Clinical trial NCT03155932
Conditions: Primary Biliary Cholangitis
Sponsor: Arena Pharmaceuticals
Start date: 2017-12-29; Completion date: 2019-01-31
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this open-label, pilot, proof of concept study is to evaluate the safety, tolerability, and efficacy of oral etrasimod (APD334) in participants with primary biliary cholangitis (PBC).

Detailed description:

Arms: arm 1: APD334 active treatment for 24 weeks.
Interventions: intervention 1: APD334
Intervention descriptions: intervention 1: APD334 active treatment for 24 weeks.

Protocol documents:
Prot_SAP_001.pdf: 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
2 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ...........................................................................................................2 
LIST OF IN-TEXT TABLES ....................................................................................................5 
LIST OF IN-TEXT FIGURES...................................................................................................5 
SYNOPSIS .................................................................................................................................6 
LIST OF ABBREVIATIONS ..................................................................................................20 
1. 
BACKGROUND ............................................................................................................23 
1.1. 
Background on Primary Biliary Cholangitis (PBC) ...........................................23 
1.1.1 
Treatment Options ............................................................................23 
1.2. 
Background on Etrasimod ..................................................................................24 
1.3. 
Rationale for Treatment, Study Design and Dose Selection ..............................28 
1.3.1. 
Rationale for Treatment ...................................................................28 
1.3.2. 
Rationale for Study Design ..............................................................29 
1.3.3. 
Rationale for Dose Selection ............................................................29 
1.4. 
Ethics and Regulatory Considerations ...............................................................30 
2. 
STUDY OBJECTIVES ..................................................................................................32 
2.1. 
Primary Objectives .............................................................................................32 
2.2. 
Secondary Objectives .........................................................................................32 
2.3. 
Exploratory Objectives .......................................................................................32 
3. 
INVESTIGATIONAL PLAN ........................................................................................33 
3.1. 
Overall Study Design and Plan ..........................................................................33 
3.2. 
Study Duration ...................................................................................................34 
3.3. 
End of Study .......................................................................................................34 
4. 
STUDY POPULATION ................................................................................................38 
4.1. 
Inclusion and Exclusion Criteria ........................................................................38 
4.1.1. 
Inclusion Criteria ..............................................................................38 
4.1.2. 
Exclusion Criteria .............................................................................40 
5. 
STUDY TREATMENT(S) ............................................................................................43 
5.1. 
Study Drug .........................................................................................................43 
5.2. 
Dosage, Administration and Accountability ......................................................43 
5.2.1. 
Dose-stopping Rules ........................................................................44 
5.3. 
Investigational Product Retention at Study Site .................................................44 
5.4. 
Study Restrictions ..............................................................................................44 
5.5. 
Safety and Dose Escalation Review Committee ................................................44 
6. 
STUDY PROCEDURES ................................................................................................45 
6.1. 
Informed Consent ...............................................................................................45 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
3 
6.2. 
Screening Failures ..............................................................................................45 
6.3. 
Medical History ..................................................................................................45 
6.4. 
Physical, 
 and Neurological Examinations ............................45 
6.4.1. 
Physical Examination .......................................................................45 
6.4.3. 
Neurological Examination ................................................................45 
6.5. 
Vital Signs ..........................................................................................................46 
6.6. 
Electrocardiography ...........................................................................................46 
6.6.1. 
ECG Equipment ...............................................................................46 
6.6.2. 
ECG Acquisition ..............................................................................46 
6.6.3. 
ECG Assessment ..............................................................................46 
6.9. 
Clinical Laboratory Tests ...................................................................................47 
6.9.1. 
List of Laboratory Parameters ..........................................................48 
6.9.3. 
Urinalysis .........................................................................................49 
6.9.4. 
Sample Collection ............................................................................50 
6.9.5. 
Blood Volume ..................................................................................50 
6.11.1. 
Patient 5-D Pruritus Scale ................................................................50 
6.11.2. 
Patient PBC-40 Quality of Life Scale ..............................................50 
6.12. Hematologic Assessments ..................................................................................50 
6.12.1. 
Complete Blood Count .....................................................................50 
6.13. Pharmacokinetic Assessments ............................................................................50 
6.14. C4 and 
..............................................................................................51 
6.15. Adverse Events Assessments .............................................................................51 
6.15.1. 
Adverse Event Reporting .................................................................51 
6.15.2. 
Serious Adverse Events and Expedited Reporting of Adverse 
Events ...............................................................................................52 
6.15.3. 
Assessment of Adverse Event Severity ............................................54 
6.15.4. 
Assessment of Adverse Event Relationship to Study 
Medication ........................................................................................54 
6.15.5. 
Assessment of Adverse Event Outcome ..........................................55 
6.15.6. 
Action Taken for Adverse Event ......................................................55 
6.15.7. 
Action Taken for Study Drug ...........................................................55 
6.15.8. 
Follow-up of Adverse Events Present at Last Scheduled 
Study Visit ........................................................................................55 
6.16. Drug-Induced Liver Injury (DILI) Surveillance ................................................55 
6.16.1. 
Close Observation for Possible DILI ...............................................56 
6.16.2. 
Study Drug Discontinuation for Suspected DILI .............................56 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
4 
6.17. Concomitant Medications and Procedures .........................................................57 
6.17.1. 
Permitted Medications for the Treatment of PBC ............................57 
6.17.2. 
Excluded Medications ......................................................................57 
6.18. Removal of Patients from the Trial or Study Drug ............................................58 
6.18.1. 
Handling of Withdrawals .................................................................58 
6.18.2. 
Replacements ...................................................................................58 
6.19. Study and Site Discontinuation ..........................................................................59 
7. 
Visit Procedures .............................................................................................................60 
7.1. 
Screening Period (5 to 8 weeks) .........................................................................60 
7.1.1. 
Screening Visit 1 ..............................................................................60 
7.1.2. 
Screening Visit 2 ..............................................................................61 
7.2. 
Treatment Period (24 weeks) .............................................................................62 
7.3. 
Follow-Up Period ...............................................................................................67 
8. 
DATA MANAGEMENT ...............................................................................................68 
8.1. 
Data Collection ...................................................................................................68 
8.2. 
Data Coding ........................................................................................................68 
8.2.1. 
Adverse Events .................................................................................68 
8.2.2. 
Concomitant Medications and Non-Drug Treatments .....................68 
8.2.3. 
Medical History ................................................................................68 
9. 
PLANNED STATISTICAL METHODS .......................................................................69 
9.1. 
Hypotheses .........................................................................................................69 
9.2. 
Sample Size and Power Calculations .................................................................69 
9.3. 
Analysis Populations ..........................................................................................69 
9.4. 
Demographics and Baseline Characteristics ......................................................69 
9.5. 
Efficacy Endpoints .............................................................................................69 
9.6. 
Statistical Methods .............................................................................................70 
9.6.1. 
Efficacy Analysis .............................................................................70 
9.6.2. 
Subgroup Analyses ...........................................................................70 
9.6.3. 
Pharmacokinetic Analysis ................................................................70 
9.6.4. 
Interim Analysis ...............................................................................70 
9.7. 
Safety Analysis ...................................................................................................70 
9.7.1. 
Adverse Events .................................................................................70 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
5 
9.7.2. 
Physical Examinations .....................................................................71 
9.7.3. 
Concomitant Medication ..................................................................71 
9.7.4. 
Vital Signs ........................................................................................71 
9.7.6. 
Clinical Laboratory Values ..............................................................71 
9.7.7. 
Safety ECG (12-lead ECG) ..............................................................71 
10. 
REGULATORY REQUIREMENTS .............................................................................72 
10.1. Pre-Study Documentation ..................................................................................72 
10.2. Investigator Obligations .....................................................................................72 
10.3. Patient Confidentiality ........................................................................................72 
10.4. Informed Consent ...............................................................................................72 
10.5. Independent Ethics Committee (IEC) Human Research Ethics 
Committee (HREC) ............................................................................................73 
11. 
PROTOCOL MANAGEMENT AND ADMINISTRATIVE 
CONSIDERATIONS .....................................................................................................74 
11.1. Study Documentation .........................................................................................74 
11.2. Protocol Interpretation and Compliance ............................................................74 
11.3. Study Monitoring ...............................................................................................74 
12. 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ..................................................75 
13. 
REFERENCES ...............................................................................................................77 
SPONSOR PROTOCOL SIGNATURE PAGE ......................................................................80 
 
Appendix 1 
Summary of Changes by Amendment .................................................81 
 
LIST OF IN-TEXT TABLES 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Schematic of APD334-010 Study Design ............................................33 
 
 




Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
7 
Background 
Etrasimod is an orally available, selective, sphingosine 
1-phosphate 1 (S1P1) receptor modulator. S1P is a signaling 
sphingolipid required by lymphocytes to exit the lymphoid tissue 
and enter the bloodstream via a chemotactic gradient. The S1P1 
receptor is a physiological mediator that has been shown to 
regulate lymphocyte recirculation between lymphoid tissue and 
blood. Binding and internalization of the S1P1 receptor may 
result in lymphocyte retention within lymphoid tissue, with 
subsequent reduction in peripheral lymphocyte count and 
lymphocyte availability for recruitment to sites of inflammation. 
S1P1 receptor surface expression is required for S1P gradient-
mediated lymphocyte migration out of lymphoid tissue into the 
circulation1. 
Modulators of the S1P1 receptor, such as etrasimod, block 
lymphocyte migration out of the lymph tissue through 
internalization of the receptor, resulting in a sequestration of 
lymphocytes 1. Recent clinical development of S1P1 receptor 
modulators has demonstrated their effect on resulting 
lymphocyte sequestration, and their potential for treating 
multiple autoimmune and chronic inflammatory diseases. 
Rationale for use of etrasimod in treatment of PBC 
Histologically, PBC is characterized by florid bile duct lesions 
with damage to biliary epithelial cells, dense portal 
inflammatory infiltrate and progressive loss of small intrahepatic 
bile ducts. T cells are important players in the pathogenesis of 
PBC. The disease results from a chronic inflammatory process in 
which T cells attack the small bile duct epithelial cells. These 
epithelial cells eventually disappear, causing cholestasis and 
further progression of PBC. The T cells seem to be of both 
CD4+ and CD8+ origin, as shown by immunohistochemical 
staining in portal and periportal areas 2. The trigger of this 
autoimmune disease is unknown, but genome-wide association 
studies have suggested the importance of certain HLA variants 
and other immune-related genes, such as components of the IL-
12 signaling cascade. Furthermore, more than 95% of patients 
also develop a humoral autoimmune response to mitochondrial 
proteins (i.e., antimitochondrial antibodies, AMA) 2,3. 
The reduced peripheral lymphocyte availability seen with the 
S1P1 modulator etrasimod is expected to decrease both CD4+ 
and CD8+ T cell recruitment to sites of inflammation, such as 
around the bile ducts. In addition to S1P1 modulation, the 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
8 
activation of S1P4 and S1P5 receptors may confer additional 
immunomodulatory effects that could translate into efficacy for 
the treatment of PBC. NK cells appear to be involved in the 
pathogenesis of PBC: their levels are increased in blood and 
liver of patients with strong cytotoxic activity against biliary 
epithelial cells4, and resting as well as activated NK cells express 
S1P1, S1P4 and S1P5 receptors. The S1P5 receptor has been 
reported to be involved in chemotaxis of NK cells 
5. Other cells that may be potentially blocked by etrasimod include 
neutrophils, which were recently observed to be S1P4 dependent 6. 
Compared with other S1P1 receptor modulators such as 
fingolimod, etrasimod has shown overall more selective activation 
of S1P1, S1P4 and S1P5 receptors7 and may thus represent a novel 
and suitable approach for treating patients with PBC. 
Objectives: 
Primary objective: 
Safety 
• To assess the safety and tolerability of etrasimod in 
patients with PBC. 
Secondary objectives: 
Efficacy and PK 
• To evaluate the efficacy (i.e., changes in alkaline 
phosphatase [ALP] levels from baseline) of etrasimod 
in patients with PBC. 
• To assess single dose and steady-state PK of etrasimod 
in patients with PBC. 
Exploratory objectives: 
• To assess the pharmacodynamic (PD) response 
(lymphocyte counts and subsets thereof). 
• To assess serum high sensitivity C-reactive protein 
(hsCRP), alanine transaminase (ALT), aspartate 
transaminase (AST), gamma-glutamyl transferase (GGT), 
AMA, 
 total IgG and IgM, 
 and 7-alpha 
hydroxy 4-cholesten-3- one (C4). 
• To assess quality of life (QoL) and incidence of pruritus 
and fatigue. 
• 
 
• To assess changes in Schirmer 
 tests in patients 
with abnormal results at screening. 
Study Design 
This pilot, open-label, single arm, proof of concept, multicenter 
study will evaluate orally administered etrasimod for 24 
consecutive weeks in PBC patients who had an inadequate 
response to ursodeoxycholic acid (UDCA). 




Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
10 
study medication is planned 1 day before the end of the 
treatment visit at Week 24. 
Follow-up Visit/End of Study Visit: 
Visit Week 26, 2 weeks after end of treatment: Patients will 
return to the study site for the final visit, and final procedures 
will be performed per Schedule of Procedures and Visits (Table 
1). 
Premature Discontinuation: All procedures planned for Weeks 
24 and 26 visits should be performed for all patients who 
discontinue the study prematurely. 
Dose-stopping 
Rules: 
Any of the following findings in a patient during treatment will 
lead to a stop in etrasimod dosing in the affected patient: 
1. Certain ECG changes (see details in text below), or 
2. Clinical evidence of drug-induced liver injury (DILI; as 
described in 6.15) 
As described in the study plan above, at the discretion of the PI, 
the dose of etrasimod may be adjusted from 2 mg q.d. back to 1 
mg q.d. if deemed necessary. If the patient is on 1 mg, the PI 
may discontinue etrasimod treatment if deemed necessary based 
on the dose-stopping rules. 
Close Observation for Possible DILI: 
It is critical to initiate close observation immediately upon 
detection and confirmation of early signals of possible DILI, and 
not to wait until the next scheduled visit or monitoring interval. 
Close observation is mandatory for any study subject who meets 
one or more of the following “possible DILI” laboratory criteria: 
• ALT or AST that is <ULN at baseline, followed by 
ALT or AST increase to >3 × ULN 
• ALT or AST that is >ULN at baseline, followed by 
ALT or AST increase to >2 × baseline 
• ALP >2 × baseline 
• Total bilirubin >1.5 × ULN 
Close observation includes: 
• Repeating liver enzyme and serum bilirubin tests 
within 48-72 hours. Then, repeating liver enzyme and 
serum bilirubin tests two or three times weekly. 
Frequency of retesting can decrease to once a week or 
less if abnormalities resolve, abnormalities stabilize, or 
the study drug has been discontinued and the subject is 
asymptomatic.  
• Obtaining a more detailed history of symptoms and 
prior or concurrent diseases.  




Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
12 
Study Site(s): 
Multicenter. 
Study Population: 
Patients with confirmed PBC diagnosis who fulfill the eligibility 
criteria. 
Inclusion Criteria: 
Inclusion and exclusion criteria that refer to an assessment being 
performed “at screening” are referring to Screening Visit 1 unless 
specified otherwise. 
1. Males or females aged 18 to 80 years (inclusive) at the time of 
screening, with confirmed PBC diagnosis based upon at least 2 
of 3 criteria: 
• AMA titer >1:40 on immunofluorescence or M2 positive by 
enzyme-linked immunosorbent assay (ELISA) or positive 
PBC-specific antinuclear antibodies (anti-GP210 and/or 
anti-SP100) 
• ALP >1.5 × ULN for at least 6 months 
• Liver biopsy findings consistent with PBC 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
13 
2. Use of UDCA for at least 6 months prior to screening (stable 
dose for at least 3 months immediately prior to screening) 
4. Patients must have the following laboratory parameters at 
screening  
• ALP >1.5 × ULN but <10 × ULN (at all screening visits) 
• ALT and AST <5 × ULN (at all screening visits) 
• Total bilirubin <ULN (at all screening visits) 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
14 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
15 
8. AST, ALT, ALP, and total bilirubin must have 2 values at least 
4 weeks apart that are within 20% of each other. 
Exclusion Criteria 
1. Chronic liver disease of a non-PBC etiology. However, PBC 
patients accompanied with primary Sjögren’s syndrome (pSS) 
are eligible to be enrolled. 
2. History or evidence of clinically significant hepatic 
decompensation: 
3. Medical conditions that may cause non-hepatic increases in 
ALP (e.g., Paget’s disease) 
7. Infection with hepatitis C virus anytime in the past; confirmed 
active infection with hepatitis B virus at screening. 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
16 
13. Treatment with obeticholic acid (OCA) or fibrates (including 
bezafibrate) within 30 days prior to Day 1. 
14. Other immunosuppressive, immunomodulating or 
antineoplastic agents not listed in Permitted Medications section 
(6.17.1) within 30 days prior to Day 1 (or not meeting the 
stability time period for concomitant medications indicated as 
permitted). 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
17 
Duration of the 
Study (per 
Patient): 
Up to 34 weeks total: with 5 to 8 weeks for screening, followed 
by a 24-week treatment period (including a 12-week 1 mg 
treatment period followed by a 12-week 2 mg treatment period if 






Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
20 
 
LIST OF ABBREVIATIONS 
 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
AMA 
anti-mitochondrial antibodies 
ANA 
anti-nuclear antibodies 
AST 
aspartate aminotransferase (SGOT) 
AV 
atrio-ventricular 
bpm 
beats per minute 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
CRP 
C-reactive protein 
CRO 
contract research organization 
D 
Day 
DILI 
drug-induced liver injury 
ECG 
Electrocardiogram 
ED50 
half maximal dose 
 
 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
  
  
FU 
follow up 
 
 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
 
 
HCV 
hepatitis C virus 
HREC 
human research ethics committee (AUS) 
 
 
HR 
heart rate 
ICH 
International Conference on Harmonization 
ICF 
informed consent form 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
21 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
INR 
international normalized ratio 
 
 
 
 
kg 
Kilogram 
LDH 
lactate dehydrogenase 
L 
Liter 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
 
 
NK 
natural killer 
NOAEL 
no observed adverse effect level 
 
  
OTC 
over-the-counter 
PBC 
peripheral biliary cholangitis 
PBL 
peripheral blood lymphocyte 
PD 
Pharmacodynamics 
PFT 
pulmonary function test 
PGA 
Physicians Global Assessments 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
p.o. 
per os (orally) 
 
 
pSS 
primary Sjögren’s syndrome 
PVG 
Pharmacovigilance 
q.d. 
quaque die (once daily) 
SAP 
statistical analysis plan 
S1P 
sphingosine 1-phosphate 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
sec 
Second 
SOP(s) 
standard operating procedure(s) 
t1/2 
elimination half-life 
tmax 
the median time to reach maximum plasma concentration 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
22 
  
  
 
 
UDCA 
ursodeoxycholic acid 
ULN 
upper limit of normal 
VS 
vital signs 
 
 
WBC 
white blood cell 
WHO 
World Health Organization 
WHODRUG 
World Health Organization Drug Dictionary 
 
 
 
 
 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
23 
1. 
BACKGROUND 
1.1. 
Background on Primary Biliary Cholangitis (PBC) 
PBC is a rare, autoimmune, chronic, cholestatic liver disease, and is the most common 
cholangiopathy observed in adults 3. It is characterized by a progressive bile duct injury from 
portal and periportal inflammation causing cholestasis, fibrosis, and eventually leading to 
liver cirrhosis. Although the precise cause of disease is unknown, there is evidence of liver 
immune infiltration and systemic aberrant immunity in PBC patients 2. PBC affects 
individuals of all ethnic origins and accounts for 0.6%-2.0% of deaths from cirrhosis 
worldwide. Incidence rates for Europe, North America, and Australia range from 0.33 to 5.8 
per 100,000 inhabitants and prevalence is 1.91 to 40.2 per 100,000 inhabitants, respectively. 
PBC disproportionately affects women (10:1 women to men ratio) 8,9. 
The pathogenesis of PBC includes both adaptive and innate immune responses and evidence 
indicates that environmental, infectious, and genetic factors are involved 3. Approximately 7-
34% of patients with PBC have overlapping Sjögren’s syndrome10 and approximately 10% of 
patients with PBC have autoimmune hepatitis as well 11. Chronic inflammation of the small 
interlobular bile ducts leads to cholangitis, ductopenia, and ductal proliferation 3. These bile 
ductal injuries gradually progress to cholestasis, biliary fibrosis, and cirrhosis, which will 
eventually lead to liver failure if untreated. The risk of hepatocellular, colorectal and 
hepatobiliary cancers is also increased in patients with advanced stage PBC 12. 
The diagnosis of PBC is based on a sustained elevation of serum markers of cholestasis (i.e., 
ALP), and the presence of serum AMA directed against the E2 subunit of the mitochondrial 
pyruvate dehydrogenase complex 10. Other autoantibodies, such as ANA, are often identiﬁed 
in patients with PBC. The ANAs anti-Sp100 and anti-gp210 have a high speciﬁcity for PBC 
and could be helpful when AMA is negative 10. 
Historically, PBC is characterized by florid bile duct lesions with injuries to biliary epithelial 
cells, an extensive portal inflammatory infiltrate, and progressive loss of small intrahepatic 
bile ducts 3. The most frequent symptoms in PBC patients are fatigue and pruritus, occurring 
in nearly 80% and 20-70% of patients, respectively 10. However, at the time of diagnosis, 
most patients are asymptomatic and are identified through the presence of abnormal liver 
enzymes during routine physical exams. Patients with PBC have a shorter survival than 
healthy subjects. In one follow-up study, the 10-year survival of PBC patients was 59%, 
compared with an expected 81% in the age- and sex-matched healthy population13. Patients 
with advanced PBC have a median survival of only 1.4-4.1 years 3. 
1.1.1 
Treatment Options 
There is no cure for PBC. Liver transplantation is the only potentially curative treatment 
option for PBC patients. Furthermore, post-transplant recurrence of PBC is reported up to 
34% 10,14. The only pharmacological agents approved for the treatment of PBC are 
ursodeoxycholic acid (UDCA, 7β-epimer of the primary human bile acid chenodeoxycholic 
acid [CDCA], approved in the US in 1997) and obeticholic acid (OCA, approved in the US in 
2016). Reports suggest that 10-20 mg/kg/day UDCA delays the need for transplantation or 
prolongs survival without liver transplantation; however, an estimated 40% of PBC patients 
are incomplete biochemical responders (reduction in ALP) to long-term UDCA monotherapy 
10,15. Reduction of ALP with UDCA has been recognized as a surrogate marker of slower 
disease progression and improved transplant-free overall survival 15. PBC patients who do not 




Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
25 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
26 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
27 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
28 
1.3. 
Rationale for Treatment, Study Design and Dose Selection 
1.3.1. 
Rationale for Treatment 
S1P1 receptor signaling on certain lymphocyte subpopulations allows their exit from lymph 
nodes along a S1P gradient. Functional antagonism, through agonism and subsequent 
internalization, of these S1P1 receptors results in retention of certain lymphocyte 
subpopulations in lymph nodes and prevents their egress to the bloodstream. It is through this 
mechanism that etrasimod may potentially reduce inflammation and autoimmune response in 
PBC. Lymphocyte lowering has been correlated with clinical efficacy for S1P functional 
antagonists in MS (fingolimod, ponesimod, siponimod, ozanimod)25, psoriasis (ponesimod)26 
and ulcerative colitis (ozanimod) 27. This same mechanism may also be useful in treating a 
variety of different inflammatory and autoimmune diseases. The availability of lymphocyte 
trafficking agents such as etrasimod would offer PBC patients an anti-
inflammatory/autoimmune response, oral, and potentially more convenient treatment. 
T cells are important players in the pathogenesis of PBC. The disease results from a chronic 
inflammatory process in which T cells attack the small bile duct epithelial cells. These 
epithelial cells eventually disappear, causing cholestasis and further progression of PBC. The 
T cells seem to be of both CD4+ and CD8+ origin, as shown by immunohistochemical 
staining in portal and periportal areas 2. The trigger of this autoimmune disease is unknown, 
but genome-wide association studies have suggested the importance of certain HLA variants 
and other immune-related genes, such as components of the IL-12 signaling cascade. 
Furthermore, more than 95% of patients also develop a humoral autoimmune response to 
mitochondrial proteins 2,3. 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
29 
The reduced peripheral lymphocyte availability seen with the S1P1 modulator etrasimod is 
expected to decrease T cell recruitment to sites of inflammation, such as around the bile 
ducts. In addition to S1P1 modulation, the receptor activity with S1P4 and S1P5 may confer 
additional immunomodulatory effects that could translate into efficacy for the treatment of 
PBC. NK cells appear to be involved in the pathogenesis of PBC: their levels increased in 
blood and liver of patients with strong cytotoxic activity against biliary epithelial cells 4, and 
resting as well as activated NK cells express S1P1, S1P4 and S1P5 receptors. The S1P5 
receptor has been reported to be involved in chemotaxis of NK cells5. Other cells that may 
possibly be blocked by etrasimod include neutrophils, which are S1P4 dependent 6. 
In addition to immune cells, S1P receptors are expressed in hepatocytes, of which S1P1 and 
S1P2 appear most dominant. Inhibition of S1P1, but not S1P2 receptors, reduced bile salt 
(glycochenodeoxycholic acid)-induced apoptosis in rat hepatocytes, indicating potential 
therapeutic benefits in PBC 28. Furthermore, it has been reported that S1P1 may be involved in 
processes promoting liver fibrosis, suggesting that blockade of the S1P1 pathway may help 
attenuate liver fibrosis 29. 
Together, this evidence suggests that immune cells, in addition to hepatocytes, play a role in 
PBC and that S1P1, and possibly S1P4 and S1P5, receptor modulation may represent a novel 
therapeutic approach in PBC. 
The aim of the proposed clinical study is to evaluate the role of S1P receptor modulation in 
the setting of PBC. Next generation S1P receptor modulators with improved side effect 
profiles, such as etrasimod, may represent a novel therapy for PBC patients. 
1.3.2. 
Rationale for Study Design 
This is an open-label, multicenter, dose escalation study to evaluate the safety, tolerability, 
PK and efficacy of two oral etrasimod daily doses (1 mg and 2 mg) for a total of 24 weeks 
(12 weeks at each dose level) in up to 20 patients with early stage PBC. In each patient, 1 mg 
daily will be evaluated initially for 12 weeks followed by a potential dose escalation to 2 mg 
daily based on each individual patients’ safety and PK data. The open- label nature of the 
study allows for each subject to be evaluated closely for dose escalation based on their safety 
and PK data. The pharmacological activity and efficacy of etrasimod will also be evaluated. 
Clinically, PBC is monitored by assessing biochemical markers primarily, ALP levels, and 
other liver enzymes including gamma- glutamyltransferase (GGT) and bilirubin. Given the 
nature of these measures it is reasonable to plan an initial evaluation of clinical response 
without inclusion of placebo controls in this study. 
A 3-month (12-week) treatment period for each dose level was chosen to assess the safety, 
efficacy and pharmacodynamic activity in patients. This timeframe is judged appropriate to 
establish an initial safety and clinical effect of etrasimod in PBC patients. Although this study 
is only including patients with early stage of PBC disease, it is possible that clearance of 
estrasimod may be decreased and systemic exposure increased. For this reason, the study was 
designed to assess the PK of the low dose (1 mg) after the initial dose on Day 1 and on Week 
2 (i.e. steady-state) in each patient prior to allowing a dose escalation to 2 mg at Week 12. 
1.3.3. 
Rationale for Dose Selection 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
30 
1.4. 
Ethics and Regulatory Considerations 
The study will be conducted in compliance with the International Conference on 
Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), applicable local 
regulatory requirements, the study protocol, and where applicable, sponsor and/or Contract 
Research Organization (CRO) Standard Operating Procedures (SOPs). The protocol and 
informed consent will be submitted for consideration by the appropriate IEC and written 
approval from the Chair or designated deputy of the IEC is required before clinical activities 
of the study can commence. 
Any changes to the protocol will be made by means of a formal written protocol amendment. 
All amendments will require IEC approval before implementation except when changes to 
the protocol are required immediately to eliminate hazards to the volunteer/patient or when 
the changes involve only logistical or administrative aspects of the trial (for example, change 
of medical monitor, change in telephone number, etc.). 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
31 
 
 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
32 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
Safety 
• To assess the safety and tolerability of etrasimod in patients with PBC. 
2.2. 
Secondary Objectives 
Efficacy and PK 
• To evaluate the efficacy (i.e., changes in ALP levels from baseline) of etrasimod 
in patients with PBC. 
• To assess single dose and steady-state PK of etrasimod in patients with PBC. 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To assess the PD response (lymphocyte counts and subsets thereof). 
• To assess serum hsCRP, ALT, AST, GGT, AMA, 
 C4, 
, total 
IgG and IgM. 
• To assess QoL and incidence of pruritus and fatigue. 
• 
. 
• To assess changes in Schirmer 
 tests in patients with abnormal results 
at screening. 
 
 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
 
Confidential 
33 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This is an open label, single arm, multi-center clinical study to assess the safety and 
tolerability, PK and efficacy of etrasimod in patients with PBC. The trial will include adult 
patients, 18-80 years of age, with a confirmed PBC diagnosis, and who had an inadequate 
response to UDCA. 
The screening period will last 5 to 8 weeks and will be followed by a 24-week treatment 
period. All patients will receive 1 mg etrasimod for 12 weeks followed by a potential dose 
increase to 2 mg etrasimod for 12 weeks. Those patients who do not dose escalate will remain 
on 1 mg etrasimod for the duration of the study through Week 24 (Figure 1). During the 
treatment period, patients will need to take 1 tablet of study medication (p.o. q.d.). The last 
dose is planned to be taken one day before the end of the treatment period (during Week 24). 
A follow-up visit will take place 2 weeks after the end of treatment. Please refer to the 
Schedule of Procedures and Visits (Table 1) for the detailed plan. 
Figure 1. 
Schematic of APD334-010 Study Design 
a  Screening Visit 1 is to occur between Week -8 and Week -5. Screening Visit 2 is to occur at least 4 weeks 
from Screening Visit 1. For patients with ALP, ALT, AST, or total bilirubin values from Screening Visits 1 
and 2 that are not within 20% of each other (see Inclusion Criterion 9), an unscheduled visit within the 
screening period may be conducted to repeat these assessments. 
The study will consist of the following periods:  
Screening Period (5 to 8 weeks before baseline visit): 
Each patient will be asked to visit the study site at least 2 times for screening assessments 
within the 8 weeks prior to the planned start of the treatment (Day 1). Screening Visit 1 is to 
occur between Week -8 and Week -5. Screening Visit 2 is to occur at least 4 weeks from 
Screening Visit 1. For patients with ALP, ALT, AST, or total bilirubin values from Screening 
Visits 1 and 2 that are not within 20% of each other (see Inclusion Criterion 9), an 
unscheduled visit within the screening period may be conducted to repeat these assessments.  
All patients must be consented before any study specific procedure is performed and written 
informed consent must be obtained. Patients will then undergo screening procedures to 
determine eligibility. 
Dose Titrate to 2 mg
Open-Label Treatment Period
Follow-Up
Period
Screening
Perioda
Remain on 1 mg
D-1
Wk 4
Wk 8
Wk 16
Wk 20
Wk 12
Wk 24
Wk -8
Wk 2
Wk 14
D1
Wk
1 mg
- or -
N = up to 20. Dose escalation at Wk 12 will be determined on an individual basis using available PK and safety data  




Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
             27 June 2018 
Confidential 
35 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
             27 June 2018 
Confidential 
36 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
             27 June 2018 
Confidential 
37 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
38 
4. 
STUDY POPULATION 
The study population will consist of up to twenty (20) PBC patients without cirrhosis who fulfill 
eligibility (inclusion & exclusion) criteria. 
4.1. 
Inclusion and Exclusion Criteria 
Each patient must meet the inclusion and exclusion criteria described below to be enrolled in the 
study. Inclusion and exclusion criteria that refer to an assessment being performed “at screening” 
are referring to Screening Visit 1 unless specified otherwise. 
4.1.1. 
Inclusion Criteria 
1. Males or females aged 18 to 80 years (inclusive) at the time of screening, with 
confirmed PBC diagnosis based upon at least 2 of 3 criteria: 
• AMA titer >1:40 on immunofluorescence or M2 positive by enzyme-linked 
immunosorbent assay (ELISA) or positive PBC-specific antinuclear antibodies (anti-
GP210 and/or anti-SP100) 
• ALP >1.5 × ULN for at least 6 months 
• Liver biopsy findings consistent with PBC 
2. Use of UDCA for at least 6 months prior to screening (stable dose for at least 3 months 
immediately prior to screening) 
4. Patients must have the following laboratory parameters at screening 
• ALP >1.5 × ULN but <10 × ULN (at all screening visits) 
• ALT and AST <5 × ULN (at all screening visits) 
• Total bilirubin <ULN (at all screening visits) 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
39 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
40 
8. AST, ALT, ALP, and total bilirubin must have 2 values at least 4 weeks apart that are 
within 20% of each other. 
4.1.2. 
Exclusion Criteria 
1. Chronic liver disease of a non-PBC etiology. However, PBC patients accompanied 
with pSS are eligible to be enrolled. 
2. History or evidence of clinically significant hepatic decompensation: 
3. Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget’s 
disease). 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
41 
7. Infection with hepatitis C virus anytime in the past; confirmed active infection with 
hepatitis B virus at screening. 
13. Treatment with OCA within 30 days prior to Day 1. 
14. Other immunosuppressive, immunomodulating or antineoplastic agents not listed in 
Permitted Medications section below within 30 days prior to Day 1 (or not meeting the 
stability time period for concomitant medications indicated as permitted). 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
42 
 






Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
45 
6. 
STUDY PROCEDURES 
6.1. 
Informed Consent 
Prior to undergoing any study specific procedures, each subject must sign a written Informed 
Consent Form (ICF) that has been approved by the investigator’s designated Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC) and by the sponsor. All patients will be 
informed of the nature of the protocol and investigational therapy, their possible hazards, and 
their right to withdraw at any time, and will sign a form indicating their consent to participate 
prior to the initiation of study procedures. The signed ICF should be included in the patient’s 
medical record, which should also contain written documentation indicating that informed 
consent was obtained. Study procedures will be conducted only after a written informed consent 
has been obtained and documented appropriately in the source data. 
6.2. 
Screening Failures 
A screening failure is defined as a patient who has signed the ICF, does not meet all the entry 
criteria as outlined in this protocol and has not been randomized or received study medication. A 
screening log will be maintained by the Investigator or designee, indicating the reason for the 
screening failure. 
6.3. 
Medical History 
A complete medical history will be collected at screening. Concomitant medications, recent 
illnesses, and participation in other investigational drug studies will also be recorded. The 
examinations will be performed as outlined in Schedule of Procedures and Visits (Table 1). 
6.4. 
Physical,
 and Neurological Examinations 
6.4.1. 
Physical Examination 
The examinations will be performed as outlined in Schedule of Procedures and Visits (Table 1). 
The physical examination will be performed by the investigator. It will include assessments of 
general appearance, skin, head (eyes, ears, nose, and throat), neck, thyroid, lungs, heart, 
abdomen, back, lymph nodes, and extremities, and body weight. Height will only be obtained at 
screening. Patients with eye disturbances indicating macular edema, such as blurred vision in 
combination with metamorphopsia, must be referred to an ophthalmologist for further 
examination. 
6.4.3. 
Neurological Examination 
The neurological examination includes assessments of the neurological system (cranial nerves, 
motor and sensory function, coordination, and mental status). In addition, monitoring for PML 
will be performed 
 using a subjective PML checklist (refer 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
46 
 The examinations will be performed as outlined in Schedule of Procedures 
and Visits (Table 1). 
6.5. 
Vital Signs 
Supine (laying face upward) blood pressure, heart rate, temperature, and respiratory rate will be 
measured after the patient has been resting for 5 minutes. Vitals signs will be measured prior to 
any blood draw or any other invasive procedure that occurs at the same visit or time point. Vital 
signs will be measured according to the time points in the Schedule of Procedures and Visits 
(Table 1). Vital signs are to be measured 
 of the scheduled timepoint. 
6.6. 
Electrocardiography 
6.6.1. 
ECG Equipment 
Safety ECGs will be recorded from an ECG machine (12-lead). Safety ECGs will be printed and 
reviewed on-site by the PI or other physician (e.g., cardiologist). Typically, all safety ECGs will 
be obtained as single tracings, with the exception of the pretreatment ECG obtained on Day 1, 
which is a triplicate recording. 
6.6.2. 
ECG Acquisition 
The safety ECG equipment will be set according to ECG and 
. 
6.6.3. 
ECG Assessment 
Safety ECGs will be performed as outlined in Schedule of Procedures and Visits (Table 1).  
ECGs are to be measured 
 of the scheduled timepoint. 
The PI or designee (physician) will be responsible for review and interpretation of safety ECG 
on-site and determining if the ECG is normal, abnormal “not clinically significant” or abnormal 
“clinically significant”. Abnormalities of particular interest include increased PR and QTc 
intervals, either absolute prolongations or clinically noteworthy increases from baseline values. 




Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
48 
In the event of abnormal clinical laboratory values, the physician will make a judgment whether 
or not the abnormality is clinically significant. If clinically significant, it will be captured and 
recorded as an AE. 
6.9.1. 
List of Laboratory Parameters 
Laboratory tests will include the following: 
Serum Chemistry 
Albumin (ALB) 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT; SGPT) 
Amylase 
Aspartate aminotransferase (AST; SGOT) 
Bicarbonate 
Blood urea nitrogen (BUN)  
Calcium (Ca) 
Chloride (Cl) 
Creatinine 
Creatine kinase and MB subtype (if elevated) (% and total MB)* 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lactate dehydrogenase (LDH)  
Lipase 
Magnesium 
Phosphate 
Potassium (K) 
Sodium (Na)  
Total bilirubin 
Direct bilirubin 
Total protein 
 
Serum Chemistry Lipid Panel 
High-density-lipoprotein (HDL) 
Low-density-lipoprotein (LDL) 
Total cholesterol (TC) 
Triglycerides (TG) 
 
Hematology  
     Hematocrit (Hct) 
Hemoglobin (Hb) 
Lymphocyte subsets (CD4, CD8 and NK cells) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell count (RBC) 
White blood cell count (WBC) with differential (% and absolute counts) 
Coagulation 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
49 
Prothrombin time (PT) 
Activated partial thromboplastin time (PTT) 
International Normalized Ratio (INR) 
Additional tests 
 
Urine dipstick test 
Follicle stimulating hormone (FSH)  
 
AMA 
 
Additional tests at screening 
 
HBsAg  
Anti-HCV 
 
QuantiFERON 
Thyroid-stimulating hormone (TSH) 
Triiodothyronine (free T3) 
Thyroxine (free T4) 
 
* alternatively, this can be done by troponin test (T and or I) 
6.9.3. 
Urinalysis 
Urinalysis will follow the local practice at the study site (as dipstick). Tests will be performed as 
outlined in Schedule of Procedures and Visits (Table 1). Parameters for clinical laboratory tests 
include the following: 
• appearance + color 
• specific gravity 
• pH 
• leukocytes 
• protein 
• glucose 
• nitrites 
• ketones 
• urobilinogen 
• bilirubin 
• blood/erythrocytes 
Microscopic urinalysis will be performed when there is a positive or abnormal macroscopic 
urinalysis result as deemed necessary by the investigator. 






Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
52 
laboratory finding), symptom, or disease temporally associated with the use of the study 
medication, whether or not related to the product. AEs can be any of the following: 
• Unfavorable changes in general condition 
• Subjective or objective signs/symptoms 
• Concomitant disease or accidents 
• Clinically relevant adverse changes in laboratory parameters observed in a patient in 
the course of a clinical study 
• Pre-existing conditions which worsen in severity or frequency or which have new 
signs/symptoms associated with them 
Lymphopenia will not be captured as an AE because it is an expected pharmacologic effect of 
the drug. 
AEs will be elicited at the time indicated in the schedule. Any adverse or unexpected events, 
signs and symptoms will be fully recorded on the AE Form including details of intensity, onset, 
duration, outcome and relationship to the drug as determined by the PI. Whenever possible, a 
constellation of signs and symptoms should be recorded as a unifying diagnosis (e.g., self-limited 
fever, runny nose, cough, and scratchy throat should be captured as an upper respiratory 
infection rather than by the individual signs and symptoms). AEs may also be reported at any 
time. The type and duration of follow-up of patients after AEs will be documented. 
6.15.2. 
Serious Adverse Events and Expedited Reporting of Adverse Events 
An SAE is any untoward medical occurrence that at any dose results in the following outcomes: 
• Death 
• Is life-threatening 
• Required/Prolonged hospitalization 
• Disability/Incapacity 
• Congenital anomaly/birth defect 




Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
54 
(Day 1 to Week 24) until 30 days after the last dose of study drug should be reported to the 
sponsor contact and IEC in the same manner as an SAE. 
Pregnancies will be followed every trimester through the first well baby visit. For female 
partners whom become pregnant by male study patients during the course of the study, 
reasonable efforts will be made to collect information on the partner’s pregnancy through the 
first well baby visit as provided by the male study patient. 
6.15.3. 
Assessment of Adverse Event Severity 
The severity of each AE will be assessed at onset by a nurse and/or physician. When recording 
the outcome of the AE the maximum severity of the AE experienced will also be recorded. The 
severity of the AE will be graded according to the CTCAE v4.03 31 definitions, listed below: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age- 
appropriate instrumental Activities of Daily Living (ADL)*. 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
Activities of Daily Living: 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
6.15.4. 
Assessment of Adverse Event Relationship to Study Medication 
The relationship of an AE to investigational product(s) will be classified using modified WHO 
criteria (Edwards and Biriell, WHO Collaborating Centre for International Drug Monitoring 
1994) as follows: 
Related: a clinical event, including laboratory test abnormality, with a reasonable time sequence 
to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on withdrawal. Re-challenge 
information is not required to fulfill this definition; or an event that could also be explained by 
concurrent disease or other drugs or chemicals where information on drug withdrawal may be 
lacking or unclear. 
Not related: a clinical event, including laboratory test abnormality, with sufficient evidence to 
accept that there is no causal relationship to drug administration (e.g., no temporal relationship to 
drug administration, because the drug was administered after onset of event; investigation shows 
that the drug was not administered; proof of other cause; etc.); or an event with a temporal 
relationship to drug administration which makes a causal relationship improbable, and in which 
other drugs, chemicals or underlying disease provide plausible explanations. 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
55 
6.15.5. 
Assessment of Adverse Event Outcome 
Outcome of AEs will be defined according to ICH Guideline E2B. 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Recovering/Resolving 
• Not recovered/not resolved 
• Fatal 
• Unknown 
 
6.15.6. 
Action Taken for Adverse Event 
Action taken for AEs will be documented according to the following: 
• Concomitant medication or other treatment 
• Withdrawal from the study 
 
6.15.7. 
Action Taken for Study Drug 
Any action taken with study drug will be defined according to ICH Guideline E2B and 
documented in the CRF according to the following: 
• Drug withdrawn 
• None (not changed) 
• Dose interrupted 
• Unknown 
• Not applicable 
 
6.15.8. 
Follow-up of Adverse Events Present at Last Scheduled Study Visit 
Adverse events present at the last study day (Week 26/Exit) that require follow-up or a repeat 
laboratory test will be followed up initially for 30 days according to the site’s standard practice 
for AE follow-up. AEs that have not resolved or stabilized at 30 days after the last patient’s last 
study dose, will be reviewed with the sponsor on an individual basis to determine whether the 
database will be locked and subsequently updated once the events of ongoing AEs are resolved 
or whether database lock will be held. 
6.16. Drug-Induced Liver Injury (DILI) Surveillance 
In July 2009, the FDA released a Guidance for Industry entitled “Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation,” which reviews the importance of DILI surveillance in drug 
development. DILI has been the most frequent single cause of safety-related drug marketing 
withdrawals for the past 50 years, and hepatotoxicity discovered after approval for marketing has 
limited the use of many drugs. Furthermore, the guidance addresses how laboratory 
measurements that signal the potential for DILI can be obtained and evaluated during drug 
development. 
Given the fact that all subjects enrolled in this study have pre-existing liver disease (i.e., PBC) 
and baseline elevations in laboratory tests of liver health (ALP, ALT and/or AST), DILI 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
56 
surveillance is of critical importance to patient safety. Therefore, in collaboration with the FDA 
and after careful consideration of the principles outlined in the DILI guidance, the sponsor has 
established procedures to ensure early detection of possible DILI and study drug discontinuation 
in the context of suspected DILI. 
6.16.1. 
Close Observation for Possible DILI 
It is critical to initiate close observation immediately upon detection and confirmation of early 
signals of possible DILI, and not to wait until the next scheduled visit or monitoring interval. 
Close observation is mandatory for any study patient who meets one or more of the following 
“possible DILI” laboratory criteria: 
• ALT or AST that is <ULN at baseline, followed by ALT or AST increase to >3 × 
ULN 
• ALT or AST that is >ULN at baseline, followed by ALT or AST increase to >2 × 
baseline 
• ALP >2 × baseline 
• Total bilirubin >1.5 × ULN 
Close observation includes: 
• Repeating liver enzyme and serum bilirubin tests within 48-72 hours. Then, 
repeating liver enzyme and serum bilirubin tests two or three times weekly. 
Frequency of retesting can decrease to once a week or less if abnormalities 
resolve, abnormalities stabilize, or the study drug has been discontinued and the 
subject is asymptomatic.  
• Obtaining a more detailed history of symptoms and prior or concurrent diseases.  
• Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets.  
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis; hypoxic/ischemic hepatopathy; and biliary 
tract disease.  
• Obtaining a history of exposure to environmental chemical agents.  
• Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, 
direct bilirubin).  
• Considering consultations, imaging studies, and/or therapeutic interventions, as 
required.  
6.16.2. 
Study Drug Discontinuation for Suspected DILI 
Should any patient who meets “possible DILI” laboratory criteria have persistence or worsening 
of lab data (i.e., ALT, AST, ALP, and/or total bilirubin) after one week of close observation, 
study drug must be discontinued. In addition, immediate study drug discontinuation is mandatory 
for any study patient who meets one or more of the following “suspected DILI” clinical criteria:  




Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
58 
• Investigational agents, other than etrasimod from 30 days prior to Day 1 and during 
the study. 
 
6.18. Removal of Patients from the Trial or Study Drug 
The study may be terminated early if, in the opinion of the sponsor, investigator, or IEC, an 
unacceptable risk to the safety and welfare of patients is posed by the continuation of the study in 
light of review of the key safety data. Evidence of macular edema in patients requires study drug 
discontinuation. 
Patients will be free to withdraw from the study at any time should they so wish. A patient may 
be withdrawn from the study for any of the following reasons (including but not limited to): 
• Clinical investigator may remove a patient if, in his/her opinion, it is in the best 
interest of the patient (including decisions based on the dose-stopping rules). 
• Withdrawal of consent: Any patient may withdraw his/her consent from the study at 
any time. The investigator should make a reasonable attempt to document the 
specific reason why consent was withdrawn. 
• Deviation/noncompliance with the protocol or study drug. 
• An AE. 
• Lost to follow up. 
 
6.18.1. 
Handling of Withdrawals 
Although a patient is not obliged to give his/her reason for withdrawing prematurely, the 
investigator will make a reasonable effort to obtain the reason while fully respecting the patient’s 
rights. If there is a medical reason for withdrawal, the patient will remain under the supervision 
of the study physician until in satisfactory health. Reasonable efforts will be made to contact a 
patient who fails to attend any follow-up appointments, in order to ensure that he/she is in 
satisfactory health. 
If a patient is prematurely discontinued from this study, every attempt will be made to follow the 
Week 24/EOS visit procedures. If consented by the patient, effort will be made to conduct a 
follow-up visit within 2 weeks of discontinuation (Table 1), if the patient has received at least 1 
dose of the study drug. 
6.18.2. 
Replacements 
Patients who terminate early from the study due to reasons other than AEs will be replaced. 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
59 
6.19. Study and Site Discontinuation 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
• Patient enrollment is unsatisfactory. 
Additionally, if more than three patients develop a CTCAE Grade 3 or higher event in the same 
category, or if three or more patients meet one of the individual stopping rules, the safety and 
dose escalation review committee (5.5) will convene to evaluate the findings. Further, dosing 
will be stopped in randomized patients and no new patients will be randomized until the safety 
and dose escalation review committee reviews and evaluates the findings. 
The sponsor will notify the investigator and IEC if the study is placed on hold, or if the sponsor 
decides to discontinue the study or development program. 
The sponsor has the right to replace a site at any time. Reasons for replacing a site may include, 
but are not limited to, the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Non-compliance with the ICH guidelines for GCP 
 
 






Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
62 
− 
 
• Obtain urine sample for: 
− Urinalysis 
7.2. 
Treatment Period (24 weeks) 
7.2.1. 
 
 procedures for all subjects are as follows: 
• Record medical history  
• Verify inclusion and exclusion criteria for eligibility 
• 
 
• Perform physical exam and neurological exam 
• Perform 12-lead ECG 
 
• 
 
• Measure vital signs 
 
• Record any concomitant medications 
• Record any AEs  
• 
 
• Obtain blood samples for: 
− PK at up to 
 
− Chemistry, including ALP 
− Complete blood count and lymphocyte subsets 
− Fasting lipid panel 
− 
 
− Coagulation 
• Obtain urine sample for:  
− Urinalysis 
− Pregnancy test (female subjects only) 
• Dispense study drug (1 mg etrasimod) and administer tablet at the clinic 
7.2.2. 
 
 procedures for all subjects are as follows: 
• 
 
• Perform physical exam and neurological exam 




Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
64 
7.2.4. 
 
The safety and dose escalation review committee will review the PK and safety data from each 
PBC patient and will make individualized recommendations on whether a patient will remain at 
the 1 mg dose or escalate to the 2 mg dose at Week 12 as described in 5.5.   
 procedures for all subjects are as follows: 
• 
 
• Perform physical exam and neurological exam 
• Record any concomitant medications 
• Record any AEs  
• Obtain blood samples for: 
− Chemistry, including ALP 
− Complete blood count and lymphocyte subsets 
− Fasting lipid panel 
− Pregnancy test (female subjects only) 
− 
 
− Coagulation 
• Obtain urine sample for:  
− Urinalysis 
 procedures for all subjects who dose escalate are as follows: 
• Perform 12-lead ECG 
  
• 
  
• Measure vital signs 
 
• Obtain blood samples for: 
− PK 
 
• Dispense study drug (2 mg etrasimod) and administer tablet at the clinic  
 procedures for all subjects who do not dose escalate are as follows: 
• Perform 12-lead ECG 
  
• Measure vital signs 
  




Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
66 
− Complete blood count and lymphocyte subsets 
− Pregnancy test (female subjects only) 
− Coagulation (Week 16 only) 
• Obtain urine sample for:  
− Urinalysis 
 procedures for all subjects who dose escalate are as follows: 
• Dispense study drug (2 mg etrasimod) and administer tablet at the clinic 
 procedures for all subjects who do not dose escalate are as follows: 
• Dispense study drug (1 mg etrasimod) and administer tablet at the clinic 
7.2.7. 
 
 procedures for all subjects are as follows: 
• 
 
• Measure body weight and calculate BMI 
• Perform physical exam and neurological exam 
• Perform 12-lead ECG 
 
• Measure vital signs 
 
• Record any concomitant medications 
• Record any AEs  
• 
• 
• 
• 
• 
• Obtain blood samples for: 
− PK at 
 
− Chemistry, including ALP 
− Complete blood count and lymphocyte subsets 
− Fasting lipid panel 
− Pregnancy test (female subjects only) 
− 
 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
67 
− Coagulation 
• Obtain urine sample for  
− Urinalysis 
7.3. 
Follow-Up Period  
7.3.1. 
 
 procedures for all subjects are as follows: 
• 
 
• Measure body weight and calculate BMI 
• Perform physical exam and neurological exam 
• Measure vital signs  
• Record any concomitant medications 
• Record any AEs  
• Obtain blood samples for: 
− Chemistry, including ALP 
− Complete blood count and lymphocyte subsets 
− Total serum IgG and IgM, AMA and hsCRP 
If the absolute peripheral lymphocyte count has not recovered to at least 80% of the baseline 
value, or reached normal ranges at the 2-week follow-up, the subject must return for weekly 
CBC tests until the absolute peripheral lymphocyte count has returned to at least these values. 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
68 
8. 
DATA MANAGEMENT 
8.1. 
Data Collection 
All data (ECGs, clinical laboratory data, and all other study-related data) will be collected 
according to the sponsor/CRO’s SOPs or according to study site standards, if applicable. 
8.2. 
Data Coding 
8.2.1. 
Adverse Events 
AEs will be coded using the most current Medical Dictionary for Regulatory Activities 
(MedDRA) and tabulated, including categorical information of interest such as onset and 
resolution times, time of onset relative to dose, severity at onset, maximum severity, causal 
relationship to study medication, and action taken. Whenever possible, a constellation of signs 
and symptoms should be recorded as a unifying diagnosis (e.g., self-limited fever, runny nose, 
cough, and scratchy throat should be captured as an upper respiratory infection rather than by the 
individual signs and symptoms). AEs will be regarded as ‘pre-treatment’ if they occur between 
screening and the time of administration of the first dose of etrasimod. All other AEs that occur 
after the first dose of study medication will be considered to be ‘treatment-emergent’. 
8.2.2. 
Concomitant Medications and Non-Drug Treatments 
Due to the variability in how medications are recorded, a standard naming convention is required 
to tabulate this data effectively. A common method of standardization is to categorize 
medications by their Preferred Term (PT). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO DD), Format C. 
8.2.3. 
Medical History 
Medical history will be coded using the most current MedDRA-version. 
 
 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
69 
9. 
PLANNED STATISTICAL METHODS 
Summary statistics will be provided to describe efficacy and safety measures. Confidence 
interval of key efficacy measures will be also produced for non-inferential comparisons with 
historical data. 
9.1. 
Hypotheses 
There are no formal hypothesis tests specified in this open-label study due to the lack of a control 
treatment group. 
9.2. 
Sample Size and Power Calculations 
There is no formal sample size estimation for this proof-of-concept open label study. A sample 
size of 20 subjects is reasonable to assess the efficacy and safety of etrasimod in the target 
population. 
9.3. 
Analysis Populations 
Efficacy endpoints will be analyzed in enrolled patients who have baseline and at least one post-
baseline measure. 
Safety endpoints will be analyzed in enrolled patients who received at least one dose of the study 
drug. 
9.4. 
Demographics and Baseline Characteristics 
All baseline patient characteristics of demographic data (age, height, weight, race), disease 
history, medical history (abnormalities only), physical examination (abnormalities only), and 
concomitant medications at study entry will be listed for all patients. 
Demographic data will be summarized and tabulated. Continuous variables will be summarized 
using number of observations (n), mean, standard deviation (SD), median, minimum, and 
maximum. Frequencies and percentages will be reported for all categorical data. 
9.5. 
Efficacy Endpoints 
• change from baseline to Week 12 and 24 in serum ALP concentration. 
• change from baseline to Weeks 12 and 24 in: 
o Complete blood counts (including lymphocytes and subsets thereof). 
o hsCRP, ALT, AST, GGT, 
 C4 and 
 serum 
concentrations. 
o Total serum IgG, IgM, and AMA. 
o QoL, pruritus and fatigue (using the PBC-40 score and 5-D pruritus scales). 
o Ophthalmological examinations: 
• 
The Schirmer Test 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
70 
9.6. 
Statistical Methods 
9.6.1. 
Efficacy Analysis 
There are no inferential comparisons for study endpoints. Summary statistical analyses will be 
performed for all efficacy measures. For proportion-based measures, N, frequencies, proportion 
and its 95% confidence interval (CI) will be produced. For continuous measure, N, mean, 
median, range, and SD will be produced for observed values, and additional 95% CI for change 
or percent change from baseline will be produced if applicable. 
9.6.2. 
Subgroup Analyses 
Exploratory analysis of main study endpoints will be performed in subset of patients of medical 
interests, such as patient demographics, baseline ALP levels, baseline disease characteristics, 
biomarker, previous disease treatment received, etc. 
 
 
9.6.3. 
Pharmacokinetic Analysis 
Pharmacokinetic parameters of etrasimod, and its metabolites (if possible) will be calculated 
using non-compartmental methods. 
 
 
Individual etrasimod plasma concentrations at specified time points will be listed for each 
patient. Individual plasma concentration-time points of etrasimod will be plotted on both a linear 
and a semi-logarithmic scale for each dose level. 
 
9.6.4. 
Interim Analysis 
An informal interim analysis of safety and efficacy will be performed when up to half the 
patients have finished 12 weeks of treatment. 
9.7. 
Safety Analysis 
Safety and tolerability will be assessed by a review of all safety parameters including AEs, 
laboratory safety parameters, 
 vital signs, and ECG. AEs will only be presented as 
summary tabulations. When assessing change from baseline, a baseline measurement is also 
required. Baseline for the safety analysis is defined as the average of the pre- dose 
measurements. No missing data will be imputed for the safety analysis. For continuous variables, 
summary statistics (N, mean [or median], SD, mean [or median] change/percent change) and 
95% CI will be produced if applicable; for proportion-based measures, N, frequencies, 
proportion and its 95% CI will be produced. 
9.7.1. 
Adverse Events 
AEs will be coded using the most current MedDRA and tabulated, including categorical 
information of interest such as onset and resolution times, time of onset relative to dose, severity 
at onset, maximum severity, causal relationship to study medication, and action taken. AEs will 
be regarded as ‘pre-treatment’ if they occur between screening and the time of administration of 
the first dose of etrasimod. All other AEs that occur after the first dose of study medication will 
be considered to be ‘treatment-emergent’. 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
71 
Pre-treatment and treatment-emergent AEs will be listed by patients, in terms of seriousness, 
severity and intensity (assessed according to the CTCAE v4.03; 14Jun2010 definitions 31). 
TEAEs will be classified according to system organ class. 
9.7.2. 
Physical Examinations 
Physical examination results (abnormalities only) at each study visit will be listed. 
9.7.3. 
Concomitant Medication 
Pre-treatment and concomitant medication administered during the study will be listed. 
Concomitant medications will be coded using the WHO-DRUG Dictionary. 
9.7.4. 
Vital Signs 
Individual vital sign measurements will be summarized using descriptive statistics. Summary 
statistics will also be provided for change from baseline in vital sign measurements. Baseline is 
defined as the last pre-dose measurement. 
9.7.6. 
Clinical Laboratory Values 
Individual lab values will be listed by visit, and summarized using descriptive statistics. 
Summary statistics will also be provided for change from baseline in hematological parameters 
(e.g., lymphocytes) or other parameters. Baseline is defined as the average of the pre-dose 
measurements. A clinically significant change from baseline may be recorded as an AE if 
deemed appropriate by the PI or sponsor. 
9.7.7. 
Safety ECG (12-lead ECG) 
Individual safety ECG (12-lead) values will be listed by visit, and summarized using descriptive 
statistics. Intervals to be provided for each ECG are: RR, PR, QRS, QT, QTc, QTcB, and QTcF. 
Post-screening ECGs will be compared with the baseline ECG. Any clinically significant change 
from baseline may be recorded as an AE if deemed appropriate by the PI or sponsor. 
 
 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
72 
10. REGULATORY REQUIREMENTS 
10.1. Pre-Study Documentation 
The sponsor must receive the following documentation prior to initiation of the trial: 
• Protocol signature page signed and dated by the principal investigator (PI) 
• Curriculum vitae of the PI and sub-investigators, updated within last two years 
• Current medical licenses for the PI and all sub-investigators 
• Financial disclosure form signed by the PI and all sub-investigators if applicable to 
local regulations 
• Copy of the IEC (HREC) approval letter for the study and approved ICF 
• IEC (HREC) membership list 
• Copy of the regulatory authority approval (if applicable as per local guidelines) 
Additional country-specific documentation may be required per international regulatory 
authorities. 
10.2. Investigator Obligations 
The PI is responsible for ensuring that all study site personnel, including sub-investigators and 
other study staff members, adhere to all country regulatory requirements and guidelines 
regarding clinical trials, including guidelines for GCP (including the archiving of essential 
documents), both during and after study completion. The PI will be responsible for the patient’s 
compliance to the study protocol. The PI is responsible for providing the sponsor an adequate 
final report shortly after he/she completes participation in the study, in accordance with ICH 
Guidelines E6, E2A, and E8. 
10.3. Patient Confidentiality 
All information obtained during the conduct of the study with respect to the patients is regarded 
as confidential. This is detailed in the written information provided to the patient. An agreement 
for disclosure of any such information will be obtained in writing and is included in both copies 
of the ICF signed by the patient. The study data shall not be disclosed to a third party without the 
written consent of the sponsor or designee. 
10.4. Informed Consent 
According to ICH Guideline E6, “Good Clinical Practice: Consolidated Guidance”, the 
investigator will obtain and document informed consent for each patient screened for this study. 
All patients will be informed in writing of the nature of the protocol and investigational therapy, 
its possible hazards, and their right to withdraw at any time, and will sign a form indicating their 
consent to participate prior to the initiation of study procedures. The patient’s medical record 
should contain written documentation indicating that informed consent was obtained. The ICF 
must be reviewed and approved by the investigator’s designated IRB/IEC and by the sponsor. 
The informed consent should include all the elements outlined in Section 4.8.10 of ICH 
Guideline E6. 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
73 
10.5. Independent Ethics Committee (IEC) Human Research Ethics 
Committee (HREC) 
This protocol and relevant supporting data are to be submitted to the appropriate IEC (HREC) 
for review and approval before the study can be initiated. Amendments to the protocol will also 
be submitted to the IEC prior to implementation of the change. The sponsor must receive a letter 
documenting the IEC approval prior to initiation of the study. If applicable to local regulations 
the following may also apply: the PI is also responsible for informing the IEC of the progress of 
the study and for obtaining annual IEC renewal. The IEC must be informed at the time of 
completion of the study and should be provided with a summary of the results of the study by the 
PI. The PI must notify the IEC in writing of any SAE or any unexpected AE according to ICH 
guidelines. 
 
 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
74 
11. PROTOCOL MANAGEMENT AND ADMINISTRATIVE 
CONSIDERATIONS 
11.1. Study Documentation 
The PI and study staff have the responsibility of maintaining a comprehensive study-related 
documentation. These files must be available for inspection by the sponsor, representatives of the 
sponsor, the IEC, and international regulatory authorities at any time, and should consist of the 
following elements: 
• Patient files, including but not limited to the completed electronic case report forms 
(eCRFs), supporting source documentation from the medical record including 
laboratory data and the ICF; 
• Regulatory files, containing the protocol with all amendments and investigator 
signature pages, copies of all other regulatory documentation, and all 
correspondence between the site and the IEC and sponsor; and 
• Drug accountability files, including a complete account of the receipt and 
disposition of the study medication (test article). 
Records are to be available for until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product (or if the application is not approved or never 
submitted, 2 years after the last shipment and delivery of the material and the appropriate 
competent regulatory authorities are notified). The sponsor will provide written notification 
when it is appropriate for the investigator(s) to discard the study-specific documents referenced 
above. 
11.2. Protocol Interpretation and Compliance 
To ensure accurate interpretation and implementation of the study, the procedures and endpoints 
defined in the protocol will be carefully reviewed by the PI and his or her staff prior to the time 
of study initiation. The Sponsor and PI will follow all reasonable means to resolve any 
differences of opinion of matters of eligibility, toxicity and other endpoints. In the event that a 
resolution cannot be reached then one or both parties may seek to terminate the study following 
the provisions outlined in the Clinical Trials Agreement. 
11.3. Study Monitoring 
The sponsor or a contracted monitor will visit the study center periodically to monitor adherence 
to the protocol, compliance with ICH guidelines, adherence to applicable regulations, and the 
maintenance of adequate and accurate clinical records. Case report forms will be reviewed to 
ensure that key safety and efficacy data are collected and recorded as specified by the protocol. 
The monitor will be permitted to access patients’ complete medical records, laboratory data, and 
other source documentation as needed to monitor the trial appropriately. 
 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
75 
12. PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
I agree to conduct the study as outlined in the protocol entitled “An Open-label, Pilot, Proof of 
Concept Study to Evaluate the Safety, Tolerability, and Efficacy of Oral Etrasimod (APD334) in 
Patients with Primary Biliary Cholangitis” in accordance with regulatory guidelines, ICH GCP 
Guidelines and the Declaration of Helsinki; and all applicable government regulations. 
These guidelines and regulations include, but are not limited to: 
• Permission to allow the sponsor, or designee, or country specific regulatory agencies 
to inspect study facilities and pertinent records at reasonable times and in a 
reasonable manner that ensures patient confidentiality. If this study is to be inspected 
by a regulatory agency, the sponsor and CRO should be notified as soon as possible. 
• Submission of the proposed clinical investigation, including the protocol and the 
consent form, to a duly constituted IEC for approval, and acquisition of written 
approval for each prior to the use of the study drug. 
• Use of written informed consent that is obtained prior to administration of study 
drug or any non-routine procedures that involve risk, and that contains all the 
elements of consent as specified in the federal regulations and has been previously 
approved by the sponsor and the IEC. 
• Submission of any proposed change in the protocol to the IEC using a signed formal 
amendment document approved by the sponsor. Any proposed changes to the 
protocol require that the informed consent also reflect such changes and that the 
revised informed consent be approved as determined by the IEC. 
• Documentation and explanation of individual protocol deviations on the appropriate 
CRF page or in letters to the sponsor. 
• Submission of written reports of SAEs to Arena Pharmaceuticals, Inc. or designated 
CRO within 24 hours after the investigator’s initial receipt of the information. 
• Submission of reports of SAEs, as outlined in the protocol, to the IEC within 15 
calendar days of their disclosure. 
• Submission of timely progress reports to the IEC and sponsor at appropriate 
intervals on a schedule determined by the IEC. 
• Maintenance of appropriate records: ICH guidelines require an investigator to 
prepare and maintain adequate and accurate case histories designed to record all 
observations and other data (such as study drug accountability) pertinent to the 
investigation on each individual enrolled in the study. These records must be 
maintained by the investigator until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the 
investigational product. 
In addition, I agree to provide all the information requested in the CRF in a manner to assure 
legibility and accuracy. To this end, I shall carefully follow the instructions for completing CRFs 
and approve with signature. 
I also agree that all information provided to me by the sponsor, including protocols, CRFs, and 
verbal and written information, will be kept strictly confidential and confined to the clinical 


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
76 
personnel involved in conducting the study. It is recognized that this information may be related 
in confidence to the IRB/IEC. I also understand that reports of information about the study or its 
progress will not be provided to anyone not involved in the study other than to the PI, or in 
confidence to the IRB/IEC or other legally constituted authority. 
 
 
 
 
 
 
 
  Principal Investigator 
 
 
 
 
 
Date 
 
 
 
 
  Printed Name 
 
 






Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
79 
32. Lindor KD, Gershwin ME, Poupon R et al. Primary biliary cirrhosis. Hepatology. 2009
Jul;50(1):291-308.
33. Chen S, Duan W, You H, Jia J. A brief review on prognostic models of primary biliary
cholangitis. Hepatol Int. 2017 Sep;11(5):412-8.


Etrasimod (APD334) 
 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
80 
 
SPONSOR PROTOCOL SIGNATURE PAGE 
Protocol Title: An Open-label, Pilot, Proof of Concept Study to Evaluate the Safety, 
Tolerability, and Efficacy of Oral Etrasimod (APD334) in Patients with Primary Biliary 
Cholangitis 
 
This study will be conducted in accordance with the International Conference on Harmonization 
(ICH) guideline for Good Clinical Practice (GCP) (E6). 
Protocol Number: 
APD334-010 
Arena Pharmaceuticals, Inc. Signatures: 
Electronic Signature Appended 
 
 
 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
81 
Appendix 1 
Summary of Changes by Amendment  
Summary of Changes for Amendment 4.0 Dated 27 June 2018 
Protocol APD334-010 was amended to allow additional tests to confirm PBC diagnosis, lower the ALP threshold from >1.67 × ULN 
to >1.5 × ULN to be consistent with the Paris II ALP criteria, add AE and concomitant assessments to Screening Visit 2, and change 
the definition of the safety baseline.  
Revised text in Amendment 4.0 is indicated in bold font, and text deleted from Version 3.0 is crossed out in the table below.  
Minor/editorial changes are not listed in the summary table.  
Section 
Amendment 3.0 
Amendment 4.0 
Reason for Change 
Synopsis: Inclusion Criteria 
4.1.1: Inclusion Criteria 
1. Males or females aged 18 to 80 
years (inclusive) at the time of 
screening, with confirmed PBC 
diagnosis based upon at least 2 of 3 
criteria: 
• AMA titer >1:40 
1. Males or females aged 18 to 80 
years (inclusive) at the time of 
screening, with confirmed PBC 
diagnosis based upon at least 2 of 3 
criteria: 
• AMA titer >1:40 on 
immunofluorescence or M2 
positive by enzyme-linked 
immunosorbent assay (ELISA) 
or positive PBC-specific 
antinuclear antibodies (anti-
GP210 and/or anti-SP100) 
We have included additional tests 
confirming PBC diagnoses allowing 
for ELISA and for other PBC-
specific auto-antibodies in cases 
whereby the AMA titer is low.  Per 
AASLD guidelines, these tests are 
indicative of PBC diagnoses.32 
Synopsis: Inclusion Criteria 
4.1.1: Inclusion Criteria 
Synopsis: Inclusion Criteria 
4.1.1: Inclusion Criteria 
3. Be on a stable dose of UDCA for 
at least 3 months prior to screening 
2. Use of UDCA for at least 6 
months prior to screening (stable 
dose for at least 3 months 
immediately prior to screening)  
UDCA dosing information is the 
same as in amendment 3 but 
consolidated under one criteria for 
amendment 4 for clarity. 
 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
82 
Section 
Amendment 3.0 
Amendment 4.0 
Reason for Change 
Synopsis: Inclusion Criteria 
4.1.1: Inclusion Criteria 
5. Patients must have the following 
laboratory parameters at screening 
ALP >1.67 × ULN but <10 × ULN 
(at all screening visits) 
4. Patients must have the following 
laboratory parameters at screening 
ALP >1.5 × ULN but <10 × ULN (at 
all screening visits) 
The ALP threshold for eligibility is 
being lowered from >1.67 × ULN to 
>1.5 × ULN to be consistent with the 
Paris II ALP criteria, which is used to 
predict prognosis in early PBC.33 An 
ALP level of >1.5 × ULN would still 
allow for detection of an efficacy 
signal in this safety study.   
Synopsis: Inclusion Criteria 
4.1.1: Inclusion Criteria 
Synopsis: Exclusion Criteria 
4.1.2: Exclusion Criteria 
Synopsis: Exclusion Criteria 
4.1.2: Exclusion Criteria 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
83 
Synopsis: Exclusion Criteria 
4.1.2: Exclusion Criteria 
3.3: End of Study (Table 1) 
3.3: End of Study (Table 1) 
New text 
Added AE and concomitant 
assessments at Screen 2. 
The AE and concomitant assessments 
were added to Screening Visit 2 for 
consistency. 
5.2.1: Dose-Stopping Rules 
New text 
As described in 3.1, at the 
discretion of the PI, the dose of 
etrasimod may be adjusted from 2 
mg q.d. back to 1 mg q.d. if 
deemed necessary. 
The text was added to be consistent 
with text already included in the 
synopsis. 
6.9.5: Blood Volume 
The total blood volume collected to 
cover all sampling procedures as 
required by the outline in Schedule 
of Procedures and Visits [Table 1]), 
is up to 270 mL during the study  
The total blood volume collected 
from each patient participating in 
the study (according to the 
sampling described in the Schedule 
of Procedures and Visits [Table 1]) is 
estimated to be 340 mL, but will 
not exceed 500 mL. 
The blood volume section was 
updated to reflect differences in 
collection tubes and sample 
processing and analysis between 
countries. 




Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
85 
Summary of Changes for Amendment 3.0 Dated 14 March 2018 
Protocol APD334-010 was amended to add Screening Visit 2 to the study design to ensure the repeat assessment of liver enzyme 
values are available in time for enrollment. Additional changes introduced in this amendment include:  
• Clarifying that tablets are to be taken at the clinic 
• Revising the fasting period to address study visits where study medication is not administered 
• Clarifying that the vital signs and ECG 
 
• Specifying that 
 C4 will not require additional blood sampling or procedures and will be determined using back-
up PK samples  
• Adding a collection window for PK blood samples, vital signs, and ECG measurements 
• Changing the abbreviated/interim physical exam to full examinations 
• Changing the medical monitor 
• Clarifying that this protocol is a Phase 2 study, not a Phase 1 study 
• Including that Protocol Amendment 2 was never released to the site  
Revised text in Amendment 3.0 is indicated in bold font, and text deleted from Version 2.0 is crossed out in the table below.  
Minor/editorial changes are not listed in the summary table.  




Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
87 
Synopsis: Test Product, Dose and 
Mode of Administration 
The protocol was clarified to state 
that tablets are to be taken at the 
clinic. 
The 
 period was revised to 
address study visits where study 
medication is not administered. 
 
 
Synopsis: Screening Period (5 to 8 
weeks before baseline visit) 
3.1: Overall Study Design and Plan 
Each patient will be asked to visit the 
study site for screening assessments 
4 to 8 weeks prior to the planned 
start of the treatment (Day 1).  
Each patient will be asked to visit the 
study site at least 2 times for 
screening assessments within the 8 
weeks prior to the planned start of 
the treatment (Day 1). Screening 
Visit 1 is to occur between Week -8 
and Week -5. Screening Visit 2 is 
to occur at least 4 weeks from 
Screening Visit 1. For patients with 
ALP, ALT, AST, or total bilirubin 
values from Screening Visits 1 and 
2 that are not within 20% of each 
other (see Inclusion Criterion 9), 
an unscheduled visit within the 
screening period may be conducted 
to repeat these assessments.  
The screening period duration was 
changed from 4-8 to 5-8 weeks to 
allow for time to evaluate liver 
enzyme values. 
 
Screening Visit 2 was added to the 
study design to ensure the repeat 
assessment of liver enzyme values 
are available in time for enrollment 
(see Inclusion Criterion 9). 
 
Synopsis: Treatment period (24 
weeks) 
3.1: Overall Study Design and Plan 




Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
89 
Synopsis:  Exclusion Criteria 
4.1.2:  Exclusion Criteria 
Synopsis:  Pharmacokinetic 
Assessments 
3.3: End of Study 
6.13: Pharmacokinetic Assessments 
New text 
All PK samples are to be collected 
 of the 
scheduled timepoint. 
A collection window for PK samples 
was added to allow some flexibility 
in collecting samples and to 
minimize the likelihood of protocol 
deviations. 
3.1: Overall Study Design and Plan  
The original Figure 1 (Schematic of 
APD334-010 Study Design) had one 
screening visit and it looked like 
treatment started on Day -1. 
Figure 1 (Schematic of APD334-010 
Study Design) was revised to include 
footnote a, which states Screening 
Visit 1 is to occur between Week -8 
and Week -5. Screening Visit 2 is to 
occur at least 4 weeks from 
Screening Visit 1. For patients with 
ALP, ALT, AST, or total bilirubin 
values from Screening Visits 1 and 2 
that are not within 20% of each other 
(see Inclusion Criterion 9), an 
unscheduled visit within the 
screening period may be conducted 
to repeat these assessments. The 
treatment bars were revised so that 
treatment starts at Day 1. 
Screening Visit 2 was added to the 
study design to ensure the repeat 
assessment of liver enzyme values 
are available in time for enrollment 
(see Inclusion Criterion 9). 
 
3.3: End of Study  
New text 
Added Screening Visit 2, the 
associated assessments, footnote a 
and footnote 8 to Table 1 (Schedule 
of Procedures and Visits). 
Table 1 (Schedule of Procedures and 
Visits) was updated to reflect the new 
visit schedule during screening. 
3.3: End of Study 
 C4 evaluations were 
included in Table 1 (Schedule of 
Procedures and Visits). 
 C4 evaluations were 
removed from Table 1 (Schedule of 
Procedures and Visits). 
Deleted reference to these 
exploratory tests in Table 1 
(Schedule of Procedures and Visits) 
as this section is used to inform sites 
on study procedures; C4/
 
will not require additional blood 
sampling. 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
90 
3.3: End of Study 
The protocol was clarified to state 
that tablets are to be taken at the 
clinic. 
The 
 period was revised to 
address study visits where study 
medication is not administered. 
 
 
3.3: End of Study 
1. Interim/abbreviated physical exam 
only. 
Deleted text 
The interim/abbreviated physical 
exam will be replaced with a full 
physical exam as this was the 
original intention. 






Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
93 
6.9.1: List of Laboratory Parameters 
Serum 
  
hsCRP 
7 alpha hydroxy 4 cholesten 3 one 
(C4)  
 
hsCRP 
Deleted reference to serum 
 
and C4 tests in this section as this 
section is used to inform sites on 
study procedures; C4/
 will 
not require additional blood 
sampling. 
6.9.5: Blood Volume 
The total blood volume collected to 
cover all sampling procedures (as 
required by the outline in Schedule 
of Procedures and Visits [Table 1]), 
is up to 215 mL during the study. 
The total blood volume collected to 
cover all sampling procedures (as 
required by the outline in Schedule of 
Procedures and Visits [Table 1]), is 
up to 270 mL during the study. 
The blood volume was revised to 
reflect changes to the study design 
and assessments. 
6.13: Pharmacokinetic Assessments 
An additional PK blood sample will 
be collected, if possible, at the time 
of any intolerable AE or SAE. 
An additional PK blood sample will 
be collected, if possible, at the time 
of any intolerable AE (an AE 
leading to study drug 
discontinuation) or SAE. 
The text was expanded upon to add 
the definition of an intolerable AE.  
6.14: C4 and 
 
New text 
C4 and 
 may be analyzed, 
if deemed necessary by the 
Sponsor, depending on ALP levels 
throughout the course of the study 
for exploratory objectives.  For this 
purpose, back up PK samples will 
be used. 
This section was created to inform 
sites on study procedures that will 
not require additional blood 
sampling. 
6.15.1: Adverse Event Reporting 
Monitoring of ongoing AEs will be 
continued up to 2 weeks after study 
medication administration. 
Monitoring of ongoing AEs will be 
continued up to 30 days after study 
medication administration. 
The text was corrected so that the 
duration of the monitoring period is 
consistent with the rest of the 
protocol. 
7: Visit Procedures 
New section 
Added a list of procedures for each 
visit to reflect the information in 
Table 1 (Schedule of Procedures and 
Visits) 
The Visit Procedures section was 
added to clarify which assessments 
are to be performed at each visit. 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
94 
Appendix 2: 5-D Pruritus Scale 
Appendix contained an example of 
the 5-D Pruritus Scale 
The appendix and 5-D Pruritus Scale 
example were deleted. 
The 5-D Pruritus Scale will be 
provided to clinics outside of the 
protocol. 
Appendix 3: PBC-40 Quality of Life 
Assessment 
Appendix contained an example of 
the PBC-40 Quality of Life 
Assessment 
The appendix and PBC-40 Quality of 
Life Assessment example were 
deleted. 
The PBC-40 Quality of Life 
Assessment will be provided to 
clinics outside of the protocol. 
  
 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
95 
Summary of Changes for Amendment 2.0 Dated 07 February 2018 
Protocol APD334-010 was amended to primarily add or clarify criteria and procedures to improve patient safety.  
Revised text in Amendment 2.0 is indicated in bold font, and text deleted from Version 1.0 is crossed out in the table below.  
Minor/editorial changes are not listed in the summary table.  
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
Global Change 
The screening period was up to 4 
weeks long, and the total study 
duration was up to 30 weeks. 
The screening period is now 4 to 8 
weeks long, and the total study 
duration is now up to 34 weeks. 
Baseline values should be established 
by at least two samples obtained at 
least 4 weeks to 8 weeks apart to 
account for disease-related changes 
in liver enzymes. 
Global Change 
dose escalation committee 
safety and dose escalation 
committee 
The name of the dose escalation 
committee was revised to the safety 
and dose escalation committee to 
better reflect its function. 
Synopsis: Dose-stopping Rules 
 
Any of the following findings in 
patients during treatment will lead to 
a stop in etrasimod dosing: 
Any of the following findings in a 
patient during treatment will lead to a 
stop in etrasimod dosing in the 
affected patient: 
The text was rephrased to make it 
clear that the stop in dosing will 
occur only in the affected patient. 
Synopsis: Dose-stopping Rules 
5.2.1: Dose-stopping Rules 
2.  ALT/AST >3 x baseline level and 
>ULN, or 
Total bilirubin >2 x baseline level 
and >1.8 mg/dL (30.8 umol/L) 
2.  Clinical evidence of drug-
induced liver injury (DILI; as 
described in 6.15) 
This dose-stopping rule was revised 
to reflect the new study drug 
discontinuation for suspected DILI 
criteria added to this version of the 
protocol. 
Synopsis: Dose-stopping Rules 
6.15.1: Close Observation for 
Possible DILI 
New text 
Close Observation for Possible 
DILI: 
It is critical to initiate close 
observation immediately upon 
detection and confirmation of early 
signals of possible DILI, and not to 
wait until the next scheduled visit 
or monitoring interval. Close 
observation is mandatory for any 
study subject who meets one or 
To further protect patient safety, a 
detailed clinical management plan is 
included to evaluate and respond to 
cases of new elevations (or new 
elevations from baseline) in 
transaminases or tests of liver 
function.  
 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
96 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
more of the following “possible 
DILI” laboratory criteria: 
• ALT or AST that is <ULN at 
baseline, followed by ALT or 
AST increase to >3 x ULN 
• ALT or AST that is >ULN at 
baseline, followed by ALT or 
AST increase to >2 × baseline 
• ALP >2 × baseline 
• Total bilirubin >1.5 × ULN 
Synopsis: Dose-stopping Rules 
6.15.1: Close Observation for 
Possible DILI 
New text 
Close observation includes: 
• Repeating liver enzyme and 
serum bilirubin tests within 48-
72 hours. Then, repeating liver 
enzyme and serum bilirubin tests 
two or three times weekly. 
Frequency of retesting can 
decrease to once a week or less if 
abnormalities resolve, 
abnormalities stabilize, or the 
study drug has been discontinued 
and the subject is asymptomatic.  
• Obtaining a more detailed 
history of symptoms and prior or 
concurrent diseases.  
• Obtaining a history of 
concomitant drug use (including 
nonprescription medications and 
herbal and dietary supplement 
preparations), alcohol use, 
recreational drug use, and 
special diets.  
To further protect patient safety, a 
detailed clinical management plan is 
included to evaluate and respond to 
cases of new elevations (or new 
elevations from baseline) in 
transaminases or tests of liver 
function.  
 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
97 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
• Ruling out acute viral hepatitis 
types A, B, C, D, and E; 
autoimmune or alcoholic 
hepatitis; nonalcoholic 
steatohepatitis; hypoxic/ischemic 
hepatopathy; and biliary tract 
disease.  
• Obtaining a history of exposure 
to environmental chemical 
agents.  
• Obtaining additional tests to 
evaluate liver function, as 
appropriate (e.g., INR, direct 
bilirubin).  
• Considering consultations, 
imaging studies, and/or 
therapeutic interventions, as 
required. 
Synopsis: Dose-stopping Rules 
6.15.2: Study Drug Discontinuation 
for Suspected DILI 
New text 
Study Drug Discontinuation for 
Suspected DILI: 
Should any patient who meets 
“possible DILI” laboratory criteria 
have persistence or worsening of 
lab data (i.e., ALT, AST, ALP, 
and/or total bilirubin) after one 
week of close observation, study 
drug must be discontinued. In 
addition, immediate study drug 
discontinuation is mandatory for 
any study patient who meets one or 
more of the following “suspected 
DILI” clinical criteria:  
To further protect patient safety, a 
detailed clinical management plan is 
included to evaluate and respond to 
cases of new elevations (or new 
elevations from baseline) in 
transaminases or tests of liver 
function.  
 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
98 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
• ALT or AST <2 × ULN at 
baseline, followed by ALT or 
AST increase to >5 × baseline 
• ALT or AST ≥2 × ULN but <5 × 
ULN at baseline, followed by 
ALT or AST increase to >3 × 
baseline 
• ALT or AST increase to >2 × 
baseline AND concomitant total 
bilirubin increase to >2 × 
baseline 
• ALT or AST increase to >2 × 
baseline AND concomitant INR 
increase >0.2 
• Clinical signs and symptoms of 
liver inflammation, including but 
not limited to fatigue, nausea, 
vomiting, right upper quadrant 
pain or tenderness, fever, rash, 
jaundice, icterus, and/or 
eosinophilia (>5%) 
Synopsis: Dose-stopping Rules 
Synopsis: Dose-stopping Rules 
6.6.3: ECG Assessment 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
99 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
Synopsis: Inclusion Criteria 
4.1.1: Inclusion Criteria 
1. Males or females aged 18 to 75 
years (inclusive) at the time of 
screening, with confirmed PBC 
1. Males or females aged 18 to 80 
years (inclusive) at the time of 
screening, with confirmed PBC 
The upper limit of the age range for 
inclusion into the study was 
increased from 75 to 80 years to 
increase the number of subjects 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
100 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
diagnosis based upon at least 2 
of 3 criteria: 
diagnosis based upon at least 2 
of 3 criteria: 
eligible for study participation.  
Safety-related criteria already 
included in the study will exclude 
elderly subjects who are not 
appropriate for this study. 
Synopsis: Inclusion Criteria 
4.1.1: Inclusion Criteria 
2. Inadequate response to UDCA 
defined by an ALP >1.67 × 
ULN after 6 months of UDCA 
at a minimum dose of 
13 mg/kg/day 
2. Inadequate response to UDCA 
defined as ALP >1.67 × ULN 
after 6 months of UDCA 
therapy 
The UDCA dose required to meet 
study inclusion was removed to 
better reflect clinical practices.  
Synopsis: Inclusion Criteria 
4.1.1: Inclusion Criteria 
3. Be on a stable dose of UDCA 
for at least 6 months prior to 
screening 
3. Be on a stable dose of UDCA 
for at least 3 months prior to 
screening 
For inclusion in the study, a patient 
must have had an inadequate 
response to UDCA after 6 months of 
therapy but only on a stable dose for 
3 months.   This timeframe is suitable 
to demonstrate that the patient’s 
disease state is fairly stable at the 
time of screening.  
Synopsis: Inclusion Criteria 
4.1.1: Inclusion Criteria 
Synopsis: Inclusion Criteria 
 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
101 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
Synopsis: Exclusion Criteria 
4.1.1: Inclusion Criteria 
New text 
9. AST, ALT, ALP, or total 
bilirubin must have 2 values 4 
weeks apart that are within 20% 
of each other. 
A criterion requiring subjects to have 
stable liver enzymes and bilirubin 
concentrations during screening was 
added to exclude subjects with 
evidence of worsening liver function. 
Synopsis: Exclusion Criteria 
4.1.2: Exclusion Criteria 
2. History or evidence of 
clinically significant hepatic 
decompensation: 
2. History or evidence of 
clinically significant hepatic 
decompensation: 
The symptoms and clinical 
presentation of clinically significant 
hepatic decompensation were 
clarified. 
Synopsis: Exclusion Criteria 
4.1.2: Exclusion Criteria 
Synopsis: Exclusion Criteria 
4.1.2: Exclusion Criteria 








Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
105 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
6.9: Clinical Laboratory Tests 
Tests will be performed in the local 
laboratory as per study site standards. 
Tests will be performed in the 
central laboratory. If the patient 
lives in a remote area, laboratory 
testing for close observation for 
possible DILI may be performed 
locally and the results promptly 
communicated to the clinic. 
Clarified that a local laboratory may 
be used for patients who live in 
remote areas for DILI monitoring to 
allow for a more rapid assessment of 
liver function.  
6.9.1: List of Laboratory Parameters 
6.9.5: Blood Volume 
The total blood volume collected to 
cover all sampling procedures (as 
required by the outline in Schedule 
of Procedures and Visits [Table 1]), 
is up to 200 mL during the study. 
The total blood volume collected to 
cover all sampling procedures (as 
required by the outline in Schedule of 
Procedures and Visits [Table 1]), is 
up to 215 mL during the study. 
The blood volume was updated to 
account for the 6 optional PK 
samples added to this amendment 
6.15 Drug-Induced Liver Injury 
(DILI) Surveillance 
New text 
In July 2009, the FDA released a 
Guidance for Industry entitled 
“Drug-Induced Liver Injury: 
Premarketing Clinical 
Evaluation,” which reviews the 
importance of DILI surveillance in 
drug development. DILI has been 
the most frequent single cause of 
safety-related drug marketing 
withdrawals for the past 50 years, 
and hepatotoxicity discovered after 
approval for marketing has limited 
the use of many drugs. 
Furthermore, the guidance 
addresses how laboratory 
measurements that signal the 
potential for DILI can be obtained 
and evaluated during drug 
development. 
Background information regarding 
the importance of DILI monitoring 
was added to provide context for the 
clinic staff. 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
106 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
Given the fact that all subjects 
enrolled in this study have pre-
existing liver disease (i.e., PBC) 
and baseline elevations in 
laboratory tests of liver health 
(ALP, ALT and/or AST), DILI 
surveillance is of critical 
importance to patient safety. 
Therefore, in collaboration with 
the FDA and after careful 
consideration of the principles 
outlined in the DILI guidance, the 
sponsor has established procedures 
to ensure early detection of 
possible DILI and study drug 
discontinuation in the context of 
suspected DILI. 
6.18: Study and Site Discontinuation 
New text. 
Additionally, if more than three 
patients develop a CTCAE grade 3 
or higher event in the same 
category, or if three or more 
patients meet one of the individual 
stopping rules, the safety and dose 
escalation review committee (5.5) 
will convene to evaluate the 
findings. Further, dosing will be 
stopped in randomized patients 
and no new patients will be 
randomized until the safety and 
dose escalation review committee 
reviews and evaluates the findings. 
Expanded upon the definition of the 
original stopping criteria “incidence 
or severity of AEs in this or other 
studies indicating a potential hazard 
to patients.” 


Etrasimod (APD334) 
Arena Pharmaceuticals, Inc. 
Clinical Trial Protocol: APD334-010 Amendment 04 
27 June 2018 
Confidential 
107 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
12: References