the DB phase. Laboratory 
assessments from the DB phase Week 52 visit should be used to determine OLE 
eligibility if the DB phase Week 56 visit and OLE phase Day 1 visit are planned to 
be completed on the same day. Lab assessments from the DB Week 56 visit may be 
used for OLE eligibility assessment if less than 45 days from that visit. If greater than 
45 days have elapsed from DB phase Week 56 visit, subjects should complete an 
unscheduled visit where all lab assessments required for DB phase Week 56 are 
retested. The results from the re-test must be available and assessed for eligibility 
prior to the Day 1 visit. Subjects must also be clinically stable based on the 
investigator’s medical judgement and key enrollment criteria to enter the OLE. Clinic 
visits during the 52-week OLE phase will occur at Day 1 and Weeks 2, 13, 26, 39 
and 52 with a final end of study (EOS) visit approximately at Week 56. The primary 
objective of the OLE phase is to assess long-term safety and treatment effect as 
measured by biochemical tests after an additional 52 weeks of treatment. 
 
SFU Phase 
All subjects who participated in the DB phase that have significant histologic findings 
other than NASH on the Week 52 or ET liver biopsy and received active seladelpar 
for at least 6 months will be asked to enroll in the SFU phase. Subjects in the placebo 
dosing group will not be enrolled into the SFU phase. After informed consent is 
obtained, an SFU visit will be performed at 6 months ± 4 weeks, after the Week 52 
or ET liver biopsy. A liver biopsy will be obtained to reassess the status of the original 
significant histologic findings. Other study procedures performed during the visit 
include a physical exam, vital signs, safety laboratory assessments, exploratory liver 
injury biomarker assessments, and FibroScan®. Subjects with resolution or 
stabilization of the observed histologic findings will have completed the SFU phase, 
and no further visits or assessments will be required. Subjects with worsening of the 
observed histologic findings will be followed up by phone at 3-month intervals and 
may be requested to have additional SFU visits with a repeat of some or all of the 
above procedures. 


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Statistics 
Populations for Analysis: 
Safety: Any subject who receives at least one dose of study drug.  
Intent-to-Treat (ITT): Any subject who is randomized and receives at least one 
dose of study drug. 
Modified Intent-to-Treat (mITT): Any subject who is randomized, receives at 
least one dose of study drug, and has Baseline and Week 12 MRI-PDFF.  
Modified Intent-to-Treat with Biopsy (mITTb): Any subject who is randomized, 
receives at least one dose of study drug and has Baseline and Week 52/early 
termination (ET) liver biopsies.  
Per-Protocol (PP): Any subject who is randomized and receives at least one dose of 
study drug, has Baseline and Week 52/ET liver biopsies and does not have a protocol 
violation that is deemed to impact the efficacy analysis.  
Population Analyses: 
The safety analysis will be conducted on the Safety population. Efficacy analyses 
will be conducted on the ITT, mITT, mITTb, and the PP populations. The mITT 
population will be used for the primary efficacy analysis. 
Statistical Methods: 
All statistical comparisons will be made at a two-sided alpha of 0.05. Treatment 
comparisons of the primary efficacy endpoint will be tested using a hierarchical 
“fixed-sequence” approach to assess clinical benefit of each of the seladelpar dose 
levels versus placebo, starting first with the 50 mg dose at a 5% alpha level. If 
positive, the seladelpar 20 mg dose will be compared to placebo at a 5% alpha level. 
If both seladelpar 20 mg and 50 mg doses are statistically superior to placebo then 
the testing will continue to the 10 mg dose vs placebo.  
Additional consideration for the testing procedures for alpha control will be discussed 
in the statistical analysis plan (SAP). 
Sample Size: 
A sample size of 175 subjects (50 subjects per each dose of seladelpar and 25 subjects 
for placebo) provides at least 80% power to detect a pairwise treatment difference of 
at least 20% between the active and placebo groups with respect to a relative change 
from baseline in hepatic fat fraction, as assessed by MRI-PDFF at Week 12. Power 
calculations were performed using a standard t-test, allowed for a 12% dropout rate 
(6 subjects per seladelpar arm, 3 subjects for the placebo arm), and a pooled standard 
deviation of 26 for the relative change endpoint.  
Primary Efficacy Analysis: 
Pairwise comparisons between each dose of seladelpar versus placebo with respect 
to the relative change in hepatic fat fraction as assessed by MRI-PDFF at Week 12 
will be conducted using analysis of covariance (ANCOVA). The LS means, 
standard errors, 95% confidence intervals (CIs), and p-values will be provided from 
an ANCOVA model with percent change from baseline in MRI-PDFF as the 


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dependent variable, treatment group, diabetic status, and fibrosis stage as factors 
and baseline MRI-PDFF as a covariate. 
Relative change will be calculated as:  
[MRI-PDFFWEEK12 – MRI-PDFFBASELINE] ×100 / MRI-PDFFBASELINE. 
Top-Line Results 
The 12-week Primary Analysis, including top-line results for efficacy and safety, will 
be provided and communicated when it becomes available and before study 
completion. These results will be provided by treatment group, but individual patient 
data will remain blinded and the study will continue as a double-blind study until its 
completion. Details of the conduct of the Primary Analysis will be provided in the 
SAP. 
Secondary Efficacy Analyses: 
Comparisons between each seladelpar dose versus placebo with respect to the 
absolute change in hepatic fat fraction as assessed by MRI-PDFF at Week 12, 26 and 
52 will be conducted using mixed model repeated measures analyses, with factors for 
scheduled time point, treatment, time point by treatment interaction, baseline diabetic 
status, and fibrosis stage, with the baseline hepatic fat fraction as a covariate. 
Supportive analyses will be conducted using Wilcoxon rank-sum tests, stratified by 
diabetic status and fibrosis stage.  
Comparisons between each seladelpar dose versus placebo with respect to the relative 
change in hepatic fat fraction as assessed by MRI-PDFF at Week 26 and 52 will be 
conducted using mixed model repeated measures analyses with factors for scheduled 
time point, treatment, time point by treatment interaction, baseline diabetic status, 
and fibrosis stage, with the baseline hepatic fat fraction as a covariate. Supportive 
analyses will be conducted using Wilcoxon rank-sum tests, stratified by diabetic 
status and fibrosis stage. 
Each seladelpar dose will be compared versus placebo for the number and percent of 
subjects with normalization of hepatic fat content (<5%) at Week 12, 26, and 52 using 
Cochran-Mantel-Haenszel tests, stratified by diabetic status and fibrosis stage. 
Similar analyses will be performed for:  
• 
number and percent of subjects with an absolute change > 5% on MRI-PDFF 
at Week 12, 26, and 52 
• 
number and percent of subjects with a relative decrease in hepatic steatosis 
of > 30% on MRI-PDFF at Week 12, 26, and 52 
• 
number and percent of subjects with reversal of NASH with no worsening of 
fibrosis as defined by centrally scored histology assessment at 52 weeks of 
treatment 
• 
number and percent of subjects with improvement by at least one stage in 
fibrosis (NASH Clinical Research Network Classification) without 
worsening of NASH 
• 
number and percent of subjects with a 2-point decrease in NAS 
Efficacy-related laboratory data will be summarized by laboratory parameter, 
treatment group and study visit for the DB and OLE phases. 


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Safety data, including AEs, safety laboratory results, significant histologic findings, 
physical examination results, vital signs, and ECG will be summarized by treatment 
group and/or listed for the DB, OLE and SFU phases. 
Full details on the statistical methodology to be used will be included in an SAP to 
be developed prior to study unblinding. 


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Table 1: 
Schedule of Assessments - Double-Blind (DB) Phase 
Study Periods 
Screen 
Baseline 
Treatment 
Follow-up 
 
Visits (±7 days) 
Week -10 
to Day -1 
Day 1  
W4 
W8 
W12 
W19 
W26 
W32 
W39 
W45 
W5211  
W5611  
ET 
UNS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Contact1 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AE/TEAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical Exam 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X2 
Vital Signs, Weight, Height3 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
ECG 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
X4 
Hematology5 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Biochemistry5 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Exploratory Biochemistry5 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
Hep B and Hep C Tests5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test6 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Back-up Blood Sample5 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
FibroScan®  
X 
 
 
 
 
 
 
 
 
 
X9 
 
X9 
 
MRI-PDFF 
X 
 
 
 
X 
 
X 
 
 
 
X9 
 
X9 
 
LiverMultiScan 
X 
 
 
 
X 
 
X 
 
 
 
X9 
 
X9 
 
MRE (where available)  
X 
 
 
 
 
 
 
 
 
 
X9 
 
 X9 
 
Liver Biopsy7 
X8 
 
 
 
 
 
 
 
 
 
X9 
 
  X9 
 
Study Drug Compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Study Drug Accountability 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Study Drug Dispensing 
 
X10 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
1. Subject contact will be performed over phone contact or email communication. A follow-up Unscheduled Visit may be scheduled if deemed necessary by investigator. 
2. Symptoms-directed (brief) physical examination is only allowed at an Unscheduled Visit. 
3. Height will be measured only at the initial screening visit. 
4. ECG will be performed at the Unscheduled visit only if the subject has cardiac-related symptoms. 
5. Blood will be collected after at least an 8-hour overnight fast and prior to dosing. If the subject forgets to fast, the site will continue to draw labs. Subjects should not be dosed with 
study drug until blood is collected. 
6. Applicable for women of childbearing potential only. 
7. PT, INR, and platelets must be performed with results available prior to performing any new liver biopsy.   
8. A new liver biopsy should only be performed on a potentially eligible subjects, based on screening labs and imagining (per Appendix A). If a potential subject had a liver biopsy 90 
days prior to the initial screening visit, and the pathology slides are available for review, the Baseline liver biopsy can be waived. 
9 The end of treatment (EOT) liver biopsy, MRI-PDFF, MRE, LiverMultiScan and FibroScan® should be performed 52 weeks (±1 week) from the Day 1 visit. 
10. The first dose of study drug will be administered onsite. 
11 Informed consent for the OLE may be obtained at either Week 52 or Week 56 for subjects still in the DB phase. The Week 56 visit may also serve as the Day 1 visit for the OLE if 
consent has been obtained and the OLE eligibility criteria are met. 
 
 
 


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Table 2: 
Schedule of Assessments – Open-Label Extension (OLE) Phase 
Visits (±7 days) 
Day 1 
OLE-W2 
OLE-W13 
OLE-W26 
OLE-W39 
OLE-W52 
(EOT) 
OLE-W56 
(EOS) 
OLE-ET 
OLE-UNS 
Informed Consent 1 
X1 
 
 
 
 
 
 
 
 
Eligibility Assessment2 
X1 
 
 
 
 
 
 
 
 
AE/TEAE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
X 
 
X 
X5 
Prior and Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Brief Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory Biochemistr3 
X 
X 
X 
X 
X 
X 
X 
X 
 
Back-up Blood Sample 3 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine Pregnancy Test 4 
X 
 
 
X 
 
X 
 
X 
 
Study Drug Compliance 
 
 
X 
X 
X 
X 
 
X 
X 
Study Drug Accountability 
 
 
X 
X 
X 
X 
 
X 
 
Study Drug Dispensing 
X 
 
X 
X 
X 
 
 
 
 
1. 
Informed Consent may occur at Week 52 or Week 56 in the DB phase if subject is still active in the DB phase.   
2. 
Eligibility Assessment may occur on or any time after the Week 56 visit in the DB phase and after informed consent.   
3. 
An Unscheduled Visit for laboratory assessment for OLE eligibility if more than 45 days have elapsed from the Week 56 laboratory results from the DB phase. The results must be available prior to 
the Day 1 visit 
4. 
Applicable for women of childbearing potential only. 
5. 
ECG will be performed at the Unscheduled visit only if the subject has cardiac-related symptoms. 
 
 


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Table 3: 
Schedule of Assessments – Safety Follow Up Extension (SFU) Phase 
Study Periods 
SFU 
Visit(s) 
Phone Contact 
UNS 
Informed Consent1 
X 
 
 
Subject Contact2 
X 
X2 
 
Medical History 
X 
 
X 
AE/TEAE 
X 
X 
X 
Prior and Concomitant Medications 
X 
X 
X 
Complete Physical Exam 
X 
 
X 
Vital Signs, Weight 
X 
 
X 
Hematology3 
X 
 
X 
Biochemistry3 
X 
 
X 
Exploratory Biochemistry3 
X 
 
X 
Back-up Blood Sample3 
X 
 
X 
FibroScan® 
X4 
 
X5 
Liver Biopsy6 
X4 
 
X5 
1. Informed consent for the Safety Follow Up (SFU) must be obtained before doing any of the procedures but may occur on or after the Week 52 or Early Termination visit.  
2. Subject contact will be performed over phone contact, approximately every 12 weeks. A follow-up Unscheduled Visit may be scheduled if deemed necessary by investigator 
3. Blood will be collected after at least an 8-hour overnight fast. If the subject forgets to fast, the site will continue to draw labs.  
4. The SFU FibroScan® and liver biopsy should be performed 6 months (±4 week) from the Week 52 or Early Termination visit. 
5. An additional FibroScan® and/or liver biopsy may be considered if subject’s histological findings, other than NASH, have not resolved or stabilized. 
6. Prothrombin time (PT), International Normalized Ratio (INR), and platelets must be performed with results available prior to performing any new liver biopsy. 
 
 
 


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1 
INTRODUCTION  
1.1 
NASH  
Nonalcoholic steatohepatitis (NASH) defines a subgroup of nonalcoholic fatty liver disease where 
steatosis coexists with hepatic cell injury (apoptosis and hepatocyte ballooning), and inflammation 
(Chalasani et al., 2012). NASH is closely associated with overweight/obesity, type 2 diabetes 
mellitus, and cardiometabolic conditions that define the metabolic syndrome (Ratziu et al., 2010). 
Because of the prevalence of these comorbidities, NASH is emerging as the most common chronic 
liver disease. 
NASH promotes liver fibrosis and some patients progress to cirrhosis, liver failure, hepatocellular 
carcinoma, or require liver transplantation (Vernon et al., 2011). Compared with the general 
population, liver-related mortality is increased 10-fold in NASH patients (Ekstedt et al., 2006). 
NASH is also a multisystem disease that could worsen insulin resistance, the metabolic syndrome, 
and systemic inflammation (Yki-Jarvinen et al., 2014). Consequently, NASH patients also have an 
increased rate of cardiovascular events. and the leading cause of death is cardiovascular events 
(Vernon et al., 2011). 
There are currently no approved therapies for NASH. 
1.2 
Seladelpar 
1.2.1 Overview 
Seladelpar is a potent and selective PPAR- agonist. Seladelpar is being developed for the 
treatment of primary biliary cholangitis (PBC) in subjects with inadequate response to 
ursodeoxycholic acid (UDCA) or who are intolerant to UDCA, for the treatment of homozygous 
familial hypercholesterolemia (HoFH), and NASH. Seladelpar could also be developed for other 
disorders of lipid metabolism or disorders characterized by chronic intra-hepatic cholestasis. 
1.2.2 Mechanism of Action 
Seladelpar is a potent and selective peroxisome proliferator receptor delta (PPAR-) agonist, and 
is a key regulator of lipid metabolism, cholesterol transport, bile acid synthesis, and 
inflammation/fibrosis. Ligand binding to PPAR- results in activation and repression of its target 
genes by which it regulates the above processes. In the liver, PPAR- is expressed in hepatocytes, 
cholangiocytes, Kupffer and stellate cells (Iwaisako et al., 2012; Xia et al., 2012).  
The activity of seladelpar in NASH was studied in a diabetic, dyslipidemic obese mouse model 
(the foz/foz mouse model; Haczeyni et al., 2017). Seladelpar reversed NASH pathology and 
reduced fibrosis while improving insulin sensitivity and decreasing inflammation. These effects 
appear to be a consequence of its effects on lipid metabolism including reduction of lipotoxic 
species, which are key pathological drivers of NASH and fibrosis. 
For more detailed information, see the Seladelpar Investigator’s Brochure. 
1.2.3 Seladelpar in NASH 
In a preclinical diabetic obese mouse model of nonalcoholic steatohepatitis (NASH), the foz/foz 
mouse model (Haczeyni et al., 2017), seladelpar reversed NASH in all treated mice, and completely 


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eliminated ballooning while reducing inflammation and steatosis. The activities observed with 
seladelpar treatment in mice included reduction in hepatic fat (including lipotoxic lipids, free and 
total cholesterol), reduction in staining for Kupffer cell and macrophage infiltrates, decreased 
collagen deposition, decreased serum levels of alanine aminotransferase (ALT), and reversal of 
hyperglycemia, hyperinsulinemia, and insulin resistance.   
In a phase 2 study of seladelpar in obese patients with mixed dyslipidemia, a population that is 
presumed to include patients with fatty liver disease, seladelpar treatment for 8 weeks decreased 
TG and LDL-C levels. Additionally, seladelpar decreased small dense pro-atherogenic LDL 
lipoproteins, increased HDL-C concentrations, and HOMA-IR, hs-CRP, ALP, and GGT 
(Bays et al., 2011; Choi et al., 2012). Thus, the cardiovascular, metabolic and anti-inflammatory 
activities observed in patients further justify the evaluation of seladelpar as a candidate for the 
treatment of NASH. 
The interim analysis of the 12-week primary endpoint for the DB phase of this ongoing study 
provided initial clinical experience with seladelpar in NASH patients. A total of 181 subjects, with 
biopsy-confirmed NASH and a liver fat content (LFC) greater than 10%, were randomized into the 
trial to receive either placebo or seladelpar 10 mg, 20 mg, or 50 mg once-daily. The enrolled 
subjects had established NASH with a mean NAFLD Activity Score (NAS) of 5.2 at baseline, with 
83% of subjects having stage 2 or stage 3 fibrosis and mean LFC by magnetic resonance 
imaging-proton density fat fraction (MRI-PDFF) of 21%. The primary endpoint was the relative 
change in LFC from baseline to 12 weeks. The study remains blinded and will continue to 52 weeks 
with assessments including a liver biopsy, non-invasive imaging evaluations, and biomarker 
assessments of inflammation and fibrosis. Changes in LFC as measured by MRI-PDFF at week 12 
demonstrated minimal reductions in liver fat that were not significant when compared to placebo. 
However, treatment with seladelpar resulted in robust and clinically meaningful reductions in 
markers associated with liver injury, including ALT, ALP and GGT, in a dose-dependent manner. 
Treatment with seladelpar also resulted in reductions in LDL-C and TG. There were no significant 
changes in high-density lipoprotein cholesterol. The most common (>5%) treatment emergent 
adverse events included nausea, constipation, dizziness, headache, gastroesophageal reflux disease 
and upper abdominal pain. The majority of treatment emergent adverse events (TEAE) were mild 
to moderate in severity and deemed unrelated to study drug. There were two serious adverse events 
that occurred after randomization through week 12, neither of which were deemed to be related to 
study drug. 
Based on the identified pharmacologic activities in vitro, in animals and in humans as well as the 
treatment effect and safety/tolerability profile to date, seladelpar represents a potentially important 
therapeutic option for the treatment of NASH. 
1.3 
Nonclinical Experience  
Please see the Investigator’s Brochure for details on the nonclinical studies conducted with 
seladelpar. 
1.4 
Human Experience 
Please see the Investigator’s Brochure for details on the clinical studies conducted with seladelpar. 


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1.5 
Rationale for Dose Selection in the DB Phase 
The proposed dosing for the DB phase of the study is 10, 20, and 50 mg administered once daily 
for up to 52 weeks.  
The clinical experience thus far with seladelpar at daily doses of 50 mg and 100 mg for 8 weeks in 
obese males and females with mixed dyslipidemia (Bays et al., 2011), and at a daily dose of up to 
200 mg for 3 weeks in healthy volunteers, indicates that seladelpar was well tolerated and appeared 
generally safe.  
The beneficial treatment effects in the dyslipidemia study (lowering of TG, LDL-C, free fatty acids, 
and hs-CRP) do not appear to be meaningfully better at 100 mg/day than at 50 mg/day. Because 
the baseline characteristics of the study population enrolled in the Phase 2 mixed dyslipidemia 
study (obese, hyperlipidemic, insulin resistant, hypertension) overlaps with the NASH population, 
it is anticipated that the beneficial metabolic effect of seladelpar at doses of 50 mg/day will be 
translated to the NASH population. Thus, this dose has been selected as the maximum dose to be 
studied in the proposed NASH study. 
In PBC, studies have indicated that seladelpar at dose of 2, 5, and 10 mg, retains a relevant clinical 
activity to improve markers of cholestasis, markers of inflammation, and improve metabolic 
markers. There was a dose ranging activity from 2 to 10 mg/day with 10 mg/day demonstrating the 
best risk/benefit profile. For these reasons, a seladelpar a dose of 10 mg/day has been selected for 
the proposed NASH study as the dose with a potentially minimal level of activity. 
The dose of 20 mg/day has been selected to complete the approximate 2-log dose range evaluation 
in the study. Given there are no approved treatments for NASH, the risks versus benefit of 
seladelpar in NASH patients at doses of 10, 20, and 50 mg/day is acceptable. 
1.6 
Rationale for Dose Selection in the OLE Phase 
The proposed seladelpar daily doses to be studied in the OLE phase of the study is 50 mg dosed 
daily for an additional 52 weeks. This dose and duration of exposure are supported by the estimated 
safety exposure margins from the repeat dose toxicity studies of 26 weeks in Sprague-Dawley rats 
and 52 weeks in cynomolgus monkeys (Table 4).  
Table 4: 
Estimated Safety Exposure Margin of Seladelpar for NASH 
Species 
Rat (26-week) 
Monkey (52-week) 
  
M 
F 
M 
F 
NOAEL (mg/kg/day) 
15 
80 
1 
5 
AUC (ng*h/mL) 
26,900 
77,300 
2,450 
12,000 
Margin (AUC) NASH – 50 mg 
9.9X 
28X 
0.9X 
4.4X 
AUC=area under the concentration versus time curve; NOAEL=no-observed-adverse-effect-level.  
The dose selection is further supported by the treatment effect and safety/tolerability at the 12-week 
primary endpoint interim analysis from the ongoing DB phase of this study. Although there was 
no significant reduction in liver fat content, seladelpar significantly decreased key markers of 
hepatic injury (ALT, ALP, GGT) in a dose dependent manner was the greatest magnitude of effect 
observed with the 50 mg dose (Table 5). ALT declined up to 37.5% or 32 U/L in 12 weeks. These 


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reductions in ALT are significantly greater than the 17 U/L threshold that has been correlated with 
histologic improvement in NASH. GGT also decreased significantly, suggesting a reduction in 
hepatocellular oxidative stress. Significant reductions in ALP at 12 weeks were observed, 
supportive of a decrease in hepatocellular bile acids. The marked changes in these liver enzymes 
collectively suggest the potential to impact ballooning and lobular inflammation, the two key 
components of NASH resolution. 
Table 5: 
Mean Relative Changes in Hepatic Injury Biomarkers Observed from 
Baseline to Week 12 in Study CB8025-21730 
%, LS Mean (SE) 
Placebo 
(n = 27) 
10 mg 
(n = 53) 
20 mg 
(n = 51) 
50 mg 
(n = 50) 
ALT 
-8.9 (5.1) 
p=0.08 
-22.9 (3.8) 
p<0.0001 
-32.0 (4.0) 
p<0.0001 
-37.5 (4.0) 
p<0.0001 
AST 
-12.9 (5.8) 
p=0.03 
-11.6 (4.4)  
p=0.009 
-15.2 (4.5) 
p=0.001 
-17.3 (4.5)  
p=0.0002 
GGT 
-4.5 (4.3) 
p=0.3 
-28.2 (3.2)  
p<0.0001 
-37.6 (3.3) 
p<0.0001 
-43.1 (3.4)  
p<0.0001 
AP 
4.4 (2.9) 
p=0.12 
-19.1 (2.1) 
p<0.0001 
-25.1 (2.2) 
p<0.0001 
-33.4 (2.2) 
p<0.0001 
* LS=Least Squares. SE=Standard error. P-values are for relative change from baseline. 
 
Seladelpar demonstrated a favorable safety and tolerability profile at all doses evaluated in this 
study. The most common (>5%) TEAEs in the overall total population are listed in Table 6. The 
majority of TEAEs were mild in severity and deemed unrelated to study drug. Lipid and metabolic 
parameters remained stable or improved, supportive of a favorable cardiovascular risk profile. In 
general, the TEAEs were comparable across the dosing groups, with no overt safety signals to 
suggest the 50 mg dose is more poorly tolerated than the overall study population. 
 
 


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Table 6: 
Most Common (>5%) Treatment Emergent Adverse Events Observed from 
Baseline to Week 12 in Study CB8025-21730 
n (%) 
Placebo 
(n = 27) 
10 mg 
(n = 53) 
20 mg 
(n = 51) 
50 mg 
(n = 50) 
Total 
(n= 181) 
Arthralgia 
1 (3.7) 
3 (5.7) 
4 (7.8) 
2 (4.0) 
10 (5.5) 
Abdominal Pain 
(Upper) a 
- 
- 
- 
- 
11 (6.1) 
Constipation 
1 (3.7) 
3 (5.7) 
4 (7.8) 
4 (8.0) 
12 (6.6) 
Dizziness 
2 (7.4) 
3 (5.7) 
4 (7.8) 
2 (4.0) 
11 (6.1) 
Fatigue 
1 (3.7) 
2 (3.8) 
3 (5.9) 
3 (6.0) 
9 (5.0) 
GERD 
3 (11) 
4 (7.5) 
2 (3.9) 
3 (6.0) 
12 (6.6) 
Headache a 
- 
- 
- 
- 
14 (7.7) 
Nausea 
3 (11.1) 
7 (13.2) 
6 (11.8) 
6 (12.0) 
22 (12.2) 
Rash a 
- 
- 
- 
- 
9 (5.0) 
Upper Resp. Infection 
2 (7.4) 
5 (9.4) 
1 (2.0) 
2 (4.0) 
10 (5.5) 
Urinary Tract Infection 
- 
- 
- 
- 
10 (5.5) 
Worsening T2D 
2 (7.4) 
4 (7.5) 
1 (2.0) 
3 (6.0) 
10 (5.5) 
Vomiting 
1 (3.7) 
1 (1.9) 
4 (7.8) 
3 (6.0) 
9 (5.0) 
a Certain TEAEs presented as study total in order to not unblind the specific dosing groups  
 
In summary, the aggregate of the nonclinical and clinical data to date support the 50 mg dose as 
the selected single dose in the OLE in order to optimally assess the long-term continued safety and 
tolerability at the dose with greatest magnitude of effect on relevant biomarkers. 
1.7 
Rationale for SFU Phase 
A key secondary endpoint of the current study is change from Baseline in fibrosis and NASH 
histology at Week 52/End of Treatment. As part of the assessment plan for the histologic 
endpoint, an initial batch 52-week biopsies (n=112) were grouped for pathology review. Two 
highly experienced NASH pathologists, blinded to study treatment, convened on 20 November 
2019 to initiate the reading of the initial Week 52/End of Treatment biopsy slides. The 
NASH-CRN scoring system for NASH and fibrosis was used as well as the identification of any 
portal inflammation or other significant non-NASH incidental findings. Upon reading the initial 
set of slides, the pathologists identified significant non-NASH histologic findings in 31 subjects. 
These findings included histopathology consistent with interface hepatitis, bile duct injury and/or 
porto-sinusoidal vascular disease (PSVD) and were described as concerning and atypical in 
NASH.  
In contrast to the histological findings, there were no biochemical signals of drug-induced liver 
disease or injury during the study period. A review of TEAEs in subjects with histological 
findings did not reveal any outlier events and were consistent with the full population. In 


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addition, no significant liver-related adverse effects or clinical evidence of hepatic 
decompensation have been observed in the full population dosed to date, nor in the 31 subjects 
with histological findings.  
These findings were reported to the FDA, and upon review a decision was made to terminate and 
unblind the Phase 2 studies in NASH (CB8025-21730). Follow-up correspondence from the FDA 
has requested CymaBay to obtain additional histologic, laboratory and imaging assessments in 
order to assess the resolution or persistence of the histologic findings as well potentially identify 
any predictive markers for these unexpected events. Information collected during the SFU phase 
will be used to assess on-going subject safety. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
1. To evaluate the effect of seladelpar on hepatic fat fraction, as assessed by magnetic resonance 
imaging-proton density fat fraction (MRI-PDFF) at Week 12 in the DB phase 
2. To evaluate the safety and tolerability of seladelpar in subjects with NASH in the DB, OLE 
and SFU phases 
1.2 
Secondary Objectives 
1. To evaluate the effect of seladelpar on MRI-PDFF at Week 26 and Week 52 in the DB phase 
2. To evaluate the effect of seladelpar on histological improvement of NAFLD activity score 
(NAS) at week 52 in the DB phase 
3. To evaluate the effect of seladelpar on histological improvement of fibrosis at week 52 in the 
DB phase 
4. To evaluate the effect of seladelpar on metabolic biochemical markers and biochemical markers 
of inflammation over 52 weeks of treatment in the DB and OLE phases 
2.3 
Exploratory Objectives 
1. To evaluate the effect of seladelpar on biochemical markers of fibrosis in the DB and OLE 
phases 
2. To evaluate the effect of seladelpar on fibrosis and inflammation as assessed by magnetic 
resonance elastography (MRE) and LiverMultiScan (LMS) in the DB phase 
3. To evaluate AST/platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score in the DB and OLE 
phases 
4. To assess markers of target engagement as measured by 7-α-hydroxy-4-cholesten-3-one (C4), 
serum bile acids and fatty acid oxidation (FAO tests) in the DB and OLE phases 
5. To evaluate histology, biochemical markers and imaging parameters during the SFU phase in 
subjects with significant histologic findings on the Week 52 or Early Termination (ET) liver 
biopsy 


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3 
STUDY DESIGN 
DB Phase 
This phase of the study is designed as a dosing ranging proof-of-concept study to evaluate the 
safety and potential efficacy effects of seladelpar on MRI-PDFF. The study includes liver biopsies 
to confirm that subjects have histological evidence of NASH at screening and to evaluate 
histological improvement in NASH and fibrosis after 52 weeks of treatment.  
Approximately 175 subjects will be randomly assigned to receive placebo, seladelpar 10 mg/day, 
seladelpar 20 mg/day or seladelpar 50 mg/day (1:2:2:2 ratio). Subjects will be stratified by diabetic 
status (yes/no) and fibrosis stage (F1 versus F2-3). Study drug (placebo or seladelpar) will be taken 
in a blinded manner orally once a day for a period of 52 weeks.  
The screening period will be up to 10 weeks, the blinded treatment period will be up to 52 weeks, 
and a follow-up period of 4 weeks after the last dose of study drug. During the treatment period, 
the first on-treatment visit will occur 4 weeks after initiation of the study drug. Subjects will then 
be evaluated in clinic every 4 weeks until Week 12. After Week 12, visits will be 6-7 weeks apart.  
Subjects will also be contacted by phone or email at Weeks 19, 32 and 45. The amount of fat in the 
liver will be evaluated by MRI-PDFF at baseline, Weeks 12, 26, and 52. A liver biopsy will be 
performed twice during the study: at baseline and at Week 52.  
The primary efficacy analysis will be the change from baseline to Week 12 in MRI-PDFF. The 
study will continue in a blinded fashion until the Week 52 biopsy is collected.  
OLE Phase 
All subjects who participate in the DB phase, complete the 52-week biopsy and the 56-week 
follow-up labs, and meet the specified enrollment criteria will be offered participation in the OLE 
phase of the study. Subjects will not be required to have any additional liver histology, imaging or 
elastography assessments for enrollment or on-treatment assessments of treatment effect. The OLE 
Day 1 visit may be combined with the Week 56 visit in the DB phase. Informed Consent may occur 
at Week 52 or Week 56 in the DB phase for subjects still active in the DB phase or any time prior 
to any OLE procedures in patients who have completed the DB phase. Eligibility assessment may 
occur on or after the Week 56 in the DB phase. Laboratory assessment for OLE suitability may be 
required if more than 45 days have elapsed since last lab collection to anticipated first OLE dosing. 
If greater than 45 days have elapsed since the last lab collection, subjects must complete an 
unscheduled visit where all labs collected at Week 56 will be retested, with the results available 
and assessed prior to the Day 1 visit. Subjects must also be clinically stable based on the 
investigator’s medical judgement and key enrollment criteria to enter the OLE. Clinic visits during 
the 52-week OLE phase will occur at Day 1 and Weeks 2, 13, 26, 39 and 52 with a final EOS visit 
at approximately Week 56 visit. The primary objective of the OLE phase is to assess long-term 
safety and treatment effect as measured by biochemical tests after an additional 52 weeks of 
treatment. 
 
 
 
 


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SFU Phase 
All subjects who participated in the DB phase that have significant histologic findings other than 
NASH on the Week 52 or ET liver biopsy and received active seladelpar for at least 6 months 
will be asked to enroll in the SFU phase. Subjects in the placebo dosing group will not be 
enrolled into the SFU phase. After informed consent is obtained, an SFU visit will be performed 
at a minimum of 6 months after the Week 52 or ET liver biopsy. A repeat liver biopsy will be 
obtained to reassess the status of the original significant histologic findings. Other study 
procedures performed during the visit include a physical exam, vital signs, safety laboratory 
assessments, exploratory liver injury biomarker assessments, and FibroScan®. Subjects with 
resolution or stabilization of the observed histologic findings will have completed the SFU phase, 
and no further visits or assessments will be required. Subjects worsening of the observed 
histologic findings will be followed up by phone at 3-month intervals and may be requested to 
have additional SFU visits with a repeat of some or all of the above procedures. 
 


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4 
STUDY POPULATION 
4.1 
DB Phase Eligibility Criteria 
Inclusion Criteria 
1. Must be able to provide written informed consent (signed and dated) and any authorizations 
required by local law 
2. 18 to 75 years old (inclusive) 
3. Histological evidence of definite NASH on a liver biopsy (obtained during the screening period 
or historical liver biopsy obtained no more than 90 days prior to the initial screening visit) 
4. NAS of 4 points or greater with a score of at least 1 point in each component (steatosis, lobular 
inflammation, and ballooning) 
5. Fibrosis stage 1, 2, or 3 on liver biopsy 
6. MRI-PDFF ≥ 10%  
7. Females of reproductive potential must use at least one barrier contraceptive and a second 
effective birth control method during the study and for at least 30 days after the last dose of 
study drug. Male subjects who are sexually active with female partners of reproductive 
potential must use barrier contraception and their female partners must use a second effective 
birth control method during the study and for at least 90 days after the last dose of study drug. 
Exclusion Criteria  
1. Significant alcohol consumption, defined as more than 2 drink units per day (equivalent to 20g) 
in women and 3 drink units per day (equivalent to 30g) in men, or inability to reliably quantify 
alcohol intake 
2. Treatment with drugs associated with NAFLD (amiodarone, methotrexate, oral glucocorticoids 
at doses greater than 5 mg/day, tamoxifen, estrogens at doses greater than those used for 
hormone replacement or contraception, anabolic steroids (such as testosterone) and valproic 
acid for more than 4 weeks within the last 2 months prior to the initial screening 
3. Treatment with pioglitazone or high-dose vitamin E (>400 IU/day) within the last 2 months 
prior to the initial screening  
4. Initiation of treatment with a glucagon-like peptide-1 (GLP-1) agonist or a dose change within 
the last 2 months prior to the initial screening 
5. Prior or planned bariatric surgery (a prior reversed sleeve gastrectomy is permitted) 
6. Poorly controlled type 2 diabetes mellitus as defined by hemoglobin A1c (HbA1c) of 9.5% or 
higher or type 1 diabetes mellitus 
7. Diabetic patients who are taking sodium/glucose cotransporter 2 (SGLT-2) inhibitors must be 
on a stable dose within 2 months prior to the initial screening and throughout the study 
8. Significant weight loss within the last 6 months (e.g., > 10%) 
9. Use of any weight loss medication 3 months prior and during the study period 
10. Body mass index (BMI) < 18.5 kg/m2 


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11. Hepatic decompensation defined as the presence of any of the following:  
• Serum albumin less than 3.5 g/dL 
• INR greater than 1.4 unless due to therapeutic anticoagulants 
• Total bilirubin greater than 2 mg/dL with the exception of Gilbert syndrome 
• History of esophageal varices, ascites, or hepatic encephalopathy 
12. Other chronic liver diseases: 
• Active hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg) 
• Active hepatitis C as defined by presence of hepatitis C virus antibody (HCV) plus a 
positive HCV RNA  
• History or evidence of current active autoimmune hepatitis  
• History or evidence of PBC 
• History or evidence of primary sclerosing cholangitis 
• History or evidence of Wilson’s disease  
• History or evidence of alpha-1-antitrypsin deficiency  
• History or evidence of hemochromatosis 
• History or evidence of drug-induced liver disease, as defined by exposure and history 
• Known bile duct obstruction 
• Suspected or proven liver cancer 
13. ALT > 200 U/L 
14. AST < 20 U/L 
15. Creatine kinase > upper limit of normal (ULN) 
16. Serum creatinine > ULN 
17. Platelet < lower limit of normal (LLN) 
18. Inability to obtain a liver biopsy 
19. History of biliary diversion 
20. Known history of human immunodeficiency virus (HIV) infection 
21. History of malignancy diagnosed or treated within 2 years 
• Recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted 
• Cervical carcinoma in-situ is allowed if appropriately treated prior to Screening 
• Participants under active evaluation for malignancy are not eligible 
22. Active substance abuse, based on Investigator judgment, including inhaled or injected drugs, 
within 1 year prior to the initial screening 
23. Females who are pregnant or breastfeeding 
24. Patients unable to undergo MRI-PDFF due to: 
• Contraindication to MRI examination  


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• Severe claustrophobia impacting ability to perform MRI during the study, despite mild 
sedation/treatment with an anxiolytic 
• Weight or girth exceeds the scanner capacities 
25. Treatment with any other investigational therapy or device within 30 days or within five 
half-lives, whichever is longer, prior to the initial screening 
26. Active, serious medical disease with likely life expectancy <5 years 
27. Any other condition(s) that would compromise the safety of the subject or compromise study 
quality, as judged by the Investigator. 
4.2 
OLE Phase Enrollment Criteria Assessment 
Subjects must fulfill the following before allowing to start OLE dosing: 
• Provided informed consent to enter OLE phase on or before Day 1, prior to any procedures 
being performed. Consent may be obtained at Week 52 or Week 56 in the DB phase for 
subjects who have not completed the DB phase. Consent can be obtained after Week 56 in 
any subject who has completed the DB phase but must be prior to any OLE related study 
procedures. 
• Complete the Week 52 biopsy and Week 56 lab assessments in the DB phase  
• Meet the above Inclusion and Exclusion Criteria before Day 1 of the OLE phase, with the 
exception of the following: 
o AST <20 U/L 
o Inability to obtain a liver biopsy (no new biopsy required for OLE phase) 
o Unable to undergo MRI-PDFF (no imaging performed in OLE phase) 
Week 56 labs from the DB phase may be used for eligibility assessment if less than 45 days from 
OLE Day 1. If greater than 45 days, an Unscheduled visit must be performed to collect safety and 
eligibility labs. 
4.3 
SFU Phase Enrollment Criteria Assessment 
Subjects entering the SFU phase of the study must fulfill the following criteria: 
• Presence of significant histologic findings other than NASH on the Week 52 or Early 
Termination liver biopsy 
• Received seladelpar during the DB phase for at least 6 months.  
 
 


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5. 
STUDY OUTCOME MEASURES 
5.1 
Primary Outcome Measures 
1. Relative change in MRI-PDFF at Week 12 in the DB phase 
2. Adverse events (AEs) and treatment emergent adverse events (TEAEs), physical exams, vital 
signs, electrocardiograms (ECGs), biochemistry, hematology, and urinalysis as determined by 
investigator assessment for causality and grading by National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 in the DB, OLE and SFU 
phases 
5.2 
Secondary Outcome Measures 
1. Absolute change in MRI-PDFF at Week 12, 26, and 52 in the DB phase 
2. Relative change in MRI-PDFF at Week 26 and 52 in the DB phase 
3. Proportion of subjects with a relative decrease in MRI-PDFF ≥ 30% at Week 12, 26, and 52 in 
the DB phase 
4. Proportion of subjects with normalization of MRI-PDFF (defined as an absolute fat fraction of 
< 5%) at Week 12, 26, and 52 in the DB phase 
5. Proportion of subjects with an absolute MRI-PDFF change > 5% at Weeks 12, 26, and 52 in 
the DB phase 
6. Proportion of subjects with reversal of NASH and no worsening of hepatic fibrosis at Week 52 
in the DB phase. The reversal of NASH is defined as the absence of hepatocellular ballooning 
(score of 0) and no or minimal inflammation (score of 0 or 1)  
7. Proportion of subjects with improvement by at least one stage in fibrosis without worsening of 
NASH in the DB phase 
8. Proportion of subjects with a 2-point improvement in NAS in the DB phase 
9. Percent and absolute change in alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), gamma-glutamyl transferase (GGT) in the DB and OLE phases 
10. Percent and absolute change in total cholesterol (TC), high-density lipoprotein cholesterol 
(HDL-C), and low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein 
cholesterol (non-HDL), homeostatic model assessment of insulin resistance (HOMA-IR) in the 
DB and OLE phases 
11. Percent and absolute change in high-sensitivity C-reactive protein (Hs-CRP) and fibrinogen in 
the DB and OLE phases 
5.3 
Exploratory Outcome Measures 
1. APRI and FIB-4 in the DB and OLE phases 
2. Enhanced Liver Fibrosis (ELF) score and its components (hyaluronic acid [HA], procollagen 
III N-terminal peptide [PIIINP], tissue inhibitor of matrix metalloproteinases [TIMP-1]) in the 
DB and OLE phases 
3. MRE changes at Week 52 in the DB phase 


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4. LMS (iron corrected T1 – cT1) changes at Week 12, 26, and 52 in the DB phase  
5. FibroScan® changes (kPa and CAP) at Week 52 and at SFU visits 
6. C4, serum bile acids and FAO tests in DB and OLE phases 
5.4 
Safety Outcome Measures 
In those subjects with significant histological findings other than NASH in the of treatment biopsy 
(Week 52 or Early Termination), resolution, worsening or no change in significant histologic 
findings on biopsy at the SFU visits. 
 
 


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6 
STUDY MEDICATIONS  
6.1 
Clinical Supplies 
6.1.1 Investigational Product, Dosage, and Mode of Administration 
In the DB phase, seladelpar will be supplied in a blinded fashion in 5 mg, 10 mg, and 25 mg 
capsules. Matching placebo capsules will also be provided.  
The study drug (seladelpar or placebo) will be administered orally, once daily. The subject will 
take 2 capsules daily, approximately at the same time each day. If dose adjustment occurs, the study 
drug might be administered at doses of 5 mg, 10 mg, and 25 mg. In case of dose adjustment, the 
subject will take 1 capsule daily. 
In the OLE phase, Seladelpar will be supplied only as 25 mg capsules. No placebo capsules will 
be provided. 
6.1.2 Packaging, Labeling and Shipping 
The Sponsor will provide the Investigator with packaged study drug labeled in accordance with 
specific country regulatory requirements. For the subjects who meet the criteria for dose adjustment 
(per Section 7.4), the subject will be instructed to use the same study drug kit but take 1 capsule 
per day instead of 2 capsules per day. 
6.1.3 Accountability of Clinical Supplies  
The Investigator or a designee will keep a record of the dates and amounts of study medication 
received, the amount dispensed to study subjects, and the amount unused. 
6.1.4 Stability of Study Medication 
All supplies of medication must be stored as defined on the primary packaging to ensure quality. 
6.2 
Randomization 
Randomization will only be done in the DB phase. Subjects will be centrally randomized in a 
blinded manner to placebo or seladelpar in a 1:2:2:2 scheme (placebo: seladelpar 10 mg: 20 mg: 
50 mg). In addition, randomized subjects will be stratified by diabetic status (yes/no) and fibrosis 
stage (Stage F1 vs. Stage F2-3). 
6.2.1 Randomization/Registration Procedure 
Once all laboratory, imaging evaluations and liver biopsy report are available and the subject has 
been confirmed to meet all the inclusion and none of the exclusion criteria, the subject will be 
invited to Day 1 visit (Baseline). Randomization will occur at Day 1 visit via a centrally 
administered Interactive X Response Technology System (IXRS) and dosing will be initiated. 
6.2.2 Emergency Unblinding 
In the event of a medical emergency, where knowledge of the subject’s treatment assignment is 
necessary per the medical judgment of the Investigator, the Investigator or the Sponsor can break 
the blind. The unblinding must be clearly justified and explained by a comment in the source 


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documentation, along with the date on which the code was broken and the identity of the person 
authorizing the unblinding.  
6.3 
Method of Administration and Compliance  
Study drug (seladelpar or placebo) will be dispensed on Study Day 1, and at Weeks 4, 8, 12, 26 
and 39 in the DB phase. Subjects will be instructed to take study drug orally once daily. 
Study drug (seladelpar) will be dispensed on Study Day 1, and at OLE Weeks 13, 26 and 39 of the 
OLE phase. 
Compliance with study drug administration and study drug accountability will be evaluated on all 
study visits during the treatment period, between Study Day 1 and the Week 52 End of Treatment 
(EOT) visit. Compliance and accountability will also be performed on the Early Termination Visit 
(if applicable). 
6.4 
Concomitant Medications and Procedures  
The use of concomitant medications or procedures (defined below), must be documented on the 
subject’s electronic Case Report Form (eCRF). AEs related to the administration of these 
medications or procedures must also be documented on the appropriate section in the eCRF. 
6.4.1 Concomitant Medications  
A concomitant medication is any drug or substance other than the study drug (seladelpar or 
placebo), including over-the-counter medications, herbal medications, and vitamin supplements, 
administered during subjects’ participation in this trial.  
Subjects will be instructed about a healthy lifestyle and appropriate diet to follow during study 
participation. 
6.4.1.1 Permitted Concomitant Medications  
• Hypertension, hyperlipidemia and type 2 diabetes mellitus will be managed in conjunction 
with the subject’s treating physician 
• GLP-1 agonists are permitted, if taken at a stable dose. SGLT-2 inhibitors should be kept 
at a stable dose whenever possible, but dose changes may be considered in consultation 
with the medical monitor 
• There are no restrictions on these concomitant medications during the SFU phase 
6.4.1.2 Prohibited Concomitant Medications 
The following medications are prohibited during the DB and OLE phases only: 
• Obeticholic acid 
• Fibrates (e.g., fenofibrate) 
• High-dose Vitamin E (> 400 IU/day) 
• Pioglitazone 
• Weight loss medications 3 months prior to and during the study period 


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6.4.2 Concomitant Procedures  
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) or 
diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed during subjects’ 
participation in this trial. Subjects will be allowed to receive required procedures to treat new or 
existing medical conditions. 
 
 


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7 
STUDY PROCEDURES  
7.1 
Study Schedule for DB Phase 
The schedule of study procedures is presented in Table 1. 
The total duration of a subject’s participation is up to 66 weeks, during the DB phase, and consists 
of the following periods: 
• Screening: Up to 10 weeks 
• Treatment: Up to 52 weeks 
• Follow-up: 4 weeks 
Visits which occur within ± 7 days of the planned date will not be considered as protocol violations.  
Imaging and biopsy procedures that occur out of window (more than ± 7 days of the planned visit 
date) will be considered as protocol violations.  Additional visits may be scheduled to evaluate an 
abnormal laboratory value or reported AE.  
7.1.1 DB Screening (Week -10 to Day -1) 
All screening procedures must be completed within 10 weeks. After signing an informed consent 
form (ICF), the following screening procedures will be performed: 
• Medical history, including: 
o NASH history and detailed treatment history 
o Review of medications and prior procedures 
o Alcohol consumption review as relates to Eligibility Criterion #1 
o Results of prior liver biopsies and FibroScan®  
o Concomitant medications used in the last 6 months, including any anti-NASH, 
antidiabetic, statin, and fibrate medications, pioglitazone and Vitamin E 
o The subject’s medical chart will be reviewed for evidence of other forms of chronic 
liver disease (as per Eligibility Criterion #11 & 12), as well as for HIV infection 
• Vital signs, weight and height will be collected 
• Complete physical examination will be performed prior to Day 1 
• 12-lead ECG will be performed 
• Fasting blood samples for hematology and biochemistry, hepatitis B and hepatitis C, and 
serum pregnancy test in women of childbearing potential will be collected 
• A back-up blood sample will be collected  
• FibroScan® will be performed  
• AEs occurring after the ICF is signed will be recorded 
• Subjects will be instructed about a healthy lifestyle and appropriate diet to follow during 
study participation 


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• Subjects who are eligible for the study based on the review of medical history, concomitant 
medications, procedures, and laboratory parameters will be invited to have imaging tests 
performed, including: 
o MRI-PDFF 
o LMS 
o MRE (at selected centers where MRE are available) 
o Laboratory tests can be repeated at the Investigator’s discretion. PT, INR, and 
platelets must be performed and results available per the window specified by the 
local biopsy center. 
• Baseline Liver Biopsy: Subjects who meet all non-biopsy related inclusion criteria and none 
of the exclusion criteria will be invited to have a liver biopsy (if not already available as 
per Inclusion Criterion #3). Subjects that have had a liver biopsy done previously per 
standard of care within 90 days of the initial screening visit, and if the pathology slides are 
available for review and of an adequate quality, the Baseline liver biopsy can be waived  
For more detailed information about screening activities, please refer to Appendix A. 
Once results of the Baseline liver biopsy are available, the subject’s eligibility will be confirmed. 
Subjects who meet all inclusion criteria and none of the exclusion criteria will be invited to DB 
Day 1 (Baseline) visit.  
7.1.2 DB Day 1 (Baseline) Visit 
• Randomization 
• AEs since the last visit will be evaluated 
• Medication history, including baseline medications and procedures since last visit will be 
reviewed  
• Vital signs and weight will be collected 
• Complete physical examination will be performed 
• 12-lead ECG will be performed 
• Fasting blood samples for hematology, biochemistry, exploratory biochemistry, serum 
pregnancy test in women of childbearing potential will be collected (pre-dose of study drug) 
• Back-up blood sample will be collected 
• Study drug will be dispensed per the subject’s randomization with instructions to take orally 
once a day. The first dose of study drug will be administered onsite. 
• Subjects will be instructed about a healthy lifestyle and appropriate diet to follow during 
study participation 
If a subject terminates study participation at any point after Day 1, an Early Termination Visit will 
be completed. 


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7.1.3 DB Week 4 and Week 8 Visits 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Vital signs and weight will be collected 
• Complete physical examination will be performed 
• Fasting blood samples for hematology, biochemistry, and exploratory biochemistry will be 
collected (pre-dose of study drug) 
• Back-up blood sample will be collected  
• Compliance with study drug administration and drug accountability will be evaluated 
• 
Additional study drug will be dispensed 
7.1.4 DB Week 12 Visit 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Vital signs and weight  
• Complete physical examination will be performed 
• Fasting blood samples for hematology, biochemistry, exploratory biochemistry, and serum 
pregnancy test in women of childbearing potential will be collected (pre-dose of study drug) 
• Back-up blood sample will be collected  
• Compliance with study drug administration and drug accountability will be evaluated 
• Additional study drug will be dispensed  
• MRI-PDFF LMS will be performed (as closely as possible to Week 12 visit, ±1 week from 
the planned visit date) 
7.1.5 DB Week 19, Week 32, and Week 45 Contact 
Subjects will be contacted by phone or email for the following: 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Compliance with study drug administration 
• After phone/email contact, Unscheduled Visit may be scheduled, if deemed necessary by 
Investigator  
7.1.6 DB Week 26 Visit 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 


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• Vital signs and weight will be collected 
• 12-lead ECG will be performed 
• Complete physical examination will be performed 
• Fasting blood samples for hematology, biochemistry, exploratory biochemistry, and serum 
pregnancy test in women of childbearing potential will be collected (pre-dose of study drug) 
• Back-up blood sample will be collected  
• Compliance with study drug administration and drug accountability will be evaluated 
• Additional study drug will be dispensed  
• MRI-PDFF LMS will be performed (as closely as possible to Week 26 visit, ±1 week from 
the planned visit date) 
7.1.7 DB Week 39 Visit 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Vital signs and weight will be collected 
• Complete examination will be performed 
• Fasting blood samples for hematology, biochemistry, and exploratory biochemistry, serum 
pregnancy test in women of childbearing potential will be collected (pre-dose of study drug) 
• Back-up blood sample will be collected 
• Compliance with study drug administration and drug accountability will be evaluated 
• Additional study drug will be dispensed  
7.1.8 DB Week 52 End of Treatment (EOT) Visit 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Vital signs and weight will be collected 
• Complete physical examination will be performed 
• Fasting blood samples for hematology, biochemistry, exploratory biochemistry, and serum 
pregnancy test in women of childbearing potential will be collected 
• Back-up blood sample will be collected 
• 12-lead ECG will be collected 
• Compliance with study drug administration and final drug accountability will be evaluated. 
Unused drug will be collected 
• FibroScan® will be performed as closely as possible to Week 52 visit (±1 week from 
planned Week 52 visit date) 


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• MRI-PDFF, LMS, and MRE (at selected centers) will be performed as closely as possible 
to Week 52 and as contemporaneously as possible to and no more than 2 weeks before or 
after the planned Week 52 visit date 
• A new liver biopsy will be performed ±1 week from the planned Week 52 visit date. PT, 
INR, and platelets must be collected and results available per the window specified by the 
local biopsy center. Week 52 biopsy will be performed  
• Subjects will discontinue DB study drug dosing at the Week 52 visit. No additional study 
drug should be taken after that visit and the imaging and/or biopsy procedure(s) must be 
done within 1 week of the Week 52 visit 
• Subjects may consent to the OLE phase at this visit 
7.1.9 DB Week 56 End of Study (EOS) Visit 
All subjects will be followed through the Week 56 visit in the DB phase or 4 weeks after their 
last dose of study drug:  
• Any previously dispensed study drug should be returned to site staff and accountability 
completed   
The following procedures will be performed: 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Vital signs and weight will be collected 
• Complete physical examination will be performed 
• 12-lead ECG will be performed 
• Fasting blood samples for hematology, biochemistry, exploratory biochemistry, serum 
pregnancy test in women of childbearing potential will be collected 
• Back-up blood sample will be collected 
• Subjects may consent to OLE phase at this visit if they have not consented at Week 52 
• The Week 56 DB study visit may be combined with Day 1 of the OLE 
• Complete pre-entry assessment for OLE 
• Dispense OLE study drug if eligible 
7.1.10 DB Early Termination (ET) Visit 
If a subject terminates study participation at any point after Day 1, an Early Termination Visit 
will be completed: 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Vital signs and weight will be collected 


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• Complete physical examination will be performed 
• 12-lead ECG will be collected 
• Fasting blood samples for hematology, biochemistry, exploratory biochemistry, serum 
pregnancy test in women of childbearing potential will be collected 
• Back-up blood sample will be collected 
• Compliance with study drug administration and drug accountability will be evaluated 
For subjects who terminated from study after Week 26, liver biopsy, MRI-PDFF, LMS and MRE 
(at selected centers) will be performed:  
• FibroScan® will be performed as close as possible to ET visit (±1 week from ET visit date). 
• MRI-PDFF, LMS and MRE will be performed as closely as possible to ET visit and as 
contemporaneously as possible to and no more than 1 week before or after the ET visit 
• Liver biopsy will be performed as closely as possible to ET visit (±1 week from ET visit 
date). PT, INR, and platelets must be performed with results available per the window 
specified by the local biopsy center 
Subjects that early terminate from the study will not be eligible for the OLE. 
7.1.11 DB Unscheduled (UNS) Visit 
Unscheduled visits may be conducted at the Investigator’s discretion and/or when repeat of 
laboratory assessments is needed. The following assessments may be performed if determined 
necessary by the investigator: 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Vital signs and weight will be collected 
• Fasting blood samples for biochemistry and hematology will be collected (pre-dose of study 
drug) 
• A brief symptom-directed physical examination  
• For subjects with symptoms suggestive for cardiac origin (e.g., chest pain), ECG will be 
performed.  
• Compliance to study drug will be evaluated 
• Additional assessments may be performed, as deemed necessary by the Investigator 
 
 


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7.2 
OLE Phase Study Schedule 
The schedule of study procedures is presented in Table 2. 
The total duration of a subject’s participation is up to 56 weeks during the OLE phase:  
OLE periods are: 
• OLE Treatment: Up to 52 weeks 
• OLE Follow-up: 4 weeks 
Visits which occur within ± 7 days of the planned date will not be considered as protocol violations.  
Imaging and biopsy procedures that occur out of window (more than ± 7 days of the planned visit 
date) will be considered as protocol violations.  Additional visits may be scheduled to evaluate an 
abnormal laboratory value or reported AE. 
Laboratory assessments from the DB phase Week 52 visit should be used to determine OLE 
eligibility if the DB phase Week 56 visit and OLE Day 1 visit are planned to be completed on the 
same day. Lab assessments from the DB Week 56 visit may be used for OLE eligibility assessment 
if less than 45 days from that visit. If greater than 45 days have elapsed from DB phase Week 56 
visit, subjects should complete an unscheduled visit where all lab assessments required for DB 
phase Week 56 are retested. The results from the re-test must be available and assessed for 
eligibility prior to the Day 1 visit. 
7.2.1 OLE Day 1 Visit 
• Review enrollment eligibility criteria 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Symptom-driven physical examination, vital signs and weight 
• Fasting blood samples for hematology, biochemistry, exploratory biochemistry, and serum 
or urine pregnancy test in women of childbearing potential will be collected   
• Back-up blood sample will be collected 
• 
Dispense study drug  
7.2.2 OLE Week 2, Week 13, Week 26, Week 39 Visit 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Symptom-driven physical examination vital signs and weight 
• Fasting blood samples for hematology, biochemistry, and exploratory biochemistry 
• Urine pregnancy test in women of childbearing potential (Weeks 13 and 26 only)   
• Back-up blood sample will be collected 
• Compliance with study drug administration and drug accountability will be evaluated. 
Unused drug will be collected (Weeks 13, 26, 39 only) 


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• Dispense new study drug (Weeks 13, 26, 39 only) 
7.2.3 OLE Week 52 End of Treatment (EOT) or Early Termination Visits 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Symptom-driven physical examination, vital signs and weight 
• 12-lead ECG will be performed 
• Fasting blood samples for hematology, biochemistry, and exploratory biochemistry 
• Urine pregnancy test in women of childbearing potential will be collected   
• Back-up blood sample will be collected 
• Compliance with study drug administration and final drug accountability will be evaluated. 
Unused drug will be collected 
• Any unused study drug should be returned at this visit. 
7.2.4 OLE Week 56 End of Study (EOS) Visit 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Symptom-driven physical examination, vital signs and weight 
• Fasting blood samples for hematology, biochemistry, and exploratory biochemistry 
• Back-up blood sample will be collected  
7.2.5 OLE Unscheduled (UNS) Visits 
Unscheduled visits may be conducted at the Investigator’s discretion and/or when repeat of 
laboratory assessments is needed. The following assessments may be performed if determined 
necessary by the investigator:  
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Vital signs and weight 
• Fasting blood samples for biochemistry and hematology 
• Symptom-directed physical examination, vital sign and weight 
• Compliance to study drug will be evaluated 
• Additional assessments may be performed, as determined by the Investigator 


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7.3 
SFU Phase Study Schedule 
 
The schedule of study procedures is presented in Table 3. 
The total duration of a subject’s participation is up to 1 year after the Week 52 or Early Termination 
liver biopsy. The initial SFU visit will be performed 6 months ± 4 weeks, from the date of the Week 
52 or Early termination liver biopsy. Subjects with worsening of the observed histologic findings 
will be followed up by phone at 3-month intervals and may be requested to have additional SFU 
visits with a repeat of some or all of the above procedures. 
7.3.1 SFU Visit 
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Vital signs and weight will be collected 
• Complete physical examination will be performed 
• Blood samples for hematology, biochemistry, exploratory biochemistry, and serum 
pregnancy test in women of childbearing potential will be collected. Back-up blood 
samples will be collected.  
• FibroScan® will be performed  
• A new liver biopsy will be performed ±1 week from the planned SFU visit date. PT, INR, 
and platelets must be collected and results available per the window specified by the local 
biopsy center.  
7.3.2 SFU Unscheduled (UNS) Visits 
Unscheduled visits may be conducted at the Investigator’s discretion and/or when repeat of 
laboratory assessments is needed. The following assessments may be performed if determined 
necessary by the investigator:  
• TEAEs will be evaluated 
• Concomitant medications and procedures since last visit will be reviewed 
• Vital signs and weight 
• Blood samples for biochemistry and hematology 
• Symptom-directed physical examination, vital sign and weight 
• Additional assessments may be performed, as determined by the Investigator 
7.4 
Study Assessments 
7.4.1 Medical History and Physical Examination  
In the DB phase, medical history at Screening will include NASH history, detailed treatment 
history, liver biopsy history, FibroScan® results, and a review of medications and prior procedures.  


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In the DB phase, complete physical examinations will include a full review of the following 
systems: general, skin, eyes, nose/sinuses, ears, mouth/throat, neck, breasts, and respiratory, 
cardiac, gastrointestinal, peripheral vascular, genitourinary, musculoskeletal, neurologic, mental 
health, endocrine and hematologic. 
Brief, symptom-directed physical examinations are allowed for Unscheduled visits in both study 
phases and for a condition that warrants the exam, as determined by the Investigator.  
Any clinically significant change in physical examination findings that occur after signing the ICF 
at the initial screening visit will be recorded as an AE.  
In the OLE phase, symptomatic-directed physical examinations will be performed at scheduled 
OLE clinic visits. 
In the SFU phase, complete physical examinations will include a full review of the following 
systems: general, skin, eyes, nose/sinuses, ears, mouth/throat, neck, breasts, and respiratory, 
cardiac, gastrointestinal, peripheral vascular, genitourinary, musculoskeletal, neurologic, mental 
health, endocrine and hematologic. 
7.4.2 Vital Signs and Weight/Height 
Vital sign measurements include temperature, heart rate, respiratory rate, and blood pressure, 
recorded in the sitting position after at least 5 minutes rest. Vital signs may be obtained more 
frequently if a condition develops that warrants additional monitoring. 
Height measurement will be performed at Baseline only; weight will be taken at each study visit 
per the Schedule of Assessments (Table 1 and Table 2). 
7.4.3 Electrocardiogram 
A 12-lead ECG will be obtained in supine position after at least 5 minutes of rest (DB phase only). 
7.4.4 Laboratory Tests  
Blood samples for laboratory testing will be collected after at least an 8-hour overnight fast and 
prior to dosing. If the subject forgets to fast, the site will continue to draw labs. Subjects should not 
be dosed with study drug until blood is collected. Additional details about sample collection, 
processing, handling and laboratory determination techniques are provided in the Laboratory 
Manual. If lab sample is not analyzable or reported for any reason, medical monitor will be 
consulted to assess whether a recollection/retest is required. 
Laboratory testing will be as follows: 
Biochemistry:  
Albumin, Aldolase, ALT, Amylase, ALP, AST, Bicarbonate, BUN/Urea, Chloride, CK (if 
> ULN, CK-BB, CK-MB, and CK-MM), Conjugated Bilirubin, Creatinine, eGFR, Free 
Fatty Acid, GGT, HDL-C, Insulin, LDH, LDL-C, Lipase, non-HDL, Potassium, Total 
Protein, Sodium, TC, TG, Total Bilirubin, Troponin I, Unconjugated Bilirubin, Venous 
Blood Glucose, Uric Acid 
 
 


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Hematology:  
Erythrocyte Count (RBC), Hemoglobin, Hematocrit, Leukocyte Count (white blood cell 
count [WBC]), WBC Differential (absolute and percentage), Platelets, PT/INR 
Exploratory Biochemistry: 
Fibrinogen, hs-CRP, ELF score, HA, PIII-NP, TIMP-1, C4, serum bile acids, FAO markers 
Back-Up Blood Sample:  
One of the blood samples collected at each study visit will be archived as a back-up sample. 
These samples can be stored for up to 5 years following completion of the study and used 
to measure drug levels, potential new biochemical markers, and/or to replace any missing 
or discarded samples.  
Serum Pregnancy Test: Serum pregnancy test in women of childbearing potential only.  
Hepatitis B and C Testing: At screening only. The tests will include HBsAg and HCV antibody 
and HCV RNA if HCV AB is positive. 
7.4.5 Liver Biopsy (DB and SFU Phases Only) 
A liver biopsy will be performed twice during the trial: during the screening period (Baseline liver 
biopsy), approximately Week 52 after the Baseline liver biopsy or after early termination visit (if 
withdrawn after Week 26 visit), and approximately 6 months after Week 52 or after early 
termination visit, in SFU phase for those subjects who have significant histological findings other 
than NASH (Table 3). 
Liver biopsy will be used to determine histological improvement in NASH and fibrosis. Liver 
biopsies will generally be obtained from the right lobe of the liver, however, if the Baseline biopsy 
is obtained from the left lobe, then the Week 52/ET liver biopsy must also be obtained from the 
left lobe. Biopsies should be performed using a 16G or larger biopsy instrument and samples should 
be at least 1.5 cm in length.  
Baseline Liver Biopsy: An eligible subject must have histological evidence of definite NASH on 
a liver biopsy and a NAS of 4 points or greater, with a score of at least 1 point in each component 
(steatosis, lobular inflammation, and ballooning). This will be used for enrollment into the DB 
phase. A new Baseline biopsy is not required for enrollment into the OLE phase. 
Subjects who meet all non-biopsy related inclusion criteria and none of the exclusion criteria will 
be invited to have a liver biopsy (if not already available as per Inclusion Criterion #3). If subjects 
had a liver biopsy done previously per standard of care but within 90 days prior to the initial 
screening visit, and if the pathology slides are available for review and of an adequate quality, the 
Baseline liver biopsy can be waived. 
Week 52/ET Liver Biopsy: The Week 52 and ET liver biopsy will be performed ± 1 week from 
the scheduled study visit.  
SFU Liver Biopsy: The SFU liver biopsy will be performed in eligible subjects at 6 months ±4 
weeks, from the Week 52/ET liver biopsy.  


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Pre-Liver Biopsy Instructions: The subject must have PT, INR and platelets performed with 
results available per the window specified by the local biopsy center. Subjects will be instructed, 
if possible, to fast 6 to 8 hours prior to the scheduled liver biopsy.  
Liver Biopsy Analysis: Central reader will review and analyze the tissue samples. The NAS and 
fibrosis score will be calculated using the NASH CRN criteria for the biopsies collected in the DB 
phase. The SFU biopsy will only be evaluated for persistence or resolution of the non-NASH 
significant histologic findings; NAS and fibrosis will not be scored on these samples. 
7.4.6 Imaging Tests  
7.4.6.1 MRE Exam (DB Phase Only) 
MRE exam will be used to evaluate liver fibrosis through a noninvasive imaging technique. As 
collagen deposition associated with fibrosis imparts parenchymal rigidity, the leading biomarker 
for assessing fibrosis is through elastography. MRE uses a modified phase-contrast pulse sequence 
to visualize rapidly propagating mechanical shear waves (typically delivered at around 60 Hz). 
Cross-sectional elastogram images will be created depicting the stiffness generated from the wave 
propagation information. Technically, elastography assessments can be accomplished with most 
magnetic resonance scanners by adding hardware to generate mechanical waves and adding 
specific software for acquisition and processing. Because the waves can be visualized and analyzed 
deep into the liver, MRE evaluates a large portion of the liver and can be performed in conjunction 
with conventional MRI. For these reasons, MRE is considered to be a reliable, highly accurate, and 
precise method for assessing hepatic fibrosis. 
Clinical sites will screen subjects for MRI safety and eligibility per institutional standards. 
MRE Exam Schedule and Timing: MRE will be performed at selected centers and only in the 
DB phase. Subjects will undergo two MRE exams. Clinical sites will determine the logistics of 
scheduling the MRE exam. 
• The first MRE exam will be performed during the screening period (prior to the invasive 
Baseline liver biopsy), as contemporaneously as possible to, and no more than 90 days from 
the Baseline liver biopsy  
• The second MRE exam will be performed as contemporaneously as possible to, and no 
more than 1 week before or after the Week 52/ET liver biopsy  
After completion of the exam, clinical sites will transfer MRE images to the Central MRI Reader.  
Pre-MRE Exam Instructions: Subjects will be instructed, if possible, to fast for 4 or more hours 
prior to the scheduled MRE exam but will be allowed to take necessary medications and small 
quantities of water. 
MRE Exam Analysis: Central MRI Reader will review and analyze images. The liver fibrosis 
(stiffness) will be calculated.  
7.4.6.2 MRI-PDFF Exam (DB Phase Only) 
MRI-PDFF exam will be used to quantify the hepatic proton density fat fraction noninvasively. 
The fat fraction is the proportion of mobile protons in liver tissue attributable to fat and thus, is a 
noninvasive magnetic resonance-based biomarker of liver triglyceride concentration. 


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To quantify the fat fraction, the MRI-PDFF exam will use a fast spoiled gradient recalled echo 
(FSPGR) sequence that uses a low flip angle to reduce T1 bias, acquires multiple echoes after a 
single excitation to measure and correct for T2*decay, and uses spectral modeling to address fat-
water and fat-fat signal interference effects. Using MR spectroscopy as the reference standard, the 
proposed MRI technique measures hepatic fat fraction accurately in human subjects at 1.5T or 3T 
and across different vendors. The technique provides high within-examination and 
between-examination precision. Linearity is maintained across the entire relevant biological range 
from <1% to >40% hepatic fat fraction. The technique is robust to minor variations in acquisition 
parameters, including those that may be encountered during usage in a clinical trial. 
The FSPGR sequence proposed for imaging-based hepatic fat fraction quantification can be 
implemented on any up-to-date clinical scanner and can be used at clinical centers with access to 
such a scanner. Moreover, the technique is imaging based and covers the whole liver, thus 
providing information on both the quantity and distribution of hepatic fat fraction. These 
characteristics represent critical advantages over the alternative technique of single-voxel proton 
MR spectroscopy to measure hepatic fat fraction in a multicenter clinical trial.  
Clinical sites will screen subjects for MRI safety per institutional standards and will determine the 
logistics of scheduling the MRI-PDFF exam. 
MRI-PDFF Exam Schedule and Timing: Subjects will undergo four MRI-PDFF examinations 
in the DB phase only. The goal will be to schedule the second, third, and fourth MRI exams at the 
same or similar time of day as the first MRI-PDFF exam. 
• The first MRI-PDFF exam will be performed during the screening period prior to the 
Baseline liver biopsy but as contemporaneously as possible to and no more than 90 days 
from the Baseline liver biopsy  
• The second MRI-PDFF exam will be performed as close as possible to the Week 12 visit 
(±1 week from planned visit date) 
• The third MRI-PDFF exam will be performed as close as possible to the Week 26 visit 
(±1 week from planned visit date) 
• The fourth MRI-PDFF exam will be performed as contemporaneously as possible to and 
no more than 1 week before or after the Week 52/ET Visit (if applicable) 
Pre-MRI-PDFF Exam Instructions: Subjects will be instructed, if possible, to fast for 4 or more 
hours prior to the scheduled MRI-PDFF exam. However, they will be allowed to take necessary 
medications and small quantities of water. 
MRI-PDFF Exam Performance: Subjects will be positioned supine with a phased-array coil 
centered over the liver. After localizing sequences, an axial multi-echo-echo two dimensional 
FSPGR sequence will be performed through the liver. Imaging parameters will be selected as 
appropriate for 1.5T or 3T scanners. After completion of the exam, clinical sites will transfer MRI 
images to the Central MRI Reader.  
MRI-PDFF Exam Analysis: The Central MRI Reader will review and analyze images. The 
analysts will place 3 regions of interest on a PDFF image. The fat fraction will be calculated from 
all pixel values within the selected regions of interest and reported as the average value for each 
image.  


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7.4.6.3 FibroScan® Exam (DB and SFU Phases Only) 
FibroScan® exam will be used to evaluate liver fibrosis through a noninvasive imaging technique. 
FibroScan® uses a modified ultrasound probe to measure the velocity of a shear wave. Cross-
sectional elastogram images will be created depicting the stiffness generated from the wave 
propagation information. FibroScan® is considered to be a reliable, highly accurate, and precise 
method for assessing hepatic fibrosis. 
Clinical sites will screen subjects for FibroScan® safety per institutional standards. 
FibroScan® Exam Schedule and Timing: Subjects will undergo FibroScan® exams at centers 
when the test is available. Clinical sites will determine the logistics of scheduling the FibroScan® 
exam. 
• The first FibroScan® exam will be performed during the screening period prior to the 
Baseline liver biopsy  
• The second FibroScan® exam will be performed as closely as possible to Week 52/ (±1 
week from planned Week 52 visit date)/±1 week from ET visit date (if applicable) 
• FibroScan® exam will be performed in conjunction with each SFU biopsy 
Pre-FibroScan Exam Instructions: Subjects will be instructed, if possible, to fast for 4 or more 
hours prior to the scheduled FibroScan® exam but will be allowed to take necessary medications 
and small quantities of water. 
FibroScan Exam Analysis: Local Reader will review and analyze scans.  
7.4.6.4 LMS Exam (DB Phase Only) 
LMS is a noninvasive medical imaging software tool which, combined with MRI, can be a 
diagnostic tool to assess patients with liver disorders. The LMS provides quantitative measure of 
liver fat, and correlates iron and fibro-inflammation using multi-parametric MRI. The tool is U.S. 
FDA 510(k) cleared to aid clinicians in the diagnosis of liver disorders and abnormalities.  
Clinical sites will determine the logistics of scheduling the LMS exam and follow any additional 
provided guidelines on the use of this imaging software tool. Subjects will undergo 
4 LiverMultiScan examinations during the DB phase only. 
• LMS Exam Schedule and Timing: Subjects will undergo 4 LMS examinations  
• The first LMS exam will be performed during the screening period (prior to the Baseline 
liver biopsy), as contemporaneously as possible to and no more than 90 days from the 
Baseline liver biopsy  
• The second LMS exam will be performed as close as possible to the Week 12 visit (±1 week 
from planned visit date) 
• The third LMS exam will be performed as close as possible to the Week 26 visit (±1 week 
from planned visit date) 
• The fourth LMS exam will be performed as contemporaneously as possible to and no more 
than 1 week before or after the Week 52/ET Visit (if applicable)  
LMS Exam Analysis: The Central MRI Reader will review and analyze images.  
 


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8 
ADVERSE EVENTS 
8.1 
General 
8.1.1 Definition of Adverse Events (AEs) 
An AE is any medical occurrence in a subject administered a pharmaceutical product in a clinical 
study, regardless of a causal relationship with this treatment. An AE can, therefore, be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not related to the medicinal 
product. 
An AE includes any condition (including a pre-existing condition) that: 1) was not present prior to 
study treatment, but appeared or reappeared following initiation of study treatment, or 2) was 
present prior to study treatment, but worsened during study treatment. This would include any 
condition resulting from concomitant illnesses, reactions to concomitant medications, or 
progression of disease states. Pregnancy should be documented as an adverse event and should be 
reported to the clinical monitor and to the Sponsor immediately upon learning of the event. 
Pregnancies will be followed up through delivery or termination of the pregnancy. 
8.1.2 Definition of Serious AEs (SAEs) 
A serious adverse event (SAE) is any medical occurrence that: 
• Results in death 
• Is life-threatening (was at risk of death) at the time of the event  
• Requires in-patient hospitalization or prolongation of an existing hospitalization 
• Results in persistent or significant disability/incapacity defined as a substantial disruption 
of a person’s ability to conduct normal life functions 
• Is a congenital anomaly/birth defect 
• Is an important medical event that, when based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above in the definition for an SAE. Examples of such events include 
allergic bronchospasm, requiring intensive treatment at an emergency room or at home, 
blood dyscrasias, convulsions that do not result in in-patient hospitalization, or the 
development of drug dependency or drug abuse 
8.1.3 AE Severity  
The severity of an AE will be graded from 1 to 5 according to Table 7 and CTCAE version 
4.0 criteria (Appendix C).   
The CTCAE general guideline will be used to assess AE severity. Not all Grades are appropriate 
for all AEs. Therefore, some AEs listed in the CTCAE have fewer than five options for Grade 
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Table 7: 
Grading of AE Severity 
Grade 
Clinical Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living.  
Grade 4 
Life-threatening consequences; urgent intervention indicated.  
Grade 5 
Death related to AE 
8.1.4 Adverse Event Outcome 
Subjects will be followed until AEs have either resolved, returned to baseline status, or are deemed 
stable or commensurate with ongoing disease processes, per the Investigational judgment. 
One of the four outcomes listed below must be recorded: 
Resolved – The subject has fully recovered from the event with no residual effects observable or 
returned to baseline status. 
Resolved with sequelae – The subject has recovered from the event with some residual effects 
observable. 
Ongoing – Effects of the event are still present, regardless of whether the effect is changing or 
stable and persistent. 
Fatal outcome (for serious adverse events only) 
8.1.5 Relationship to Treatment  
The relationship or association of the AE to a study treatment will be characterized as “unrelated”, 
“unlikely,” “possible,” “probably”, or “definite”, as shown in Table 88. 
Table 8: 
AE Relationship Attribution 
Relationship 
Attribution 
Description 
Unrelated to the study drug 
Unrelated 
The AE is clearly not related to the study drug 
Unlikely 
The AE is doubtfully related to the study drug 
Related to the study drug 
Possible 
The AE is maybe related to the study drug 
Probable 
The AE is likely related to the study drug 
Definite 
The AE is clearly related to the study drug 
8.1.6 Action Taken with Study Medication  
As a consequence of an AE, the action taken with study drug can be: 
• None: no changes were made to study drug administration or dose 


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• Permanently discontinued: study drug was stopped and not restarted 
• Temporarily interrupted, restarted at the same dose: dosing was temporarily interrupted or 
delayed due to the AE and restarted at the same dose 
• Temporarily interrupted, restarted at a decreased dose: dosing was temporarily interrupted 
or delayed due to the AE and restarted at a decreased dose 
• Dose decreased: study drug dose was decreased without previous study drug interruption 
• Not applicable: e.g. in case the AE occurred after signing the ICF but before the 
administration of study drug was commenced 
8.2 
Recording, Reporting and Follow-Up of Adverse Events 
Details about the safety reporting process are presented in the Safety Reporting Plan. 
All AEs must be recorded by the Investigator in the eCRF, regardless of association with the use 
of the study treatment. An AE will be recorded any time after the time of signed ICF and captured 
until the last study visit.  
To avoid colloquial expressions, the AE should be reported in standard medical terminology. 
Whenever possible, the AE should be evaluated and reported as a diagnosis rather than as 
individual signs or symptoms. If a definitive diagnosis is not possible, the individual signs and 
symptoms should be recorded.  
For each AE, the Investigator or an adequately qualified designee will evaluate and report the onset, 
duration, severity, seriousness, and relationship to (association with) the study treatment, and 
indicate the action taken. 
Abnormal laboratory findings will be determined by review of all laboratory data collected on the 
subjects. At each visit, the Investigator is responsible for assuring that the subject is questioned 
regarding all potential AE and concurrent illnesses. 
Any laboratory abnormalities deemed clinically significant by the Investigator should be reported 
as an AE. A clinically significant abnormality is a confirmed abnormality that is changed 
sufficiently from baseline, so that in the judgment of the Investigator, a change in management is 
warranted. This alteration may include monitoring the laboratory test further, initiating other 
diagnostic tests or procedures, or administering treatment. Whenever possible, the etiology of the 
abnormal findings will be documented in the eCRF. Repeated, additional tests and/or other 
evaluations required to establish the significance and etiology of an abnormal result should be 
obtained when clinically indicated. 
Any clinically significant laboratory abnormalities that are either unexplained or considered 
treatment-related should be promptly reported to the Sponsor. Any additional relevant laboratory 
results obtained by the Investigator during this study will be supplied to the Sponsor and recorded 
in the eCRF. 
A change in diabetes medication dose may not be reported as an adverse event, however, 
Worsening of Diabetes from baseline must be documented as an adverse event during the course 
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8.2.1 SAE Reporting Process 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of SAEs including Suspected Unexpected Serious Adverse Reactions (SUSARs) per 
the International Conference on Harmonization (ICH) guidelines E2A and ICH E6, and per the 
United States Code of Federal Regulations (CFR); 21 CFR § 312.32. Country specific regulatory 
requirements will be followed in accordance with local country regulations and guidelines. 
Independent Ethics Committees will be notified of any SAE according to applicable regulations. 
Any SAE, including death due to any cause, that occurred from the signing of ICF through, 
regardless of relationship to the study treatment, must be reported immediately (no later than 
24 hours) by the Investigator to the Sponsor’s representative (safety vendor) using the SAE Report 
Form. Planned hospitalizations or procedures will not be considered as SAEs. 
The criteria for seriousness will be indicated on the SAE Report Form as follows: 
• Hospitalization or prolongation of hospitalization 
• Life threatening 
• Death 
• Persistent or significant disability/incapacity  
• Congenital anomaly 
• Other important medical events 
The outcome for the event will be listed on the SAE Report Form as follows: 
• Resolved 
• Resolved with sequelae 
• Ongoing 
• Fatal 
If additional information regarding a previously submitted SAE is obtained, a follow-up SAE must 
be sent to the Sponsor’s representative (safety vendor). 
The Sponsor and/or its designee will identify and report to regulatory authorities within the required 
timeframes, all serious and unexpected suspected adverse reactions (SUSARs) and clinically 
important increases in rate of serious suspected adverse reactions. 
SAEs must be collected and reported by the Investigator for the whole period from the signing of 
ICF until the last study visit. If the event of death occurs after the last study visit, the death will not 
have to be reported as an SAE.  
The Investigator will document all available information regarding the SAE on the standard form. 
The Investigator should not wait to receive additional information to fully document the event 
before notifying the Sponsor’s representative of an SAE. The initial notification should include, as 
a minimum, sufficient information to permit identification of: 
• Subject’s study number  
• Time and date of study drug administration 


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• Time and date of the start of the event and either the date and time of the resolution of the 
event or a statement that the event is ongoing  
• A brief description of the event and actions taken  
• Investigator’s opinion of the relationship of the event and the investigational product  
Follow-up report(s) should follow the initial report, using the SAE form detailing relevant aspects 
of the adverse events in question. Where applicable, information from relevant hospital case 
records and autopsy reports should be obtained. All source information provided to the Sponsor 
must be appropriately anonymized.   
8.2.2 Follow-up of Reported AEs  
SAEs recorded during the study will be followed by the Investigator until resolution or 
stabilization. 
After the Post-Treatment Visit, non-serious AEs should be followed up until they resolve or have 
failed to resolve, for a duration determined by the Investigator.  
Follow-up procedures will be determined by the nature of the event and the judgment of the 
Investigator. 
8.3 
Distribution of Responsibilities 
Details about the distribution of safety responsibilities are presented in the Safety Reporting Plan. 
8.4 
Safety Monitoring Criteria, Dose Adjustment, and Withdrawal Criteria  
Enrolled subjects with the following lab abnormalities will be monitored closely and may be 
discontinued from the study drug or go through study drug dose adjustment if criteria are met as 
outlined in Tables 9, Table 10, and 11.  
8.4.1 Drug-Induced Liver Injury (DILI) Safety Monitoring 
 
Table 9: 
DILI Criteria for Participants with Normal Baseline ALT and AST 
 
ALT or AST during Study 
Treatment 
Other Concurrent Parameters 
Required during ALT or AST 
Elevation 
Study Action 
ALT, AST and Total 
Bilirubin ≤ ULN 
ALT or AST > 8 × ULN 
-- 
Stop study drug 
permanently 
ALT or AST > 5 × ULN for 
more than 2 weeks 
-- 
ALT or AST > 3 × ULN 
AND total bilirubin > 2 × ULN 
OR INR > 1.5 
ALT or AST > 3 × ULN 
AND clinical symptoms* 
* Clinical symptoms: appearance of fatigue, nausea, right upper quadrant pain or tenderness, fever, rash, jaundice 
and/or eosinophilia (> 5%). 
 
 


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Table 10: 
DILI Criteria for Participants with Abnormal Baseline ALT or AST 
 
ALT or AST during Study 
Treatment 
Other Concurrent Parameters 
Required during ALT or AST 
Elevation 
Study Action 
ALT or AST > ULN  
ALT or AST > 2 × baseline 
measurement (BLM) 
AND concomitant total bilirubin 
> 2 × BLM OR INR increase by 
0.2 
Stop study drug 
permanently 
Regardless of ALT or AST 
levels 
Clinical symptoms* AND 
concomitant total bilirubin > 2 × 
BLM 
ALT or AST ≥ ULN but < 
2 × ULN  
ALT or AST > 5 × BLM 
-- 
Interrupt study 
drug 
ALT or AST ≥ 2 × ULN 
but < 5 × ULN 
ALT or AST > 3 × BLM 
ALT or AST ≥ 5 × ULN 
ALT or AST > 2 × BLM 
* Clinical symptoms: appearance of fatigue, nausea, right upper quadrant pain or tenderness, fever, rash, jaundice 
and/or eosinophilia (> 5%). 
• 
Interrupt study drug: Repeat AST, ALT, total bilirubin, and PT/INR within 3 days and 
closely observe the participant (see Appendix B). Study drug can be restarted at the same 
dose level only if a firm competing etiology is identified and liver tests return to baseline. 
Down titration to a lower dose can also be considered at this time  
• 
Stop study drug permanently: Repeat AST, ALT, total bilirubin, and PT/INR within 3 
days and closely observe the participant (see Appendix B) 
• 
If close observation of a participant is not possible, stop study drug permanently 
 
 
 


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8.4.2 Muscle Safety Monitoring 
 
Table 11: 
Muscle Injury Safety Criteria for Study Drug Interruption or Stopping Rules 
Creatine Kinase 
(CK) during 
Study Treatment 
Grade 3 
CTCAE 
Myalgia or 
Myopathy 
Repeat CK Test Results 
Study Action 
CK > 2.5 × ULN 
 
Not observed 
CK level is ≤ 2.5 × ULN 
• Study drug may be reinitiated at this time at 
the current dose level. 
Not observed 
CK level is > 2.5 × ULN 
• Study drug should remain held and CK testing 
should be performed weekly until CK ≤ 2.5 × 
ULN. Study drug may then be reinitiated at 
this time at a decreased dose level as outlined 
in Section 6.1.1 of the study protocol. 
Observed 
CK level is ≤ 2.5 × ULN 
• Study drug may be reinitiated at the current 
dose level once symptoms are resolved. 
• Study drug should be permanently 
discontinued if symptoms reappear after re-
challenge and there is no clinical explanation. 
Observed 
CK level is > 2.5 × ULN 
• Study drug should remain held and CK 
testing should be performed weekly until CK 
≤ 2.5 × ULN and clinical symptoms are 
resolved.  
• Study drug may then be reinitiated at this 
time at a decreased dose level as outlined in 
Section 6.1.1 of the study protocol. 
• Study drug should be permanently 
discontinued If symptoms reappear after re-
challenge and there is no clinical explanation. 
The participant should continue to be routinely 
monitored until complete resolution of 
symptoms or study completion, whichever 
comes first. 
 
8.4.3 Cardiac Safety Monitoring 
• Subjects with new symptoms suggestive of cardiac origin (e.g. left-sided chest pain, etc.): 
Interrupt study drug. Perform ECG and Troponin I, AST, CK, CK-MB within 5 days. 
Follow the subject weekly until the event resolution or stabilization. Study drug can be 
resumed if the event is deemed related to the subject pre-existing condition 
8.4.4 Pancreatic Safety Monitoring 
• If serum lipase > 3 × ULN with clinical symptoms of acute pancreatitis, interrupt study 
drug and repeat the test within 3 days  


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• If test is confirmed, perform abdominal imaging to exclude an alternative cause for the 
event 
• Study drug may be reinitiated at the same or lower dose if there is no evidence of acute 
pancreatitis or an alternative etiology for the pancreatitis is identified 
8.4.5 Withdrawal Criteria and Replacement of Subjects 
Subjects may be discontinued from the study for the following reasons: 
• Entered the study in violation of this protocol 
• Required the use of a prohibited concomitant medication  
• Withdrawal of Informed Consent 
• At the discretion of the Investigator for medical reasons  
• Female subjects who become pregnant  
• At the discretion of the Investigator or Sponsor for noncompliance  
• Significant protocol deviation  
• Administrative decision by the Investigator or Sponsor or designee  
• Lost to follow-up 
The date the subject is withdrawn and the reason for discontinuation will be recorded in the eCRF.  
Subjects will not be considered to have completed the study if, for any reason, they do not complete 
the liver biopsy and clinical laboratory assessments at the End-of-Study Visit (Week 52).  
If a subject withdraws from the study, he/she will not be replaced.  
8.5 
Precautions 
8.5.1 Pregnancy 
No specific studies have been performed to determine the reproductive and developmental toxicity 
of seladelpar.  
As a precaution, women of childbearing potential participating in this study must use one barrier 
contraceptive and a second effective birth control method during the study and for at least 30 days 
after the last dose. Male subjects who are sexually active with female partners of reproductive 
potential must use barrier contraception and their female partners must use a second effective birth 
control method during the study and for at least 90 days after the last dose of study drug. Sexual 
abstinence, defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments, is acceptable as an effective birth control method. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial 
and the preferred and usual lifestyle of the subject. 
A second effective birth control method includes the following:  
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation: 


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• oral 
• intravaginal 
• transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
• oral 
• injectable 
• implantable 
• Intrauterine device (IUD)  
• Intrauterine hormone-releasing system (IUS)  
• Bilateral tubal occlusion  
• Vasectomized partner 
8.6 
Study Stopping Rules 
If any of the three criteria below are met and adverse events are considered related to study drug, 
the study must be stopped:  
• Three participants develop the same Grade 3 CTCAE related to study drug,   
• Two participants develop any Grade 4 CTCAE related to study drug, or 
• One participant develops a Grade 5 CTCAE 
 
 
 


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9 
STUDY TERMINATION 
CymaBay Therapeutics, Inc. reserves the right to discontinue the study if it becomes aware of 
information concerning the quality or safety of the trial medication (based on recommendation 
from Medical Monitor), as well as other important information that may affect proper conduct of 
the trial. Should the study be discontinued by the Sponsor, then the Investigator, Ethics Committee, 
and competent authorities should be notified by the Sponsor or Sponsor’s delegate, in accordance 
with applicable regulatory regulations. 
The study may be prematurely terminated by the Investigator, due to specific clinical observations 
relating to safety concerns. If the Investigator intends to prematurely terminate the trial at his/her 
site, he/she must immediately inform the Sponsor on his/her intention as well as of the reasons 
why. 
 
 


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10 
DATA MANAGEMENT AND STATISTICAL ANALYSES 
10.1 
Data Management 
10.1.1 Processing of Electronic Case Report Forms  
Electronic CRFs (eCRFs) will be completed for all study subjects enrolled in the study. At 
scheduled monitoring visits, eCRFs will be verified against source documentation. Upon 
completion of this review, finalized eCRFs will be submitted to the Sponsor’s designated Contract 
Research Organization (CRO). Any subsequent changes to the eCRFs will be performed in 
accordance with the CRO’s Standard Operating Procedures (SOP) for editing and clarifying 
eCRFs. 
10.1.2 Database  
Data entry will be performed through username and password-protected access to a secure 
database. All data will be entered using electronic eCRFs. Internally developed programs for 
plausibility, consistency, and out-of-range data fields will supplement the review of the data. A 
100% manual review of AEs, drug accountability and termination summary data, will be performed 
by Data Management personnel. The Medical Dictionary for Regulatory Activities (MedDRA) 
coding thesaurus will be used to classify AEs, medical history and concomitant procedures while 
the World Health Organization (WHO) Drug classification will be used to code medications. 
10.1.3 Data Discrepancies 
After all subjects complete the study and data discrepancies are resolved, protocol deviations 
during both enrollment and study execution will be reviewed. Significant protocol deviations and 
procedural discrepancies will be discussed. All data will be included in the safety analyses. 
10.2 
Statistical Analysis 
Full details on the statistical methodology to be used will be included in a SAP to be developed 
prior to study unblinding. 
10.2.1 Sample Size Estimation  
A sample size of 175 subjects (50 subjects per each dose of seladelpar and 25 subjects for placebo) 
provides at least 80% power to detect a pairwise treatment difference of at least 20% between the 
active and placebo groups with respect to a relative change from baseline in hepatic fat fraction, as 
assessed by MRI-PDFF at Week 12. Power calculations were performed using a standard t-test, 
allowed for a 12% dropout rate (6 subjects per seladelpar arm, 3 subjects for the placebo arm), and 
a pooled standard deviation of 26 for the relative change endpoint.  
10.2.2 Analysis Populations 
The safety analysis will be conducted on the Safety Population. Efficacy analyses will be conducted 
on the intent-to-treat (ITT) population, the modified intent-to-treat (mITT) population, the 
modified intent-to-treatment population with biopsy (mITTb), and the per-protocol (PP) 
populations. The mITT population will be used for the primary efficacy analysis. 


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10.2.2.1 
Safety Population  
The Safety population is defined as any subject who receives at least one dose of study drug.  
10.2.2.2 
Intent-to-Treat Population (ITT) 
The Intent-to-Treat (ITT) population is defined as any subject who is randomized and receives at 
least one dose of study drug. 
10.2.2.3 
Modified Intent-to-Treat Population (mITT)  
The mITT population is defined as any subject who is randomized, receives at least one dose 
of study drug, and has Baseline and Week 12 MRI-PDFF.  
10.2.2.4 
Modified Intent-to-Treat Population with Biopsy (mITTb)  
The mITTb population is defined as any subject who is randomized, receives at least one dose of 
study drug, and has Baseline and Week 52/ET liver biopsies.  
10.2.2.5 
Per-protocol population (PP)  
The PP population is defined as any subject who is randomized and receives at least one dose of 
study drug, has Baseline and Week 52/ET liver biopsies, and does not have a protocol violation that 
is deemed to impact the efficacy analysis.  
10.2.3 Demographics and Baseline Characteristics  
Demographic and baseline characteristics (medical histories, physical examinations, and 
concomitant medications) will be summarized using descriptive statistics (mean, standard 
deviation, median, minimum and maximum) for continuous variables and frequency distributions 
(counts and percentages) for discrete variables. 
10.2.4 Efficacy Analysis 
10.2.4.1 
Primary Efficacy Analysis  
Pairwise comparisons between each dose of seladelpar versus placebo with respect to the relative 
change in hepatic fat fraction as assessed by MRI-PDFF at Week 12 will be conducted using 
ANCOVA. The LS means, standard errors, 95% CIs, and p-values will be provided from the 
ANCOVA model with percent change from baseline in MRI-PDFF as the dependent variable, 
treatment group, diabetic status, and fibrosis stage as factors and baseline MRI-PDFF as covariates. 
Relative change will be calculated as  
[MRI-PDFFWEEK12 – MRI- PDFFBASELINE] ×100 / MRI-PDFFBASELINE. 
All statistical comparisons will be made at a two-sided alpha of 0.05.  
Other analyses will be secondary. 
In primary, mITT analyses, subjects with missing efficacy data will be considered unimproved on 
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10.2.4.1.1 
Top-Line Results 
The 12-week Primary Analysis, including top-line results for efficacy and safety, will be provided 
and communicated when it becomes available and before study completion. These results will be 
provided by treatment group, but individual patient data will remain blinded and the study will 
continue as a double-blind study until its completion. Details of the conduct of the Primary Analysis 
will be provided in the SAP.  
10.2.4.2 
Secondary Efficacy Analysis 
Comparisons between each seladelpar dose versus placebo with respect to the absolute change in 
hepatic fat fraction as assessed by MRI-PDFF at Week 12, 26 and 52 will be conducted using 
mixed model repeated measures analyses, with factors for scheduled time point, treatment, time 
point by treatment interaction, baseline diabetic status, and fibrosis stage, with the baseline hepatic 
fat fraction as a covariate. Supportive analyses will be conducted using Wilcoxon rank-sum tests, 
stratified by diabetic status and fibrosis stage.  
Comparisons between each seladelpar dose versus placebo with respect to the relative change in 
hepatic fat fraction as assessed by MRI-PDFF at Week 26 and 52 will be conducted using mixed 
model repeated measures analyses with factors for scheduled time point, treatment, time point by 
treatment interaction, baseline diabetic status, and fibrosis stage, with the baseline hepatic fat 
fraction as a covariate. Supportive analyses will be conducted using Wilcoxon rank-sum tests, 
stratified by diabetic status and fibrosis stage. 
Each seladelpar dose will be compared versus placebo for the number and percent of subjects with 
normalization of hepatic fat content (<5%) at Week 12, 26, and 52 using Cochran-Mantel-Haenszel 
tests, stratified by diabetic status and fibrosis stage. Similar analyses will be performed for:  
• Number and percent of subjects with an absolute change > 5% on MRI-PDFF at Week 
12, 26, and 52 
• Number and percent of subjects with a relative decrease in hepatic steatosis of > 30% 
on MRI-PDFF at Week 12, 26, and 52 
• Number and percent of subjects with reversal of NASH with no worsening of fibrosis 
as defined by centrally scored histology assessment at 52 weeks of treatment 
• Number and percent of subjects with decrease by at least one stage in fibrosis (NASH 
Clinical Research Network Classification) without worsening of NASH 
• Number and percent of subjects with a 2-point improvement in NAS score 
Efficacy-related laboratory data will be summarized by laboratory parameter, treatment group and 
study visit for the DB and OLE phases. 
Alpha control procedures for testing of the secondary efficacy endpoints will be described in the 
SAP. 
10.2.5 Safety Analysis  
Safety analysis will be conducted on the Safety Population.  
Safety data, including AEs, safety laboratory results, physical examination results, vital signs, and 
ECG will be summarized by treatment group and/or listed. 


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The safety measures will be incidence rate of AEs and TEAEs, ECG, biochemistry, hematology 
and urinalysis, physical exams and vital signs as measured by NCI CTCAE Version 4.0. 
Safety data will be summarized by study treatment (placebo vs. seladelpar) and by seladelpar dose 
administered during the treatment period for the DB, OLE and SFU phases. Baseline values in the 
DB and OLE phases for laboratory tests, vital signs, and electrocardiograms will be defined as the 
last evaluation performed prior to administration of study drug. Baseline values in the SFU phase 
for laboratory tests, vital signs, and electrocardiograms will be defined as the last evaluation prior 
to obtaining informed consent for the SFU phase. 
10.2.5.1 
Adverse Events 
The subset of AEs occurring after the first dose of study drug will be considered to be TEAEs in 
the DB and OLE phases. The incidence of TEAEs will be tabulated. All AEs will be reported and 
tabulated for the SFU phase; there is no TEAE subset for this study phase. 
10.2.5.2 
Vital Signs 
Descriptive statistics and mean or median change from baseline will be determined for vital signs 
(temperature, heart rate, respiratory rate, blood pressure) at each assessment. Vital signs collected 
at all study time points will be recorded in the eCRF and analyzed or listed. 
10.2.5.3 
Physical Examination 
Clinically significant abnormalities on physical examination will be recorded as AEs in the eCRF. 
10.2.5.4 
Laboratory Tests 
Descriptive statistics for the result and change from baseline will be summarized for each 
laboratory test by study treatment and visit. Abnormal laboratory values will be graded by the 
investigator as “clinically significant” or “not clinically significant”, where applicable. Clinically 
significant abnormal laboratory values will be reported as AEs, after study treatment has been 
initiated. Investigators may repeat laboratory tests for any parameter that is abnormal and/or 
clinically significant. 
10.2.5.5 
Electrocardiograms 
Clinically significant abnormalities on ECGs will be recorded as AEs in the eCRF. Summaries of 
ECG parameters by study treatment and visit will be prepared.  
10.2.5.6 
Concomitant Medications 
Concomitant medications will be listed and summarized by World Health Organization Drug 
Classification (WHODrug) for Drug Statistics Methodology, Anatomical Therapeutic Chemical 
(ATC) system class, generic term, and treatment group. 
 
 


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11 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
11.1 
Study Monitoring 
The Investigators and institution(s) will permit trial-related monitoring of the eCRF data by 
CymaBay Therapeutics, Inc. or their assignee by providing direct access to source data and/or 
documents. The study monitor will verify the CRFs against the source documentation. Deviations 
from the protocol with regard to subject enrollment or study conduct will also be noted in the source 
documentation, in the eCRF and a complementary database. A Sponsor representative will visit the 
site to initiate the study, prior to the first treatment of the first subject, and at agreed upon times 
throughout the study, including at the end of the study. Medication dispensing, and clinical drug 
supply records will be 100% verified at the study site by the study monitor. It is understood that all 
subject specific information is confidential and no documentation that can link study information 
to the specific subject will be collected or retained by the Sponsor. 
11.2 
Audits and Inspections 
Regulatory authorities, the EC, and/or CymaBay Therapeutics Inc. or its designee(s) may request 
access to all source documents, eCRF data, and other study documentation for on-site audit or 
inspection. Direct access to these documents must be guaranteed by the Investigator, who must 
provide support at all times for these activities. 
It is understood that all subject specific information is confidential and no documentation that can 
link study information to the specific subject will be collected or retained by the Sponsor. 
11.3 
Ethics Committees 
The Investigators will provide ethics committees with all information impacting the risk profile of 
the drug. The trial will not commence until written ethics committee approval for the protocol and 
ICF is received by the Sponsor. The Investigator has the responsibility to conform to all of the local 
requirements for periodic updates and notification to the committee. 
 
 


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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
Clinical data will be recorded in eCRF. Data will be verified and confirmed by the Investigators. 
All data that will be used in the primary efficacy analyses and the safety analysis will be source 
documents verified by the monitors. Additionally, the Sponsor will conduct audit reviews of 
monitored eCRFs. 
A final audit of the electronic database against the final eCRF will be done. 
13 
ETHICS 
13.1 
Ethics Review 
The protocols, ICFs, any information provided to the subject, recruitment advertisements, and any 
amendments to these items must be reviewed and approved by the EC prior to their use in the trial.  
The study will not start before written approval by EC(s) has been obtained and the local regulatory 
requirements have been complied with. 
The EC must meet all the appropriate International Committee on Harmonisation (ICH) 
requirements for composition, documentation, and operational procedures.  
13.2 
Ethical Conduct of the Study 
The study will be conducted in strict accordance with the Declaration of Helsinki, ICH Good 
Clinical Practice (GCP) guidelines, applicable laws and regulations, and the procedures outlined in 
EC approved version of this protocol.  
13.3 
Written Informed Consent 
There will be a separate ICFs for the DB phase and the OLE phase. 
The subject must give consent to participate in the trial, only after having been fully informed by 
the Investigator or a person designated by him/her of the nature, significance, and implications of 
the trial, as well as to the associated risks involved. Such meetings must be carried out on an 
individual basis and adapted to the educational background and previous knowledge of the subject. 
Participation in this meeting should be documented in the subject’s file. The subject must be 
allowed ample time to inquire about details and to decide whether or not to participate in the study. 
Written informed consent will be obtained for all subjects enrolled in the trial and before study 
related activities are performed on a subject. The process of obtaining written informed consent 
will be documented in the source documents of the subject. Only ICFs approved by the EC will be 
used. 
The ICF must be personally dated and signed by the investigator or qualified person delegated by 
the investigator to conduct the consent and the subject. The original document will be retained by 
the Investigator and filed in the Investigator’s Site File. 
 
 


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14 
RETENTION OF RECORDS 
All study related material, including source documents, eCRFs, competent authority, and EC 
correspondence and analyses, and any other documentation required by applicable laws and 
regulations will be maintained for 15 years after completion of the study, or notification from the 
Sponsor that the data can be destroyed, whichever comes first. 
15 
PROTOCOL AMENDMENTS 
Any change or addition to this protocol will only be made when a protocol amendment has been 
written, approved, and signed by CymaBay Therapeutics, Inc. and the Principal Investigator before 
the change or addition can be considered effective. This amendment must also be submitted to the 
EC for approval and, when necessary, competent authority approval before implementation. 
Protocol amendments may affect consent forms of current and future subjects. CymaBay 
Therapeutics, Inc. will clearly specify when a protocol amendment includes safety, procedural, 
and/or efficacy information that will require specific ICF text changes. 
16 
DISCLOSURE OF INFORMATION 
Information concerning the investigational medication and patent application processes, scientific 
data or other pertinent information is confidential and remains the property of CymaBay 
Therapeutics, Inc. The Investigator may use this information for the purposes of the study only. It 
is understood by the Investigator that CymaBay Therapeutics, Inc. will use information developed 
in this clinical study in connection with the development of the investigational medication and, 
therefore, may disclose it as required to other clinical investigators and to regulatory agencies. In 
order to allow the use of the information derived from this clinical study, the Investigator 
understands that he/she has an obligation to provide complete test results and all data developed 
during this study to the Sponsor.  
The Investigator may not submit for publication or presentation the results of this study without 
first receiving written authorization from CymaBay Therapeutics, Inc. CymaBay Therapeutics, Inc. 
agrees that, before it publishes any results of the study, it shall provide the Investigator with at least 
30 days for review of the pre-publication manuscript prior to the submission of the manuscript, to 
the publisher. 
 
 


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17 
REFERENCES 
Bays HE, Schwartz S, Littlejohn T, 3rd, et al. MBX-8025, a novel peroxisome proliferator receptor-
delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with 
and without atorvastatin. J Clin Endocrinol Metab 2011; 96(9): 2889-2897. 
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty 
liver disease: practice guideline by the American Gastroenterological Association, American 
Association for the Study of Liver Diseases, and American College of Gastroenterology. 
Gastroenterology 2012; 142(7): 1592-1609. 
Choi YJ, Roberts BK, Wang X, et al. Effects of the PPAR-δ agonist MBX-8025 on atherogenic 
dyslipidemia. Atherosclerosis 2012; 220(2): 470-476. 
Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and 
elevated liver enzymes. Hepatology 2006; 44(4): 865-873. 
Haczeyni F, Wang H, Barn V, et al. The selective peroxisome proliferator–activated receptor-delta 
agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in 
diabetic obese mice. Hepatology Communications 2017; 1(7): 663-674. 
Iwaisako K, Haimerl M, Paik YH, et al. Protection from liver fibrosis by a peroxisome proliferator-
activated receptor delta agonist. Proc Natl Acad Sci USA 2012; 109(21): E1369-1376. 
Jones D, Boudes PF, Swain MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in 
patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a 
double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet 
Gastroenterol Hepatol 2017; 2(10): 716-726. 
Ratziu V, Bellentani S, Cortez-Pinto H, et al. A position statement on NAFLD/NASH based on the 
EASL 2009 special conference. J Hepatol 2010; 53(2): 372-384. 
Vernon G, Baranova A and Younossi ZM. Systematic review: the epidemiology and natural history 
of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol 
Ther 2011; 34(3): 274-285. 
Xia X, Jung D, Webb P, et al. Liver X receptor beta and peroxisome proliferator-activated receptor 
delta regulate cholesterol transport in murine cholangiocytes. Hepatology 2012; 56(6): 2288-2296. 
Yki-Järvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic 
syndrome. Lancet Diabetes Endocrinol 2014; 2(11): 901-910. 
 
 


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APPENDIX A – ELIGIBILITY LOG (DB PHASE) 
All Screening procedures will be completed within 10 weeks. DB phase Screening activities will 
be performed during multiple screening visits. Screening visits can be combined but must follow 
the listed below order.  
Screening Visit 1:  
• Medical History review (including alcohol consumption review per Exclusion Criterion 
#1) 
• Review of previous FibroScan® result (if available) 
• Review of previous imaging tests (ultrasound, computed tomography, MRI) (if available) 
• Review of previous liver biopsy (if available) 
• NASH history review, including evaluation of risk factors associated with NASH (obesity, 
diabetes, race, etc.) 
• Concomitant Medications review, including the use of anti-NASH, antidiabetic, statins, 
and fibrate medications.  
• Physical Examination, ECG, vitals, weight, and height measurements 
• Collection of blood 
 
Screening Visit 2:  
• FibroScan®  
• Laboratory tests can be repeated at the Investigator’s discretion 
 
Screening Visit 3:  
• MRI-PDFF 
• LMS 
• MRE (at selected sites where available) 
• Laboratory tests can be repeated at the Investigator’s discretion. PT, INR, and Platelets 
must be performed per the window specified by the local biopsy center 
 
Subjects who meet all inclusion criteria and none of the exclusion criteria, including MRI-PDFF, 
will be invited for Screening Visit 4. 
Screening Visit 4:  
• Baseline liver biopsy  
• Laboratory tests can be repeated at the Investigator’s discretion 
 
 


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APPENDIX B – CLOSE OBSERVATION CRITERIA FOR DILI EVENTS 
The “close observation” will be performed on subjects meeting the DILI safety monitoring criteria 
per Section 7.4.1. If “close observation” is not feasible, study drug must be stopped. 
1. Comprehensive Medical History and Health Status Review 
a. Provide detailed history of current liver-related symptoms (eg., right upper quadrant 
pain or tenderness, nausea, vomiting, fatigue) 
b. Provide all current diagnoses, diseases, procedures, and symptoms 
c. Provide comprehensive medical history including prior diagnoses, procedures and 
symptoms 
d. Provide concomitant drug use, including prescription medications, nonprescription 
medications, herbal supplements, dietary supplements, alcohol use, recreational 
drug use, special diets and exposure to environmental chemical agents 
e. Provide comprehensive medication and drug use history, including nonprescription 
medications, herbal supplements, dietary supplements, alcohol use, recreational 
drug use, special diets and exposure to environmental chemical agents 
2. Laboratory Testing 
a. Repeat ALT, AST, bilirubin (total), and PT/INR within 5 days  
b. Monitor the subject every 5 days until the lab abnormality stabilization 
c. After lab abnormality is stabilized, monitor the subject once a week until the event 
resolution 
3. Rule out the following diagnoses: 
a. Acute viral hepatitis types A, B, C, D and E  
b. Autoimmune or alcoholic hepatitis 
c. Hypoxic/ischemic hepatopathy 
d. Biliary Tract Disease 
 
 
 


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APPENDIX C – NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (NCI CTCAE) 
The NCI CTCAE will be used to assess an AE severity. The NCI CTCAE will be provided as a 
separate document with the study protocol, but may also be accessed here:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.0/ 
 


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INVESTIGATOR’S PROTOCOL SIGNATURE PAGE 
PROTOCOL CB8025-21730 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study Followed by Open-Label 
Extension and Safety Follow-Up Phases to Evaluate the Activity of Seladelpar in Subjects 
with Nonalcoholic Steatohepatitis (NASH)  
 
PROTOCOL VERSION NUMBER:  
Version 3.0   
DATE OF PROTOCOL: 
 
 
20-DEC-2019 
SPONSOR:  
CymaBay Therapeutics, Inc. 
7575 Gateway Blvd, Suite 110 
Newark, CA 94560 
United States of America 
 
I have read all pages of this clinical study protocol for which CymaBay Therapeutics, Inc. is the 
Sponsor. I agree to conduct the study as outlined in the protocol and to comply with all the terms 
and conditions set out therein. I confirm that I will conduct the study in accordance with ICH GCP 
guidelines and the provisions of Declaration of Helsinki. I will also ensure that sub-Investigator(s) 
and other relevant members of my staff have access to copies of this protocol, and the ICH GCP 
guidelines and Declaration of Helsinki, to enable them to work in accordance with the provisions 
of these documents. 
 
Investigator: 
  
Printed Name: 
  
Signature: 
  
Date (DD/MM/YYYY): 
  
Site Address: 
  
 
  
 
  
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
Unique Protocol ID: CB8025-21730 
 
 
Official Title: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study Followed by 
Open-Label Extension and Safety Follow-Up Phases to Evaluate the Activity of Seladelpar in 
Subjects with Nonalcoholic Steatohepatitis (NASH) 
 
 
NCT number: NCT03551522 
 
 
Protocol Version Number: Version 2.0 
 
Date: 28-FEB-2020 
 


STATISTICAL ANALYSIS PLAN 
 
A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study 
Followed by Open-Label Extension and Safety Follow-Up Phases to 
Evaluate the Activity of Seladelpar in Subjects with Nonalcoholic 
Steatohepatitis (NASH) 
 
Protocol Number: 
CB8025-21730 
Study Phase: 
Phase 2 
Investigational Product: 
Seladelpar 
IND Number: 
133253 
Sponsor: 
CymaBay Therapeutics, Inc. 
7999 Gateway Blvd, Suite 130 
Newark, CA 94560 
U.S.A. 
Protocol Versions: 
V1.1 / 16-FEB-2018 
V1.2 / 26-MAR-2018 
 
V2.0 / 13-SEP-2019 
 
V3.0 / 20-DEC-2019 
SAP: 
V2.0 / 28-FEB-2020 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains confidential information, which should not be disclosed, copied, referred 
to, released or published without written approval from CymaBay Therapeutics. Any 
supplemental information that may be added to this document is also confidential and proprietary 
to CymaBay Therapeutics and must be kept in confidence in the same manner as the contents of 
this document. 




CymaBay Therapeutics, Inc. 
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Statistical Analysis Plan 
Protocol: CB8025-21730 
V2.0 
28-FEB-2020 
 
Page 3 of 22 
 
TABLE OF CONTENTS 
SUMMARY OF CHANGES ................................................................................................. 5 
LIST OF TERMS AND ABBREVIATIONS ........................................................................ 6 
1. 
INTRODUCTION ..................................................................................................... 7 
1.1 
Study Termination ..................................................................................................... 7 
2. 
STUDY OBJECTIVES AND STUDY DESIGN ...................................................... 7 
2.1 
Study Objectives ........................................................................................................ 7 
2.1.1 
Primary Objectives .............................................................................................. 7 
2.1.2 
Secondary Objectives .......................................................................................... 7 
2.1.3 
Exploratory Objectives ....................................................................................... 8 
2.2 
Study Design .............................................................................................................. 8 
2.3 
Study Outcome Measures .......................................................................................... 9 
2.3.1 
Efficacy Outcome Measures ............................................................................... 9 
2.3.2 
Safety Outcome Measures ................................................................................ 10 
3. 
STATISTICAL METHODOLOGY ........................................................................ 10 
3.1 
Baseline, Endpoint, and Other Statistical Considerations ....................................... 10 
3.2 
Analysis Populations ............................................................................................... 12 
3.2.1 
Safety Population .............................................................................................. 12 
3.2.2 
Intent-to-Treat Population ................................................................................. 12 
3.2.3 
Modified Intent-to-Treat Population ................................................................. 12 
3.2.4 
Modified Intent-to-Treat Population with Biopsy ............................................ 12 
3.3 
Subject Disposition .................................................................................................. 12 
3.4 
Demographics and Baseline Characteristics ............................................................ 13 
3.5 
Prior/Concomitant Medications ............................................................................... 13 
3.6 
Study Drug Exposure and Compliance.................................................................... 13 
3.7 
Analysis of Efficacy ................................................................................................ 14 
3.7.1 
Descriptive Statistics ......................................................................................... 14 
3.7.2 
Analyses of Hepatic Fat Fraction by MRI-PDFF ............................................. 14 
3.7.3 
Analyses of Liver Biopsy Results ..................................................................... 16 
3.7.4 
Analyses of Other Efficacy Endpoints .............................................................. 16 
3.8 
Analysis of Safety .................................................................................................... 17 
3.8.1 
Adverse Events ................................................................................................. 17 
3.8.2 
Clinical Laboratory Assessments ...................................................................... 18 
3.8.3 
12-Lead Electrocardiogram .............................................................................. 20 
3.8.4 
Physical Examination ........................................................................................ 21 
3.8.5 
Vital Signs, Weight, BMI ................................................................................. 21 
3.8.6 
Other Safety Parameters ................................................................................... 21 


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3.9 
Safety Follow-up Phase ........................................................................................... 21 
4. 
SAMPLE SIZE DETERMINATION ...................................................................... 21 
5. 
CHANGES FROM PROTOCOL ............................................................................ 21 
6. 
PROGRAMMING SPECIFICATIONS .................................................................. 22 
 
 




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Page 6 of 22 
 
LIST OF TERMS AND ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
APRI 
AST/Platelet Ratio Index 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
C4 
7-α-hydroxy-4-cholesten-3-one 
CI 
Confidence Interval 
BMI 
Body Mass Index 
DB 
Double-Blind 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELF 
Enhanced Liver Fibrosis Score 
ET 
Early Termination 
FAO 
Fatty Acid Oxidation 
FIB-4 
Fibrosis-4 
GGT 
Gamma-glutamyl Transferase 
HA 
Hyaluronic Acid 
HDL-C 
High Density Lipoprotein Cholesterol 
HOMA-IR 
Homeostasis Model Assessment of Insulin Resistance 
hs-CRP 
High Sensitivity C-Reactive Protein 
ITT 
Intent-to-Treat 
LDL-C 
Low Density Lipoprotein Cholesterol   
LLN 
Lower Limit of Normal 
mITT 
Modified Intent-to-Treat 
mITTb 
Modified Intent-to-Treat Population with Biopsy 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-Model Repeated-Measures 
MRE 
Magnetic Resonance Elastrography 
MRI-PDFF 
Magnetic Resonance Imaging-estimated Proton Density Fat Fraction 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NAS 
NAFLD Activity Score 
NASH 
Nonalcoholic Steatohepatitis 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
Non-HDL 
Non High Density Lipoprotein Cholesterol 
OLE 
Open-Label Extension 
PIIINP 
Procollagen III N-Terminal Peptide 
PP 
Per-Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SFU 
Safety Follow-Up 
TC 
Total Cholesterol 
TEAE 
Treatment Emergent Adverse Event 
TIMP-1 
Tissue Inhibitor of Matrix Metaloproteinases 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 


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Statistical Analysis Plan 
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Page 7 of 22 
 
1. 
INTRODUCTION 
This document provides a description of the statistical methods and procedures to be implemented 
for the analyses of data from the study with protocol number CB8025-21730.  Any deviations from 
this Statistical Analysis Plan (SAP) will be documented in the final clinical study report. 
1.1 
Study Termination 
On November 25, 2019, CymaBay Therapeutics announced that the company was terminating the 
study. The decision to terminate that study based on atypical histological findings observed in the 
first 86 centrally read, end of treatment biopsies from study subjects.  Planned, blinded histological 
assessments of the first tranche of liver biopsies in the trial revealed atypical histological findings, 
including histology characterized as an interface hepatitis presentation, with or without biliary 
injury.   
At the time of study termination, 181 subjects were randomized and enrollment had been closed. 
Eleven subjects had been dosed in the open-label extension (OLE) phase under protocol V2.0 (13-
SEP-2019). Week 12 topline primary efficacy analysis was conducted per protocol, after a 
database freeze of the necessary electronic case report forms and prior to study cancellation and 
unblinding, in June 2019.  
In order to protect patient safety, and aid further investigation to better understand the findings 
leading to study termination, the study was unblinded December 11, 2020 prior to database lock 
of the double-blind (DB) and OLE phases of the study. There will be two database locks: the first 
for the DB and OLE phases of the study, and the second after the completion of the safety follow-
up (SFU) phase. This SAP describes analyses for DB, OLE, and SFU phases, and will be finalized 
prior to the main study DB database lock (DB and OLE phases) and the analyses will be conducted 
after the respective database lock.  
2. 
STUDY OBJECTIVES AND STUDY DESIGN  
2.1 
Study Objectives 
2.1.1 Primary Objectives 
1. To evaluate the effect of seladelpar on hepatic fat fraction, as assessed by magnetic 
resonance imaging-proton density fat fraction (MRI-PDFF) at Week 12 in the DB phase 
2. To evaluate the safety and tolerability of seladelpar in subjects with nonalcoholic 
steatohepatitis (NASH) in the DB, OLE, and SFU phases 
2.1.2 Secondary Objectives 
1. To evaluate the effect of seladelpar on hepatic fat fraction, as assessed by MRI-PDFF at 
Week 26 and Week 52 in the DB phase 
2. To evaluate the effect of seladelpar on histological improvement of nonalcoholic fatty liver 
disease (NAFLD) activity score (NAS) at Week 52 in the DB phase 
3. To evaluate the effect of seladelpar on histological improvement of fibrosis at Week 52 in 
the DB phase 
4. To evaluate the effect of seladelpar on metabolic biochemical markers and biochemical 
markers of inflammation over 52 weeks of treatment in the DB and OLE phases 


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2.1.3 Exploratory Objectives 
1. To evaluate the effect of seladelpar on biochemical markers of fibrosis in the DB and OLE 
phases 
2. To evaluate the effect of seladelpar on fibrosis and inflammation as assessed by magnetic 
resonance elastography (MRE) and LiverMultiScan in the DB phase 
3. To evaluate aspartate aminotransferase (AST)/platelet ratio index (APRI) and Fibrosis-4 
(FIB-4) score in the DB and OLE phases 
4. To assess markers of target engagement as measured by 7-α-hydroxy-4-cholesten-3-one 
(C4), serum bile acids and fatty acid oxidation (FAO tests) in the DB and OLE phases 
5. To evaluate histology, biochemical markers and imaging parameters during the SFU phase 
in subjects with significant histologic findings on the Week 52 or Early Termination (ET) 
liver biopsy 
2.2 
Study Design 
DB Phase 
This phase of the study is designed as a dosing ranging proof-of-concept study to evaluate the 
safety and potential efficacy effects of seladelpar on MRI-PDFF. The study includes liver biopsies 
to confirm that subjects have histological evidence of NASH at screening and to evaluate 
histological improvement in NASH and fibrosis after 52 weeks of treatment. 
The study is planning to enroll approximately 175 male and female subjects. Subjects will be 
randomly assigned to receive placebo, seladelpar 10 mg/day, seladelpar 20 mg/day or seladelpar 
50 mg/day (1:2:2:2 ratio). Subjects will be stratified by diabetic status (yes/no) and fibrosis stage 
(F1 versus F2-3). Study drug (placebo or seladelpar) will be taken in a blinded manner orally once 
a day for a period of 52 weeks. 
The screening period will be up to 10 weeks, the blinded treatment period will be up to 52 weeks, 
and a follow-up period of 4 weeks after the last dose of study drug (i.e. Week 56). During the 
treatment period, the first on-treatment visit will occur 4 weeks after initiation of the study drug. 
Subjects will then be evaluated in clinic every 4 weeks until Week 12. After Week 12, visits will 
be 6-7 weeks apart. Subjects will also be contacted by phone or email at Weeks 19, 32 and 45. The 
amount of fat in the liver will be evaluated by MRI-PDFF at baseline, Weeks 12, 26, and 52. A 
liver biopsy will be performed twice during the DB phase: at baseline and at Week 52. 
The primary efficacy analysis will be the change from baseline to Week 12 in MRI-PDFF. The 
study will continue in a blinded fashion until the Week 52 biopsy is collected. 
The schedule of assessments for the DB phase can be found in Protocol Table 1. 
OLE Phase 
All subjects who participate in the DB phase, complete the 52-week biopsy and the 56-week 
follow-up labs, and meet the specified enrollment criteria will be offered participation in the OLE 
phase of the study. Subjects will not be required to have any additional liver histology, imaging or 
elastography assessments for enrollment or on-treatment assessments of treatment effect. The OLE 
Day 1 visit may be combined with the Week 56 visit in the DB phase. Informed Consent may 
occur at Week 52 or Week 56 in the DB phase for subjects still active in the DB phase or any time 
prior to any OLE procedures in patients who have completed the DB phase. Eligibility assessment 


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Page 9 of 22 
 
may occur on or after the Week 56 in the DB phase. Laboratory assessment for OLE suitability 
may be required if more than 45 days have elapsed since last lab collection to anticipated first OLE 
dosing. If greater than 45 days have elapsed since the last lab collection, subjects must complete 
an unscheduled visit where all labs collected at Week 56 will be retested. Subjects must also be 
clinically stable based on the investigator’s medical judgement and key enrollment criteria to enter 
the OLE. All eligible subjects will receive seladelpar 50 mg regardless of dose received during the 
DB phase. Clinic visits during the 52-week OLE phase will occur at Day 1 and Weeks 2, 13, 26, 
39 and 52 with a final EOS visit at approximately Week 56 visit. The primary objective of the 
OLE phase is to assess long-term safety and treatment effect as measured by biochemical tests 
after an additional 52 weeks of treatment. 
The schedule of assessments for the OLE phase can be found in Protocol Table 2. 
SFU Phase 
All subjects who participated in the DB phase that have significant histologic findings other than 
NASH on the Week 52 or ET liver biopsy and received active seladelpar for at least 6 months will 
be asked to enroll in the SFU phase. Subjects in the placebo dosing group will not be enrolled into 
the SFU phase. After informed consent is obtained, an SFU visit will be performed at a minimum 
of 6 months after the Week 52 or ET liver biopsy. A repeat liver biopsy will be obtained to reassess 
the status of the original significant histologic findings. Other study procedures performed during 
the visit include a physical exam, vital signs, safety laboratory assessments, exploratory liver 
injury biomarker assessments, and FibroScan. Subjects with resolution or stabilization of the 
observed histologic findings will have completed the SFU phase, and no further visits or 
assessments will be required. Subjects worsening of the observed histologic findings will be 
followed up by phone at 3-month intervals and may be requested to have additional SFU visits 
with a repeat of some or all of the above procedures. 
2.3 
Study Outcome Measures 
2.3.1 Efficacy Outcome Measures 
The primary efficacy outcome measure is the relative change (i.e. percent change) in MRI-PDFF 
at Week 12 in the DB phase. 
The secondary efficacy outcome measures related with MRI-PDFF are: 
 observed change in MRI-PDFF at Weeks 12, 26, and 52 in the DB phase; 
 relative change (i.e. percent change) in MRI-PDFF at Weeks 26 and 52 in the DB phase; 
and 
 proportion of subjects with a relative decrease in MRI-PDFF ≥ 30% (i.e. percent change 
≤ -30%) at Weeks 12, 26, and 52 in the DB phase. 
 proportion of subjects with an observed MRI-PDFF change ≥ 5% (reduction, i.e. change 
≤ -5%) at Weeks 12, 26, and 52 in the DB phase. 


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The secondary efficacy outcome measures related with liver biopsy include the following: 
 proportion of subjects with reversal of NASH and no worsening of hepatic fibrosis 
(centrally scored histology at 52 weeks) in the DB phase. The reversal of NASH is defined 
as the absence of hepatocellular ballooning (score of 0) and no or minimal inflammation 
(lobular inflammation score of 0 or 1);  
 proportion of subjects with improvement by at least one stage in fibrosis without worsening 
of NASH (i.e. improvement by at least one fibrosis stage without worsening of NAFLD 
activity score) in the DB phase; and 
 proportion of subjects with a ≥ 2-point improvement in NAS in the DB phase. 
Other secondary efficacy outcome measures include the following: 
 relative (percent) and observed change in alanine aminotransferase (ALT), AST, gamma-
glutamyl transferase (GGT) in the DB and OLE phases;  
 relative (percent) and observed change in total cholesterol (TC), high-density lipoprotein 
cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), non-high-density 
lipoprotein cholesterol (non-HDL), homeostatic model assessment of insulin resistance 
(HOMA-IR) in the DB and OLE phases; and 
 relative (percent) and observed change in high-sensitivity C-reactive protein (hs-CRP) in 
the DB and OLE phases. 
The exploratory efficacy variables include the following:  
 MRE changes at Week 52 in the DB phase; and 
 LiverMultiScan (iron corrected T1 – cT1) changes at Weeks 12, 26, and 52 in the DB phase. 
2.3.2 Safety Outcome Measures 
The primary safety outcome measures include adverse events (AEs) and treatment emergent 
adverse events (TEAEs), physical exams, vital signs, electrocardiograms (ECGs), biochemistry, 
and hematology (National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE], Version 5.0) and pre-defined laboratory changes of interest. 
3. 
STATISTICAL METHODOLOGY 
3.1 
Baseline, Endpoint, and Other Statistical Considerations 
Unless otherwise stated, only data collected during the DB phase will be summarized. Data 
collected during the OLE and SFU phases will be listed only.  
Baseline Definition 
Baseline for the DB phase for all efficacy and safety variables will be defined as the last scheduled 
value obtained prior to the first dose of study drug. If the measurement at this visit is missing, the 
last measurement prior to the first dose of study drug will be used as baseline. The scheduled 
baseline visit for MRI-PDFF, FibroScan, LiverMultiScan, MRE, and liver biopsy is Screening. 
For all other efficacy and safety variables, the scheduled baseline visit is Day 1 pre-dose. 




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3.2 
Analysis Populations 
The safety analysis will be conducted on the Safety Population. In the event of treatment allocation 
errors, subjects will be analyzed for safety according to the treatment they received. Efficacy 
analyses will be conducted on the Intent-to-Treat (ITT) Population, the Modified Intent-to-Treat 
(mITT) Population, and the Modified Intent-to-Treat Population with biopsy (mITTb). In the event 
of treatment allocation errors, subjects will be analyzed for efficacy according to the treatment to 
which they were randomized. The mITT Population will be used for the primary efficacy analysis. 
All analyses except MRI-PDFF will be repeated on the following subgroups: 
 Subjects in the mITTb Population with atypical biopsy findings at Week 52/ET 
 Subjects in the mITTb Population without atypical biopsy findings at Week 52/ET 
3.2.1 Safety Population 
The Safety Population is defined as any subject who receives at least one dose of study drug.  
3.2.2 Intent-to-Treat Population 
The ITT Population is defined as any subject who is randomized and receives at least one dose of 
study drug.  
3.2.3 Modified Intent-to-Treat Population 
The mITT Population is defined as any subject who is randomized, receives at least one dose of 
study drug, and has Baseline and Week 12 MRI-PDFF.  
3.2.4  Modified Intent-to-Treat Population with Biopsy 
The mITTb Population is defined as any subject who is randomized, receives at least one dose of 
study drug, and has Baseline and Week 52/ET liver biopsies.  
3.3 
Subject Disposition 
The reason given for each screen failure will be listed. Subject disposition will be provided for all 
randomized subjects. The number and percentage of subjects in each of the following disposition 
categories will be presented: 
 Subjects who are randomized, 
 Subjects in each analysis population including the biopsy subgroups,  
 Subjects who complete Week 12, 
 Subjects who complete the DB phase of the study,  
 Subjects who withdraw from the DB phase of the study, 
 Subject who dose in the OLE, 
 Subjects who complete the OLE phase of the study,  
 Subjects who withdraw from the OLE phase of the study, and 
 Subjects entering the SFU phase (i.e. subjects that received seladelpar and had atypical 
biopsy findings at Week 52/ET). 
For randomized subjects who withdraw from the study, the primary reason for the withdrawal will 
be listed and summarized. For any subject that withdrawal on or after November 25, 2019, the 
reason for withdrawal will be “study cancelled by Sponsor.” 


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3.4 
Demographics and Baseline Characteristics 
Demographics (age, sex, race, and ethnicity), body weight, height, body mass index (BMI), HbA1c, 
hs-CRP, and stratification groups (diabetic status and fibrosis stage) will be summarized by 
randomized treatment using descriptive statistics for the Safety Population and repeated for each 
mITT Population, mITTb Population, and biopsy subgroups. 
Baseline MRI-PDFF, liver enzymes (ALT, AST, GGT), fibrosis stage, NAS, LiverMultiScan, and 
MRE, FibroScan, TC, LDL-C, HDL-C, triglycerides, HbA1c, and HOMA-IR will also be 
summarized for disease characteristics. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
V20.1.  The number and percentage of subjects with medical history will be summarized by 
preferred term within system organ class and by treatment group. 
Alcohol consumption collected at screening will be listed. 
3.5 
Prior/Concomitant Medications 
The use of any prior medication or concomitant medication will be listed for all subjects. 
Medications will be coded using World Health Organization (WHO) Drug Dictionary September 
2017G B3 version. The number and percentage of subjects taking concomitant medications will 
be summarized by preferred term within anatomical therapeutic chemical (ATC) term and by 
treatment group for the Safety Population, mITT Population, mITTb Population, and biopsy 
subgroups.  
A concomitant medication in the DB phase is defined as any medication taken on or after the first 
dose of study drug in the DB phase (includes those that began prior to study drug dosing but were 
ongoing or ended on or after the first dose of study drug). Medications that start on or after the 
first dose of study drug in the OLE phase are excluded. 
Concomitant procedures will be listed. 
3.6 
Study Drug Exposure and Compliance 
Days of overall exposure to study drug in the DB phase will be summarized by treatment group 
for the Safety Population, mITT Population, mITTb Population, and biopsy subgroups using 
descriptive statistics. Exposure in days is defined as: 
date of last dose of study drug – date of first dose + 1 
If the date of last dose of study drug from the DB phase end of study electronic case report form 
(eCRF) is unknown, it will be imputed based on the following priorities if available for the subject: 
1. If day is unknown but month and year are known, the last day of the month will be used 
2. Day prior to Week 52/End of Treatment Visit from the “date of visit” eCRF 
3. Day prior to Early Termination Visit from the “date of visit” eCRF 
4. Day of study completion/early termination from the DB phase end of study eCRF 
5. Last available visit date from the “date of visit” eCRF 
In addition, a contingency table will be provided to display the number and percentage of subjects 
with exposure in the following categories: 


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 1 to ≤4 weeks (1-28 days), 
 >4 to ≤8 weeks (29-56 days), 
 >8 to ≤12 weeks (57-84 days), 
 >12 to ≤26 weeks (85-182 days),  
 >26 to ≤39 weeks (183-273 days), 
 >39 to ≤52 weeks (274-364 days), and 
 >52 weeks (>364 days). 
Percent compliance will be calculated as:  
100 × 𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
𝑑𝑎𝑦𝑠 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒× 2
 
If bottles were dispensed but not returned, 0 returned tablets will be assumed in the calculation (i.e. 
this assumes all tablets were used). Percent compliance with the study drug during the 12-week 
treatment period in the DB phase and the whole 52-week treatment DB period will be summarized 
by treatment group for the Safety Population, mITT Population, mITTb Population, and biopsy 
subgroups using descriptive statistics. Additionally the number and percentage of subjects within 
each treatment group with overall compliance in the following categories will be provided: <80%, 
80% to 120%, and >120%. 
Study drug interruptions and planned dose changed will be listed but will not be factored into the 
compliance calculation.  
3.7 
Analysis of Efficacy 
3.7.1 Descriptive Statistics 
All data will be listed for the randomized subjects. Descriptive statistics of the baseline, change 
from baseline and/or relative (percent) change from baseline to each post-baseline visit will be 
presented by treatment group for each efficacy measurement. 
3.7.2 Analyses of Hepatic Fat Fraction by MRI-PDFF 
Summary statistics (number of subjects, mean, standard deviation, median, minimum, and 
maximum) for MRI-PDFF at all visits and the change and relative (percent) change from baseline 
will be provided for the ITT and mITT Population. 
3.7.2.1 Primary Efficacy Analysis 
The primary efficacy outcome measure is the relative change (i.e. percent change) in MRI-PDFF 
at Week 12. 
Relative (percent) change in MRI-PDFF = 100 × (Week 12 – Baseline) / Baseline. 
An analysis will be performed on the relative (percent) change from baseline to Week 12 in 
MRI-PDFF using analysis of covariance (ANCOVA) model with treatment and stratification 
groups (diabetic status and fibrosis stage) as factors and baseline MRI-PDFF as a covariate using 
the mITT Population and repeated based on the PP Population with MRI-PDFF. The LS means, 
standard errors, 95% confidence intervals (CIs), and p-values will be provided. All statistical 
comparisons will be made at a two-sided alpha of 0.05. Adjusting for multiplicity, treatment 


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comparisons of the primary efficacy endpoint will be tested using a hierarchical “fixed-sequence” 
approach to assess clinical benefit of each of the seladelpar dose levels versus placebo, starting 
first with the 50 mg dose at a 5% alpha level. If positive, the seladelpar 20 mg dose will be 
compared to placebo at a 5% alpha level. If both seladelpar 50 mg and 20 mg doses are statistically 
superior to placebo then the testing will continue to the 10 mg dose vs placebo. Regardless of 
significance level achieved, p-values will be presented in the summary tables for informational 
purposes but claims of statistical significance will not be made unless the rules of the hierarchical 
testing approach are achieved. 
The SAS sample code is listed: 
***********************************************************************  
  TREATMENT: 0 (placebo), 1 (seladelpar 10mg), 2 (seladelpar 20mg), or 
             3 (seladelpar 50mg) 
  DIABSTAT: diabetic status (yes or no)  
  FSTAGE: Fibrosis Stage (F1 or F2-3) 
  BASE: baseline MRI-PDFF 
  PCHG: percent change from baseline to Week 12 in MRI-PDFF 
**********************************************************************;  
proc glm data=ADEFF;  
  class TREATMENT DIABSTAT FSTAGE;  
  model PCHG = TREATMENT DIABSTAT FSTAGE BASE;  
  lsmeans TREATMENT / e pdiff cl;  
  estimate "Seladelpar 10mg : Placebo" TREATMENT -1 1 0 0;  
  estimate "Seladelpar 20mg : Placebo" TREATMENT -1 0 1 0;  
  estimate "Seladelpar 50mg : Placebo" TREATMENT -1 0 0 1;  
run; 
The p-value from the Shapiro-Wilk normality test of the residuals from the model above will be 
provided. If it is <0.01, the ANCOVA model specified above will be performed on the log-
transformed data, and the results will be back-transformed to relative (percent) change. If the 
residuals of this transformed model are still not normal, then non-parametric analyses will be 
explored. 
3.7.2.2 Hepatic Fat Fraction Treatment Goals 
The secondary efficacy outcome measures related to MRI-PDFF treatment goals are: 
 proportion of subjects with a relative decrease in MRI-PDFF ≥ 30% (i.e. percent change 
≤ -30%) at Weeks 12, 26, and 52; 
 proportion of subjects with an observed MRI-PDFF change ≥ 5% (reduction, i.e. change 
≤ -5%) at Weeks 12, 26, and 52. 
For each endpoint, the number and percentage of responders will be provided by treatment group 
and by stratification group. Cochran-Mantel-Haenszel tests will be performed adjusting for 
stratification groups (diabetic status and fibrosis stage). The general association p-value will be 
provided. Then for each seladelpar treatment group compared to placebo, the odds ratio, 95% 
confidence interval, and Breslow-Day test for homogeneity of the odds ratio p-value will be 
provided. The analysis will be performed on the ITT Population and repeated for the mITT 
Population. Subjects with missing data will be considered unimproved on the outcome measure. 
***********************************************************************  
  TREATMENT: 0 (placebo), 1 (seladelpar 10mg), 2 (seladelpar 20mg), or 


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             3 (seladelpar 50mg) 
  DIABSTAT: diabetic status (yes or no)  
  FSTAGE: Fibrosis Stage (F1 or F2-3) 
  RESPONDER: yes or no 
**********************************************************************;  
proc freq data=ALT;  
   tables DIABSTAT*FSTAGE*TREATMENT*RESPONDER / cmh;  
   weight COUNT;  
run;  
3.7.3 Analyses of Liver Biopsy Results 
All endpoints will be summarized and analyzed based on the mITTb Population and biopsy 
subgroups.  
Responder outcome measures include: 
 proportion of subjects with reversal of NASH and no worsening of hepatic fibrosis 
(centrally scored histology at 52 weeks). The reversal of NASH is defined as the absence 
of hepatocellular ballooning (score of 0) and no or minimal inflammation (lobular 
inflammation score of 0 or 1);  
 proportion of subjects with improvement by at least one stage in fibrosis without worsening 
of NASH (i.e. improvement by at least one fibrosis stage without worsening of NAFLD 
activity score); and 
 proportion of subjects with a ≥ 2-point improvement in NAS. 
For each endpoint, the number and percentage of responders will be provided by treatment group 
and by stratification group. Cochran-Mantel-Haenszel tests will be performed adjusting for 
stratification groups (diabetic status and fibrosis stage). The general association p-value will be 
provided. Then for each seladelpar treatment group compared to placebo, the odds ratio, 95% 
confidence interval, and Breslow-Day test for homogeneity of the odds ratio p-value will be 
provided. Subjects with missing data will be considered unimproved on the outcome measure.  
3.7.4 Analyses of Other Efficacy Endpoints 
All endpoints will be summarized and analyzed based on the ITT Population and repeated on the 
mITTb Population and biopsy subgroups. Since these endpoints are for exploratory purposes, no 
adjustments for multiplicity will be made. Summaries will exclude OLE phase visits. All OLE data 
will be listed. 
3.7.4.1 ALT, AST, and GGT 
The relative (percent) change from baseline in ALT, AST, and GGT at Weeks 4, 8, 12, 26, 39, 52, 
and 56 will be analyzed using a MMRM. No imputation will be performed. The factors in the 
model will be stratification groups (diabetic status and fibrosis stage), treatment group, baseline 
value, visit, and the treatment group by visit interactions. An unstructured covariance matrix will 
be used (TYPE=UN).  


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3.7.4.2 TC, HDL-C, LDL-C, Non-HDL, and HOMA-IR 
The percent change from baseline in TC, HDL-C, LDL-C, Non-HDL, and HOMA-IR at Weeks 4, 
8, 12, 26, 39, 52, and 56 will be analyzed using a MMRM. No imputation will be performed. The 
factors in the model will be stratification groups (diabetic status and fibrosis stage), treatment 
group, visit, and the treatment group by visit interactions. An unstructured covariance matrix will 
be used (TYPE=UN). The same model will be repeated on the subgroups of subjects on lipid 
lowering medication and HMG COA reductase inhibitors. 
3.7.4.3 Triglycerides 
The relative (percent) change from baseline in triglycerides at Weeks 4, 8, 12, 26, 39, 52, and 56 
will be analyzed using a MMRM on the log-transformed data. No imputation will be performed. 
The factors in the model will be stratification groups (diabetic status and fibrosis stage), treatment 
group, baseline value, visit, and the treatment group by visit interactions. An unstructured 
covariance matrix will be used (TYPE=UN). The same model will be repeated on the subgroups 
of subjects on lipid lowering medication and HMG COA reductase inhibitors. 
3.7.4.4 Hs-CRP  
The relative (percent) change from baseline in hs-CRP at Weeks 4, 8, 12, 26, 39, 52, and 56 will 
be analyzed using a MMRM on the log-transformed data. No imputation will be performed. The 
factors in the model will be stratification groups (diabetic status and fibrosis stage), treatment 
group, baseline value, visit, and the treatment group by visit interactions. An unstructured 
covariance matrix will be used (TYPE=UN).  
3.7.4.5 Other Efficacy Variables 
LiverMultiScan 
The observed change and relative (percent) change from baseline in LiverMultiScan (cT1 whole 
median) will be summarized.  
Fibroscan 
Results from the FibroScan, if available, will be summarized. 
3.8 
Analysis of Safety 
The safety endpoints for this study include: AEs, safety laboratory assessments, physical 
examinations, vital signs, and ECGs.  The safety endpoints will be summarized based on the Safety 
Population and repeated on the mITTb Population and biopsy subgroups. Missing values will not 
be imputed. Safety data will be summarized by study treatment (placebo vs. seladelpar) and by 
seladelpar dose. 
3.8.1 Adverse Events 
An AE is any medical occurrence in a subject administered a pharmaceutical product in a clinical 
study, regardless of a causal relationship with this treatment. An AE can, therefore, be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 


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temporally associated with the use of a medicinal product, whether or not related to the medicinal 
product.  
For analysis, a TEAE is defined as any AE that occurred after the first dose of double-blind study 
drug and up to 30 days after last dose of double-blind study drug, or one day before the first dose 
of OLE phase, whichever is earlier.  
Only AEs in the DB phase will be included in the summary tables. AEs beginning after the first 
dose of the OLE phase will be excluded from summaries but will be included in listings. 
A summary overview of TEAEs will be provided, which presents the number and percentage of 
subjects in each treatment group from the Safety Population, including number of events, 
satisfying each of the following categories: 
 Any TEAEs, 
 Maximum severity of TEAEs, 
 Study drug-related TEAEs, 
 Maximum severity of study drug-related TEAEs, 
 All serious AEs (SAEs), 
 All study drug-related SAEs, 
 AEs leading to death, 
 AEs leading to dose decreased or temporary interruption, 
 AEs leading to study drug discontinuation, and 
 Study drug-related AEs leading to study drug discontinuation. 
Adverse events will be coded using MedDRA. The number and percentage of subjects with 
TEAEs, including the number of TEAEs, will be summarized by their MedDRA preferred term 
within system organ class and by treatment.  For subject count summaries, multiple AE events 
with the same MedDRA coded terms (preferred term and system organ class) from the same 
subject will only be counted once. Similar summaries will be provided for drug-related TEAEs. 
The number and percentage of subjects with TEAEs will be summarized by reported maximum 
severity within each MedDRA preferred term within system organ class and by treatment.  Similar 
summaries will be provided for SAEs, for drug-related TEAEs, and for TEAEs beginning in the 
DB phase 12 week treatment period. 
Listings will be provided of all AEs, including SAEs and AEs leading to study drug 
discontinuation. 
3.8.2 Clinical Laboratory Assessments 
3.8.2.1 Chemistry, Hematology, and Other lab assessments 
Descriptive statistics of each chemistry (including HbA1c) and hematology parameter will be 
presented for baseline values and for values and the relative (percent) changes and changes from 
baseline at each post-baseline visit. These will be presented by treatment group for each parameter 
using the Safety Population.  
The relative (percent) change from baseline in alkaline phosphatase, total bilirubin, and direct 
bilirubin at each scheduled treatment visit will be analyzed using a MMRM. No imputation will 
be performed. The factors in the model will be stratification groups (diabetic status and fibrosis 






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3.8.4 Physical Examination 
Physical examination findings will be tabulated as a shift table from baseline to the worst post-
dose result in the DB phase. Results after dosing in the OLE phase will be excluded 
3.8.5 Vital Signs, Weight, BMI 
Vital signs parameters (systolic blood pressure, diastolic blood pressure, heart rate, temperature, 
respiratory rate), weight, and BMI will be summarized using descriptive statistics for the Safety 
Population. The relative (percent) change from baseline will also be presented. 
3.8.6 Other Safety Parameters 
Other safety data will be listed. 
3.9 
Safety Follow-up Phase 
After the final database lock, the study data listings will be updated to include all data that is 
collected during the SFU phase. Summary of baseline characteristics, demographics and safety 
data of subjects who participate SFU phase may be summarized if applicable.   
4. 
SAMPLE SIZE DETERMINATION 
A sample size of 175 subjects (50 subjects per each dose of seladelpar and 25 subjects for placebo) 
provides at least 80% power to detect a pairwise treatment difference of at least 20% between the 
active and placebo groups with respect to a relative change from baseline in hepatic fat fraction, 
as assessed by MRI-PDFF at Week 12. Power calculations were performed using a standard t-test, 
allowed for a 12% dropout rate (6 subjects per seladelpar arm, 3 subjects for the placebo arm), and 
a pooled standard deviation of 26 for the relative change endpoint. 
5. 
CHANGES FROM PROTOCOL 
The Protocol specified use of NCI CTCAE version 4.0. However, version 5.0 has become available 
and will be used for summaries.  
Due to the early termination of the study, the following will not be analyzed: 
 MMRM and Wilcoxon rank-sum analysis of MRI-PDFF 
 proportion of subjects with normalization of MRI-PDFF (defined as a fat fraction of < 5%) 
at Weeks 12, 26, and 52 in the DB phase 
 CMH analysis of biopsy endpoints 
 Summaries of APRI and FIB-4 in the DB and OLE phases (all reported data will still be 
listed) 
 Summaries of fibrinogen in the DB and OLE phases (all reported data will still be listed) 
 Summaries of enhanced liver fibrosis score (ELF) and its components (hyaluronic acid 
[HA], procollagen III N-terminal peptide [PIIINP], tissue inhibitor of matrix 
metalloproteinases [TIMP-1]) in the DB and OLE phases (all reported data will still be 
listed) 
 Summaries of C4, serum bile acids, and FAO tests in DB and OLE phases (all reported 
data will still be listed) 


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 PP Population 
6. 
PROGRAMMING SPECIFICATIONS 
Statistical analyses will be performed using SAS® version 9.4. The Medpace standard operating 
procedures will be followed for the validation of all SAS programs and outputs. The mock-ups for 
SAS-generated tables/figures/listings will be prepared in a separate document and finalized before 
database lock for the study.