Conditions: Primary Biliary Cholangitis
Keywords: PBC Primary Biliary Cholangitis (PBC)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 265
Healthy volunteers: no

Brief summary:
A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the safety and efficacy of seladelpar in subjects with primary biliary cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA)

The participants might enter the ongoing open-label safety study (NCT03301506) following this double-blind study.

Detailed description:
Primary:

* To evaluate the safety and effect on cholestasis of two seladelpar regimens (5 mg/day titrated to 10 mg/day and 10 mg/day) over 52 weeks of treatment compared to placebo

Key Secondary:

* To evaluate the effect of seladelpar on normalization of alkaline phosphatase (AP) levels
* To evaluate the effect of seladelpar on pruritus

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: seladelpar 5-10 mg intervention 2: seladelpar 10 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Seladelpar 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remainder of double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label long term safety study. Subjects will continue the seladelpar dose (5 or 10 mg) received during the double-blinded study intervention 2: Seladelpar 10 mg for double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label safety study. Subjects will continue the seladelpar dose (10 mg) received during the double-blinded study intervention 3: One capsule daily for double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label long term safety study. Subjects on placebo will be re-randomized to initiate seladelpar at 5 or 10 mg once daily

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
Unique Protocol ID: CB8025-31735 
 
 
Official Title: A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the safety 
and efficacy of seladelpar in subjects with primary biliary cholangitis (PBC) and an inadequate 
response to or an intolerance to ursodeoxycholic acid (UDCA) 
 
NCT number: NCT03602560 
 
Protocol Version Number: Version 1.0 
 
Date: 3-JUL-2018 


CymaBay Therapeutics, Inc 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL 
Page 1 of 94 
CB8025-31735 
PROTOCOL TITLE: 
A 52-week, placebo-controlled, randomized, Phase 3 study to 
evaluate the safety and efficacy of seladelpar in subjects with 
primary biliary cholangitis (PBC) and an inadequate response 
to or an intolerance to ursodeoxycholic acid (UDCA) 
PROTOCOL 
VERSION NUMBER: 
Version 1.0 
DATE OF PROTOCOL: 
3-JUL-2018
PROTOCOL NUMBER: 
CB8025-31735 
SPONSOR: 
CymaBay Therapeutics, Inc. 
7575 Gateway Blvd, Suite 110 
Newark, CA 94560 
United States of America 
SPONSOR CONTACT: 
 
EudraCT number: 
2018-001171-20 
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 
 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
Page 3 of 94 
TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS ..................................................................................7 
2 
LIST OF SPONSOR CONTACTS ..........................................................................9 
3 
SYNOPSIS .............................................................................................................10 
4 
INTRODUCTION .................................................................................................27 
4.1 
Primary Biliary Cholangitis (PBC) ..................................................................27 
4.2 
Seladelpar .........................................................................................................28 
4.2.1 
Overview ..............................................................................................28 
4.2.2 
Mechanism of Action ...........................................................................28 
4.3 
Nonclinical Investigations with Seladelpar .....................................................28 
4.4 
Human Experience ...........................................................................................28 
4.4.1 
Phase 1 Studies ....................................................................................29 
4.4.2 
Phase 2 Studies in PBC Patients ..........................................................29 
4.4.3 
Phase 2 Studies in Non-PBC Patients ..................................................31 
4.5 
Risk/Benefit Assessment .................................................................................31 
4.5.1 
Potential Benefits .................................................................................31 
4.5.2 
Potential Risks .....................................................................................32 
4.5.2.1 
Non-clinical Safety Findings ......................................................32 
4.5.2.2 
Human Safety..............................................................................32 
4.6 
Rationale for Dose Selection ...........................................................................33 
4.7 
Conclusions ......................................................................................................33 
5 
STUDY OBJECTIVES ..........................................................................................34 
5.1 
Primary Objectives...........................................................................................34 
5.2 
Secondary Objectives.......................................................................................34 
5.3 
Exploratory Objectives ....................................................................................34 
6 
STUDY POPULATION ........................................................................................35 
6.1 
Selection Criteria .............................................................................................35 
6.1.1 
Inclusion Criteria .................................................................................35 
6.1.2 
Exclusion Criteria ................................................................................35 
7 
STUDY DESIGN...................................................................................................37 
7.1 
Treatment and Allocation of Subjects ..............................................................38 
7.2 
Study Duration .................................................................................................39 
7.3 
Study Outcome Measurements ........................................................................39 
7.3.1 
Primary Measures ................................................................................39 
7.3.2 
Key Secondary Measures .....................................................................39 
7.3.3 
Other Secondary Measures ..................................................................39 
7.3.4 
Exploratory Measures ..........................................................................40 
8 
STUDY MEDICATIONS ......................................................................................41 


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8.1 
Clinical Supplies ..............................................................................................41 
8.1.1 
Investigational Product (Study Drug), Dosage and Mode of 
Administration .....................................................................................41 
8.1.2 
UDCA, Dosage and Mode of Administration......................................41 
8.1.3 
Packaging, Labeling and Shipping ......................................................41 
8.1.3.1 
Dose Up-titration ........................................................................41 
8.1.3.2 
Dose Down-titration....................................................................41 
8.1.4 
Accountability of Clinical Supplies .....................................................41 
8.1.5 
Replacement Study Drug and UDCA ..................................................42 
8.1.6 
Storage of Study Drug and UDCA ......................................................42 
8.2 
Randomization .................................................................................................42 
8.2.1 
Randomization Procedure ....................................................................42 
8.3 
Emergency Unblinding ....................................................................................42 
8.4 
Method of Administration and Compliance ....................................................42 
8.5 
Concomitant Medications and Procedures.......................................................42 
8.5.1 
Concomitant Medications ....................................................................43 
8.5.1.1 
Allowed Concomitant Medication: .............................................43 
8.5.1.2 
Prohibited Concomitant Medication ...........................................43 
8.5.2 
Concomitant Procedures ......................................................................43 
9 
STUDY PROCEDURES .......................................................................................44 
9.1 
Study Schedule.................................................................................................44 
9.1.1 
Screening (Week -4 to Week -2) .........................................................44 
9.1.2 
Run-In (Week -2 to Day 1) ..................................................................45 
9.1.3 
Treatment Period ..................................................................................46 
9.1.4 
Post-Treatment Follow-Up ..................................................................52 
9.1.5 
Early Termination Visit .......................................................................52 
9.1.6 
Unscheduled Visit ................................................................................53 
9.2 
Study Assessments ...........................................................................................53 
9.2.1 
Medical History and Physical Examination .........................................53 
9.2.2 
Vital Signs and Weight/Height ............................................................54 
9.2.3 
Electrocardiograms ..............................................................................54 
9.2.4 
Laboratory Tests ..................................................................................54 
9.2.5 
Liver Elastography ...............................................................................55 
9.2.6 
Liver Biopsy.........................................................................................56 
9.2.7 
Pruritus Numerical Rating Scale (NRS) ..............................................56 
9.2.8 
5-D Itch Scale ......................................................................................56 
9.2.9 
PBC-40 QoL ........................................................................................57 
9.2.10 
PGI-S and PGI-C .................................................................................57 
9.3 
Dose Titration ..................................................................................................57 


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10 
ADVERSE EVENTS .............................................................................................58 
10.1 
General .............................................................................................................58 
10.1.1 
Definition of Adverse Events...............................................................58 
10.1.2 
Definition of Serious AEs (SAEs) .......................................................58 
10.1.3 
AE Severity ..........................................................................................58 
10.1.4 
Adverse Event Outcome ......................................................................59 
10.1.5 
Relationship to Study Drug ..................................................................59 
10.1.6 
Action Taken with Study Medication ..................................................60 
10.2 
Recording, Reporting, and Follow-up of Adverse Events ...............................60 
10.2.1 
SAE Reporting Process ........................................................................61 
10.2.2 
Follow-up of Reported AEs .................................................................62 
10.3 
Distribution of Responsibilities .......................................................................62 
10.4 
Safety Monitoring Criteria and Withdrawal Criteria .......................................62 
10.4.1 
Liver Safety Monitoring ......................................................................62 
10.4.2 
Muscle Safety Monitoring ...................................................................63 
10.4.3 
Serum Creatinine Monitoring ..............................................................64 
10.4.4 
Pancreatic Safety Monitoring ..............................................................64 
10.4.5 
Additional Withdrawal Criteria and Replacement of Subjects ............64 
10.5 
Precautions .......................................................................................................65 
10.5.1 
Pregnancy .............................................................................................65 
11 
STUDY TERMINATION .....................................................................................66 
12 
DATA HANDLING CONSIDERATIONS ...........................................................67 
12.1 
Processing of Electronic Case Report Forms...................................................67 
12.2 
Database ...........................................................................................................67 
12.3 
Data Discrepancies...........................................................................................67 
13 
STATISTICAL ANALYSES ................................................................................68 
13.1 
General Statistical Considerations ...................................................................68 
13.2 
Determination of Sample Size .........................................................................68 
13.3 
Analysis Sets ....................................................................................................69 
13.3.1 
Safety Set .............................................................................................69 
13.3.2 
Intent to Treat Analysis Set (ITT) ........................................................69 
13.3.3 
Modified Intent to Treat Analysis Set ..................................................69 
13.3.4 
Per Protocol (PP) Analysis Set ............................................................69 
13.4 
Analysis Time Points .......................................................................................69 
13.5 
Handling of Drop-Outs and Missing Data .......................................................69 
13.6 
Disposition, Demographics and Baseline Characteristics ...............................70 
13.7 
Efficacy Analysis .............................................................................................70 
13.8 
Safety Analysis ................................................................................................73 


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14 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................74 
14.1 
Study Monitoring .............................................................................................74 
14.1.1 
Source Documents ...............................................................................74 
14.1.2 
Case Report Forms ...............................................................................74 
14.1.3 
Protocol Deviations ..............................................................................74 
14.2 
Audits and Inspections .....................................................................................74 
14.2.1 
Trial Auditing.......................................................................................74 
14.2.2 
Trail Monitoring...................................................................................74 
14.3 
Ethics Committees ...........................................................................................75 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................76 
16 
ETHICS..................................................................................................................77 
16.1 
Ethics Review ..................................................................................................77 
16.2 
Ethical Conduct of the Study ...........................................................................77 
16.3 
Written Informed Consent ...............................................................................77 
17 
RETENTION OF RECORDS ...............................................................................78 
18 
PROTOCOL AMENDMENTS .............................................................................79 
19 
DISCLOSURE OF INFORMATION AND PUBLICATION POLICY ...............80 
20 
REFERENCES ......................................................................................................81 
 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ...........................................................................25 
 
LIST OF FIGURES 
Figure 1 
Mean Percent Changes in AP in PBC Phase 2 Studies ..............................30 
Figure 2 
Median Percent Change in ALT in PBC Phase 2 Studies .........................30 
Figure 3 
Study Diagram – Clinical Study CB8025-31735.......................................38 
 


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1 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AMA 
Anti-mitochondrial antibodies 
ANCOVA 
Analysis of covariance 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
BA 
Bile acids 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
C4 
7α-hydroxy-4-cholesten-3-one 
CDCA 
Chenodeoxycholic acid 
CERC 
Critical Event Review Committee 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CMH 
Cochran-Mantel-Haenszel 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ELF 
Enhanced liver fibrosis  
ELISA 
Enzyme linked immunosorbent assay 
FGF19 
Fibroblast growth factor 19 
FIB-4 
Fibrosis-4 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HA 
Hyaluronic acid 
HBsAg 
Hepatitis B Surface Antigen 
HCV 
Hepatitis C Virus 
HDL-C 
High density lipoprotein cholesterol 
HoFH 
Homozygous familial hypercholesterolemia 
hs-CRP 
High sensitivity C-reactive protein 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent ethics committee 
IgM 
Immunoglobulin M 
INR 
International normalized ratio 


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ITT 
Intent to treat 
IXRS 
Interactive voice/web response system 
LDH 
Lactate dehydrogenase 
LDL-C  
Low density lipoprotein cholesterol  
LOCF 
Last observation carried forward 
M1, M2, M3 
Seladelpar (MBX-8025) metabolites 
MBX-8025 
Seladelpar 
MedRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End-Stage Liver Disease 
mITT 
Modified intent to treat 
MMRM 
Mixed models repeated measures 
NAFLD 
Non-alcoholic fatty liver disease 
NASH 
Nonalcoholic steatohepatitis 
NCI  
National Cancer Institute  
NRS 
Numerical rating scale 
OCA 
Obeticholic acid 
PBC 
Primary biliary cholangitis 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PMM 
Pattern-mixture model 
PP 
Per protocol 
PPAR 
Peroxisome proliferator-activated receptor 
Pro-C3 
N-terminal type III collagen propeptide 
PT 
Prothrombin time 
QoL 
Quality of life 
RBC 
Erythrocyte count 
SAE 
Serious adverse event 
SD 
Standard deviation 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
UDCA 
Ursodeoxycholic acid 
ULN 
Upper limit of normal 
VAS 
Visual analogue scale 
WBC 
Leukocyte count 
WHO 
World Health Organization 
 


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2 
LIST OF SPONSOR CONTACTS 
Sponsor Contact: 
 
CymaBay Therapeutics, Inc. 
7575 Gateway Blvd, Suite 110 
Newark, CA 94560 
United States of America  
 
 
 
 
The Sponsor will notify the investigator(s) in writing with any change to the above 
information. 


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3 
SYNOPSIS 
Study Number 
CB8025-31735  
Title 
A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the 
safety and efficacy of seladelpar in subjects with primary biliary cholangitis 
(PBC) and an inadequate response to or intolerance to ursodeoxycholic acid 
(UDCA) 
Phase 
3 
Objectives 
Primary:  
• 
To evaluate the safety and effect on cholestasis of two seladelpar 
regimens (5 mg/day titrated to 10 mg/day and 10 mg/day) over 52 weeks 
of treatment compared to placebo 
Key Secondary:  
• 
To evaluate the effect of seladelpar on normalization of alkaline 
phosphatase (AP) levels 
• 
To evaluate the effect of seladelpar on pruritus 
Other Secondary: 
• 
To evaluate the effect of seladelpar on quality of life (QoL) 
• 
To evaluate the effect of seladelpar on other measures of cholestasis, 
metabolic outcomes, and PBC prognosis criteria 
• 
To evaluate the effect of seladelpar on PBC clinical outcomes 
Exploratory: 
• 
To evaluate the effect of seladelpar on markers of inflammation, bile acid 
synthesis, levels of autotaxin, and markers of liver fibrosis 
Study Outcome 
Measures 
Primary Measures: 
• 
Response on the composite endpoint of AP and total bilirubin at 
12 months:  
o AP < 1.67 × upper limit of normal (ULN), and 
o ≥ 15% decrease in AP, and 
o Total bilirubin ≤ ULN  
• 
Assessment of treatment-emergent AEs (TEAEs) (National Cancer 
Institute [NCI] Common Terminology Criteria for Adverse Events 
[CTCAE] Version 4.0), biochemistry and hematology  
1. Key Secondary: 
• 
Proportion of subjects with AP ≤ 1.0 × ULN at 12 months  
• 
Change from baseline in pruritus numerical rating scale (NRS) at 
6 months 
Other Secondary: 
• 
PBC-40 QoL at 6 and 12 months 
• 
PBC-40 QoL itch domain, and 5-D itch questionnaire 


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• 
Response on the composite endpoint at 6 months 
• 
Proportion of subjects with AP < 1.67 × ULN and AP < 1.5 × ULN at 6 
and 12 months 
• 
Proportion of subjects with AP ≤ 1.0 × ULN at 6 months and 12 months 
• 
Change from baseline in pruritus NRS at 12 months 
• 
Absolute and relative changes in AP 
• 
Proportion of subjects with PBC response criteria (Barcelona, Paris I and 
II, Toronto I and II, Rotterdam)  
• 
Change in UK-PBC and GLOBE risk scores 
• 
Absolute and relative changes in alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), 
bilirubin (total, direct, and indirect), low density lipoprotein cholesterol 
(LDL-C), high density lipoprotein cholesterol (HDL- C), triglycerides, 
and total cholesterol  
• 
The first occurrence of any of the following events: 
o Overall Death 
o Liver transplantation 
o MELD score ≥15 
o Uncontrolled ascites (diuretic resistant) 
o Hospitalization for new onset or recurrence of any of the 
following: 
 
variceal bleeding 
 
hepatic encephalopathy (as defined by a West Haven 
score ≥ 2) 
 
spontaneous bacterial peritonitis (confirmed by culture 
from diagnostic paracentesis) 
o Hepatocellular carcinoma 
o Advanced PBC as defined by the Rotterdam criteria (albumin 
below low limit of normal (LLN) AND total bilirubin above 
ULN)  
Exploratory Measures: 
• 
C4 (7α-hydroxy-4-cholesten-3-one), fibroblast growth factor 19 
(FGF19), N-terminal type III collagen propeptide (Pro-C3) 
• 
Haptoglobin, fibrinogen and high-sensitivity C-reactive protein (hs-
CRP), homocysteine, immunoglobulin M (IgM) 
• 
Autotaxin  
• 
Enhanced liver fibrosis (ELF) score, fibrosis-4 (FIB-4) score, Lok-Index, 
non-alcoholic fatty liver disease (NAFLD) fibrosis score  
• 
Liver elastography (at selected centers) 


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Design 
Double-blind, randomized, placebo controlled, 52 weeks dose ranging 
(placebo, 5/10 mg/day, and 10 mg/day), parallel treatment groups  
Subjects on 5/10 mg who are tolerating study drug but who are not responding 
to the therapy based on composite endpoint, will have dose adjustment 
performed after 6 months of treatment.  
 
Treatment Groups 
• 
Seladelpar 5/10 mg 
• 
Seladelpar 10 mg 
• 
Placebo 
Number of Subjects 
Approximately 240 subjects total with approximately 80 subjects per group   
Number of 
Investigational Sites 
Approximately 140 worldwide 
Randomization 
1:1:1 
Stratification 
Randomization will be stratified by the following factors: 
• 
AP < 350 U/L and ≥ 350 U/L 
• 
Pruritus NRS < 4 and NRS ≥ 4  
Duration 
Screening: up to 2 weeks 
Run-In: 2 weeks 
Treatment: 52 weeks with an option to enter a long-term study (CB8025-
31731) 
Follow-up: 4 weeks (if not enrolled in the long-term study) 
Total Duration: up to 60 weeks  
Test Product, 
Formulation, Dose, 
Frequency, 
Administration 
Route   
Seladelpar 
Placebo 
Capsules 
Identical-looking capsules 
5 and 10 mg 
NA 
Once a day  
Once a day 
Oral 
Oral 
 
Population 
PBC subjects with an inadequate response to UDCA or intolerance to 
UDCA 


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Criteria for 
Eligibility 
Inclusion Criteria: 
Subjects must meet all of the following criteria to be eligible for study 
participation: 
1. Must have given written informed consent (signed and dated) and 
any authorizations required by local law 
2. 18 to 75 years old (inclusive) 
3. Male or female with a diagnosis of PBC, by at least two of the 
following criteria: 
• 
History of AP above ULN for at least six months 
• 
Positive anti-mitochondrial antibody (AMA) titers (>1/40 on 
immunofluorescence or M2 positive by enzyme linked 
immunosorbent assay [ELISA]) or positive PBC-specific 
antinuclear antibodies 
• 
Documented liver biopsy result consistent with PBC 
4. On a stable and recommended dose of UDCA for the past twelve 
months OR intolerant to UDCA (last dose of UDCA > 3 months prior to 
Screening) 
5. AP ≥ 1.67 × ULN 
6. 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 90 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  
Exclusion Criteria: 
Subjects must not meet any of the following criteria to be eligible for study 
participation: 
1. 
Previous exposure to seladelpar (MBX-8025) 
2. 
A medical condition, other than PBC, that in the investigator’s opinion 
would preclude full participation in the study or confound its results 
(e.g., cancer) 
3. 
AST above 3 × ULN 
4. 
ALT above 3 × ULN 
5. 
Total bilirubin above 2.0 × ULN 
6. 
Advanced PBC as defined by the Rotterdam criteria (albumin below 
LLN AND total bilirubin above 1 × ULN) 
7. 
Creatine kinase (CK) above 1.0 × ULN 
8. 
eGFR below 60 mL/min/1.73 m2 (calculated by MDRD formula) 
9. 
International normalized ratio (INR) above 1.0 × ULN 
10. Platelet count below 100 × 103/µL 
11. Presence of clinically significant hepatic decompensation, including: 


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- 
History of liver transplantation, current placement on liver 
transplantation list, or current MELD score ≥ 15 
- 
Complications of portal hypertension, including known esophageal 
varices, history of variceal bleeds or related interventions (e.g., 
transjugular intrahepatic portosystemic shunt placement), relevant 
ascites, hepatic encephalopathy 
- 
Cirrhosis with complications, including history or presence of 
spontaneous bacterial peritonitis 
12. Other chronic liver diseases:  
a. Current features of auto-immune hepatitis as determined by the 
investigator based on immunoserology, liver biochemistry and 
histology 
b. Primary sclerosing cholangitis determined by presence of 
diagnostic cholangiographic findings  
c. History or clinical evidence of alcoholic liver disease 
d. History or clinical evidence of alpha-1-antitrypsin deficiency 
e. Biopsy confirmed nonalcoholic steatohepatitis 
f. History or evidence of Gilbert’ Syndrome with elevated total 
bilirubin 
g. History or evidence of hemochromatosis 
h. Hepatitis B defined as presence of hepatitis B surface antigen 
(HBsAg)  
i. 
Hepatitis C defined as presence of HCV RNA 
13. Known history of HIV 
14. Evidence of significant alcohol consumption 
15. Evidence of drug abuse 
16. Subjects with inadequate response to obeticholic acid (OCA) or 
intolerance to OCA: OCA must be discontinued 30 days prior to 
Screening 
17. Use of colchicine, methotrexate, azathioprine, or long-term systemic 
corticosteroids (> 2 weeks) within two months prior to Screening 
18. Use of fibrates within 30 days prior to Screening 
19. Use of simvastatin within 7 days prior to Screening 
20. Use of an experimental or unapproved treatment for PBC within 
30 days prior to Screening 
21. Use of experimental or unapproved immunosuppressant within 30 days 
prior to Screening 
22. Treatment with any other investigational therapy or device within 
30 days or within five half-lives, whatever is longer, prior to Screening 
23. For females, pregnancy or breast-feeding 
24. Any other condition(s) that would compromise the safety of the subject 
or compromise the quality of the clinical study, as judged by the 
investigator 


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Procedures 
Screening (Week -4): 
After signing an informed consent form (ICF), subjects will enter the 
Screening period to confirm eligibility. Demographics will be collected. A 
medical history will be taken, including PBC history, results of prior liver 
biopsy and liver elastography (FibroScan), and alcohol consumption. The 
subject’s medical chart will be reviewed for evidence of other forms of 
chronic liver disease as well as for HIV infection. Detailed treatment history 
will be collected, including previous exposure to UDCA, OCA as well as 
other medications taken for PBC and its symptoms. Vital signs will be 
collected. Height and weight will be collected. Complete physical 
examination will be performed as well as a 12-lead electrocardiogram 
(ECG). Blood samples will be taken for hematology, biochemistry, AMA, 
Hepatitis B and C. If unexpected elevation of CK or INR is noted, re-test 
will be allowed. Women of child-bearing potential will have a serum 
pregnancy test performed. Urine drug screen will be performed. E-diary 
training will be performed, and subjects will complete the pruritus NRS. 
UDCA will be dispensed, and subjects will be instructed to switch their pre-
study UDCA to study supply UDCA. Subjects will be instructed to continue 
UDCA regimen (dose and frequency) as close as possible to regimen taken 
prior to the study participation and as recommended per investigator’s 
clinical judgment.  
Run-In (Week -2): 
Subjects who have been deemed eligible during the Screening period will 
return for Run-In period.  
AEs since the last visit will be evaluated. Medication history including 
medications since the last visit will be reviewed. Vital signs and weight will 
be collected. Symptom-directed physical examination will be performed. 
Blood samples will be taken for hematology, biochemistry, and exploratory 
measures. Women of child-bearing potential will have a serum pregnancy 
test performed. Back-up blood sample will be collected. E-diary will be 
dispensed and re-training will be performed, if needed. The subject will 
complete the pruritus NRS, 5-D itch, PBC-40 QoL, and patient global 
impression of severity (PGI-S) using e-diary. The subject will be instructed 
to use e-diary to evaluate pruritus NRS on a daily basis and 5-D itch on a bi-
weekly basis from the Run-In visit through the first six month of study drug 
treatment. UDCA accountability will be performed. 
Baseline liver biopsy will be performed on subjects willing to undergo the 
procedure to evaluate PBC stage and activity. PT and INR must be 
performed within 2 weeks prior to liver biopsy. If liver biopsy was 
performed within 1 year from Day 1, Baseline liver biopsy can be waived. 
For these instances sites will attempt to collect biopsy material. A follow up 
liver biopsy will be performed after at least 3 years (± 3 months) of 
treatment during the long-term study (CB8025-31731). 
 
 


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
Page 16 of 94 
Day 1: 
Subjects will be randomized into the study.  
AEs since the last visit will be evaluated. Medication history including 
medications since the last visit will be reviewed. Vital signs and weight will 
be collected. A complete physical examination and ECG will be performed. 
Blood samples will be taken for hematology, biochemistry, exploratory 
measures (including fat-soluble vitamins). Back-up blood sample will be 
collected. Women of child-bearing potential will have a serum pregnancy 
test performed. PBC-40 and PGI-S questionnaires will be performed. A 
review of pruritus NRS and 5-D itch data collected via e-diary since the 
previous visit will be performed. Subjects will be reminded to use e-diary to 
evaluate pruritus NRS on a daily basis. Liver elastrography (e.g., FibroScan) 
will be performed at selected sites. Subjects will be dispensed with the study 
drug to be taken orally once a day. Study drug dosing will be initiated 
immediately. UDCA will be dispensed. UDCA accountability will be 
performed.  
If a subject terminates study participation at any point after Day 1, an Early 
Termination visit will be completed. 
Month 1 (Week 4 ± 3 days): 
AEs since the last visit will be evaluated. Concomitant medication history 
since the last visit will be reviewed. Vital signs and weight will be collected. 
Brief symptom-directed physical examination will be performed. Blood 
samples will be taken for hematology, biochemistry, exploratory measures. 
Back-up blood sample will be collected. Women of child-bearing potential 
will have a serum pregnancy test. Subjects will complete PBC-40 QoL, 
PGI-S and patient global impression of change (PGI-C). A review of 
pruritus NRS and 5-D itch data collected via e-diary since the previous visit 
will be performed. Study drug and UDCA accountability will be evaluated. 
Month 3 (Week 12 ± 7 days):  
AEs since the last visit will be evaluated. Concomitant medication history 
since the last visit will be reviewed. Vital signs and weight will be collected. 
Brief symptom-directed physical examination will be performed. Blood 
sample will be taken for hematology, biochemistry, exploratory measures. 
Back-up blood sample will be collected. Women of child-bearing potential 
will have a serum pregnancy test performed. The subject will complete 
PBC-40 QoL, PGI-S and PGI-C. A review of pruritus NRS and 5-D itch 
data collected via e-diary since the previous visit will be performed. Study 
drug and UDCA accountability will be evaluated. Study drug and UDCA 
will be dispensed.  
Contact 1 (Week 19 ± 7 days): 
Subjects will be contacted by phone or email for the following: AEs will be 
evaluated, concomitant medications and procedures since last visit will be 
reviewed. Compliance with study drug administration will be evaluated. 
Unscheduled visit might be scheduled, if deemed necessary by investigator.  


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
Page 17 of 94 
Month 6 (Week 26 ± 7 days): 
AEs will be evaluated. Concomitant Medications will be reviewed. Vital 
signs and weight will be collected. Complete physical examination will be 
performed. A 12-lead ECG will be performed. Blood samples will be taken 
for hematology, biochemistry, exploratory measures. Back-up blood sample 
will be collected. Women of child-bearing potential will have a serum 
pregnancy test performed. The subject will complete 5-D itch, PBC-40 QoL, 
PGI-S and PGI-C. A review of pruritus NRS and 5-D itch data collected via 
e-diary since the previous visit will be performed. Starting from this visit, 
the subject will be instructed to fill out the NRS questionnaire via e-diary 
for 7 consecutive days every month through the Month 12 visit; 5-D itch 
will be collected at the clinic visits only. Study drug and UDCA 
accountability will be evaluated. Liver elastography (e.g. FibroScan) will be 
performed at selected sites. Study drug and UDCA will be dispensed. 
Double-blind evaluation for dose up-titration will be performed. Dose up-
titration will be requested if the following criteria are met:  
No safety 
concerns limiting 
up-titration 
AND  
One of the following criteria: 
o 
AP ≥ 1.67 × ULN, OR  
o 
< 15% decrease in AP comparing to 
baseline value, OR 
o 
Total bilirubin > 1 × ULN  
Dose Adjustment Visit (2 weeks after Month 6 ± 3 days) 
All subjects will return to the clinic in two weeks after Month 6 visit for 
dose adjustment. For subjects who have safety concerns limiting up-
titration, Dose Adjustment visit will still occur to evaluate subjects’ status. 
Subjects will be instructed to not to take study drug at home prior to the 
clinic visit. TEAEs will be evaluated. Concomitant medications will be 
reviewed. Vital signs and weight will be collected. A brief symptom-
directed physical examination will be performed. A blood sample will be 
taken for hematology, biochemistry, and exploratory biochemistry. A back-
up serum sample will be collected. Study drug accountability will be 
evaluated. Additional assessments as determined by the Investigator. Dose 
up-titration will be performed, and the new dose of study drug will be 
administered. 
For subjects who meet the up-titration criteria: subjects on 5 mg will be 
dispensed seladelpar10 mg; subjects on 10 mg will be dispensed seladelpar 
10 mg, and subjects on placebo will be dispensed matched placebo. Study 
drug will be dispensed in a blinded manner. Subjects will immediately start 
dosing. 
Contact 2 (Week 32 ± 7 days): 
Subjects will be contacted by phone or email for the following: AEs will be 
evaluated, concomitant medications and procedures since last visit will be 
reviewed. Compliance with study drug administration will be evaluated. 
Unscheduled visit might be scheduled, if deemed necessary by investigator. 


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
Page 18 of 94 
Month 9 (Week 39 ± 7 days): 
AEs will be evaluated. Concomitant Medications will be reviewed. Vital 
signs and weight will be collected. Brief symptom-directed physical 
examination will be performed. Blood sample will be taken for hematology, 
biochemistry, exploratory measures. Back-up blood sample will be 
collected. Women of child-bearing potential will have a serum pregnancy 
test performed. The subject will complete 5-D itch, PBC-40 QoL, PGI-S 
and PGI-C. A review of pruritus NRS data collected via e-diary since the 
previous visit will be performed. Study drug and UDCA accountability will 
be evaluated. Study drug and UDCA will be dispensed. 
Contact 3 (Week 45 ± 7 days): 
Subjects will be contacted by phone or email for the following: AEs will be 
evaluated, concomitant medications and procedures since last visit will be 
reviewed. Compliance with study drug administration will be evaluated. 
Unscheduled visit might be scheduled, if deemed necessary by investigator. 
Month 12 (Week 52 ± 7 days): 
AEs will be evaluated. Concomitant Medications will be reviewed. Vital 
signs and weight will be collected. Complete physical examination will be 
performed. A 12-lead ECG will be performed. Blood sample will be taken 
for hematology, biochemistry, exploratory measures (including fat-soluble 
vitamins). Back-up blood sample will be collected. Women of child-bearing 
potential will have a serum pregnancy test performed. The subject will 
complete 5-D itch, PBC-40 QoL, PGI-S and PGI-C. A review of pruritus 
NRS data collected via e-diary since the previous visit will be performed. 
E- diary will be collected. Study drug and UDCA accountability will be 
evaluated. Study supply of UDCA will be switched to pre-study supply 
UDCA. Liver elastography (e.g. FibroScan) will be performed at selected 
sites. At the end of the visit, all subjects will be invited to participate in the 
long-term study (CB8025-31731).  
Subjects who consent to participate in CB8025-31731 will have the 
Month 12 visit combined with the Day 1 visit of CB8025-31731. Subjects 
on seladelpar will continue dosing; subjects on placebo will initiate 
seladelpar (5 or 10 mg). 
Subjects who do not consent to participate in CB8025-31731 will stop study 
drug and enter the four-week follow-up period.  
Post-Treatment Follow-up: 
Four weeks post-treatment, subjects will return to the clinic for a follow-up 
visit. This will be the subject’s last visit. 
AEs will be evaluated. Concomitant medications will be reviewed. Vital 
signs and weight will be collected. Complete physical examination will be 
performed, as well as a 12-lead ECG. Blood sample will be taken for 
hematology, biochemistry, and exploratory measures. Back-up serum 
sample will be collected. Women of child-bearing potential will have a 
serum pregnancy test performed.  


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
Page 19 of 94 
Early Termination Visit: 
AEs will be evaluated. Concomitant Medications will be reviewed. Vital 
signs and weight will be collected. Complete physical examination will be 
performed as well as a 12-lead ECG. Blood sample will be taken for 
hematology, biochemistry, and exploratory measures (including fat-soluble 
vitamins). Back-up serum sample will be collected. Women of child-bearing 
potential will have a serum pregnancy test performed. The subject will 
complete pruritus NRS, 5-D itch, PBC-40 QoL, PGI-S and PGI-C. A review 
of pruritus NRS data collected via e-diary since the previous visit will be 
performed. E-diary will be collected. Liver elastography (e.g. FibroScan) 
will be performed at selected sites. Study drug and UDCA accountability 
will be evaluated. Study supply of UDCA will be switched to pre-study 
supply of UDCA 
Unscheduled Visit: 
AEs will be evaluated. Concomitant Medications will be reviewed. Brief 
symptom-directed physical examination will be performed. Blood samples 
will be taken for biochemistry and hematology. Additional assessments as 
determined by the investigator. 
UDCA 
Subjects with inadequate response to UDCA will continue their UDCA 
intake in approximately the same dose as prior to the study participation and 
as recommended per investigator’s clinical judgment. 
Concomitant 
Treatment 
Subjects will be allowed to receive required medication to treat new or 
existing medical conditions. 
Prohibited 
Treatment 
Obeticholic acid 
Fibrates (e.g. fenofibrate, bezafibrate) 
Simvastatin 
Colchicine, methotrexate, azathioprine 
Systemic corticosteroids (> 2 weeks) 
Dose titration 
Subject will have a dose evaluation performed at the Month 6 visit to 
determine if dose up-titration is necessary. Dose evaluation will be done in a 
double-blind manner. 
Dose up-titration will occur if the following criteria are met: 
No safety 
concerns 
limiting up-
titration 
AND 
One of the following criteria: 
o AP ≥ 1.67 × ULN, OR  
o < 15% decrease in AP comparing to 
baseline value, OR 
o Total bilirubin > 1 × ULN  
Subjects who meet the criteria will receive the up-titrated dose at the Dose 
Adjustment visit (2 weeks after Month 6 visit). Subjects on 5 mg will be up-
titrated to 10 mg; subjects on 10 mg will continue 10 mg; and subjects on 
placebo will continue placebo.  
Subjects who do not meet the up-titration criteria will continue the study at 
the initially assigned dose.  


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
Page 20 of 94 
Safety Monitoring 
and Drug 
Interruption  
Liver Safety Monitoring 
1. Elevation of ALT/AST 
Normal ALT/AST at baseline  
• 
ALT/AST > 5 × ULN and total bilirubin ≤ 1 × ULN: Interrupt 
study drug. Repeat AST, ALT, total bilirubin, and INR within 3 
days and closely follow the subject (see Appendix B). Study 
medication can be restarted only if a firm competing etiology is 
identified, and liver tests return to baseline. 
• 
ALT/AST > 5 × ULN and total bilirubin > 1 × ULN: 
o Subjects with normal total bilirubin at baseline: Stop study 
drug. Repeat AST, ALT, total bilirubin, and INR within 3 
days and closely follow the subject (see Appendix B). 
o Subjects with elevated total bilirubin at baseline: 
 
Total bilirubin > 1.5 × baseline: Stop study drug. 
Repeat AST, ALT, total bilirubin, and INR within 3 
days and closely follow the subject (see 
Appendix B). 
 
Total bilirubin ≤ 1.5 × baseline: Interrupt study 
drug. Repeat AST, ALT, total bilirubin, and INR 
within 3 days and closely follow the subject (see 
Appendix B). Study medication can be restarted only 
if a firm competing etiology is identified, and liver 
tests return to baseline. 
Elevated ALT/AST at baseline: 
• 
ALT/AST > 3 × baseline AND INR ≤ 1.5 × ULN AND no liver-
related symptoms (e.g., nausea, vomiting, right upper quadrant pain, 
loss of appetite, dark urine, or jaundice): Continue study drug. 
Repeat AST, ALT, total bilirubin, and INR within 3 days. Closely 
follow the subject (see Appendix B). 
• 
ALT/AST > 3 × baseline AND INR > 1.5 × ULN AND no liver-
related symptoms (e.g., nausea, vomiting, right upper quadrant pain, 
loss of appetite, dark urine, or jaundice): Interrupt study drug. 
Repeat AST, ALT, total bilirubin, and INR within 3 days and closely 
follow the subject (see Appendix B). Study drug can be restarted 
only if a firm competing etiology is identified, and liver tests return 
to baseline. 
2. Liver-related symptoms (e.g., nausea, vomiting, right upper quadrant 
pain, loss of appetite, dark urine, or jaundice) AND ALT/AST 
> 3 × baseline (irrespective of baseline levels): Interrupt study drug. 
Repeat AST, ALT, total bilirubin, and INR within 3 days. Closely 
follow the subject (see Appendix B). Study drug can be restarted only if 
a firm competing etiology is identified, and liver tests return to baseline. 
3. Elevation of total bilirubin > 1.5 × baseline, regardless of ALT or AST 
levels, AND indicators of immunological reaction (e.g., rash, 
eosinophilia > 5%) OR liver-related symptoms (e.g., nausea, vomiting, 
right upper quadrant pain, loss of appetite, dark urine, or jaundice): 


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
Page 21 of 94 
Interrupt study drug. Repeat AST, ALT, total bilirubin, and INR 
within 3 days and closely follow the subject (see Appendix B). Study 
medication can be restarted only if a firm competing etiology is 
identified and liver tests return to baseline. 
4. Hepatic decompensation (e.g., decompensated cirrhosis with gastro-
esophageal variceal bleeding, ascites, or hepatic encephalopathy) during 
the study: Stop study drug and closely follow the subject (see 
Appendix B). 
5. Close monitoring of a subject is not possible (see Appendix B): Stop 
study drug.  
 
Muscle Safety Monitoring 
I. 
CK > 5 × ULN with musculoskeletal symptoms: Stop study drug. 
Repeat the test within 3 days. Follow the subject weekly until 
resolution or stabilization.  
II. 
CK > 5 × ULN without musculoskeletal symptoms: repeat the test 
within 3 days. If on repeat test CK is > 2.5 × ULN, stop study 
drug. Follow the subject weekly until the event resolution or 
stabilization.  
III. 
CK > 2.5 × ULN and ≤ 5 × ULN regardless to musculoskeletal 
symptoms: repeat the test within 3 days. If the test is confirmed, 
study drug will be continued at a decreased dose. For subjects on 
5 mg, the study drug will be switched to placebo. 
Serum Creatinine Monitoring 
I. 
Serum Creatinine > 2.0 × ULN: Stop study drug. The subject 
should be monitored weekly until resolution or stabilization.  
II. 
Serum Creatinine > 1.5 × ULN and ≤ 2.0 × ULN: interrupt study 
drug. Repeat the test within 3 days. If the test is confirmed and no 
alternative etiology is identified, stop study drug. If alternative 
etiology is identified, study drug may be restarted after serum 
creatinine returns to baseline values. The subject should be 
monitored weekly until event resolution or stabilization.  
Pancreatic Safety Monitoring 
I. 
Amylase > 3 × ULN and/or lipase > 3 × ULN without clinical 
symptoms of acute pancreatitis: repeat the test within 3 days. If the 
test confirms suspicion, interrupt study drug. Abdominal imaging 
is to be performed to exclude an alternative cause for the event. 
Study drug might be restarted only if a firm competing etiology of 
acute pancreatitis is identified. 
II. 
Amylase > 3 × ULN and/or lipase > 3 × ULN with clinical 
symptoms of acute pancreatitis: Interrupt study drug. Repeat the 
test within 3 days. Abdominal imaging is to be performed to 
exclude an alternative cause for the event. Study drug might be 
restarted only if a firm competing etiology of acute pancreatitis is 
identified 


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
Page 22 of 94 
Statistics 
Study Populations: 
The Safety population includes any subject who receives at least one dose of 
study drug. 
The Intent to Treat (ITT) population includes any subject randomized into 
the study. 
The Modified Intent to Treat (mITT) population includes any subject who is 
randomized into the study and receives at least one dose of study drug.  
The Per-Protocol (PP) population includes any subject who receives at least 
one dose of study drug, has at least one post baseline AP and total bilirubin 
evaluation, and does not have a protocol violation that is deemed to impact 
the efficacy analysis. 
Subjects will be analyzed according to randomized treatment assignment. 
Analysis Sets: 
Safety analysis will be conducted on the safety analysis set. Efficacy 
analysis will be conducted on the mITT analysis set and the PP analysis set. 
The mITT analysis set will be used for the primary efficacy analysis.  
Baseline is defined as the arithmetic mean of multiple pre-treatment 
measurements (Screening, Run-In, Day 1, and UNS if applicable) preceding 
the first administration of study drug, or as the last measurement prior to the 
first administration of study drug if only single value is available. 
Descriptive statistics such as means, medians, minimum, maximum and 
measures of dispersion will be presented. 
Primary analysis: 
The primary efficacy analysis will be based on the following composite 
endpoint evaluated after 52 weeks of treatment: 
• 
AP < 1.67x ULN, 
• 
AP decrease of ≥ 15%, and 
• 
Total bilirubin ≤ ULN 
Treatment comparisons of the primary efficacy endpoint will be tested using 
a gateway method. A hierarchical “fixed-sequence” approach will be used to 
evaluate the primary endpoint as follows: 
1. The composite endpoint and seladelpar 10 mg vs placebo if negative 
stop 
2. If positive, then:  
3. The composite endpoint and for seladelpar 5/10 mg vs placebo, if 
negative stop 
This testing procedure maintains the overall Type I error for the primary 
efficacy endpoint at 5%. Additional details including a schematic for the 
testing sequence can be found in the statistical analysis section of the 
protocol.  


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
Page 23 of 94 
All inferential tests will be performed at the 5% alpha level.  
Response rates will be calculated based on the observed case analysis (i.e., 
[n=observed responder]/[N=modified Intention to Treat (mITT) 
population]) 
The primary efficacy analysis will be conducted on the mITT analysis set 
using the Cochran-Mantel-Haenszel (CMH) General Association test. The 
CMH analysis will be stratified by baseline AP randomization (AP level 
< 350 U/L and ≥ 350 U/L) and pruritis NRS < 4 and NRS ≥ 4.  
In the primary analysis, subjects who discontinue treatment will be 
considered non-responders. Sensitivity analyses will be performed on the 
primary efficacy endpoint using observed data only. The robustness of the 
primary analysis will be explored using several sensitivity analyses based on 
different subject populations including treating subjects who discontinue 
study treatment: 
• 
As responders 
• 
Same as primary analysis except based on the ITT Set. 
• 
Same as primary analysis except based on the PP Set. 
• 
Same as primary analysis except impute dropouts as non-responders 
in the seladelpar arm and as responders in the placebo arm (i.e. 
worst-case analysis). 
• 
Same as primary analysis except impute missing data using a 
pattern-mixture model (PMM) which considers different 
mechanisms for missing data.  
• 
Same as primary analysis except specify the proportion of patients 
achieving a decrease in AP as at least 10%, 20%, and 40%. 
• 
Using Medians instead of arithmetic means for baseline values 
Key Secondary Analyses:  
• 
normalization of AP at 12 months (i.e. AP ≤ ULN), and 
• 
change from baseline in the weekly averaged peak pruritus NRS 
over 6 months 
Type I error for key secondary efficacy analysis will be maintained using 
the hierarchical fixed-sequence. The fixed sequence approach for the 
primary and secondary analyses is as follows: 
• 
If the primary efficacy analysis is positive for 10 mg vs placebo and 
5/10 mg vs placebo, then the two key secondary endpoints will be 
analysed hierarchically in the following order: 
1. Normalization of AP at month 12: seladelpar 10 mg vs placebo, if 
negative stop, if positive then; 
2. Normalization of AP at month 12: seladelpar 5/10 mg vs placebo if 
negative stop, if positive then; 
3. Absolute change from baseline to month 6 in pruritus NRS: 
seladelpar 10 mg vs placebo if negative stop, if positive then; 


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
Page 24 of 94 
4. Absolute change from baseline to month 6 in pruritus NRS: 
seladelpar 5/10 mg vs placebo, stop 
Normalization of AP is a responder analysis and will be conducted in the 
mITT set using the same approach specified for the primary efficacy 
analysis. 
Additional analyses of pruritus, including durability of response to 
Month 12, will be described in SAP. 
Other Analyses: 
• 
The first occurrence any of the following events: 
o Overall Death 
o Liver transplantation 
o MELD score ≥ 15 
o Uncontrolled ascites (diuretic resistant) 
o Hospitalization for new onset or recurrence of any of the 
following: 
 
variceal bleeding 
 
hepatic encephalopathy (as defined by a West 
Haven score ≥ 2) 
 
spontaneous bacterial peritonitis (confirmed by 
culture from diagnostic paracentesis) 
o Hepatocellular carcinoma 
o Advanced PBC as defined by the Rotterdam criteria (low 
serum albumin AND total bilirubin above 1 × ULN) 
Clinical events will be validated by a Critical Event Review Committee 
(CERC) composed of independent clinical experts familiar with hepatic 
diseases.  
Sample size:  
The planned sample size is 240 subjects (80 subjects in each of the 
3 groups). The placebo group responder rate is estimated at less than 15%. 
The seladelpar 10 mg dose group responder rate is estimated at 40%. With 
the use of a 2-sided test of equality of binomial proportions based on 
Pearson chi-square test at the 5% level of significance, a sample size of 
80 subjects per group will provide greater than 90% power to detect a 
difference between the 10 mg seladelpar group and the placebo group. 
Normalization of AP is estimated to have a placebo response rate of 5%. 
A 2-sided test of equality of binomial proportions based on Pearson chi-
square test at the 5% level of significance yields a sample size of 80 subjects 
per group. This sample size provides more than 90% power to detect a 
difference of 30% between the seladelpar and placebo groups. 
Change in pruritus NRS sample size calculation was based on a 2-sample 
2-sided t-test at the 5% alpha level. The standard deviation is 3. Under these 
assumptions, a total of 23 subjects per group provides ≥90% power to detect 
a treatment difference of ≥ 3 between the 10 mg seladelpar and placebo 
groups. 
 


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 0.1, 30-APR-2018 
CONFIDENTIAL 
Page 25 of 94 
Table 1 
Schedule of Assessments 
Visit 
Screening 
Run-In 
Randomi-
zation 
Month 
1 
Month 
3 
Contact 
11 
Month 
6 
Dose 
Adjust 
Contact 
21 
Month 
9 
Contact 
31 
Month 
1212 
Follow 
Up 
ET 
UNS 
Target Day  
W-4 to -2 
W -2 
Day 1 
W 4 
W 12 
W 19 
W 26 
W28 
W 32 
W 39 
W 45 
W 52 
4W after 
W52 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Evaluation2 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Up-Titration  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE 
 
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 
X 
Vital Signs and Weight 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X4 
X 
X4 
X4 
 
X 
X4 
 
X4 
 
X 
X 
X 
X4 
ECG 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
Hematology5, 6 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
Biochemistry5 
X7 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
Exploratory Measures5 
X8 
X 
X8 
X 
X 
 
X 
X 
 
X 
 
X8 
X 
X8 
 
Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test9 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Back-up Blood Sample5 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus NRS10 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
5-D itch10 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
PBC-40 QoL10 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
PGI-S10 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
PGI-C10 
 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Liver Elastography 
(selected sites)  
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Liver Biopsy11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
UDCA Dispense 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Study Drug Dispense 
 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
Study Drug 
Compliance and 
Accountability 
 
 
 
X 
X 
X13 
X 
X 
X13 
X 
X13 
X 
 
X 
 
UDCA Accountability 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 


CymaBay Therapeutics, Inc 
 
Protocol CB8025-31735 
Protocol Version 0.1, 30-APR-2018 
CONFIDENTIAL 
Page 26 of 94 
Abbreviations:  AE=adverse event; AMA=anti-mitrochondrial antibodies; ECG=electrocardiogram; ET=Early Termination; NRS=numerical rating scale; PBC=primary biliary cholangitis; PGI-
C=patient global impression of change; PGI-S; patient global impression of severity; QoL=quality of life; UDCA=ursodeoxycholic acid; UNS=Unscheduled visit; W=week.  
1. 
Subject contact will be performed by phone or email communication. 
2. 
All subjects will be evaluated for dose up-titration in a blinded manner. For subjects who met the up-titration criteria, dose up-titration will be requested. Dose up-titration will occur at Dose 
Adjustment visit. 
3. 
Including PBC history, liver biopsy, liver elastography, alcohol consumption, evidence of other form of liver disease, and HIV.  
4. 
Symptoms-directed (brief) physical examination. 
5. 
Blood will be collected after at least an 8-hour overnight fast. If the subject forgets to fast prior to the blood collection, the site will record it in the source document and continue to draw 
labs.  
6. 
PT and INR will also be performed locally at the Screening visit, Run-In, and during the treatment period if deemed necessary by the Investigator. 
7. 
If at Screening an unexpected abnormal CK level is observed, re-test the subject to confirm eligibility. 
8. 
Screening visit: only AMA will be performed. Fat-soluble vitamins will be performed at Day 1, Week 52 and ET (if applicable) only.  
9. 
Serum pregnancy test will be performed in women of childbearing potential only. Additional on-treatment pregnancy testing may be performed at the investigator’s discretion or per local 
regulatory requirements. 
10. Pruritus NRS, 5-D itch, PBC-40, and PGI-S and PGI-C data will be collected via e-diary. Subjects will be asked to complete (1) pruritus NRS: on a daily basis from the Run-In Visit and 
through the first 6 months of treatment. After six months NRS will be collected for seven consecutive days during each month up to the Month 12 visit. (2) 5-D itch will be collected bi-
weekly from the Run-In Visit up until the Month 6 visit; after Month 6 5-D itch will be collected at clinic visit only. 3)  PBC-40, PGI-S, PGI-C will be collected during the clinic visits only.  
11. Only subjects willing to undergo liver biopsy. PT and INR must be performed within 2 weeks prior to liver biopsy. If a subject had liver biopsy performed within 1 year from Day 1, sites 
will attempt to collect biopsy material. A follow up liver biopsy will be performed after 3 years (± 3 months) of treatment during long-term study (CB8025-31731).  
12. Subjects will be invited to participate in the long-term study (CB8025-31731). Subjects who consent to participate in CB8025-31731 will have the Month 12 visit combined with the Day 1 
visit in the CB8025-31731 study and continue dosing. 
13. Only study drug compliance to be evaluated 
 


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4 
INTRODUCTION 
4.1 
Primary Biliary Cholangitis (PBC) 
Primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis) is a serious 
and potentially life threatening autoimmune disease of the liver characterized by impaired 
bile flow (cholestasis) and accumulation of toxic bile acids (BA). 
The hallmark of PBC is cholestasis with an accompanying elevation in serum biomarkers 
including alkaline phosphatase (AP), gamma glutamyl transferase (GGT) and, depending on 
the severity of the disease, bilirubin and liver transaminases. Serologically, PBC is 
characterized by the presence of anti-mitochondrial antibodies (AMA) in nearly all patients 
(Selmi, 2010). Clinical symptoms of PBC include pruritus and fatigue, which can be quite 
disabling for some patients. PBC peak incidence occurs in the fifth decade of life and is 
uncommon in persons under 25 years of age (Kaplan, 2005). The histopathology in the livers 
of PBC patients is characterized by portal inflammation and immune-mediated destruction of 
intrahepatic bile ducts. These changes occur at different rates and with varying degrees of 
severity. The loss of bile ducts leads to decreased bile secretion and the retention 
hydrophobic BA within the liver, resulting in hepatocellular injury, fibrosis, cirrhosis and 
eventually liver failure (Kaplan, 2005; Kumagi, 2008; Lindor, 2007). PBC is a chronic 
debilitating disease whose progression is associated with an increased risk of hepatocellular 
carcinoma and liver related mortality (Kaplan, 2005; Kumagi, 2008; Lindor, 2007).  
The diagnosis of PBC often occurs at an early stage when following up on abnormal liver 
tests, especially elevated AP. After excluding extra-hepatic biliary obstruction, the presence 
of either AMA, or less often, the histological confirmation by liver biopsy establishes the 
diagnosis (Lindor, 2009). Fifty to 60% of patients are asymptomatic at diagnosis. Overt 
symptoms develop within two to four years in most asymptomatic patients, although one-
third may remain symptom-free for years (Kaplan, 2005). Fatigue and pruritus are the most 
common presenting symptoms (Kaplan, 2005). Fatigue has been noted in up to 78% of 
patients and can be a significant cause of disability. The severity of fatigue is independent of 
the severity of the liver disease and there is no proven treatment (Kaplan, 2005). Pruritus, 
whose cause is uncertain, occurs in 20 to 70% of patients and can be extremely debilitating 
(Rishe, 2008). Other findings of PBC include jaundice, hypercholesterolemia, osteopenia and 
osteoporosis and coexisting autoimmune diseases (Kaplan, 2005; Kumagi, 2008). Portal 
hypertension is a late complication of the disease (Kaplan, 2005). 
The first line therapy for PBC is ursodeoxycholic acid (UDCA), a non-cytotoxic BA that has 
been the mainstay of treatment for more than twenty years (Poupon, 1997). However, up to 
40 percent of patients have persistent elevation of AP and/or bilirubin despite UDCA and are 
considered inadequate responders (Corpechot, 2008). 
Obeticholic acid (OCA), a synthetic analogue of chenodeoxycholic acid (CDCA), was 
approved under the provisions of accelerated approval regulations (21 Code of Federal 
Regulations [CFR] 314.500) in the United States and European Union on 27 May 2016 and 
12 December 2016, respectively. The approval was based on OCA’s ability to significantly 
decrease AP levels and maintain a normal total bilirubin when, used as an add-on therapy in 


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PBC patients who are inadequate responders to UDCA or, as a monotherapy in PBC patients 
who are intolerant to UDCA (Ocaliva, 2016). 
In summary, despite the previously mentioned therapeutic interventions and recent approval 
of OCA, it is evident that many PBC patients do not respond adequately to therapy and 
continues to have a progression of their disease (Kaplan, 2005; Kumagi, 2008; 
Momah, 2014) and additional treatments are needed. 
4.2 
Seladelpar 
4.2.1 
Overview 
Seladelpar (MBX-8025) is an oral, once-daily administered, potent and selective peroxisome 
proliferator-activated receptors (PPAR) δ agonist (Bays, 2011; Jones, 2017). Seladelpar is 
being developed for the treatment of PBC in subjects with inadequate response to UDCA or 
intolerance to UDCA and in nonalcoholic steatohepatitis (NASH). 
4.2.2 
Mechanism of Action 
PPARδ agonists have been shown to affect the transport, storage and metabolism of lipids 
(Barish, 2006). Seladelpar improves cholestasis notably by decreasing the synthesis of bile 
acids in hepatocytes thus preventing their toxic accumulation. The decreased synthesis results 
in part from the down regulation of the gene for CYP7A1, the key enzyme for the synthesis 
of bile acids. Seladelpar also decreases the synthesis of cholesterol as well as inhibiting its 
dietary absorption; these effects decrease the amount of cholesterol available as substrate for 
bile acid synthesis, thereby enhancing its effect on CYP7A1 in reducing total bile acid pools. 
Each of the above actions of seladelpar have been demonstrated in PBC patients 
(Jones, 2017). In addition, seladelpar exerts anti-inflammatory effects (Jones, 2017) that are 
of potential benefit in the treatment of PBC. 
For more detailed information, see the Investigator’s Brochure (IB). 
4.3 
Nonclinical Investigations with Seladelpar 
Please see the IB for details on the nonclinical studies conducted with seladelpar. 
4.4 
Human Experience 
Across the clinical development program, seladelpar was evaluated in 6 Phase 1 studies and 
4 Phase 2 studies. Seladelpar tested doses have ranged from single dose studies in healthy 
volunteers (1, 5, 15, 60, 120, and 360 mg), to daily long-term dosing in Phase 2 studies in 
patients with mixed dyslipidemia (50 and 100 mg once a day), homozygous familial 
hypercholesterolemia (HoFH; ascending doses 50, 100, and 200 mg once a day), and PBC 
(2, 5, 10, 50, and 200 mg once a day). In these Phase 2 studies, treatment ranged from 8 to 12 
weeks. In the ongoing Phase 2 PBC study, seladelpar is now being tested for 52 weeks at the 
end of which subjects are entering long-term extension study and continue dosing beyond 52 
weeks.  


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4.4.1 
Phase 1 Studies  
Six Phase 1 clinical studies have been conducted in healthy subjects. The aims of these 
studies were to evaluate the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of seladelpar. A total of 147 healthy subjects have been dosed with 
either seladelpar, seladelpar in combination with other agents, or placebo in the 6 completed 
clinical studies. Seladelpar was administered as a solution in sterile water, or as a hard gelatin 
capsule. In the 6 Phase 1 clinical studies, seladelpar was generally well tolerated. There were 
no deaths or serious adverse events (SAEs) recorded. All adverse events (AEs) were mild or 
moderate in severity. The type and incidence of AEs were generally similar across the 
various seladelpar and placebo dose groups. Please see the IB for more complete details on 
the Phase 1 studies conducted with seladelpar. 
4.4.2 
Phase 2 Studies in PBC Patients 
As of 2018, CymaBay conducted 3 clinical studies with seladelpar in PBC subjects.  
Study CB8025-21528 was the first clinical study of the seladelpar for the treatment of PBC 
(Jones, 2017). It was a double-blind, randomized, placebo-controlled, 12-week dose-ranging 
study (referred to as the “high dose” study) in adult PBC patients who had an inadequate 
response to UDCA. Subjects were randomly assigned to receive 50 mg/day seladelpar, 
200 mg/day seladelpar, or placebo in a 1:1:1 ratio. The study was terminated approximately 
mid-way through enrollment (41 subjects had enrolled) after 3 patients experienced, rapid, 
asymptomatic and reversible Grade 3 elevations in alanine aminotransferase (ALT) (one case 
at 50 mg and two cases at 200 mg). Although CymaBay elected to terminate the study early 
when a transaminase elevation signal was observed, all subjects receiving seladelpar, 
including subjects with transaminase elevation, exhibited a pronounced decrease in AP that 
was evident after the first 2 weeks and was sustained for the duration of the study (Figure 1; 
Panel A). Subjects who received seladelpar beyond 2 weeks showed a consistent and 
continual decrease in AP. All subjects who received seladelpar for 12 weeks normalized their 
AP levels (Jones, 2017). This study also provided important information supporting the 
mechanism of action of seladelpar for the treatment of PBC. Treatment with seladelpar was 
associated with a decrease in C4, which represents a serum marker for the rate of hepatic BA 
synthesis. C4 reflects the activity of CYP7A1, the rate limiting enzyme for the synthesis of 
BA.  
A second Phase 2 study (CB8025-21629) is currently underway in PBC patients who either 
have had an inadequate response to UDCA or are intolerant to UDCA. The aim of this study 
is to further evaluate the safety and efficacy of seladelpar at lower doses. The interim 
analysis was performed to evaluate the data up to 12 weeks evaluated seladelpar doses of 2, 5 
and 10 mg/day. Data up to 26 weeks evaluated doses of 5 and 10 mg/day. After 12 weeks, 
patients on 5 mg could escalate to 10 mg if their AP treatment goal was not achieved. As of 
January 2018, 71 patients were exposed to at least one dose of seladelpar, of whom 53 
received 12 weeks of treatment and 42 received 26 weeks of treatment. The 5 and 10 mg 
doses show consistent, meaningful, and reproducible decreases in AP levels (Figure 1; Panel 
B). At baseline, mean AP was 358, 333, and 262 IU/L in the 2, 5, and 10 mg groups, 
respectively. At 12 weeks, changes in AP were -21%, -33%, and -45% in the 2 (N=6), 5 
(N=25), and 10 (N=22) mg groups, respectively. At 26 weeks, 69%, 67%, and 79% of 




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Seladelpar did not increase pruritus. Baseline median pruritus visual analogue scale (VAS) 
was 10 and 40 in the 5 and 10 mg group, respectively, and patients in the 10 mg group 
experienced consistent decreases during follow up (-24% at week 26). Seladelpar was 
generally safe and well tolerated, with no transaminase elevation safety signal. There were 6 
serious AEs and none were deemed related to seladelpar. As a result of interim analysis, it 
was concluded that seladelpar doses of 10 mg, or 5 mg adjusted to 10 mg, demonstrates 
potent anti-cholestatic efficacy that is maintained over 26 weeks.  
A third study (CB8025-31731) is also underway in PBC patients who completed 
CB8025-21629 study and willing to continue the treatment with seladelpar beyond 52 weeks. 
4.4.3 
Phase 2 Studies in Non-PBC Patients 
Study M8025-20711 was a multicenter randomized, double-blind, placebo-controlled study 
to evaluate the safety, tolerability, PK and efficacy of seladelpar at doses 10 and 100 mg in 
moderately obese hyperlipidemic subjects with or without concomitant atorvastatin 
(Bays, 2011; Choi, 2012).  
Study CB8025-21427 was a pilot study of seladelpar in the treatment of HoFH. The study 
was a 12-week, open label, multicenter, non-controlled, monthly dose escalation study 
(seladelpar: 50, 100, and 200 mg; p.o. daily) in adults with genetically confirmed HoFH.  
For more details about the studies, please refer to the IB.  
4.5 
Risk/Benefit Assessment 
The study being proposed is a placebo-controlled, double-blind randomized study to evaluate 
safety and efficacy of seladelpar in PBC subjects. 
4.5.1 
Potential Benefits 
In previous PBC studies, subjects receiving placebo showed no relevant change, while 
subjects receiving seladelpar exhibited a pronounced decrease in AP. After 26 weeks of 
treatment with seladelpar 10 mg and 5/10 mg, 78% and 68% reached AP <1.67 × ULN, and 
32% and 26% of subjects had a normal AP, respectively. Additional biochemical markers of 
cholestasis such as GGT and 5’ nucleotidase were also reduced by seladelpar. Seladelpar also 
produced potentially beneficial metabolic and anti-inflammatory effects. 
Previous studies in PBC subjects also suggested the potential of seladelpar to improve 
pruritus, an important clinical outcome in PBC patients. A decrease in the pruritus VAS was 
noted in the 10 mg group in which approximately half of patients had a substantial level of 
itching at baseline (VAS ≥ 40 mm, or moderate to severe itch). This suggests that seladelpar 
treatment could be associated with an improvement in PBC-associated itch. 
Subjects who will successfully complete this study can be rolled over into the long-term 
study (CB8025-31731) and can continue their seladelpar treatment until seladelpar is 
commercially available or the program is discontinued; subjects on placebo will be switched 
to the active treatment with seladelpar.  


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4.5.2 
Potential Risks 
4.5.2.1 
Non-clinical Safety Findings  
Please see the IB for more complete details on the nonclinical studies conducted with 
seladelpar. 
4.5.2.2 
Human Safety 
Currently, seladelpar has been used for a maximum of 21 days in healthy volunteers at a 
maximum dose of 200 mg per day; in overweight subjects with mixed dyslipidemia, with and 
without atorvastatin, for a maximum of eight weeks and with a maximum dose of 100 mg per 
day; in subjects with HoFH, on concomitant ezetimibe and maximum statin therapy (± low 
density lipoprotein cholesterol [LDL-C] apheresis), with dose escalation from 50 mg to a 
maximum of 200 mg per day; and in subjects with PBC on concomitant UDCA for 12 weeks 
with a maximum dose of 200 mg per day and for 52 weeks and beyond with a maximum 
dose of 10 mg per day. 
Seladelpar has been associated with increases in transaminases (ALT and aspartate 
aminotransferase [AST]), particularly in subjects with PBC treated with seladelpar at doses 
50 mg and 200 mg. The increases appear to be dose dependent and population dependent. 
The increases were fully reversible upon treatment discontinuation. No clear transaminase 
elevation signal was seen in PBC subject treated with seladelpar at doses 5 and 10 mg. 
Seladelpar has been associated with a pre-clinical muscle toxicity signal. One PBC subject 
taking 200 mg per day discontinued seladelpar for acute muscle pain associated with 
increased muscle enzymes. The AE was reversible upon treatment discontinuation and was 
considered possibly related to treatment. Muscle toxicity signal was not seen in PBC subject 
treated with seladelpar at doses 5 and 10 mg. 
Seladelpar has been associated with increases in serum creatinine. These increases are 
generally mild (in the 10% range) and serum creatinine shifts are within the normal range. 
Similar increases have been observed with drugs of the PPARα class or the mixed PPARα/δ 
class. In the short term, these increases in serum creatinine have not been associated with 
relevant decreases in measured glomerular filtration rate. In the long run, data from 
controlled clinical trials do not support that PPARα or mixed PPARα/δ are associated with a 
degradation of renal function. It is hypothesized that the increase in serum creatinine is of 
muscle origin (with an increase in creatine synthesis, which is later metabolized into 
creatinine). However, caution must be exercised. One subject with HoFH and a chronic renal 
insufficiency, treated with seladelpar 100 mg and one subject with PBC treated with 
seladelpar 200 mg had serum creatinine elevation above the normal range that were 
reversible upon treatment discontinuation and considered possibly related to seladelpar. No 
subjects treated with low doses of seladelpar (up to 10 mg) experienced Grade 2 or Grade 3 
increases in serum creatinine. Therefore, it was concluded that the seladelpar at doses up to 
10 mg had no clinically relevant impact on serum creatinine levels. 


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4.6 
Rationale for Dose Selection 
In PBC studies seladelpar at dose of 2, 5, and 10 mg, retains a relevant clinical activity to 
improve markers of cholestasis and inflammation as well as metabolic markers (e.g., 
decrease in triglycerides and LDL-C). 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 and dose titration regimen of 5 mg with a potential to increase to 10 mg 
have been selected for the proposed Phase 3 study. These doses were well tolerated, appeared 
safe and were not associated with drug-induced pruritus. 
4.7 
Conclusions 
In conclusion, seladelpar demonstrated the potent and rapid decrease in biochemical markers 
of cholestasis (AP, GGT, and total bilirubin), decrease a marker of inflammation (hs-CRP) 
and decrease LDL-C in PBC subjects who had an inadequate response or intolerance to 
UDCA. In addition, the current data suggest that seladelpar has a potential to improve 
PBC-related pruritus. Lower doses of seladelpar (up to 10 mg) were generally safe and well 
tolerated. There was no evidence that seladelpar was associated with transaminase elevations 
at these doses. There was also no evidence that seladelpar induced or worsened pruritus. The 
clinical experience with seladelpar is nonetheless limited, and appropriate precautions are 
incorporated into this protocol, with careful monitoring of potential transaminase elevations. 


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5 
STUDY OBJECTIVES 
5.1 
Primary Objectives 
The primary objective of this study is to evaluate the safety and effect on cholestasis of 
2 seladelpar dose regimens (5 mg/day titrated to 10 mg/day and 10 mg/day) over 52 weeks of 
treatment compared to placebo. 
5.2 
Secondary Objectives 
The key secondary objectives of this study are to evaluate the effect of seladelpar on 
normalization of AP levels and to evaluate the effect of seladelpar on pruritus. 
Other secondary objectives of the study are to evaluate the effect of seladelpar on quality of 
life (QoL), to evaluate the effect of seladelpar on other measures of cholestasis, metabolic 
outcomes, PBC prognosis criteria, and the effect on PBC clinical outcomes.  
5.3 
Exploratory Objectives 
The exploratory objectives of the study are to evaluate the effect of seladelpar on markers of 
inflammation, bile acid synthesis, levels of autotaxin, and markers of liver fibrosis. 


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6 
STUDY POPULATION 
PBC subjects with an inadequate response to UDCA or intolerance to UDCA.  
6.1 
Selection Criteria  
6.1.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for study participation: 
1. 
Must have given written informed consent (signed and dated) and any authorizations 
required by local law 
2. 
18 to 75 years old (inclusive) 
3. 
Male or female with a diagnosis of PBC, by at least 2 of the following criteria: 
• History of AP above ULN for at least 6 months 
• Positive AMA titers (>1/40 on immunofluorescence or M2 positive by enzyme 
linked immunosorbent assay [ELISA]) or positive PBC-specific antinuclear 
antibodies 
• Documented liver biopsy result consistent with PBC 
4. 
On a stable and recommended dose of UDCA for the past twelve months OR intolerant 
to UDCA (last dose of UDCA > 3 months prior to Screening) 
5. 
AP ≥ 1.67 × ULN 
6. 
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 90 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  
 
6.1.2 
Exclusion Criteria 
Subjects must not meet any of the following criteria to be eligible for study participation: 
1. 
Previous exposure to seladelpar (MBX-8025) 
2. 
A medical condition, other than PBC, that in the investigator’s opinion would 
preclude full participation in the study or confound its results (e.g., cancer) 
3. 
AST above 3 × ULN 
4. 
ALT above 3 × ULN 
5. 
Total bilirubin above 2.0 × ULN 
6. 
Advanced PBC as defined by the Rotterdam criteria (albumin below LLN AND total 
bilirubin above 1 × ULN) 
7. 
Creatine kinase (CK) above 1.0 × ULN 
8. 
eGFR below 60 mL/min/1.73 m2 (calculated by MDRD formula)  


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9. 
International normalized ratio (INR) above 1.0 × ULN 
10. 
Platelet count below 100 × 103/µL 
11. 
Presence of clinically significant hepatic decompensation, including: 
- 
History of liver transplantation, current placement on liver transplantation list, or 
current MELD score ≥ 15 
- 
Complications of portal hypertension, including known esophageal varices, 
history of variceal bleeds or related interventions (e.g., transjugular intrahepatic 
portosystemic shunt placement), relevant ascites, hepatic encephalopathy 
- 
Cirrhosis with complications, including history or presence of spontaneous 
bacterial peritonitis 
12. 
Other chronic liver diseases:  
a. Current features of auto-immune hepatitis as determined by the investigator 
based on immunoserology, liver biochemistry and histology 
b. Primary sclerosing cholangitis determined by presence of diagnostic 
cholangiographic findings  
c. History or clinical evidence of alcoholic liver disease 
d. History or clinical evidence of alpha-1-antitrypsin deficiency 
e. Biopsy confirmed nonalcoholic steatohepatitis 
f. History or evidence of Gilbert’ Syndrome with elevated total bilirubin 
g. History or evidence of hemochromatosis 
h. Hepatitis B defined as presence of hepatitis B surface antigen (HbsAg)  
a. Hepatitis C defined as presence of HCV RNA 
13. 
Known history of HIV 
14. 
Evidence of significant alcohol consumption 
15. 
Evidence of drug abuse  
16. 
Subjects with inadequate response to OCA or intolerance to OCA: obeticholic acid 
must be discontinued 30 days prior to Screening 
17. 
Use of colchicine, methotrexate, azathioprine, or long-term systemic corticosteroids 
(> 2 weeks) within two months prior to Screening 
18. 
Use of fibrates within 30 days prior to Screening 
19. 
Use of simvastatin within 7 days prior to Screening 
20. 
Use of an experimental or unapproved treatment for PBC within 30 days prior to 
Screening 
21. 
Use of experimental or unapproved immunosuppressant within 30 days prior to 
Screening 
22. 
Treatment with any other investigational therapy or device within 30 days or within 
five half-lives, whatever is longer, prior to Screening 
23. 
For females, pregnancy or breast-feeding 
24. 
Any other condition(s) that would compromise the safety of the subject or 
compromise the quality of the clinical study, as judged by the investigator 


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7 
STUDY DESIGN  
This Phase 3 study will utilize an international, multicenter, double-blind, randomized, 
placebo-controlled 52-week dose-ranging (placebo, 5/10 mg/day, and 10 mg/day), parallel 
treatment groups design.  
This study is a pivotal study to evaluate the safety of seladelpar and its effect (± UDCA) on 
cholestasis and on pruritus in subjects with inadequate response to UDCA or intolerance to 
UDCA. The study population can also include subjects with an inadequate response to 
UDCA + OCA, or who are intolerant to OCA. 
The study is planned to enroll approximately 240 subjects. Subjects will be randomly 
assigned to receive placebo, seladelpar 5 mg titrated to 10 mg, or seladelpar 10 mg. Subjects 
will be stratified by AP level (AP < 350 U/L and ≥ 350 U/L) and presence of significant 
pruritus (pruritus numerical rating scale [NRS] < 4 and NRS ≥ 4). Subjects will be 
considered as formally entered the study at the time of randomization. 
Study drug (placebo or seladelpar) will be taken in a blinded manner orally once a day for a 
period of 52 weeks. After first 6 months of treatment, evaluation of the initially assigned 
dose will be performed in a blinded manner. Subjects assigned to the seladelpar 5/10 mg 
group who are not responders based on composite endpoint at Month 6, and are tolerating 
study drug, will be up titrated from seladelpar 5 to 10 mg for the remainder of the study. 
Those patients initially assigned to placebo or 10 mg will not have their dose changed. To 
avoid unblinding, all subjects will be invited to Dose Adjustment visit which will occur two 
weeks after Month 6 visit.  
Subjects with an inadequate response to UDCA will continue to receive UDCA throughout 
the study. Study specific UDCA supply will be provided and taken during the study 
participation. UDCA supply will be switched from pre-study supply to the study supply at 
the Screening visit and continue through the Week 52 visit. At the Week 52 visit, UDCA will 
be switched to pre-study supply. 
Subjects will be asked to use an e-diary to evaluate pruritus and quality of life during the 
study participation. E-diary will be dispensed at the Run-In visit and will include the 
following questionnaires: pruritus NRS, 5-D itch, patient global impression of severity 
(PGI-S), patient global impression of change (PGI-C), and PBC-40. Subjects will perform 
evaluation of their pruritus in a daily basis via pruritus NRS starting from the Run-In visit 
through the first 6 months of treatment. After six months, pruritus will be evaluated in a 
monthly basis using pruritus NRS for 7 consecutive days each month. 5-D itch will be 
evaluated bi-weekly from the Run-In visit up until the Month 6 visit and at each clinic visit 
from Month 6 till Month 12 visit. PBC-40, PGI-S and PGI-C will be evaluated at each clinic 
visit over the whole study duration.  
The total duration of the study for each subject will be up to 60 weeks. The Screening period 
will be up to 2 weeks, the run-in period will be 2 weeks, and treatment period will be 52 
weeks. During the treatment period, subjects will be seen in the clinic every 3 months with an 
exception of first on treatment visit which will be performed after one month after initiation 


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of the study drug. Subjects will also return 2 weeks after Month 6 visit for blinded dose-
adjustment visit. In addition, subjects will have contact visits performed over phone or email 
every 12 weeks between on-site visits. At the end of 52 weeks of treatment, subjects will be 
invited to participate in the long-term study (CB8025-31731) and continue their treatment 
with seladelpar; subjects on placebo will be switched to seladelpar. Subjects who do not want 
to continue seladelpar treatment beyond 52 weeks and decline long-term study participation 
will have a follow-up visit performed 4 weeks after the last dose of the study drug.  
Subjects will be asked to go through liver biopsy to evaluate PBC stage and activity. Subjects 
willing to undergo a procedure will have liver biopsy performed during the Run-In period. If 
liver biopsy was performed within 1 year prior to Day 1, Baseline liver biopsy can be 
waived. For these instances sites will attempt to collect biopsy material. The follow-up liver 
biopsy will be performed at least 3 years after initiation of treatment, during the long-term 
study (CB8025-31731).  
The study design implements safety criteria to monitor subjects with potential drug induced 
liver injury, muscle injury, renal injury and acute pancreatitis with actions to either stop the 
study drug, to interrupt the study drug, to down-titrate the study drug or to investigate the 
case prior to actions with the study drug.  
If a subject terminates study participation at any point after Day 1, an Early Termination visit 
will be completed. 
The primary efficacy analysis will be a responder analysis (composite point) after 12 months 
of treatment with seladelpar. The study will be blinded for the study drug until the data base 
lock.  
Figure 3 
Study Diagram – Clinical Study CB8025-31735 
 
 
7.1 
Treatment and Allocation of Subjects 
Approximately 240 PBC patients will be enrolled into the study.  
Subjects will be randomized to placebo, seladelpar 5/10 mg or seladelpar 10 mg in 1:1:1 ratio 
(approximately 80 subjects per group). Subject will be stratified by AP level (AP < 350 U/L 


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and ≥ 350 U/L) and pruritus status (pruritus NRS < 4 and NRS ≥ 4). Subjects randomized to 
5/10 mg will start treatment with seladelpar daily dose of 5 mg/day and after 6 months of 
treatment might up-titrate their dose to 10 mg/day.  
7.2 
Study Duration  
The study will be up to 60 weeks of duration and consists of the following periods: 
• Screening period: up to 2 weeks 
• Run-In: 2 weeks 
• Treatment Period: 52 weeks with an option to enter long-term study (CB8025-31731) 
• Follow-up period: 4 weeks (if not enrolled in long-term study) 
 
7.3 
Study Outcome Measurements 
7.3.1 
Primary Measures 
• Response on the composite endpoint of AP and total bilirubin at 12 months: 
o AP < 1.67 × ULN,  
o ≥ 15% decrease in AP, and 
o Total bilirubin ≤ ULN 
• Assessment of treatment-emergent AEs (TEAEs) (National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] Version 4.0), biochemistry 
and hematology 
 
7.3.2 
Key Secondary Measures 
• Proportion of patients with AP ≤1.0 × ULN at 12 months  
• Change from baseline in pruritus NRS at 6 months 
 
7.3.3 
Other Secondary Measures  
• PBC-40 QoL at 6 and 12 months 
• PBC-40 QoL itch domain, and 5-D itch questionnaire 
• Response on the composite endpoint at 6 months 
• Proportion of subjects with AP <1.67 × ULN and AP < 1.5 × ULN at 6 and 12 months 
• Proportion of subjects with AP ≤ 1.0 × ULN at 6 months 
• Change from baseline in pruritus NRS at 12 months 
• Absolute and relative changes in AP 
• Proportion of patients with PBC response criteria (Barcelona, Paris I and II, Toronto I 
and II, Rotterdam)  
• Change in UK-PBC and GLOBE risk scores 


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• Absolute and relative changes in ALT, AST, GGT, bilirubin (total, direct, and indirect), 
LDL-C, high density lipoprotein cholesterol (HDL-C), triglycerides, and total cholesterol  
• The first occurrence of any of the following: 
o Overall death 
o Liver transplantation 
o MELD score ≥15 
o Uncontrolled ascites (diuretic resistant) 
o Hospitalization for new onset or recurrence of any of the following: 
 
variceal bleeding 
 
hepatic encephalopathy (as defined by a West Haven score ≥ 2) 
 
spontaneous bacterial peritonitis (confirmed by culture from diagnostic 
paracentesis) 
o Hepatocellular carcinoma 
o Advanced PBC as defined by the Rotterdam criteria (albumin below LLN AND total 
bilirubin above 1 × ULN) 
 
7.3.4 
Exploratory Measures 
• C4 (7α-hydroxy-4-cholesten-3-one) 
• Fibroblast growth factor 19 (FGF19) 
• N-terminal type III collagen propeptide (Pro-C3) 
• Haptoglobin, fibrinogen and hs-CRP, homocysteine, immunoglobulin M (IgM) 
• Autotaxin  
• Enhanced liver fibrosis (ELF) score, fibrosis-4 (FIB-4) score, Lok-Index, non-alcoholic 
fatty liver disease (NAFLD) fibrosis score  
• Liver elastography (at selected centers) 


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8 
STUDY MEDICATIONS 
8.1 
Clinical Supplies 
Investigational product (study drug) and UDCA will be supplied for the study.  
8.1.1 
Investigational Product (Study Drug), Dosage and Mode of Administration 
Seladelpar will be supplied in a blinded fashion as 5 mg and 10 mg capsules. Matching 
placebo will be provided. The study drug (seladelpar or placebo) will be administered orally, 
once daily for the duration of to 52 weeks. The subject will take 1 capsule every day, 
approximately at the same time each day.  
8.1.2 
UDCA, Dosage and Mode of Administration. 
The standard of care UDCA will be supplied in an unblinded fashion. UDCA will be 
administered orally, one or multiple times per day at the dose as close as possible to pre-
study dose and as recommended per investigator’s clinical judgment. Pre-study UDCA will 
be switched to the study supply UDCA at the Screening visit. UDCA study supply will be 
provided for up to 56 weeks of duration (from the Screening visit through the Month 12 
visit). At the Week 52 visit, study supply UDCA will be switched to pre-study supply of 
UDCA.  
8.1.3 
Packaging, Labeling and Shipping 
The Sponsor will provide the investigator with packaged study drug and UDCA labeled in 
accordance with specific country regulatory requirements. The supplies will be shipped in 
accordance with the Pharmacy Manual. 
8.1.3.1 
Dose Up-titration 
Subjects assigned to the seladelpar 5/10 mg group who are tolerating study drug and are not 
responders based on composite endpoint according to Month 6 laboratory result, will be up 
titrated from seladelpar 5 to 10 mg. Those patients initially assigned to placebo or 10 mg will 
not have their dose changed. Dose up-titration will occur 2 weeks after Month 6 period, when 
subjects will return to the clinic for dose titration visit. Dose up-titration will be performed in 
a blinded manner. 
8.1.3.2 
Dose Down-titration 
Subjects who meet muscle safety monitoring criteria per Section 10.4.2 and eligible for the 
dose down-titration: subject who initially assigned to 10 mg will be down-titrated to 5 mg; 
subjects initially assigned to 5 mg, will be down-titrated to placebo. Subjects initially 
assigned to placebo will stay on placebo. Dose down-titration will be performed in a blinded 
manner.  
8.1.4 
Accountability of Clinical Supplies  
The investigator or a designee will keep a record of the dates and amounts of study drug and 
UDCA received, the amount dispensed to study subjects, and the amount returned from study 
subjects. 


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8.1.5 
Replacement Study Drug and UDCA 
Additional replacement study drug and UDCA will be available as required. All replacement 
shipments must be accounted for in the same manner as the initial drug supply. 
8.1.6 
Storage of Study Drug and UDCA 
All supplies of study medication and UDCA must be stored as defined in the Pharmacy 
Manual. 
8.2 
Randomization 
Subjects will be randomized in a blinded manner to placebo or seladelpar in a 1:1:1 scheme 
(placebo: seladelpar 5/10mg: seladelpar 10 mg). In addition, randomized subjects will be 
stratified by AP level (AP < 350 U/L and ≥ 350 U/L) and pruritus status (pruritus NRS < 4 
and NRS ≥ 4). 
8.2.1 
Randomization Procedure 
Randomization procedure will be performed centrally via interactive voice/web response 
system (IXRS) at Day 1 visit. A subject will be considered formally enrolled in the study at 
the time of randomization and begin study drug dosing.  
8.3 
Emergency Unblinding 
In the event of a medical emergency, where knowledge of the subject’s treatment assignment 
is necessary per the medical judgment, the investigator or the Sponsor can break the blind. 
The unblinding must be clearly justified and explained by a comment in the source 
documentation, along with the date on which the code was broken and the identity of the 
person authorizing the unblinding.  
8.4 
Method of Administration and Compliance  
Study drug will be dispensed on Day 1 and from Month 3 to Month 12 visits and will be 
taken orally once a day, according to the study schedule. 
UDCA will be dispensed at the Screening visit and from Month 3 to Month 12 visits and will 
be taken orally as recommended per investigator clinical judgment. 
Compliance to the study drug and UDCA will be assessed through drug accountability 
evaluation. Study drug and UDCA accountability will be evaluated at Month 3 though Month 
12 visits and Early Termination visits. 
8.5 
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. 


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8.5.1 
Concomitant Medications  
A concomitant medication is any drug of substance other than study drug and UDCA, 
including over-the-counter medications, herbal medications and vitamin supplements, 
administered during subjects’ participation in this trial.  
All subjects will be instructed to remain on their current diet and lifestyle, including drinking 
habits, specifically alcoholic beverages, throughout the entire study. 
8.5.1.1 
Allowed Concomitant Medication:  
Subjects will be allowed to receive required medication to treat new or existing medical 
conditions. 
8.5.1.2 
Prohibited Concomitant Medication 
Use of OCA, fibrates (e.g. fenofibrate, bezafibrate), simvastatin, colchicine, methotrexate, 
azathioprine or long-term systemic corticosteroids (> 2 weeks) will be prohibited during the 
study. 
8.5.2 
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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9 
STUDY PROCEDURES  
9.1 
Study Schedule 
The schedule of study procedures is presented in Table 1. 
The study for an individual subject consists of the following periods: 
• Screening Period: Week -4 to Week -2 
• Run-In: Week -2 to Day 1 
• Treatment Initiation: Day 1 
• Treatment Period: Day 1 through Month 12  
• Follow-up Period: 28 days after the last dose of the study drug (only applicable for subjects 
who are not willing to roll-over to long-term study (CB8025-31731). 
 
Visits, which occur within ± 3 days of the calculated date from Run-In period through the 
Month 1 visit and Dose adjustment visit and within ± 7 days of the calculated date from 
Month 3 through Month 12 will not be considered protocol violations. 
Additional visits may be scheduled to evaluate an abnormal laboratory value or reported AE. 
9.1.1 
Screening (Week -4 to Week -2) 
Subjects will review and sign the informed consent form (ICF) prior to any study-related 
procedures.  
Screening evaluations will be performed within 2 weeks prior to Run-In period.  
The evaluations of eligibility will consist of: 
• Demographic information 
• Assessment of all inclusion and exclusion criteria 
• Review of medical history, including PBC medical history, results of prior liver biopsy, 
liver elastography (e.g., FibroScan), and alcohol consumption. The subject’s medical 
chart will be reviewed for evidence of other forms of chronic liver disease as well as for 
HIV infection. 
• Documentation of prior and concomitant medications including but not limited to 
previous exposure to UDCA, OCA as well as other medications taken for PBC and its 
symptoms (including supplements and vitamins) 
• Vital signs (as described in Section 9.2.2). This will include temperature, heart rate, 
respiration rate and blood pressure  
• Height and weight measurements will be performed 
• Complete physical examination (as described in Section 9.2.1). This will include a full 
review of the following systems: general, skin, eyes, nose/sinuses, ears, mouth/throat, 


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neck, breasts, and respiratory, cardiac, gastrointestinal, peripheral vascular, genitourinary, 
musculoskeletal, neurologic, mental health, endocrine and hematologic 
• 12-lead electrocardiogram (ECG) after at least 5 minutes rest 
• Blood drawn for hematology, biochemistry, AMA, hepatitis B and hepatitis C as outlined 
in Section 9.2.4 and Appendix A. If unexpected elevation of CK or INR is noted, re-test 
is allowed. 
• Women of child-bearing potential will have a serum pregnancy test performed  
• Urine drug screen 
• E-diary training 
• Pruritus NRS evaluation.  
• UDCA will be dispensed. Subjects will be instructed to switch their pre-study UDCA to 
study supply UDCA at the time of Screening. Subjects will be instructed to continue 
UDCA regimen (dose and frequency) as close as possible to regimen taken prior to the 
study participation and as recommended per investigator’s clinical judgment.  
• Subjects who meet all inclusion criteria and do not meet any exclusion criteria will be 
invited for the Run-In visit.  
 
If an untoward event occurs at any time after the ICF is signed, it will be recorded as AE. 
Any laboratory abnormality deemed clinically significant by the investigator will be 
considered an AE. 
Subjects will be reminded of the following restrictions:  
• To comply with diet and lifestyle, including drinking habits 
• Not to use prohibited concomitant medications 
• Females of reproductive potential will be reminded to use at least one barrier 
contraceptive and a second effective birth control method during the study and for at least 
90 days after the last dose. 
• Male subjects who are sexually active with female partners of reproductive potential will 
be reminded to use barrier contraception and their female partners to use a second 
effective birth control method during the study and for at least 90 days after the last dose. 
 
9.1.2 
Run-In (Week -2 to Day 1) 
Subjects who have been deemed eligible during the Screening period will return for the Run-
In period.  
All subjects will have the following evaluations performed:  
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of medication (including supplements and vitamins) since the last visit 
• Vital signs and weight (as described at Section 9.2.2)  
• Symptom-directed (brief) physical examination (as described at Section 9.2.1)  


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• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A  
• Women of child-bearing potential will have a serum pregnancy test performed  
• Back-up blood sample will be collected 
• E-diary will be dispensed. Re-training will be performed, if needed.  
• Pruritus NRS, 5-D itch, PBC-40 and PGI-S questionnaires will be performed via e-diary. 
The subject will be instructed to use e-diary to evaluate pruritus NRS on a daily basis and 
5-D itch on a bi-weekly basis at approximately same time during the day from the Run-In 
visit through the first six month of study drug treatment. 
• UDCA accountability 
• Baseline liver biopsy: Only subjects willing to undergo the procedure to evaluate PBC 
stage and activity. PT and INR must be performed within 2 weeks prior to liver biopsy. If 
liver biopsy performed within 1 year from Day 1, baseline liver biopsy can be waived. 
For these instances sites will attempt to collect biopsy material. A follow up liver biopsy 
will be performed at least 3 years (± 3 months) of treatment during the long-term study 
(CB8025-31731). 
 
9.1.3 
Treatment Period 
Day 1 (Randomization) 
Day 1 begins the treatment period and is the date against which all subsequent visits will be 
timed with the exception of Dose Adjustment Visit and Follow Up period. At this visit 
subjects will be randomized into the study. A subject will be considered formally enrolled in 
the study at the time of randomization. On the scheduled clinic visit days, subjects will arrive 
to the clinic in the fasted state for laboratory assessments. If subjects forget to fast, this 
should be noted and the lab sample should still be collected.  
The following evaluations will be performed: 
• Randomization 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of medication (including supplements and vitamins) since the last visit 
• Vital signs and weight (as described at Section 9.2.2)  
• Complete physical examination (as described at Section 9.2.1) 
• 12-lead ECG after at least 5 minutes rest  
• Blood drawn for hematology, biochemistry, and exploratory measures (including fat-
soluble vitamins) as outlined in Appendix A  
• Back-up blood sample will be collected 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or per local regulatory requirements. 
• PBC-40 and PGI-S questionnaires via e-diary 


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• Pruritus NRS: review of previously collected data. Subjects will be reminded to use e-
diary to evaluate pruritus on a daily basis during the first six months of treatment. 
• 5-D Itch: review of previously collected data. Subjects will be reminded to use e-diary to 
evaluate pruritus on a bi-weekly basis up until the Month 6 visit. 
• Liver elastography (e.g, FibroScan): at selected sites 
• Study drug will be dispensed per the subject’s randomization with interactions to take 
orally once a day. The first dose of the study drug will be administered on site.  
• UDCA will be dispensed.  
• UDCA accountability will be performed.  
 
If a subject terminates study participation at any point after Day 1, an Early Termination visit 
will be completed. 
Month 1 
The visit will occur 4 weeks ± 3 days after Day 1 and the following evaluations will be 
performed: 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of concomitant medication (including supplements and vitamins) since 
the last visit 
• Vital signs and weight (as described at Section 9.2.2) 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) 
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A  
• Back-up blood sample will be collected 
• Women of child-bearing potential will have a serum pregnancy blood test performed. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or per local regulatory requirements. 
• PBC-40, PGI-S and PGI-C questionnaires via e-diary 
• Pruritus NRS: review of previously collected data. Subjects will be reminded to use e-
diary to evaluate pruritus on a daily basis 
• 5-D Itch: review of previously collected data. Subjects will be reminded to use e-diary to 
evaluate pruritus on a bi-weekly basis. 
• Study drug and UDCA accountability. 
 
Month 3 
The visit will occur 12 weeks ± 7 days after Day 1 and the following evaluations will be 
performed: 
• Documentation of AEs that occurred since the signing of the ICF 


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• Documentation of concomitant medication (including supplements and vitamins) since 
the last visit 
• Vital signs and weight (as described at Section 9.2.2) 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1) 
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A  
• Back-up blood sample will be collected 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or per local regulatory requirements. 
• PBC-40, PGI-S and PGI-C questionnaires via e-diary 
• Pruritus NRS: review of previously collected data. Subjects will be reminded to use e-
diary to evaluate pruritus on a daily basis 
• 5-D Itch: review of previously collected data. Subjects will be reminded to use e-diary to 
evaluate pruritus on a bi-weekly basis 
• Study drug and UDCA accountability 
• Study drug and UDCA dispense 
 
Contact 1 
The visit will occur 19 weeks ± 7 days after Day 1 over the phone or by email contact and the 
following will be performed: 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of concomitant medication (including supplements and vitamins) since 
the last visit 
• Compliance with study drug  
• Unscheduled visit scheduled, if deemed necessary by investigator 
 
Month 6 
The visit will occur 26 weeks ± 7 days after Day 1 and the following evaluations will be 
performed: 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of concomitant medication (including supplements and vitamins) since 
the last visit 
• Vital signs and weight (as described at Section 9.2.2) 
• Complete physical examination (as described at Section 9.2.1) 
• 12-lead ECG after at least 5 minutes rest  


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• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A  
• Back-up blood sample collection 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or per local regulatory requirements. 
• 5-D itch, PBC-40, PGI-S and PGI-C questionnaires via e-diary 
• Pruritus NRS: review of previously collected data. Subjects will be instructed to use e-
diary on a monthly basis for 7 consecutive days each month through the Month 12 visit. 
• 5-D Itch: review of previously collected data. Subjects will be instructed to evaluate 
pruritus via 5-D itch at the clinic visits only.  
• Liver elastography (e.g., FibroScan) - at the selected sites 
• Study drug and UDCA accountability 
• Study drug and UDCA dispense 
• Double-blind evaluation for dose up-titration will be performed. The double-blind dose 
up-titration will be requested if the following criteria are met: 
No safety 
concerns 
limiting up-
titration 
AND  
One of the following criteria: 
o AP ≥ 1.67 × ULN 
OR  
o < 15% decrease in AP comparing to baseline value  
OR 
o Total bilirubin > 1 × ULN  
 
Dose Adjustment Visit (2 weeks after Month 6 ± 3 days) 
To avoid unblinding, all subjects will be invited to Dose Adjustment visit. For subjects who 
have safety concerns limiting up-titration, Dose Adjustment visit will still occur to evaluate 
subjects’ status. Dose Adjustment visit will occur 2 weeks after Month 6 visit and the 
following evaluations will be performed. Subjects will be instructed to not to take study drug 
at home prior to the clinic visit. 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of concomitant medication (including supplements and vitamins) since 
the last visit 
• Vital signs and weight (as described at Section 9.2.2) 
• Brief symptom-directed physical examination (as described at Section 9.2.1) 
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A  
• Study drug accountability 
• Additional assessments as determined by the Investigator 


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• Dose up-titration will be performed and study drug will be dispensed in a blinded 
manner:  
o Subjects who meet the up-titration criteria: subjects on 5 mg will be dispensed 
seladelpar 10 mg; subjects on seladelpar 10 mg will be dispensed seladelpar 10 
mg, and subjects on placebo will be dispensed matching placebo. Subjects will 
immediately start dosing.  
o Subjects who do not meet the up-titration criteria will continue the initially 
assigned dose. 
 
Contact 2 
The visit will occur 32 weeks ± 7 days after Day 1 over the phone or by email contact and the 
following will be performed: 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of concomitant medication (including supplements and vitamins) since 
the last visit 
• Compliance with study drug  
• Unscheduled visit scheduled, if deemed necessary by investigator  
 
Month 9 
The visit will occur 39 weeks ± 7 days after Day 1 and the following evaluations will be 
performed: 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of concomitant medication (including supplements and vitamins) since 
the last visit 
• Vital signs and weight (as described at Section 9.2.2) 
• Brief symptom-directed physical examination (as described at Section 9.2.1) 
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A  
• Back-up blood sample collection 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or per local regulatory requirements. 
• 5-D itch, PBC-40, PGI-C and PGI-S questionnaires via e-diary 
• Pruritus NRS: review of previously collected data. Subjects will be instructed to continue 
to use e-diary on a monthly basis for 7 consecutive days each month through the Month 
12 visit. 
• Study drug and UDCA accountability 
• Study drug and UDCA dispense 


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Contact 3 
The visit will occur 45 weeks ± 7 days after Day 1 over the phone or by email contact and the 
following will be performed: 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of concomitant medication (including supplements and vitamins) since 
the last visit 
• Compliance with study drug  
• Unscheduled visit scheduled, if deemed necessary by investigator 
 
Month 12 
The visit will occur 52 weeks ± 7 days after Day 1 and the following evaluations will be 
performed: 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of concomitant medication (including supplements and vitamins) since 
the last visit 
• Vital signs and weight (as described at Section 9.2.2) 
• Complete physical examination (as described at Section 9.2.1) 
• 12-lead ECG after at least 5 minutes rest  
• Blood drawn for hematology, biochemistry, and exploratory measures (including fat-
soluble vitamins) as outlined in Appendix A  
• Back-up blood sample collection 
• Women of child-bearing potential will have a serum pregnancy test performed. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or per local regulatory requirements. 
• 5-D itch, PBC-40, PGI-S and PGI-C questionnaires via e-diary 
• Pruritus NRS: review of previously collected data. 
• E-diary will be collected 
• Liver elastography (e.g., FibroScan) - at the selected sites 
• Study drug and UDCA accountability 
Study supply of UDCA will be switched to pre-study supply of UDCA 
 
At the end of the visit, subjects will be invited to participate in the long-term study 
(CB8025-31731). 
• Subjects who consent to participate in CB8025-31731 will have the Month 12 visit 
combined with the Day 1 visit of the CB8025-31731. Subjects on seladelpar will continue 
dosing; subjects on placebo will initiate seladelpar (5 or 10 mg).  


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• Subjects who do not consent to participate in CB8025-31731 will stop study drug and 
enter the 4-week follow-up period.  
 
9.1.4 
Post-Treatment Follow-Up 
The visit will occur four weeks (28 days ± 7 days) after the last dose of the study drug. 
The following evaluations will be performed: 
• Documentation of AEs that occurred since the signing of the ICF 
• Documentation of concomitant medication (including supplements and vitamins) since 
the last visit 
• Vital signs and weight (as described at Section 9.2.2) 
• Complete physical examination (as described at Section 9.2.1) 
• 12-lead ECG after at least 5 minutes rest  
• Blood drawn for hematology, biochemistry, and exploratory measures as outlined in 
Appendix A  
• Back-up blood sample collection 
• Women of child-bearing potential will have a serum pregnancy test performed 
 
This will be the subject’s last visit. Any clinically significant abnormalities should be 
followed up by the investigator, until resolution, or stabilization of those abnormalities.  
9.1.5 
Early Termination Visit  
Subjects who discontinue participation in the study prematurely should return for an Early 
Termination Visit and the following evaluations should be performed: 
• Documentation of AEs that occurred since the signing of the ICF  
• Review and documentation of concomitant medication (including supplements and 
vitamins) since the last visit 
• Vital signs and weight (as described at Section 9.2.2) 
• Complete physical examination (as described at Section 9.2.1)  
• 12-lead ECG after at least 5 minutes rest 
• Blood drawn for hematology, biochemistry, and exploratory measures (including fat-
soluble vitamins) as outlined in Appendix A  
• Back-up blood sample will be collected 
• Women of reproductive status will have serum pregnancy test performed. Additional 
on-treatment pregnancy testing may be performed at the investigator’s discretion or per 
local regulatory requirements. 
• Pruritus NRS, 5-D itch, PBC-40, PGI-S and PGI-C questionnaires via e-diary 
• Pruritus NRS: review of previously collected data. 
• E-diary will be collected 


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• Liver elastography (e.g., FibroScan) - at the selected sites 
• Study drug and UDCA accountability 
• Study supply of UDCA will be switched to pre-study supply of UDCA 
 
Any clinically significant abnormalities should be followed up by the investigator until 
resolution or stabilization of those abnormalities. 
9.1.6 
Unscheduled Visit  
Unscheduled visit must be scheduled if Safety Monitoring Criteria are met within the 
timeline outlined in Section 10.5. An unscheduled visit might be scheduled at any time 
during the study participation if deemed necessary per the investigator’s clinical judgement. 
At any Unscheduled Visit the following evaluations will be performed:  
• Documentation of AE that occurred since the signing of the ICF 
• Review and documentation of concomitant medication (including supplements and 
vitamins) since the last visit 
• Symptom-directed (brief) physical examination (as described at Section 9.2.1)  
• Blood drawn for biochemistry and hematology  
• Additional assessments as determined by the investigator  
 
9.2 
Study Assessments 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Manual and other administrative guides, which will 
provide the study center personnel with administrative and detailed technical information that 
does not impact subject safety. 
9.2.1 
Medical History and Physical Examination  
A detailed medical history and PBC medical history will be taken at Screening.  
Complete physical examinations will be performed at Screening, Day 1, Month 6, Month 12, 
Follow-up visit, and Early Termination visit (if applicable). These will include a full review 
of the following systems: general, skin, eyes, nose/sinuses, ears, mouth/throat, neck, breasts 
(optional, per clinical judgment only), respiratory, cardiac, gastrointestinal, peripheral 
vascular, genitourinary (optional, per clinical judgment only), musculoskeletal, neurologic, 
mental health, endocrine and hematologic.  
Symptom-directed (brief) physical examinations will be performed at Run-In, Month 1, 
Month 3, Dose Adjustment Visit, Month 9, and Unscheduled visits. Brief physical 
examinations will be performed for a condition that warrants the exam as determined by the 
investigator. Subjects with platelet level above 500 × 103 µL on hematology panel will be 
evaluated for thrombolytic events.  


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Liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss of appetite, 
dark urine, or jaundice) will be evaluated at each visit from Screening through Month 12 
visit, or until Follow-up visit or Early Termination (if applicable).  
Any clinically significant change in physical examination findings that occurs after signing 
the ICF will be recorded as an AE.  
9.2.2 
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 and weight will be assessed on all in clinic visits, from Screening through Month 
12 visit, or until Follow-up visit or Early Termination (if applicable). Height measurement 
will be performed only at Screening. 
Vital signs may be obtained more frequently if a condition develops that warrants additional 
monitoring. 
9.2.3 
Electrocardiograms 
A 12-lead ECG will be obtained in supine position after at least 5 minutes of rest at 
Screening, Day 1, Month 6, Month 12, and Follow-Up period or Early Termination (if 
applicable).  
9.2.4 
Laboratory Tests  
Laboratory testing (as described below) will be performed at all clinic visits. Blood samples 
will be collected after at least an 8-hour overnight fast and prior to dosing. If the subject 
forgets to fast or takes the study drug prior to the blood collection, the site will continue to 
draw labs. 
Hematology will be assessed at all visits. 
Biochemistry will be assessed at all visits.  
Exploratory Measures will be assessed at all onsite visits with the exception of Dose 
Adjustment Visit. At the Screening visit only AMA will be tested. Fat-soluble vitamins 
(vitamins A, D, E, and K) will be tested at Day 1, Week 52, and ET visit (if applicable) only. 
Hepatitis B and C testing will be assessed at Screening only. Women of child-bearing 
potential will have a serum pregnancy test performed at each clinic visit: Screening, Run-In, 
Day 1, Month 1, from Month 3 through Month 12, and Follow-up visit or Early Termination 
(if applicable). Additional on-treatment pregnancy testing may be performed at the 
investigator’s discretion or per local regulatory requirements. 
Urine drug screen will be assessed at Screening only. 
Laboratory testing will be obtained as follows: 


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Biochemistry:  
AP, AST, ALT, GGT, protein, albumin, total bilirubin, direct bilirubin, indirect bilirubin, 
bone-specific AP, aldolase, sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN)/urea, creatinine, estimated glomerular filtration rate (eGFR), CK, venous blood 
glucose, lactate dehydrogenase (LDH), triglycerides, total cholesterol, HDL-C, and LDL-C, 
troponin I, lipase, and amylase. 
Hematology:  
Erythrocyte count (RBC), hemoglobin, hematocrit, leukocyte count (WBC), WBC 
differential (absolute and percentage), platelets, prothrombin time (PT), and INR.  
PT and INR will also be performed locally at the Screening visit, Run-In, and during the 
treatment period if deemed necessary by the Investigator. 
Exploratory Measures: 
Anti-mitochondrial antibodies, autotaxin, IgM, fibronogen, FGF19, haptoglobin, hs-CRP, 
homocysteine, hyaluronic acid (HA), procollagen III amino terminal peptide, Pro-C3, tissue 
inhibitor of metalloproteinase 1, C4 (7α-hydroxy-4-cholesten-3-one). 
Other Testing: 
HBsAg, HCV RNA; Vitamin A, Vitamin D, Vitamin E, and Vitamin K; serum pregnancy 
testing (β-HCG) 
Back-Up Blood Sample:  
Blood samples collected during the study will be archived as back-up samples. These 
samples can be stored for up to 5 years following completion of the study and used to 
measure drug level, potential new biochemical markers, and/or to replace any missing or 
discarded samples.  
Urine Drug Screen:  
Amphetamine, THC (11-nor-9-carboxy-delta-9-THC), Cocaine, Opiates, and Phencyclidine. 
Sample collection, processing and handling details are provided in the Laboratory Manual. 
9.2.5 
Liver Elastography  
Liver elastography (e.g., FibroScan) exam will be used to evaluate liver fibrosis through a 
noninvasive imaging technique. FibroScan is the most commonly used liver elastography 
method. It 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. Other liver elastography techniques might 
include shear-wave elasticity imaging, acoustic radiation force impulse imagining, 
supersonic shear imaging, or magnetic resonance elastography. For sites when different liver 
elastography techniques are available, subjects must be evaluated using the same technique 
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Liver Elastography Exam Schedule and Timing: Subjects will undergo three liver 
elastography exams at centers when the test is available: Day 1, Month 6, Month 12 visits, 
and Early Termination visit (if applicable). Clinical sites will determine the logistics of 
scheduling the liver elastography exam and complete within the study visit window.  
Liver Elastography Exam Instructions: Subjects will be instructed to fast for 4 or more hours 
(if possible) prior to the scheduled liver elastography examination but will be allowed to take 
necessary medications and small quantities of water. 
Liver Elastography Exam Analysis: Local Reader will review and analyze scans.  
9.2.6 
Liver Biopsy 
Subjects who are willing to evaluate their PBC stage and activity will have liver biopsy 
performed during Run-In period. If liver biopsy was performed within 1 year from Day 1, 
baseline liver biopsy can be waived. For these instances sites will attempt to collect biopsy 
material. This material might be used as a baseline comparison to liver biopsy that might be 
performed in at least 3 years (± 3 months) of treatment during the long-term study 
(CB8025-31731). 
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 follow-up liver biopsy (in CB8025-
31731) 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 2.0 cm in length. 
Liver biopsy will be used to determine PBC stage and activity, using appropriate central 
reporting. 
Pre-Liver Biopsy Instructions: The subject must have PT, INR and platelets performed 
within 2 weeks prior to liver biopsy. 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 samples. 
9.2.7 
Pruritus Numerical Rating Scale (NRS)  
Pruritus NRS will be used as a key secondary measure to evaluate pruritus in subjects with 
PBC.  
The test will be performed via e-diary on a daily basis from the Run-In (Week -2) visit and 
for the first six month of study drug treatment. After six month of treatment, pruritus NRS 
will be evaluated on a monthly basis over 7 consecutive days. See Appendix D for details. 
Pruritus NRS data will be collected via e-diary. 
9.2.8 
5-D Itch Scale 
The 5-D itch scale will be used as a secondary measure for the multidimensional 
quantification of pruritus over time. The 5-D itch scale is a measure of itching that has been 
validated in patients with chronic pruritus to detect changes over time. It is a brief, single 


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page, multiple choice or ‘check all boxes that apply’ form (Elman, 2010). See Appendix E 
for details. 
The test will be performed via e-diary on a bi-weekly basis from Run-In up up until the 
Month 6 visit, and at each clinic visit from Month 6 through the Month 12 visit or Early 
Termination Visit (if applicable). 5-D itch data will be collected via e-diary. 
9.2.9 
PBC-40 QoL  
The PBC-40 questionnaire will be used as a secondary measure to evaluate health-related 
QoL measures, specifically fatigue. PBC-40 is a disease-specific health related quality of life 
tool developed to specifically measure the psychometric profile of PBC patients. It covers six 
domains relevant to PBC including cognitive, social, emotional function, fatigue, itch, and 
other symptoms (Jacoby, 2005). See Appendix F for details.  
It will be performed at each clinic visit from the Run-In period through the Month 12 visit, or 
Early Termination Visit (if applicable). The questionnaire will be evaluated by the site 
personnel and the investigator will react to any evidence of deterioration. PBC-40 QoL data 
will be collected via e-diary. 
9.2.10 
PGI-S and PGI-C  
The PGI-S and the PGI-C questionnaires will be used as an anchor scale to help interpret 
within-patient change in pruritus data collected via other pruritus questionnaires. See 
Appendix G and Appendix H for details. 
9.3 
Dose Titration 
During the study participation subjects might go through dose titration for efficacy reasons. 
For subjects who have safety concerns limiting up-titration, Dose Adjustment visit will still 
occur to evaluate subjects’ status. Subject will have a dose evaluation performed at the 
Month 6 visit to determine if dose up-titration is necessary. Dose evaluation will be done in a 
double-blind manner. 
The double-blind dose up-titration will occur if the following criteria are met: 
No safety concerns 
limiting up-titration 
AND 
One of the following criteria: 
o AP ≥ 1.67 × upper limit of normal (ULN),  
OR  
o < 15% decrease in AP comparing to baseline value, 
OR 
o Total bilirubin > 1 × ULN  
 
Subjects who meet the criteria will receive the up-titrated dose at the Dose Adjustment visit 
(2 weeks after Month 6). Subjects on 5 mg will be up-titrated to 10 mg; subjects on 10 mg 
will continue 10 mg; and subjects on placebo will continue placebo.  


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10 
ADVERSE EVENTS 
10.1 
General 
10.1.1 
Definition of 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 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. 
A treatment emergent adverse event (TEAE) will be defined as any AE that newly appeared, 
increased in frequency, or worsened in severity after initiation of the study drug. For adverse 
event reporting purposes, UDCA is not considered as a study drug. 
10.1.2 
Definition of Serious AEs (SAEs) 
An 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 
 
10.1.3 
AE Severity  
The severity of an AE will be graded from 1 to 5 according to Appendix C and NCI CTCAE 
version 4.0 criteria (v4.03, 14 June 2010).  


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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 selection.  
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 
 
10.1.4 
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) 
10.1.5 
Relationship to Study Drug 
The relationship or association of the AE to a study drug will be characterized as 
“unrelated”, “unlikely”, “possible”, “probably”, or “definite”.  


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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 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 
 
10.1.6 
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 
• Permanently discontinued: study drug was stopped and not restarted 
• Temporarily interrupted: dosing was temporarily interrupted or delayed due to the AE 
and restarted at the same dose 
• Temporarily interrupted: dosing was temporarily interrupted or delayed due to the AE 
and restarted at the decreased dose 
• Not applicable: e.g., in case the AE occurred after signing the ICF but before the 
administration of study drug was commenced 
 
10.2 
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 


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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. 
10.2.1 
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 Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines E2A and E6, and per the United States 21 
CFR § 312.32. Country specific regulatory requirements will be followed in accordance with 
local country regulations and guidelines. Independent Ethics Committees (IEC) 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 defined in 
Section 10.1.2  
The outcome for the event will be listed on the SAE Report Form as defined in 
Section 10.1.4. 
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 a Serious Adverse Event.  
The investigator will document all available information regarding the SAE on the SAE 
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: 


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• Subject’s study number  
• Time and date of study drug administrations 
• 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 counter-measures 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 in eCRF 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. 
10.2.2 
Follow-up of Reported AEs  
SAEs recorded during the study will be followed by the investigator until resolution or 
stabilization. 
After the Follow-up 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. 
10.3 
Distribution of Responsibilities 
Details about the distribution of safety responsibilities are presented in the Safety Reporting 
Plan. 
10.4 
Safety Monitoring Criteria and Withdrawal Criteria   
10.4.1 
Liver Safety Monitoring  
Enrolled subjects with the following lab abnormalities should be monitored closely and may 
interrupt study drug or discontinue study drug if criteria are met: 
1. 
Elevation of ALT/AST 
Normal ALT/AST at baseline  
• ALT/AST > 5 × ULN and total bilirubin ≤ 1 × ULN: Interrupt study drug. Repeat 
AST, ALT, total bilirubin, and INR within 3 days and closely follow the subject 
(see Appendix B). Study medication can be restarted only if a firm competing etiology is 
identified and liver tests return to baseline. 
• ALT/AST > 5 ULN and total bilirubin > 1 × ULN: 
o Subjects with normal total bilirubin at baseline: Stop study drug. Repeat AST, ALT, 
total bilirubin, and INR within 3 days and closely follow the subject (see 
Appendix B). 


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o Subjects with elevated total bilirubin at baseline: 
 Total bilirubin > 1.5 × baseline: Stop study drug. Repeat AST, ALT, total 
bilirubin, and INR within 3 days and closely follow the subject (see 
Appendix B). 
 Total bilirubin ≤ 1.5 × baseline: Interrupt study drug. Repeat AST, ALT, 
total bilirubin, and INR within 3 days and closely follow the subject (see 
Appendix B). Study medication can be restarted only if a firm competing 
etiology is identified and liver tests return to baseline. 
 
Elevated ALT/AST at baseline: 
• ALT/AST > 3 × baseline AND INR ≤ 1.5 × ULN AND no liver-related symptoms (e.g., 
nausea, vomiting, right upper quadrant pain, loss of appetite, dark urine, or jaundice): 
Continue study drug. Repeat AST, ALT, total bilirubin, and INR within 3 days. Closely 
follow the subject (see Appendix B). 
• ALT/AST > 3 × baseline AND INR > 1.5 × ULN AND no liver-related symptoms (e.g., 
nausea, vomiting, right upper quadrant pain, loss of appetite, dark urine, or jaundice): 
Interrupt study drug. Repeat AST, ALT, total bilirubin, and INR within 3 days and 
closely follow the subject (see Appendix B). Study drug can be restarted only if a firm 
competing etiology is identified and liver tests return to baseline. 
 
2. Liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss of 
appetite, dark urine, or jaundice) AND ALT/AST > 3 × baseline (irrespective of 
baseline levels): Interrupt study drug. Repeat AST, ALT, total bilirubin, and INR 
within 3 days. Closely follow the subject (see Appendix B). Study drug can be 
restarted only if a firm competing etiology is identified and liver tests return to 
baseline. 
3. Elevation of total bilirubin > 1.5 × baseline, regardless of ALT or AST levels, AND 
indicators of immunological reaction (e.g., rash, eosinophilia > 5%) OR liver-related 
symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss of appetite, dark 
urine, or jaundice): Interrupt study drug. Repeat AST, ALT, total bilirubin, and 
INR within 3 days and closely follow the subject (see Appendix B). Study drug can 
be restarted only if a firm competing etiology is identified and liver tests return to 
baseline. 
4. Hepatic decompensation (e.g., decompensated cirrhosis with gastro-esophageal 
variceal bleeding, ascites, or hepatic encephalopathy) during the study: Stop study 
drug and closely follow the subject (see Appendix B). 
5. Close monitoring of a subject is not possible (see Appendix B): Stop study drug. 
 
10.4.2 
Muscle Safety Monitoring 
I. 
CK > 5 × ULN with musculoskeletal symptoms: Stop study drug. Repeat the test 
within 3 days. Follow the subject weekly until resolution or stabilization.  


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II. 
CK > 5 × ULN without musculoskeletal symptoms: repeat the test within 3 days. If 
on repeat test CK is > 2.5 × ULN, stop study drug. Follow the subject weekly until 
the event resolution or stabilization.  
III. 
CK > 2.5 × ULN and ≤ 5 × ULN regardless to musculoskeletal symptoms: repeat the 
test within 3 days. If the test is confirmed, study drug will be continued at a 
decreased dose. For subjects on 5 mg, the study drug will be switched to placebo. 
 
10.4.3 
Serum Creatinine Monitoring 
I. 
Serum creatinine > 2.0 × ULN: Stop study drug. The subject should be monitored 
weekly until resolution or stabilization.  
II. 
Serum Creatinine > 1.5 × ULN and ≤ 2.0 × ULN: Interrupt study drug. Repeat the 
test within 3 days. If the test is confirmed and no alternative etiology is identified, 
stop study drug. If alternative etiology is identified, study drug may be restarted 
after serum creatinine returns to baseline values. The subject should be monitored 
weekly until event resolution.  
 
10.4.4 
Pancreatic Safety Monitoring 
I. 
Amylase > 3 × ULN and/or lipase > 3 × ULN without clinical symptoms of acute 
pancreatitis: repeat the test within 3 days. If the test confirms suspicion, interrupt 
study drug. Abdominal imaging is to be performed to exclude an alternative cause 
for the event. Study drug might be restarted only if a firm competing etiology of acute 
pancreatitis is identified. 
II. 
Amylase > 3 × ULN and/or lipase > 3 × ULN with clinical symptoms of acute 
pancreatitis: interrupt study drug. Repeat the test within 3 days. Abdominal 
imaging is to be performed to exclude an alternative cause for the event. Study drug 
might be restarted only if a firm competing etiology of acute pancreatitis is identified. 
 
10.4.5 
Additional Withdrawal Criteria and Replacement of Subjects 
Subjects may be discontinued from the study for the following reasons: 
• Enrolled into the study in violation of this protocol 
• Required the use of a prohibited concomitant medication  
• The subject should be informed of new approved and available treatment to make an 
informed decision regarding continuation in the study. The availability of a new standard 
of care does not automatically terminate a subject from study participation. 
• 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  


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• 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.  
10.5 
Precautions 
10.5.1 
Pregnancy 
No specific human clinical studies have been performed to determine the reproductive and 
developmental toxicity of seladelpar. 
As a precaution, women of child bearing potential receiving study drug must use one barrier 
contraceptive and a second effective birth control method during the study and for at least 
90 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. Sexual abstinence defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. 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 may include:  
• combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral 
o injectable 
o implantable 
• intrauterine device  
• intrauterine hormone-releasing system  
• bilateral tubal occlusion  
• vasectomized partner 


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11 
STUDY TERMINATION 
CymaBay Therapeutics, Inc. reserves the right to discontinue the study if it becomes aware of 
information concerning the quality, 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, 
IEC, 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 Principal Investigator, due to specific 
clinical observations relating to safety concerns. If the Principal 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. 
CymaBay Therapeutics, Inc. reserves the right to discontinue the study at any time for 
administrative reasons.  


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12 
DATA HANDLING CONSIDERATIONS 
12.1 
Processing of Electronic Case Report Forms  
The study will be performed using electronic data capture (EDC). The investigator is 
responsible for prompt reporting of accurate, complete, and legible data in the eCRFs. Any 
change or correction to the eCRF after saving must be accompanied by a reason for the 
change. Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator. The investigator 
should maintain a list of personnel authorized to enter data into the eCRF. The investigator 
will maintain a Site Delegation Personnel Log to document signatures and initials of all 
persons qualified and authorized by the investigator to make entries and/or corrections to the 
source documents. 
12.2 
Database  
Data entry will be performed through username and password protected access to a secure 
database. All data will be entered using 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 and medical history, and 
the World Health Organization (WHO) Drug classification will be used to code medications. 
Electronic CRFs will be available for review by the Clinical Research Associate (CRA) and 
Sponsor and Sponsor`s designee after completion by the site. The eCRFs will be monitored 
remotely and onsite by the Clinical Research Organization (CRO) after documented training 
and in accordance with the monitoring plan. The CRA will review the eCRF data on a 
regular basis and post any queries for the site to complete prior to the scheduled onsite 
monitoring visits. Only those individuals who are qualified and authorized by the investigator 
to complete eCRFs will trained and receive passwords allowing eCRF completion.  
The completed eCRF must be electronically reviewed, signed, and dated by a qualified 
physician who is designated as Principal or Sub-investigator for the study. The investigator 
must retain the original source documents. A final pdf of the eCRFs will be provided to the 
study site by the CRO or designee at the end of the study for archival purposes.  
An electronic audit trail system will be maintained within the eCRF to track all data changes 
in the database once the data have been saved initially into the system or electronically 
loaded. 
12.3 
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. 


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13 
STATISTICAL ANALYSES 
13.1 
General Statistical Considerations 
Statistical analysis and generation of tables, figures, subject data listings, and statistical 
output will be performed using SAS Version 9.3.  
Descriptive statistics will be displayed to provide an overview of the study results. For 
categorical parameters, the number and percentage of subjects in each category will be 
presented. The denominator for percentages will be based on the number of subjects 
appropriate for analysis.  
Statistical tests of efficacy variables will be presented as 2-sided p-values rounded to 4 
decimal places. P-values less than 0.0001 will be presented as “<0.0001” and p-values 
greater than 0.9999 will be presented as “>0.9999.” Statistical comparison will be performed 
at the 0.0500 level of significance. For continuous variables, display of descriptive statistics 
will generally include n (number of subjects), mean, standard deviation (SD), median, 
minimum, and maximum.  
13.2 
Determination of Sample Size  
The placebo group responder rate is estimated at less than 15% (Nevens, 2016). The 
seladelpar 10 mg dose group responder rate is estimated at 40%. With the use of a 2-sided 
test of equality of binomial proportions based on Pearson chi-square test at the 5% level of 
significance, a sample size of 80 patients per group will provide greater than 90% power to 
detect a difference between the 10 mg seladelpar group and the placebo group. 
The key secondary efficacy analysis of normalization of AP is estimated to have a placebo 
response rate is of 5%. A 2-sided test of equality of binomial proportions based on Pearson 
chi-square test at the 5% level of significance yields a sample size of 80 patients per group. 
This sample size provides more than 90% power to detect a difference of 30% between the 
10 mg seladelpar and placebo groups. 
The key secondary efficacy analysis of change in pruritus NRS sample size calculation was 
based on a 2-sample 2-sided t-test at the 5% alpha level. The standard deviation is 3 
(Lai, 2017). Under these assumptions, a total of 23 subjects per group provides ≥90% power 
to detect a treatment difference of ≥3 (Lai, 2017) between 10 mg seladelpar and placebo 
groups. 
To account for a subject dropout rate of > 15%, the planned number of study subjects for an 
adequately powered study is 240 subjects, or 80 subjects per treatment group. 
Randomization will be centralized to ensure adequate blinding of the study. 


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13.3 
Analysis Sets 
13.3.1 
Safety Set  
The safety set is defined by any subject who receives at least one dose of study drug. 
Subjects will be included in the group based on treatment received, if this should differ from 
the treatment assignment. All safety analyses will be completed using the safety set. 
13.3.2 
Intent to Treat Analysis Set (ITT)  
The ITT analysis set is defined as any subject randomized into the study.  
13.3.3 
Modified Intent to Treat Analysis Set 
The Modified Intent to Treat (mITT) set includes any subject who is randomized into the 
study and receives at least one dose of study drug. The mITT set will be used for the primary 
efficacy analysis.  
13.3.4 
Per Protocol (PP) Analysis Set 
The Per-Protocol (PP) set includes any subject who is randomized into the study, receives at 
least one dose of study drug, has at least one post baseline AP and total bilirubin evaluation, 
and does not have a protocol violation that is deemed to impact the efficacy analysis. 
13.4 
Analysis Time Points 
Baseline is defined as the arithmetic mean of multiple pre-treatment measurements 
(Screening, Run-In, Day 1, and UNS if applicable) preceding the first administration of study 
drug, or as the last measurement prior to the first administration of study drug if only single 
value is available. 
Unless otherwise noted, all references to Day 1 refer to the day of study drug initiation for 
analytical purpose.  
Unless otherwise noted, all references to the last dose of study drug refer to the last dose of 
study drug taken across all study periods. 
The Last Visit for all assessments is the last non-missing assessment during the Treatment 
Period. All scheduled and unscheduled assessments within this time will be considered. Last 
Visit will be determined separately for each study procedure where Last Visit is mentioned 
within this document. 
13.5 
Handling of Drop-Outs and Missing Data 
Detailed descriptions of Handling Drop-Outs and Missing Data are contained in the SAP. All 
efforts will be made to prevent missing data from occurring.  
Sensitivity analyses will be performed on the primary efficacy endpoint using observed data 
only. The robustness of the primary analysis will be explored using several sensitivity 
analyses on a variety of patient populations including subjects who discontinue study drug. 


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For responder analyses, any subject who does not provide an assessment at the specified time 
point for the defining of response will be considered a non-responder. 
For efficacy endpoints that utilized an analysis of covariance (ANCOVA) model, observed 
cases will serve as the primary analysis. The robustness of the primary analysis will be 
explored using several sensitivity analyses to assess the effect of missing data. Analysis will 
be conducted where missing data is imputed using a “responders,” last observation carried 
forward (LOCF) and “worst case” methodologies. For efficacy endpoints that utilized the 
mixed models repeated measures (MMRM), no imputations will be made for missing values. 
The following additional sensitivities will be performed: 
• As responders 
• 
Same as primary analysis except based on the ITT Set. 
• Same as primary analysis except based on the PP Set. 
• Same as primary analysis except impute dropouts as non-responders in the seladelpar 
arm and as responders in the placebo arm (i.e. worst-case analysis). 
• Same as primary analysis except impute missing data using a pattern-mixture model 
(PMM) which considers different mechanisms for missing data.  
• Same as primary analysis except specify the proportion of patients achieving a 
decrease in AP as at least 10%, 20%, and 40%. 
• Using Medians instead of arithmetic means for baseline values 
 
13.6 
Disposition, Demographics and Baseline Characteristics  
The number of subjects screened, and the number and percentage of those subjects who were 
screen failures, broken down by primary reason for Screening failure will be presented 
overall and repeated by stratification group.  
Demographic and baseline characteristics (medical histories, physical examinations, and 
concomitant medications) will be summarized using descriptive statistics for continuous 
variables and frequency distributions for discrete variables. Values will be summarized and 
listed using absolute values and percentages.  
Study participants that discontinued the study along with reasons for discontinuation will be 
summarized and listed.  
13.7 
Efficacy Analysis 
Primary Efficacy Endpoint 
The primary efficacy analysis will be based on the following composite endpoint evaluated 
after 52 weeks of treatment: 
• AP < × 1.67 ULN, 


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• AP decrease of ≥ 15%, and 
• Total bilirubin ≤ ULN 
 
Treatment comparisons of the primary efficacy endpoint will be tested using a gateway 
method. A hierarchical “fixed-sequence” approach will be used to evaluate the primary 
endpoint as follows: 
1. 
The composite endpoint and seladelpar 10 mg vs placebo if negative stop 
2. 
If seladelpar 10 mg test is positive, that test the composite endpoint for seladelpar 5/10 
mg vs placebo; if negative stop 
This testing procedure maintains the overall Type I error for the primary efficacy endpoint at 
5%. Analyses for the composite endpoint will be completed using a Cochran–Mantel–
Haenszel (CMH) test stratified by the randomization stratification factor (AP level < 350 U/L 
and ≥ 350 U/L) and pruritis NRS < 4 and NRS ≥ 4 and will be conducted on the mITT 
population. If assumptions required for the CMH test including, but not limited to, small cell 
counts or all responses within a stratum are the same for both treatment groups (e.g., all 
responders within a stratum), additional data handling and analysis methodology will be used 
and described within the SAP. 
The fixed sequence approach is as follows: 
 
 
Notes: H1=Composite endpoint tested with 10 mg seladelpar vs. placebo, H2=Composite 
endpoint tested with 5/10 mg seladelpar vs. placebo, H3=AP Normalization tested with 10 
mg seladelpar vs. placebo, H4=AP Normalization tested with 5/10 seladelpar vs. placebo, 
H5= Change from baseline in the weekly averaged peak pruritus NRS over 6 months tested 
with 10 mg seladelpar vs. placebo, H6= Change from baseline in the weekly averaged peak 
pruritus NRS over 6 months tested with 5/10 mg seladelpar vs. placebo 
Statistical significance of the difference between placebo and seladelpar will be defined as a 
p-value ≤ 0.05. Sensitivity analyses will be performed on the primary efficacy endpoint using 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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observed data only. The CMH test will also be used for AP responder analyses, disease 
prognostic risk responder analyses, and subgroup analyses.  
Efficacy laboratory parameters  
Efficacy laboratory parameters will be analyzed using an ANCOVA model with absolute 
change and percent change from Baseline as the dependent variable including treatment 
group and randomization stratification factor as fixed effects and Baseline as a covariate.  
Secondary endpoints  
The key secondary efficacy analysis for normalization of AP is a responder analysis and will 
be conducted in the mITT set using the same approach specified for the primary efficacy 
analysis. 
Change from baseline in the weekly averaged peak pruritus NRS over 6 months will be 
evaluated using ANCOVA with terms for treatment factor and baseline pruritis score as 
covariates. The analysis will be limited to those subjects in the mITT analysis set with an 
NRS ≥ 4. The weekly pruritus score will be calculated by recording the daily pruritis score 
each day for seven days and then taking the median value of the seven days’ worth of daily 
recorded data. If any data are available for a given week, the available NRS results will be 
used for the calculation of the weekly median. If no NRS results are available in a given 
week, the median of the prior week will be used to impute those missing results using the last 
observation carried forward (LOCF) method.  
Sensitivity analyses will be performed using the mITT population on all responder endpoints 
using a logistic regression model with response as the endpoint and treatment group and 
randomization strata as factors. 
Other Secondary endpoints will include the first occurrence of any of the following clinical 
events: 
o Overall death 
o Liver transplantation 
o MELD score ≥ 15 
o Uncontrolled ascites (diuretic resistant) 
o Hospitalization for new onset or recurrence of any of the following: 
 variceal bleeding 
 hepatic encephalopathy (as defined by a West Haven score ≥ 2) 
 spontaneous bacterial peritonitis (confirmed by culture from diagnostic 
paracentesis) 
o Hepatocellular carcinoma 
o Advanced PBC as defined by the Rotterdam criteria (low serum albumin AND 
total bilirubin above 1 × ULN) 
 


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Clinical events will be validated by a Critical Event Review Committee (CERC) composed 
of independent clinical experts familiar with hepatic diseases.  
Other secondary and exploratory analysis will be performed using ANCOVA similar to 
efficacy laboratory parameters where appropriate.  
Tables and listing will be provided for all efficacy analysis and exploratory analysis and 
figures where appropriate. 
13.8 
Safety Analysis 
All safety analyses will be based on the Safety population. TEAEs will be summarized by 
MedDRA System Organ Class (SOC) and preferred term by severity and by causal 
relationship to seladelpar. The severity of TEAEs will be graded based on NCI CTCAE, 
Version 4.0. 
Safety laboratory parameters, liver fibrosis scores, vital signs, body weight, and body mass 
index (BMI) values (absolute and change from baseline) will be summarized by treatment 
group using descriptive statistics at baseline and at each post-baseline visit.  
An overall summary of AEs will provide the overall summary of TEAEs and the numbers 
and percentages of subjects with at least 1 TEAE, with a serious TEAE, with a TEAE that led 
to permanent withdrawal of study medication, with a drug-related TEAE, with a severe 
TEAE, and with a drug-related serious TEAE. The number and percentage of subject 
discontinuations due to TEAEs, and the number and percentage of subjects with AEs leading 
to death (if applicable), will also be summarized.  
Descriptive statistics and change from baseline will be determined for each measure of 
laboratory tests, at each assessment. Abnormal laboratory values will be graded by the 
investigator as: “clinically significant” or “not clinically significant”, where available, and all 
laboratory values will be reported. 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. 
Tables and listings will be provided for all safety analyses. 


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14 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1 
Study Monitoring 
14.1.1 
Source Documents 
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. 
14.1.2 
Case Report Forms 
Patients who have signed the ICF will be assigned a patient number and will have trial data 
entered into a CRF. CRF completion is important to the Medical Monitoring of the trial and 
should be completed promptly after each patient visit.  
14.1.3 
Protocol Deviations 
Protocol deviations are not permitted, and protocol waivers will not be granted. Deviations to 
the protocol should be avoided, except when the investigator considers patient safety to be at 
risk if action is not taken. The Sponsor is to be notified of any protocol deviations that occur.  
Deviations from the will be noted in the source documentation, in the eCRF and a 
complementary database. The Sponsor will assess any protocol deviation and decide whether 
any of these non-compliances should be reported to regulatory authorities as a serious breach 
of ICH Good Clinical Practice (GCP) and the protocol.  
14.2 
Audits and Inspections 
14.2.1 
Trial Auditing 
Regulatory authorities, IEC, 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. 
14.2.2 
Trail Monitoring 
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. 


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14.3 
Ethics Committees 
The investigators will provide IECs with all information impacting the risk profile of the 
drug. The trial will not commence until written IEC 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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15 
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 safety analyses and adverse events 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. 


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16 
ETHICS  
16.1 
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 IEC prior to their 
use in the trial.  
The study will not start before written approval by IEC(s) has been obtained and the local 
regulatory requirements have been complied with. 
The IEC must meet all the appropriate ICH requirements for composition, documentation, 
and operational procedures.  
16.2 
Ethical Conduct of the Study 
The study will be conducted in strict accordance with the Declaration of Helsinki, ICH GCP 
guidelines, applicable laws and regulations, and the procedures outlined in IEC approved 
version of this protocol.  
16.3 
Written Informed Consent 
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 IEC will be used. 
The ICF must be personally dated and signed by both the investigator and the subject. The 
original will be retained by the investigator and filed in the investigator’s Site File. A copy of 
the original must be provided to the study subject. 


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17 
RETENTION OF RECORDS 
All study related material, including source documents, eCRFs, competent authority, and IEC 
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. 


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18 
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 IEC 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. 


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19 
DISCLOSURE OF INFORMATION AND PUBLICATION POLICY 
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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20 
REFERENCES 
Bays HE, Schwartz S, Littlejohn T III, Kerzner B, Krauss RM, Karpf DB, 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):2889-97. 
Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic 
syndrome. J Clin Invest. 2006;116(3):590-7. 
Choi YJ, Roberts BK, Wang X, Geaney JC, Naim S, Wojnoonski K, et al. Effects of the 
PPAR-δ agonist MBX-8025 on atherogenic dyslipidemia. Atherosclerosis. 2012;220(2):470-
6. 
Corpechot C, Abenavoli L, Rabahi N, Chrétien Y, Andréani T, Johanet C, et al. Biochemical 
response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. 
Hepatology. 2008;48(3):871-877. 
Elman S, Hynan LS, Gabriel V, and Mayo MJ. The 5-D Itch Scale: a new measure of 
pruritus. Br J Dermatol. 2010;162(3):587-593. 
Jacoby A, Rannard A, Buck D, et al. Development, validation, and evaluation of the PBC-40, 
a disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 
2005;54(11):1622-1629. 
Jones D, Boudes PF, Swain MG, Bowlus CL, Galambos MR, Bacon BR, 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.  
Kaplan MM, Gershwin ME. Primary Biliary Cirrhosis. N Engl J Med. 2005;353(12):1261-
1273.  
Kumagi T, Heathcote EJ. Primary biliary cirrhosis. Orphanet J Rare Dis. 2008;3:1-17. 
Lai JW, Chen HC, Chou CY, Yen HR, Li TC, Sun MF, et al. Transformation of 5-D itch 
scale and numerical rating scale in chronic hemodialysis patients. BMC Nephrology. 
2017;18:56. 
Lindor K. Ursodeoxycholic Acid for the Treatment of Primary Biliary Cirrhosis. N Engl J 
Med. 2007;357(15):1524-1529.  
Lindor KD. Primary biliary cirrhosis. Hepatology. 2009;50(1):291-308. 
Momah N, Lindor KD. Primary biliary cirrhosis in adults. Expert 2014. Expert Rev 
Gastroenterol Hepatol.Expert Rev Gastroenterol Hepatol. 2014;8(4):427-433. 


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Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in 
primary biliary cholangitis. N Engl J Med. 2016;18;375(7):631-643. 
Ocaliva Prescribing Information, Intercept Pharmaceuticals 2016. 
Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined 
analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. 
Gastroenterology. 1997;113(3):884-890. 
Rishe E, Azarm A, Bergasa NV. Itch in Primary Biliary Cirrhosis: A Patients’ Perspective. 
Acta Derm Venereol. 2008;88:34–37.  
Selmi C, Affronti A, Ferrari L, and Invernizzi P. Immune-mediated bile duct injury: The case 
of primary biliary cirrhosis. World J Gastrointest Pathophysiol. 2010;1(4):118-128. 
 


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APPENDIX A – LABORATORY EVALUATIONS 
Biochemistry 
 
 
 
AP 
AST 
ALT 
GGT 
Protein 
Albumin  
Total Bilirubin  
Direct Bilirubin 
Indirect Bilirubin 
Aldolase 
Sodium 
Potassium  
Chloride 
Bicarbonate 
BUN/Urea  
Serum Creatinine  
eGFR  
CK 
Venous Glucose 
Troponin I 
LDH 
TG 
Total Cholesterol 
HDL-C 
LDL-C 
Amylase 
Lipase 
Hematology 
Exploratory 
Measures 
 
Other Tests 
RBC 
Hemoglobin 
Hematocrit 
WBC 
WBC differentials 
(abs and %) 
Platelets 
PT/INR  
AMA  
Autotoxin  
C4 
IgM 
Fibrinogen 
FGF19 
Haptoglobin 
hs-CRP 
Homocysteine  
Hyaluronic acid (HA) 
Procollagen III amino 
terminal peptide 
Tissue inhibitor of 
metalloproteinase 1 
Pro-C3 
 
Serum Pregnancy Test  
Back-up Sample  
HBsAg (Screening only) 
HCV RNA (Screening only) 
Vitamin A (D1, W52, ET only) 
Vitamin D (D1, W52, ET only) 
Vitamin E (D1, W52, ET only) 
Vitamin K (D1, W52, ET only) 
Urine Drug Screen (Screening 
only) 
 
 


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APPENDIX B – CLOSE OBSERVATION CRITERIA 
The “close observation” will be performed on subjects meeting liver safety monitoring 
criteria per Section 10.1.4. 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 (e.g., right upper 
quadrant pain or tenderness, nausea, vomiting, fatigue, loss of appetite, dark 
urine, or jaundice).  
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 3 days  
b. 
Monitor the subject every 3 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. 
NASH 
d. 
Hypoxic/ischemic hepatopathy 
e. 
Biliary Tract Disease besides PBC 
 
 


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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.  
The NCI CTCAE may also be accessed here:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 


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CONFIDENTIAL  
Page 86 of 94 
APPENDIX D – PRURITUS NRS 
Rate the intensity of the worst itching you experienced in the past 24 hours from no itching 
to worst possible itching by selecting a number. 
 
Itch Scale 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No 
itching 
 
 
 
 
 
 
 
 
 
Worst 
imaginable 
itching 
 


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Protocol Version 1.0, 3-JUL-2018 
CONFIDENTIAL  
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APPENDIX E – 5-D ITCH SCALE 
 








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APPENDIX G – PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) 
Please choose the response below that best describes the severity of your pruritus over the 
past week.  
o None 
o Mild 
o Moderate 
o Severe 
 


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CONFIDENTIAL  
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APPENDIX H – PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C) 
Please choose the response below that best describes the overall change in your pruritus since 
you started taking the study drug.  
o Very Much Better 
o Moderately Better 
o A little bit better 
o No change 
o A little worse 
o Moderate Worse 
o Very much worse  
 


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CONFIDENTIAL  
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APPENDIX I – NORMAL RANGES FOR SAFETY LABORATORY PARAMETERS 
BIOCHEMISTRY 
Conventional Units 
SI Units 
AP 
37-116 U/L 
37-116 U/L 
Albumin  
3.5-5.5 g/dL 
35-55 g/L 
ALT 
6-41 U/L 
6-41 U/L 
AST 
9-34 U/L 
9-34 U/L 
GGT 
Female : 7-38 U/L 
Male : 11-52 U/L 
Female : 7-38 U/L 
Male : 11-52 U/L 
Protein 
6.0-8.0 g/dL 
60-80 g/L 
Total Bilirubin 
0.10 – 1.10 mg/dL 
1.7-18.8 umol/L 
Direct Bilirubin 
0.00-0.20 mg/dL 
0.0-3.4 umol/L 
Indirect Bilirubin 
0.10- 1.00 mg/dL 
1.7-17.1 umol/L 
Aldolase 
<7.7 U/L 
<7.7 U/L 
Sodium 
134-144 mmol/L 
134-144 mmol/L 
Potassium 
3.5-5.1 mmol/L 
3.5-5.1 mmol/L 
Chloride 
95-110 mmol/L 
95-110 mmol/L 
Bicarbonate 
21-33 mmol/L 
21-33 mmol/L 
BUN/Urea  
5-22 mg/dL 
1.79-7.85 mmol/L 
Serum Creatinine 
Female : 0.49-1.12 mg/dL 
Male : 0.62-1.44 mg/dL 
Female : 43-99 umol/L 
Male : 55-127 umol/L 
CK 
25-210 U/L 
25-210 U/L 
Venous Glucose 
60-115 mg/dL 
3.3-6.4 mmol/L 
Troponin I 
<0.3 ng/mL 
<0.3 ug/L 
LDH 
113-226 U/L 
113-226 U/L 
TG 
50-150 mg/dL 
0.57-1.70 mmol/L 
Total Cholesterol 
100-200 mg/dL 
2.59-5.18 mmol/L 
HDL-C 
35-60 mg/dL 
0.91-1.55 mmol/L 
LDL-C 
50-130 mg/dL 
1.30-3.37 mmol/L 
Amylase 
22-123 U/L 
22-123U/L 
Lipase 
11-82 U/L 
11-82 U/L 
HEMATOLOGY 
 
 
RBC 
Female : 3.90 – 5.40 10^6/uL 
Male :  4.30 – 6.00 10^6/uL 
Female : 3.90 – 5.40 10^12/L 
Male :  4.30 – 6.00 10^12/L 
Hemoglobin 
Female : 12.0-16.0 g/dL 
Male :  13.6-18.0 g/dL 
Female : 120-160 g/L 
Male :  136-180 g/L 
Hematocrit 
Female : 35-45% 
Male :  40-52% 
Female : 0.35-0.45 
Male : 0.4-0.52 
WBC 
3.5-11.0 10^3/uL 
3.5-11.0 10^9/L 
Neutrophils, abs 
1.0-8.0 10^3/uL 
1.0-8.0 10^9/L 
Lymphocytes, abs 
1.0-5.0 10^3/uL 
1.0-5.0 10^9/L 
Eosinophils, abs 
0.0-0.8 10^3/uL 
0.0-0.8 10^9/L 
Monocytes, abs 
0.0-1.0 10^3/uL 
0.0-1.0 10^9/L 
Neutrophils, % 
40.0-80.0 % 
40.0-80.0 % 
Lymphocytes, % 
15.0-45.0 % 
15.0-45.0 % 
Eosinophils, % 
0.0-10.0 % 
0.0-10.0 % 
Monocytes, % 
0.0-12.0 % 
0.0-12.0 % 
Platelets 
140-400 10^3/uL 
140-400 10^9/L 
PT 
Reagent specific ranges  
Reagent specific ranges 
INR 
0.8-1.2 
0.8-1.2 
OTHER 
 
 
Pregnancy test (β-HCG) 
Female : 0-5 IU/L 
Female : 0-5 IU/L 
Vitamin A 
24-128 ug/dL 
24-128 ug/dL 
Vitamin D 
30-80 ng/mL 
75.0-200.0 nmol/L 
Vitamin E 
0.51-2.88 mg/dL 
0.51-2.88 mg/dL 
Vitamin K 
0.22-4.88 nmol/L 
0.22-4.88 nmol/L 
HBsAg 
Non-reactive 
Non-reactive 
HCV RNA 
Not Detected 
Not Detected 
 


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APPENDIX J – INVESTIGATOR’S PROTOCOL SIGNATURE PAGE 
CB8025-31735 
A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the safety and 
efficacy of seladelpar in subjects with Primary Biliary Cholangitis (PBC) and an inadequate 
response to or an intolerance to ursodeoxycholic acid (UDCA) 
 
PROTOCOL VERSION NUMBER:  
Version 1.0  
DATE OF PROTOCOL: 
 
 
3-JUL-2018 
 
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/MMM/YYYY): 
  
Site Address: 
  
 
  
 
  
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
Unique Protocol ID: CB8025-31735 
 
 
Official Title: A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the safety 
and efficacy of seladelpar in subjects with primary biliary cholangitis (PBC) and an inadequate 
response to or an intolerance to ursodeoxycholic acid (UDCA) 
 
NCT number: NCT03602560 
 
Version Number: Version 2.0 
 
Date: 30-APR-20 


Confidential 
CymaBay Therapeutics, Inc. 
CB8025-31735 
A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the 
safety and efficacy of seladelpar in subjects with Primary Biliary Cholangitis 
(PBC) and an inadequate response to or an intolerance to ursodeoxycholic 
acid (UDCA) 
30Apr2020 
Abbreviated Statistical Analysis Plan 
Version 2.0 
Prepared by: 
FMD K&L 
1300 Virginia Dr., Suite 408 
Fort Washington, PA 19034 




CymaBay Therapeutics, Inc. 
 
              Abbreviated Statistical Analysis Plan, Version 2.0 
 
CB8025-31735 
 
Date Issued: 30Apr2020 
 
  
 
  III
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...................................................................................................... V 
1. 
INTRODUCTION ............................................................................................................ 1 
2. 
OBJECTIVE ..................................................................................................................... 1 
3. 
INVESTIGATIONAL PLAN .......................................................................................... 1 
3.1. 
OVERALL STUDY DESIGN AND PLAN .................................................................... 1 
3.2. 
STUDY ENDPOINTS ....................................................................................................... 3 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................... 3 
4.1. 
ANALYSIS TIME POINTS ............................................................................................. 4 
4.2. 
ANALYSIS VISITS .......................................................................................................... 4 
4.3. 
SAMPLE SIZE .................................................................................................................. 5 
4.4. 
RANDOMIZATION, STRATIFICATION, AND BLINDING .................................... 6 
4.5. 
ANALYSIS SET ................................................................................................................ 6 
4.5.1. MODIFIED INTENT-TO-TREAT (MITT) ................................................................... 6 
4.5.2. SAFETY SET .................................................................................................................... 6 
5. 
SUBJECT DISPOSITION ............................................................................................... 6 
5.1. 
DISPOSITION .................................................................................................................. 6 
5.2. 
PROTOCOL DEVIATIONS/VIOLATIONS ................................................................. 7 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................... 7 
6.1. 
DEMOGRAPHICS ........................................................................................................... 8 
6.2. 
BASELINE CHARACTERISTICS ................................................................................ 8 
6.3. 
MEDICAL HISTORY ...................................................................................................... 9 
7. 
TREATMENTS AND MEDICATIONS ......................................................................... 9 
7.1. 
PRIOR AND CONCOMITANT MEDICATIONS ....................................................... 9 
7.2. 
CONCOMITANT PROCEDURES ................................................................................. 9 
7.3. 
STUDY DRUG AND EXTENT OF EXPOSURE .......................................................... 9 
8. 
EFFICACY ANALYSIS ................................................................................................. 11 
8.1. 
THE 1ST EFFICACY ENDPOINT ................................................................................ 11 
8.2. 
THE 2ND EFFICACY ENDPOINT ............................................................................... 11 
8.3. 
THE 3RD EFFICACY ENDPOINT ............................................................................... 12 
9. 
SAFETY ANALYSIS ..................................................................................................... 12 
9.1. 
ADVERSE EVENTS ...................................................................................................... 12 


CymaBay Therapeutics, Inc. 
 
              Abbreviated Statistical Analysis Plan, Version 2.0 
 
CB8025-31735 
 
Date Issued: 30Apr2020 
 
  
 
  IV 
9.2. 
SAFETY MONITORING CRITERIA AND WITHDRAWAL CRITERIA ............ 13 
9.3. 
CLINICAL LABORATORY EVALUATIONS .......................................................... 13 
9.3.1. HEMATOLOGY ............................................................................................................ 13 
9.3.2. BIOCHEMISTRY .......................................................................................................... 14 
9.4. 
ABDOMINAL ULTRASOUND .................................................................................... 14 
9.5. 
LIVER ELASTOGRAPHY ........................................................................................... 14 
9.6. 
VITAL SIGN AND WEIGHT MEASUREMENTS .................................................... 15 
9.7. 
ELECTROCARDIOGRAM .......................................................................................... 15 
9.8. 
PRURITUS NRS ............................................................................................................. 15 
10. 
INTERIM ANALYSIS ................................................................................................... 16 
11. 
MODIFICATIONS FROM APPROVED ANALYSIS PLAN ................................... 16 
12. 
REFERENCES ................................................................................................................ 17 
13. 
APPENDICES ................................................................................................................. 18 
13.1. SCHEDULE OF STUDY PROCEDURES ................................................................... 19 
13.2. DATE IMPUTATION GUIDELINE ............................................................................ 21 
13.3. SAFETY MONITORING CRITERIA AND WITHDRAWAL CRITERIA ............ 23 


CymaBay Therapeutics, Inc. 
 
              Abbreviated Statistical Analysis Plan, Version 2.0 
 
CB8025-31735 
 
Date Issued: 30Apr2020 
 
  
 
 
 V 
List of Abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AMA 
Anti-mitochondrial antibodies 
ANCOVA 
Analysis of Covariance 
AP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CK 
Creatine kinase 
CRF 
case report form 
CTMS 
Clinical Trial Management System 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
ET 
Early Termination 
GGT 
Gamma-glutamyl transferase 
HDL-C 
High density lipoprotein cholesterol 
hs-CRP 
High sensitivity C-reactive protein 
INR 
International normalized ratio 
IRT 
Interactive Response Technologies 
LDH 
Lactate dehydrogenase 
LDL-C  
Low density lipoprotein cholesterol  
LOCF 
Last observation carried forward 
M1, M2, M3 
Seladelpar (MBX-8025) metabolites 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NRS 
Numerical rating scale 
PBC 
Primary biliary cholangitis 
PPAR 
Peroxisome Proliferator-Activated Receptor 
PT 
Prothrombin time 
QoL 
Quality of life 
RBC 
Red blood cells 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
TEAE 
Treatment emergent adverse event 
TG 
Triglycerides 
UDCA 
Ursodeoxycholic acid 
ULN 
Upper limit of normal 
UNS  
Unscheduled 
WBC 
White blood cells 
WHODD 
World Health Organization Drug Dictionary 


CymaBay Therapeutics, Inc. 
 
              Abbreviated Statistical Analysis Plan, Version 2.0 
 
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Date Issued: 30Apr2020 
 
  
 
 
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1. Introduction 
This statistical analysis plan (SAP) is an abbreviated SAP which describes the analyses and 
presentations for the data collected for CymaBay’s protocol CB8025-31735 “A 52-week, 
placebo controlled, randomized, Phase 3 study to evaluate the safety and efficacy of seladelpar in 
subjects with Primary Biliary Cholangitis and an inadequate response to or an intolerance to 
ursodeoxycholic acid (UDCA)”, referred to as ENHANCE. The study is terminated early due to 
atypical histological findings from the phase 2 study of seladelpar in patients with nonalcoholic 
steatohepatitis, NASH (CB8025-21730). Therefore, this abbreviated SAP is created for the 
summary, analysis, and documentation of the collected safety data on seladelpar. Results of the 
analyses described in this SAP will be included in the abbreviated clinical study report (CSR). 
Primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis) is a serious and 
potentially life-threatening autoimmune disease of the liver characterized by impaired bile flow 
(cholestasis) and accumulation of toxic bile acids (BA). The hallmark of PBC is cholestasis with 
an accompanying elevation in serum biomarkers including alkaline phosphatase (AP), gamma 
glutamyl transferase (GGT) and, depending on the severity of the disease, bilirubin and liver 
transaminases. The first line therapy for PBC is UDCA, a non-cytotoxic BA that has been the 
mainstay of treatment for more than twenty years (Poupon, et al., 1997). However, up to 40% of 
subjects have persistent elevation of AP and/or bilirubin despite UDCA and are considered 
inadequate responders (Corpechot, et al., 2008). Obeticholic acid (OCA), a synthetic analogue of 
chenodeoxycholic acid (CDCA), was approved under the provisions of accelerated approval 
regulations in the United States and European Union on 27 May 2016 and 12 December 2016, 
respectively. The approval was based on OCA’s ability to significantly decrease AP levels and 
maintain a normal total bilirubin when, used as an add-on therapy in PBC patients who are 
inadequate responders to UDCA or, as a monotherapy in PBC patients who are intolerant to 
UDCA (Ocaliva, 2016). Despite the previously mentioned therapeutic interventions, it is evident 
that many PBC patients do not respond adequately to therapy and continues to have a 
progression of their disease (Kaplan, 2005; Kumagi, 2008; Momah, 2014) and additional 
treatments are needed. Seladelpar (MBX-8025) is an oral, once-daily administered, potent and 
selective peroxisome proliferator-activated receptors (PPAR) δ agonist (Bays, 2011; Jones, et al., 
2017). Seladelpar is being developed for the treatment of PBC in subjects with inadequate 
response to UDCA or intolerance to UDCA and in nonalcoholic steatohepatitis.  
2. Objective 
The primary objective of this abbreviated SAP is to evaluate the safety of two seladelpar 
regimens (5 mg/day titrated to 10 mg/day and 10 mg/day) over treatment compared with that of 
the placebo.   
3. Investigational Plan 
3.1. Overall Study Design and Plan 
The ENHANCE study was designed as a Phase 3 international, multicenter, double-blind, 
randomized, placebo-controlled 52-week dose ranging (placebo, 5/10 mg/day, and 10 
mg/day), parallel treatment groups study. Due to the unexpected termination of the study, the 
actual study duration may vary. 


CymaBay Therapeutics, Inc. 
 
              Abbreviated Statistical Analysis Plan, Version 2.0 
 
CB8025-31735 
 
Date Issued: 30Apr2020 
 
  
 
 
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The study planned to enroll approximately 240 subjects. Subjects were randomly assigned to 
receive placebo, seladelpar 5 mg titrated to 10 mg, or seladelpar 10 mg. Subjects were 
stratified by AP level (AP < 350 U/L and ≥ 350 U/L) and presence of significant pruritus 
(pruritus numerical rating scale [NRS] < 4 and NRS ≥ 4).  
Study drug (placebo or seladelpar) was taken in a blinded manner orally once a day for a 
period of 52 weeks. After the first 6 months of treatment, evaluation of the initially assigned 
dose was performed in a blinded manner. Subjects assigned to the seladelpar 5/10 mg group 
who were not responders based on composite endpoint (defined as subjects with AP >=1.67 
× upper limit of normal (ULN), < 15% decrease in AP, and Total bilirubin > ULN) at Month 
6, and were tolerating study drug, were up titrated from seladelpar 5 mg to 10 mg for the 
remainder of the study. Those subjects initially assigned to placebo or 10 mg did not have 
their dose changed (see Section 9.3 of the study protocol). To avoid unblinding, all subjects 
were invited to the Dose Adjustment visit which occurred two weeks after Month 6 visit. See 
Appendix 11.1 for the schedule of study procedures. 
      Subjects with an inadequate response to UDCA continued to receive UDCA throughout the 
study. Study specific UDCA supply was provided and taken during the study participation. 
UDCA supply was switched from pre-study supply to the study supply at the Screening visit 
and continued through the Week 52 visit. At the Week 52 visit, UDCA was switched to pre-
study supply. 
Subjects who met muscle safety monitoring criteria per Section 10.4.2 of the study protocol 
were eligible for dose-down titration. Subjects initially assigned to the seladelpar 10 mg 
group were down-titrated to 5 mg. Subjects initially assigned to the seladelpar 5 mg group 
were down-titrated to placebo and subjects assigned to placebo stayed on placebo.   
The planned total duration of the study for each subject was up to 60 weeks. The screening 
period was up to 2 weeks, the run-in period was 2 weeks, the planned treatment period was 
52 weeks with an option to enter the long-term study (CB8025-31731), and the follow-up 
period was 4 weeks (if not enrolled in the long-term study). Because the study was 
terminated early, the actual treatment duration varies.  
The study design implements safety criteria to monitor subjects with potential drug induced 
liver injury, muscle injury, renal injury and acute pancreatitis with actions to either stop the 
study drug, to interrupt the study drug, to down-titrate the study drug or investigate the case 
prior to actions with the study drug. 
The overall study design is illustrated as shown below: 
 


CymaBay Therapeutics, Inc. 
 
              Abbreviated Statistical Analysis Plan, Version 2.0 
 
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Date Issued: 30Apr2020 
 
  
 
 
 3
 
3.2. 
Study Endpoints 
This study was a pivotal study to evaluate the safety and efficacy of seladelpar. Due to the 
unexpected termination of the study, only limited efficacy and safety will be evaluated by the 
following endpoints: 
Efficacy: 
 Response on the composite endpoint of AP and total bilirubin at 6 months: 
o AP < 1.67 × upper limit of normal (ULN),  
o ≥ 15% decrease in AP, and 
o Total bilirubin ≤ ULN 
 Proportion of subjects with AP ≤ 1.0 × ULN at 6 months  
 Change from baseline in pruritus NRS at 3 and 6 months 
Safety: 
 Type, frequency, and severity of treatment-emergent adverse events (TEAEs) 
graded using National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE, Version 5.0) 
 Absolute and change from baseline of laboratory tests including safety laboratory 
parameters, vital signs, body weight and body mass index values 
 Change from baseline of Pruritus NRS on Month 1, 3, 6, 9 and 12 
 Liver elastography (at selected centers) 
 Abdominal ultrasound 
 
4. General Statistical Considerations 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be performed using SAS Version 9.4 or higher. 
Summary statistics will be displayed to provide an overview of the study results. For categorical 
parameters, the number and percentage of subjects in each category will be presented. The 
denominator for percentages will be based on the number of subjects appropriate for analysis. 
Statistical tests of efficacy variables will be presented as 2-sided p-values rounded to 4 decimal 
places. P-values less than 0.0001 will be presented as “<0.0001” and p-values greater than 


CymaBay Therapeutics, Inc. 
 
              Abbreviated Statistical Analysis Plan, Version 2.0 
 
CB8025-31735 
 
Date Issued: 30Apr2020 
 
  
 
 
 4
0.9999 will be presented as “>0.9999.” Unless stated otherwise, statistical comparisons will be 
performed at the 0.05 level of significance.  
The following reporting conventions apply generally to tables, listings and figures: 
 Confidence intervals (CIs) will be presented as 2-sided 95% CIs unless specified 
differently for a given analysis. 
 Summary statistics will consist of the number and percentage of subjects in each category 
for discrete variables, and the number of subjects (n), mean, standard deviation (SD), 
median, minimum, and maximum for continuous variables. 
 All mean and median values will be formatted to one more decimal place than the 
measured value, up to three decimal places. Standard deviation values will be formatted 
to two more decimal places than the measured value, up to three decimal places. 
Minimum and maximum will be formatted to the same decimal place as the measured 
value. 
 All percentages will be rounded to one decimal place. The number and percentage will be 
presented in the form XX (XX.X), where the percentage is displayed in parentheses. 
 All listings will be sorted for presentation in order of treatment arm (randomized or actual 
treatment depending on analysis set of interest), study site, subject, date of procedure or 
event, and test/parameter name (if applicable).  
 All analysis and summary tables will include the analysis set sample size (i.e., number of 
subjects) in the header. 
4.1. Analysis Time Points 
Unless specified otherwise, baseline is defined as the arithmetic mean of multiple pre-
treatment measurements (Screening, Run-in, Day 1, and unscheduled [UNS] if applicable) 
preceding the first administration of study drug, or as the last measurement prior to the first 
administration of study drug if only a single value is available.   
For assessments prior to the first date of study drug, the study day will be calculated as: 
 Assessment date – date of first dose of study drug  
For assessments on or after the first date of study drug, the study day will be calculated as: 
 Assessment date – date of first dose of study drug + 1 day 
If the assessment date is completely missing or partial, the study day will be missing.  
Unless otherwise noted, all references to Day 1 refer to the day of study drug initiation for 
analytical purposes.  Unless otherwise noted, all references to the last dose of study drug 
refer to the last dose of study drug taken across all study periods. 
4.2. Analysis Visits 
Data will be presented and analyzed according to the visit recorded in the database. In 
general, only those assessments which are assigned to an analysis visit will be included in the 
summary tables and figures and will be presented by visit.   
As subjects do not always adhere to the protocol visit schedule, the following rules are 
applied to assign actual visits to protocol visit unless specified otherwise in analysis sections. 


CymaBay Therapeutics, Inc. 
 
              Abbreviated Statistical Analysis Plan, Version 2.0 
 
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Date Issued: 30Apr2020 
 
  
 
 
 5
If a subject has 2 or more actual visits in one visit window, the visit closest to the target day 
will be used as the protocol visit for that visit window. If 2 actual visits are equidistant from 
the target day within a visit window, the later visit is used. If a visit window has no scheduled 
visits but does have unscheduled visits, then the unscheduled visit closest to the target day 
will be used. 
The visit windows and the target days for each analysis visit are listed below. 
Scheduled Visit 
Target Day 
Study Day Analysis Visit Window 
Range  
Month 1 (Week 4) 
Day 28 
Days 2 - 56 
Month 3 (Week 12) 
Day 84 
Days 57 - 133 
Month 6 (Week 26) 
Day 182 
Days 134 - 189 
Dose Adjust (Week 28) 
Day 196 
Days 190 - 235 
Month 9 (Week 39) 
Day 273 
Days 236 - 319 
Month 12 (Week 52) 
Day 364 
Days 320 - 378 
Safety Follow-up (10 Days after 
EOT) 
Day 10 after last 
dose 
Day 3 - 14 after last dose 
Safety Follow-up (4 Weeks after 
EOT) 
Day 28 after last 
dose 
> 14 days after last dose 
Study days are relative to Day 1 (which is the day of study drug initiation). 
 
For Visits Month 1 to Month 12, all scheduled and unscheduled assessments before or within 
2 days after the last dose will be considered.  
For two safety follow-up visits within one visit window, the above rules of the selection of 
two or more actual visits within one visit window will still apply.  
4.3. Sample Size 
Approximately 240 subjects from about 140 investigational sites worldwide were planned to 
be dosed in this study.  
For the composite endpoint, the placebo group responder rate is estimated at less than 15% 
(Nevens et al., 2016). The seladelpar 10 mg dose group responder rate is estimated at 40%. 
With the use of a 2-sided test of equality of binomial proportions based on the Pearson 
chi-square test at the 5% level of significance, a sample size of 64 subjects per group 
provides greater than 90% power to detect a difference of 25% between the 10 mg seladelpar 
group and the placebo group. 
The efficacy analysis of normalization of AP is estimated to have a placebo response rate of 
5%. A 2-sided test of equality of binomial proportions based on the Pearson chi-square test at 
the 5% level of significance yields a sample size of 80 subjects per group. This sample size 
provides more than 90% power to detect a difference of 30% between the 10 mg seladelpar 
and placebo groups. 
The efficacy analysis of change in pruritus NRS sample size calculation is based on a 
2-sample 2-sided t-test at the 5% alpha level. The standard deviation is 3 (Lai, 2017). Under 
these assumptions, a total of 23 subjects per group provides ≥ 90% power to detect a 
treatment difference of ≥ 3 between the 10 mg seladelpar and placebo groups. 


CymaBay Therapeutics, Inc. 
 
              Abbreviated Statistical Analysis Plan, Version 2.0 
 
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Date Issued: 30Apr2020 
 
  
 
 
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To account for subject dropout rate of > 15%, the planned number of study subjects for an 
adequately powered study is 240 subjects, or 80 subjects per treatment group. Randomization 
were centralized to ensure adequate blinding of the study. 
4.4. Randomization, Stratification, and Blinding 
Subjects were randomized in a blinded manner to placebo or seladelpar in a 1:1:1 scheme 
(placebo: seladelpar 5/10mg: seladelpar 10 mg). In addition, randomized subjects were 
stratified by AP level (AP < 350 U/L and ≥ 350 U/L) and pruritus status (pruritus NRS < 4 
and pruritus NRS ≥ 4). 
Randomization was performed centrally via Interactive Response Technologies (IRT) system 
at the Day 1 visit. A subject was considered formally enrolled in the study at the time of 
randomization and begin study drug dosing. 
4.5. Analysis Set 
4.5.1. Modified Intent-to-Treat (mITT) 
The Modified Intent-to-Treat (mITT) set includes any subject who is randomized into the 
study and receives at least one dose of study drug. The mITT set will be used as the 
analysis set for the efficacy analysis and will be analyzed based on randomized treatment. 
4.5.2. Safety Set 
The Safety set includes any subject who receives at least one dose of study drug. Tables, 
listings, and figures based on the Safety set will be based on actual treatment in the event 
that it differs from the randomized treatment assignment. All safety analyses will be 
completed using the Safety set. 
5. Subject Disposition 
5.1. Disposition 
The number and percentage of subjects who were randomized and treated, completed 
treatment, discontinued treatment with reason for treatment discontinuation, completed study, 
discontinued study with reasons of discontinuation, completed treatment and completed 
follow-up period, completed treatment and did not complete follow-up period, completed 
treatment and entered the long-term study (CB8025-31731), completed treatment and did not 
enter the long-term study will be summarized by treatment group and overall for the Safety 
set.   
The primary reasons for treatment discontinuation are collected in the End of Treatment CRF 
and will be summarized with the following categories: 
 Safety reason 
o Liver safety monitoring 
o Muscle safety monitoring 
o Serum creatinine monitoring 
o Pancreatic safety monitoring 
o Adverse events other than safety monitoring criteria 


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 Entered the study in violation of inclusion/exclusion criteria 
 Required the use of prohibited concomitant medications 
 Withdrawal of informed consent 
 At the discretion of the Investigator for medical reasons 
 Pregnancy 
 At the discretion of the Investigator or Sponsor for non-compliance 
 Significant protocol deviation 
 Administrative decision by the Investigator or Sponsor or designee 
 Lost to follow-up 
 Death 
 Other 
The decision to terminate the study was communicated to participating sites on 24 November 
2019. Due to sites utilizing different categories to capture the information (under 
Administrative decision or Other), an additional count of subjects that discontinued treatment 
on or after 24 November 2019 will be provided under ‘Study Closure’ category. 
The primary reasons for study discontinuation are collected in the End of Study CRF and will 
be summarized with the following categories: 
 Adverse event 
 Withdrawal of informed consent 
 Lost to follow-up 
 Death 
 Pregnancy 
 Other 
Similar to treatment disposition, an additional count of subjects that discontinued study on or 
after 24 November 2019 will be provided under ‘Study Closure’ category. 
5.2. Protocol Deviations/Violations 
Protocol deviations/violations will be recorded within the PPD Clinical Trial Management 
System (CTMS) and undergo cross-functional team review prior to database lock. The Study 
Deviation Guidance Document contains all potential protocol deviations, classified by CTMS 
subtype.  
Major protocol violations can be related but not limited to study inclusion/exclusion criteria, 
trial conduct, use of prohibited medications, accidental unblinding during the treatment 
period, subject dosing compliance, or subject missing assessments.  
A listing of protocol deviations and violations will be provided.  
6. Demographics and Baseline Characteristics 
The demographics, baseline characteristics and medical histories will be summarized for the 
Safety sets.  


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6.1. Demographics 
Summary statistics will be provided by treatment group for the following continuous 
variables: 
 Age (years) 
 Weight (kg) 
 Height (cm) 
 Body mass index (BMI; kg/m2)                                                                                                                          
Number and percentage will be provided by treatment group for the following categorical 
variables: 
 Age group (< 65, ≥ 65 years) 
 Sex (male, female) 
 Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
 Ethnicity (Hispanic or Latino, not Hispanic or Latino, Unknown) 
 Region (North America, Latin America, EMEA, APAC) 
6.2. Baseline Characteristics 
The following variables indicated below will be summarized descriptively: 
 
 Duration of PBC (time [in years] from diagnosis date to the informed consent date) 
 MELD score (<12, 12-15, >15) 
 Liver stiffness (kPa) 
 Fibrosis Score derived from liver Stiffness (>=F1 to <F2, >=F2 to <F3, >=F3 to <F4, 
=F4, where the cut-off values for F1, F2, F3, and F4 are 7.1, 8.8, 10.7 and 16.9, 
respectively) 
 Liver biopsy performed within 1 year from Day 1 (yes, no) 
 Liver biopsy performed during run-in (yes, no) 
 UDCA usage (yes, no) 
 Total daily UDCA dose (mg, and mg/kg) 
 Duration of prior UDCA usage (years) 
 AP concentration (U/L) 
 AP level ( < 350 U/L and ≥ 350 U/L) 
 Total bilirubin (TB) concentration (mg/dL) 
 Total bilirubin level ( ≤1xULN, >1 - ≤2xULN, > 2xULN) 
 ALT (U/L) 
 AST (U/L) 
 GGT (U/L) 
 Platelet (counts/uL) 
 INR 
 Albumin (g/dL) 
 Pruritus NRS (observed value, and categories < 4 and ≥ 4) 
 AMA status (positive, negative, equivocal) 


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6.3. Medical History 
A detailed medical history will be coded by System Organ Class (SOC) and Preferred Term 
(PT) using Medical Dictionary for Regulatory Activities (MedDRA). The dictionary version 
used for reporting the study will be described in the relevant table and listing footnotes. The 
number and percentage of subjects with any medical history will be summarized overall and 
for each system organ class (SOC) and preferred term (PT) for the Safety set. PBC history 
will be summarized for the Safety set. 
7. Treatments and Medications 
7.1. Prior and Concomitant Medications 
Concomitant medications are defined as any medications ongoing at the start of study 
treatment or with a start date on or after the date of the first dose of study treatment. Prior 
medications are defined as medications with a stop date prior to the date of the first dose of 
study treatment. 
 
Medications reported on the Prior and Concomitant medications case report form (CRF) 
pages will be coded by the World Health Organization Drug Dictionary (WHODD) version 
March 2018 format B3 and will be summarized by Anatomical Therapeutic Chemical (ATC) 
coding system class, generic name by treatment group for the Safety set. Subjects taking 
more than one medication in the same generic name or ATC class will be counted once. The 
dictionary version used for reporting the study will be described in the relevant table and 
listing footnotes. 
 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete 
medication start and stop dates will be imputed. Additional details are provided in Appendix 
11.2. 
 
7.2. Concomitant Procedures 
Concomitant procedures are defined as any therapeutic intervention (e.g. surgery/biopsy, 
physical therapy) or diagnostic assessment (e.g. blood gas measurement, bacterial cultures) 
performed during a subject’s participation in this trial.   
 
The number and percentages of subjects who had any concomitant procedures will be 
summarized by procedure and treatment group based on the Safety set.  
7.3. Study drug and Extent of Exposure 
Seladelpar was supplied in a blinded fashion as 5 mg and 10 mg capsules. Matching placebo 
was provided. The study drug (seladelpar or placebo) was administered orally, once daily for 
the duration of up to 52 weeks.  
 
Exposure to study drug will be summarized by treatment group using descriptive statistics. 
Exposure (days) is defined as the date of the last dose of study drug – date of the first dose of 
study drug + 1. The numbers and percentage of subjects with the following exposure 
categories will be summarized: 


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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 weeks to ≤ 39 weeks (182 – 273 days) 
 > 39 weeks to ≤ 52 weeks (274 – 364 days) 
 > 52 weeks (> 364 days) 
  
The total cumulative dose will be defined as the sum of the actual dose received across all 
study days. Average daily dose is cumulative dose divided by total days on study (from End 
of Study CRF). The average daily dose and cumulative dose will be summarized using 
descriptive statistics over the treatment period, using the formula as below: 
 
Cumulative dose = sum of actual dose received from all segmented periods where for each 
segment, actual dose = actual dosage (mg/day) × [end day using the dosage – start day using 
the dosage + 1]. Titration date and dose interruption date will be used for calculation of the 
end/start day. 
 
Average daily dose in each time period = cumulative dose in the treatment period/ [exposure 
days]. 
 
Exposure to UDCA will also be summarized by treatment group using descriptive statistics. 
7.4. Treatment Modifications 
7.4.1. Dose Up-Titration  
 
During the study participation subjects might go through dose titration (see Section 3.1). For 
subjects who have safety concerns limiting up-titration, the dose adjustment visit (see 
Appendix 11.1) will still occur to evaluate subjects’ status. Subjects will have a dose 
evaluation performed at the Month 6 visit to determine if dose up-titration is necessary.  Dose 
evaluation and up-titration will be done in a double-blind manner. 
The double-blind dose up-titration will occur if the following criteria are met: 
        
No safety concerns limiting up-
titration 
AND One of the following criteria: 
 AP ≥ 1.67 x ULN, 
     OR 
 < 15% decrease in AP comparing to 
baseline value, 
OR 
 Total bilirubin > 1 x ULN 
 
Subjects who meet the criteria received the up-titrated dose at the Dose Adjustment visit. 
Subjects on 5 mg were up-titrated to 10 mg; subjects on 10 mg continued 10 mg; and 
subjects on placebo continued placebo.  


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7.4.2. Dose Down-Titration  
Subjects who meet muscle safety monitoring criteria per protocol Section 10.4.2 are eligible 
for the dose down-titration: subject who initially assigned to 10 mg were down-titrated to 5 
mg; subjects initially assigned to 5 mg, were down-titrated to placebo. Subjects initially 
assigned to placebo stayed on placebo. Dose down-titration was performed in a blinded 
manner. 
A listing of Safety set subjects who experienced dose-down or interruptions due to safety 
monitoring or withdrawal criteria will be provided. Additional details on the dose-down 
titration analysis can be found in Section 8.2. 
8. Efficacy Analysis 
All efficacy analyses will be performed using the mITT analysis set. Statistical comparisons will 
be made using 2-sided tests and the overall significance level will be maintained at 0.05.  
 
8.1. The 1st Efficacy Endpoint 
The 1st efficacy endpoint is the number of responders on the composite endpoint of AP and 
total bilirubin at 6 months. A subject is designated as a responder if all three of the following 
conditions are met: 
 
 AP < 1.67 × ULN at Month 6 
 ≥ 15% decrease in AP at Month 6 
 Total bilirubin ≤ ULN at Month 6 
 
Subjects who discontinue treatment or do not provide an assessment at the specified 
timepoint for defining response will be considered as a non-responder.  
The proportion of responders will be reported with its associated 95% exact 
(Clopper-Pearson) CI for each treatment group.  Cochran-Mantel-Haenszel (CMH) test 
adjusted for both randomization stratification variables (AP level: < 350 U/L and ≥ 350 U/L; 
pruritus NRS: < 4 and ≥ 4) will be used to test the association between the treatment groups 
and p-value will be provided. CMH test will be performed for the comparison of 10 mg vs. 
placebo and 5 mg/10 mg vs. placebo separately. 
 
If assumptions required for the CMH test, including but not limited to, small cell counts or all 
responses within a stratum are the same for both treatment groups, a continuity correction 
may be applied.  In addition, Breslow-Day test will be used to detect whether the 
stratification variable is significant. 
8.2. The 2nd Efficacy Endpoint 
The 2nd efficacy endpoint is the number of responders that achieve normalization of AP at 6 
months and will be conducted using the same approach specified for the 1st efficacy analysis.   


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8.3. The 3rd Efficacy Endpoint 
The 3rd efficacy endpoint consists of the change from baseline in pruritus NRS at 3 and 6 
months and its efficacy analysis is described in conjunction with its safety analysis in Section 
9.8.   
 
9. Safety Analysis 
The purpose of this section is to describe the safety analyses for the study. All summaries of 
safety data will be based on the Safety set which reflects the actual treatment received by each 
subject.  
9.1. Adverse Events 
An AE includes any condition resulting from concomitant illnesses, reactions to concomitant 
medications, or progression of disease states. Pregnancy should be documented as an AE 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. 
 
Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAEs), 
defined as any AE that newly appeared, increased in frequency, or worsened in severity after 
initiation of the study drug and up to 30 days after the last study medication administration. 
For AE reporting purposes, UDCA is not considered as a study drug. For the summaries of 
treatment-related AEs, a treatment-related TEAE is defined as an AE which was considered 
to be related (reported as “possible”, “probably”, or “definite” on the Adverse Events CRF 
page) to any study drug. AEs with a missing relationship will be presented in the summary 
table as a relationship category of “treatment-related”. 
 
Adverse events will be coded by SOC and PT using MedDRA. The dictionary version used 
for reporting the study will be described in the relevant table and listing footnotes. The 
severity of AEs will be graded based on NCI CTCAE, Version 5.0, November 2017.  
 
An overall summary of the number and percentage of subjects with any TEAE, serious 
TEAE, Grade 3 or above TEAE, treatment-related TEAE, treatment-related serious TEAE, 
treatment-related Grade 3 or above TEAE, TEAE leading to permanent withdrawal of study 
drug, treatment-related TEAE leading to permanent withdrawal of study drug, TEAE leading 
to study discontinuation, treatment-related TEAE leading to study discontinuation, TEAEs 
leading to dose interruptions, TEAEs leading to death, and treatment-related TEAE leading 
to death, will be provided by treatment group.  
 
Tables summarizing the incidence of TEAEs in the Safety set will be generated for each of 
the following: 
 
 TEAEs by MedDRA SOC and PT; 
 TEAEs (Grade 3 or higher) by MedDRA SOC, PT and CTCAE grade; 
 Treatment-related TEAEs by SOC and PT; 
 Treatment-related TEAEs (Grade 3 or higher) by SOC, PT and CTCAE grade; 
 TEAEs presented by PT; 


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 Serious TEAEs presented by SOC and PT. 
 
Incidence tables will present TEAEs by SOC, PT, sorted by SOC by decreasing frequency of 
the number (n) and percentage of subjects (%) in the “All Seladelpar” group (then the 10 mg 
group, the 5/10 mg group and placebo group, if applicable). Counting of AEs will be by 
subject, and subjects will be counted only once within each SOC or PT. For tables 
categorized by severity, subjects with multiple events within a particular SOC or preferred 
term will be counted under the category of their most severe event with that SOC or preferred 
term. If the severity is missing for all occurrences of the AE, the subject will be counted only 
once in the ‘Missing’ category for severity. 
For the purpose of inclusion in TEAE tables, incomplete AE onset will be imputed.  
Additional details are provided in Appendix 11.2. 
Listings will be presented including the verbatim term, preferred term, and SOC as well as 
full details of TEAEs and serious AEs for all subjects in the Safety set. 
9.2. Safety Monitoring Criteria and Withdrawal Criteria 
Subjects who meet muscle safety monitoring criteria may be eligible for dose down-titration: 
subjects initially assigned to 10 mg will be down – titrated to 5 mg; subject initially assigned 
to 5 mg will be down-titrated to placebo; and subjects initially assigned to placebo will stay 
on placebo. Subjects with lab abnormalities will be monitored closely and may interrupt 
study drug or discontinue study drug if the criteria are met. A detailed description of the 
safety monitoring and withdrawal criteria including decision rules can be found in Appendix 
11.3.  
 
A listing of safety monitoring criteria met by subjects in Safety set will be provided. 
9.3. Clinical Laboratory Evaluations 
Clinical laboratory values from the central laboratory will be graded according to NCI 
CTCAE version 5.0 for selected tests. Summary tables will be presented for clinical 
laboratory tests with numeric values by treatment group for subjects in the Safety set.  
 
Hematology and Biochemistry will be assessed at all visits including early termination (ET) 
and UNS, if applicable. Hepatitis B and C testing, and urine drug screen will only be 
assessed at the screening visit.  
 
Conventional units and ranges will be used for reporting. Changes from baseline by each 
scheduled post-baseline visit will be presented.  
 
A listing of subjects with lab CTCAE Grade 2 or above will be presented by subject, visit, 
date, and lab tests. 
9.3.1. Hematology 
Erythrocyte count (RBC), hemoglobin, hematocrit, leukocyte count (WBC), WBC 
differentials (%), neutrophils, lymphocytes, eosinophils, monocytes, will be collected at 
Screening, Run-in, Day 1 and every study visit as noted in the schedule of assessments 


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(Appendix 11.1). Platelets, prothrombin time (PT), and international normalized ratio 
(INR) will also be performed locally at those above visits if deemed necessary by the 
investigator. Hematology results and change from baseline will be summarized by 
treatment and visit for the Safety set. 
9.3.2. Biochemistry 
AP, albumin, ALT, AST, GGT, protein, total bilirubin, direct/indirect bilirubin, aldolase, 
sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN)/urea, serum 
creatinine, estimated glomerular filtration rate (eGFR), cystatin C, CK, venous glucose, 
troponin I, LDH, TG, total cholesterol, HDL-C, LDL-C, amylase, lipase, and MELD will 
be collected at Screening, Run-in, Day 1 and every study visit as noted in the schedule of 
assessments (Appendix 11.1).  
 
Biochemistry parameters of special interest (ALT, AST, total bilirubin, creatinine, CK, 
amylase, lipase, and albumin), along with platelets from hematology, will be graded 
according to NCI CTCAE version 5.0. For these biochemistry parameters of special 
interest, a shift table representing the shift from the baseline grade to the most severe 
grade during treatment will be provided by treatment group for each of these laboratory 
tests. 
 
Model for End-Stage Liver Disease (MELD) score will be summarized descriptively.  
MELD  Score is defined in the following. 
MELD(i) score = 10*[0.957 x LN(creatinine mg/dL) + 0. 378 x LN(bilirubin mg/dL) + 
1.120 x LN (INR) + 0.643].  
All laboratory values are rounded to 10th decimal place when calculating the score, and 
MELD(i) is rounded to the nearest whole number. 
All laboratory values less than 1.0 will be set to 1.0 when calculating a candidate’s 
MELD(i) score. Laboratory values for creatinine greater than 4.0mg/dL will be set to 4.0 
mg/dL; sodium values less than 125 mmol/L will be set to 125 and sodium values greater 
than 137 mmol/L will be set to 137. 
If MELD(i) is less than or equal to 11 then MELD = MELD(i). 
If MELD(i) is greater than 11 then MELD = MELD(i) + (1.32 *(137 - (Na)) – 
(0.033*MELD(i)*(137 – Na)) 
 
9.4. Abdominal Ultrasound 
Subjects had two abdominal ultrasound exams at Run-In and at Week 52, or ET (if 
applicable). A listing of abdominal ultrasound results will be provided. 
9.5. Liver Elastography 
Liver elastography exam will be used to evaluate liver fibrosis through a noninvasive 
imaging technique. Subjects had three liver elastography exams at select centers at Run-In, 
Month 6, Month 12 visits, and ET visit (if applicable).  
 
Most liver elastography exams were performed using transient elastography. A table 
summary for transient elastography results and change from baseline will be presented by 


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treatment and visit for the Safety set. A listing of all liver elastography results in company 
with each subject’s cirrhosis status at baseline will be provided by subject. 
9.6. Vital Sign and Weight Measurements 
Vital signs were recorded at Screening, Run-in, Day 1 and every study visit as noted in the 
schedule of assessments (Appendix 11.1). Systolic and diastolic blood pressure, heart rate, 
respiratory rate, temperature and weight will be collected.  
 
Summary tables presenting observed values and changes from baseline will be presented for 
vital sign data, including systolic blood pressure, diastolic blood pressure, temperature, heart 
rate, respiration, weight, and body mass index (body mass index will be derived from weight 
and height) at each applicable post-baseline visit by treatment group for subjects in the Safety 
set. Changes from baseline to each scheduled post-baseline visit will be presented. 
International System of Units will be applied in presenting the results. 
9.7. Electrocardiogram 
A 12-lead electrocardiogram (ECG) were obtained in supine position after at least 5 minutes 
of rest at Screening, Day1, Month 6, Month 12, Follow-up, ET and UNS, if applicable. Heart 
rate (beats/minute), PR interval, RR interval, QRS interval, QT interval, QTcB interval, 
QTcF interval and ECG interpretation will be collected. For ECGs which are abnormal, the 
abnormality should be specified.  
 
For the Safety set, a shift table from baseline to the worst post-baseline record will be 
presented for ECG interpretation results.  
9.8. Pruritus NRS 
The weekly pruritus score will be calculated by recording the daily pruritus score each day 
for seven days and then taking the mean value of the seven days’ daily recorded data. If any 
data are available for a given week, the available NRS results will be used for the calculation 
of the weekly mean.  Only assessments before or within 2 days after the last dose will be 
used. The following analysis windows will be applied to calculate weekly means: 
Month (Week) 
Days used in calculation of weekly mean 
Month 1 (Week 4) 
Days 22 - 28 
Month 3 (Week 12) 
Days 78 - 84 
Month 6 (Week 26) 
Days 176 - 182 
Baseline pruritus NRS is defined as the mean of the all daily recorded scores during run-in. 
Change from baseline in the weekly averaged pruritus NRS for Month 1, 3, and 6 together 
with the baseline pruritus NRS, will be summarized for the Safety set by treatment and visit 
using observed cases. The summary will be repeated in subjects with baseline NRS>=4.  
 
Pruritus NRS change from baseline at 3 and 6 months will be evaluated using an analysis of 
covariance (ANCOVA) model with term for treatment factor and baseline pruritus score as 


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covariate. The LS means for the change by treatment and the associated SE, the LS means for 
the difference between treatment groups and associated 2-sided 95% CIs and 2-sided 
p-values will be derived from the model. The analysis will be repeated in subjects with 
baseline NRS>=4. 
10. Interim Analysis 
No formal or informal interim analysis for determination of efficacy is planned for this study. 
 
11. Modifications from Approved Analysis Plan 
This version 2.0 is an amendment of the approved version 1.0, to include a small degree of 
efficacy analysis.  
 
 


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12. References 
 
Bays HE, Schwartz S, Littlejohn T III, Kerzner B, Krauss RM, Karpf DB, et al. MBX-8025, a 
novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in 
dyslipidemic overweight subjects treated with and without atorvastatin. J Clin Endocrinol Metab. 
2011; 96(9): 2889-97. 
 
Carbone M, Sharp SJ, Flack S, et al. The UK-PBC Risk Scores: Derivation and Validation of a 
Scoring System for Long-Term Prediction of End-Stage Liver Disease in Primary Biliary 
Cholangitis. J of Hepatology 2016; 63 (3): 930-950. 
 
Jones D, Boudes PF, Swain MG, Bowlus CL, Galambos MR, Bacon BR, et al. Seladelpar 
(MBX-8025), A Selective PPAR- δ Agonist, in Subjects 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. 
 
Lai JW, Chen HC, Chou CY, Yen HR, Li TC, Sun MF, et al. Transformation of 5-D itch scale 
and numerical rating scale in chronic hemodialysis subjects. BMC Nephrology. 2017; 18:56. 
 
Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict long-
term histological progression in primary biliary cirrhosis. Am J Gastroenterol 2012; 105:2186-
94. 
 
Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in 
primary biliary cholangitis. N Engl J Med. 2016; 18:375(7):631-643. 
 
Poupon RE, Lindor KD, Caush-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined 
analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. 
Gastroenterology. 1997; 113(3):884-890. 
 
 


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13. Appendices 
 
 
 
 
 
 
 
 
 
 
 


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13.1. 
Schedule of Study Procedures 
Visit 
Screening 
Run-
In 
Randomization 
Month 
1 
Month 
3 
Contact 
11 
Month 
6 
Dose 
Adjust 
Contact 
21 
Month 
9 
Contact 
31 
Month 
1212 
Follow 
Up 
ET 
UNS 
Target Day 
W -4 to -2  
W -2 
Day 1 
W 4 
W 12 
W 19  
W 26 
W 28 
W 32 
W 39 
W 45 
W 52 
4 weeks 
fter W 52 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Evaluation2 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Up-Titration  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE 
 
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 
X 
Vital Signs and 
Weight 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
  X4 
X 
X4 
X4 
 
X 
X4 
 
X4 
 
X 
X 
X 
X4 
ECG 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
Hematology5,6 
X 
X 
X 
X 
X 
 
X  
X 
 
X 
 
X 
X 
X 
X 
Biochemistry5 
X7 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
Exploratory 
Measures5 
X8 
X 
X8 
X 
X 
 
X 
X 
 
X 
 
X8 
X 
X8 
 
Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
Test9 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Back-up Blood 
Sample5 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pruritus NRS10 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
5D-itch10 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
PBC-40 QoL10 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
PGI-S10 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
PGI-C10 
 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Abdominal 
Ultrasound 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Liver Elastography 
(selected sites) 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
Liver Biopsy 11 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
UDCA Dispense 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 


CymaBay Therapeutics, Inc.  
 
                                                                                 Abbreviated Statistical Analysis Plan, Version 2.0 
CB8025-31735 
                                                                                                                                                          Date Issued: 30Apr2020 
 
  
 
 
 20
Study Drug 
Dispense 
 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
Study Drug 
Compliance and 
Accountability 
 
 
 
X 
X 
X13 
X 
X 
X13 
X 
X13 
X 
 
X 
 
UDCA 
Accountability 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Abbreviation: AE=adverse events; AMA=anti-mitrochondrial antibodies; ECG=electrocardiogram; ET=Early Termination; NRS=numerical rating scale; PBC=primary biliary cholangitis; 
PGI-C=patient global impression of change; PGI-S=patient global impression of severity; QoL=quality of life; UDCA=ursodeoxycholic acid; UNS=Unscheduled visit; W=week. 
1. Subject contact will be performed over phone or email communication. 
2. All subjects will be evaluated for dose up-titration in a blinded manner. For subjects who met the up-titration criteria, dose up-titration will requested. Dose up-titration will occur at Dose 
Adjustment visit. 
3. Including PBC history, liver biopsy, liver elastography, alcohol consumption, evidence of other form of liver disease, and HIV. 
4. Symptoms-directed (brief) physical examination. 
5. Blood will be collected after at least an 8-hour overnight fast. If the subject forgets to fast prior to the blood collection, the site will record it in the source document and continue to draw 
labs. 
6. PT and INR will also be performed locally at the Screening visit, Run-In, and during the treatment period if deemed necessary by the Investigator. 
7. If at screening and unexpected abnormal CK level is observed, re-test the subject to confirm eligibility. 
8. Screening visit: only AMA will be performed. Fat-soluble vitamins will be performed at Day 1, Week 52 and ET (if applicable) only. 
9. Serum pregnancy test will be performed in women of childbearing potential only. Additional on-treatment pregnancy testing may be performed at the investigator’s discretion or per local 
regulatory requirements. 
10. Pruritus NRS, 5-D itch, PBC-40, and PGI-S and PGI-C data will be collected via e-diary. Subjects will be asked to complete (1) pruritus NRS: on a daily basis up from Run-In Visit and 
through the first 6 months of treatment. After six months NRS will be collected for seven consecutive days during each month up to the Month 12 visit. (2) 5-D itch will be collected bi-
weekly from Run-In Visit up until the Month 6 visit; after Month 6, 5-D itch will be collected at clinic visit only. 3) PBC-40, PGI-S, PGI-C will be collected during the clinic visits only.  
11. Only subjects willing to undergo liver biopsy. PT and INR must be performed within 2 weeks prior to liver biopsy. If a subject had liver biopsy performed within 1 year from Day 1, 
sites will attempt to collect biopsy material. A follow up liver biopsy will be performed after 3 years (± 3 months) of treatment during long-term study (CB8025-31731). 
12. Subjects will be invited to participate in the long-term study (CB8025-31731). Subjects who consent to participate in CB8025-31731 will have the Month 12 visit combined with the 
Day 1 visit in the CB8025-31731 study and continue dosing. 
13. Only study drug compliance to be evaluated. 


CymaBay Therapeutics, Inc.                                                                                   Abbreviated Statistical Analysis Plan, Version 2.0 
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                              Date Issued: 30Apr2020 
 
  
 
 
 
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13.2. 
Date Imputation Guideline  
If dates are missing or incomplete for an AE (including deaths) or prior/concomitant 
medications, the following rules will apply: 
Incomplete Start Date: 
If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date.  
 
Missing day and month 
 If the year is the same as the year of the first dosing date, then the day and 
month of the first dosing date will be assigned to the missing fields. 
 If the year is prior to the year of first dosing date, then December 31 will 
be assigned to the missing fields. 
 If the year is after the year of first dosing, then January 1 will be assigned 
to the missing fields. 
Missing day only  
 If the month and year are the same as the year and month of first dosing 
date, then the first doing date will be assigned to the missing day. 
 If either the year of the partial date is before the year of the first dosing date 
or the years of the partial date and the first dosing date are the same but the 
month of partial date is before the month of the first dosing date, then the 
last day of the month will be assigned to the missing day. 
 If either the year of the partial date is after the year of the first dosing date 
or the years of the partial date and the first dose date are the same but the 
month of partial date is after the month of the first dosing date, then the 
first day of the month will be assigned to the missing day. 
 If the stop date is not missing, and the imputed start date is after the stop 
date, the start date will be imputed by the stop date, i.e. set to the stop date.  
Missing day, month, and year 
 No imputation is needed; the corresponding AE will be included as TEAE 
provided the end date of the AE is after the first dose date or the end date is 
also missing. 
Incomplete Stop Date: 
If the imputed stop date is before the start date, then the imputed stop date will be 
equal to the start date. 
 


CymaBay Therapeutics, Inc.                                                                                   Abbreviated Statistical Analysis Plan, Version 2.0 
CB8025-31735    
 
                              Date Issued: 30Apr2020 
 
  
 
 
 
22
Missing day and month 
 If the year of the incomplete stop date is the same as the year of the last 
dosing date, then the day and month of the last dosing date will be assigned 
to the missing fields.  
 If the year of the incomplete stop date is prior to the year of the last dosing 
date and prior to the year of the first dosing date, then December 31 will be 
assigned to the missing fields.  
 If the year of the incomplete stop date is prior to the year of the last dosing 
date but is the same as the year of the first dosing date, then the first dosing 
date will be assigned to the missing date.  
 If the year of the incomplete stop date is after the year of the last dosing 
date, then January 1 will be assigned to the missing fields. 
Missing day only  
 If the month and year of the incomplete stop date are the same as the month 
and year of the last dosing date, then the day of the last dosing date will be 
assigned to the missing day.  
 If either the year of the partial date is not equal to the year of the last dosing 
date or the years of the partial date and the last dosing date are the same but 
the month of partial date is not equal to the month of the last dosing date, 
then the last day of the month will be assigned to the missing day.  
 
 


CymaBay Therapeutics, Inc.                                                                                   Abbreviated Statistical Analysis Plan, Version 2.0 
CB8025-31735    
 
                              Date Issued: 30Apr2020 
 
  
 
 
 
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13.3. 
Safety Monitoring Criteria and Withdrawal Criteria 
 
Liver Safety Monitoring 
1. Elevation of ALT/AST 
 
Normal ALT/AST at baseline 
• ALT/AST > 5 × ULN and total bilirubin ≤ 1 × ULN: Interrupt study drug. 
Repeat AST, ALT, total bilirubin, and INR within 3 days and closely follow the 
subject (see Appendix B of the protocol). Study medication can be restarted only if 
a firm competing etiology is identified and liver tests return to baseline. 
• ALT/AST > 5 ULN and total bilirubin > 1 × ULN: 
o Subjects with normal total bilirubin at baseline: Stop study drug. Repeat 
AST, ALT, total bilirubin, and INR within 3 days and closely follow the 
subject (see Appendix B of the protocol). 
o Subjects with elevated total bilirubin at baseline: 
 Total bilirubin > 1.5 × baseline: Stop study drug. Repeat AST, 
ALT, total bilirubin, and INR within 3 days and closely follow the 
subject (see Appendix B of the protocol). 
 Total bilirubin ≤ 1.5 × baseline: Interrupt study drug. Repeat 
AST, ALT, total bilirubin, and INR within 3 days and closely follow 
the subject (see Appendix B of the protocol). Study medication can 
be restarted only if a firm competing etiology is identified and liver 
tests return to baseline. 
Elevated ALT/AST at baseline: 
• ALT/AST > 3 × baseline AND INR ≤ 1.5 × ULN AND no liver-related symptoms 
(e.g., nausea, vomiting, right upper quadrant pain, loss of appetite, dark urine, or 
jaundice): Continue study drug. Repeat AST, ALT, total bilirubin, and INR 
within 3 days. Closely follow the subject (see Appendix B of the protocol). 
• ALT/AST > 3 × baseline AND INR > 1.5 × ULN AND no liver-related symptoms 
(e.g., nausea, vomiting, right upper quadrant pain, loss of appetite, dark urine, or 
jaundice): Interrupt study drug. Repeat AST, ALT, total bilirubin, and INR 
within 3 days and closely follow the subject (see Appendix B of the protocol). 
Study drug can be restarted only if a firm competing etiology is identified and liver 
tests return to baseline. 
 
2. Liver-related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss of 
appetite, dark urine, or jaundice) AND ALT/AST > 3 × baseline (irrespective of 
baseline levels): Interrupt study drug. Repeat AST, ALT, total bilirubin, and INR 
within 3 days. Closely follow the subject (see Appendix B of the protocol). Study 
drug can be restarted only if a firm competing etiology is identified and liver tests 
return to baseline. 
3. Elevation of total bilirubin > 1.5 × baseline, regardless of ALT or AST levels, AND 
indicators of immunological reaction (e.g., rash, eosinophilia > 5%) OR liver-


CymaBay Therapeutics, Inc.                                                                                   Abbreviated Statistical Analysis Plan, Version 2.0 
CB8025-31735    
 
                              Date Issued: 30Apr2020 
 
  
 
 
 
24
related symptoms (e.g., nausea, vomiting, right upper quadrant pain, loss of 
appetite, dark urine, or jaundice): Interrupt study drug. Repeat AST, ALT, total 
bilirubin, and INR within 3 days and closely follow the subject (see Appendix B of 
the protocol). Study drug can be restarted only if a firm competing etiology is 
identified and liver tests return to baseline. 
4. Hepatic decompensation (e.g., decompensated cirrhosis with gastro-esophageal 
variceal bleeding, ascites, or hepatic encephalopathy) during the study: Stop study 
drug and closely follow the subject (see Appendix B of the protocol). 
5. Close monitoring of a subject is not possible (see Appendix B of the protocol): 
Stop study drug. 
 
Muscle Safety Monitoring 
1. CK > 5 × ULN with musculoskeletal symptoms: Stop study drug. Repeat the test 
within 3 days. Follow the subject weekly until resolution or stabilization. 
2. CK > 5 × ULN without musculoskeletal symptoms: repeat the test within 3 days. If 
on repeat test CK is > 2.5 × ULN, stop study drug. Follow the subject weekly until 
the event resolution or stabilization. 
3. CK > 2.5 × ULN and ≤ 5 × ULN regardless to musculoskeletal symptoms: 
repeat the test within 3 days. If the test is confirmed, study drug will be continued 
at a decreased dose.  For subjects on 5 mg, the study drug will be switched to 
placebo. 
 
Serum Creatinine Monitoring 
1. Serum creatinine > 2.0 × ULN: Stop study drug. The subject should be monitored 
weekly until resolution or stabilization. 
2. Serum Creatinine > 1.5 × ULN and ≤ 2.0 × ULN: Interrupt study drug. Repeat 
the test within 3 days. If the test is confirmed and no alternative etiology is 
identified, stop study drug. If alternative etiology is identified, study drug may be 
restarted after serum creatinine returns to baseline values. The subject should be 
monitored weekly until event resolution. 
 
Pancreatic Safety Monitoring 
1. Amylase > 3 × ULN and/or lipase > 3 × ULN without clinical symptoms of acute 
pancreatitis: repeat the test within 3 days. If the test confirms suspicion, interrupt 
study drug. Abdominal imaging is to be performed to exclude an alternative cause 
for the event. Study drug might be restarted only if a firm competing etiology of 
acute pancreatitis is identified. 
2. Amylase > 3 × ULN and/or lipase > 3 × ULN with clinical symptoms of acute 
pancreatitis: interrupt study drug. Repeat the test within 3 days. Abdominal 
imaging is to be performed to exclude an alternative cause for the event. Study drug 
might be restarted only if a firm competing etiology of acute pancreatitis is 
identified.