Clinical trial NCT03072953
Conditions: Pyoderma Gangrenosum
Sponsor: Arena Pharmaceuticals
Start date: 2017-06-07; Completion date: 2018-05-22
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this Phase 2a, open label, proof-of-concept clinical study is to assess the efficacy and safety of etrasimod (APD334) in patients with Pyoderma Gangrenosum.

Detailed description:

Arms: arm 1: APD334 active treatment for 12 weeks.
Interventions: intervention 1: APD334
Intervention descriptions: intervention 1: APD334 active treatment

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Trial Protocol: APD334-011
Study Title:
A Phase 2a, Open-label, Proof of Concept Study to Determine the 
Efficacy and Safety of Etrasimod (APD334) in Patients with 
Pyoderma Gangrenosum
Study Number:
APD334-011
Study Phase:
2a
Product Name:
Etrasimod (APD334)
EudraCT Number:
NA
Indication:
Pyoderma Gangrenosum
Investigators:
Multicenter
Sponsor:
Arena Pharmaceuticals, Inc.
6154 Nancy Ridge Drive
San Diego, California 92121
United States
Sponsor Contact:
Senior Director Clinical Development
Arena Pharmaceuticals Development, GmbH
Gotthardstrasse 3
CH-6300 Zug, Switzerland
Tel: 
Mb: 
e-mail: 
Medical Monitor
, MD
Medical Director Clinical Development
Arena Pharmaceuticals Development, GmbH
Gotthardstrasse 3
CH-6300 Zug, Switzerland
Tel: 
Mb: 
Email: 
Date
Original Protocol:
08 Feb 2017
Confidentiality Statement
This document contains confidential information of Arena Pharmaceuticals, Inc.  Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law.  Persons 
receiving this information must be notified that it is confidential and may not be further disclosed.


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
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TABLE OF CONTENTS
SYNOPSIS............................................................................................................................6
LIST OF ABBREVIATIONS..............................................................................................15
1
INTRODUCTION.......................................................................................................17
1.1
Background Information ....................................................................................18
1.1.1
Rationale for Proposed Clinical Study ......................................................18
1.1.2
Summary of Preclinical Data....................................................................19
1.1.2.1
Pharmacology.................................................................................19
1.1.2.2
Nonclinical Safety ..........................................................................19
1.1.3
Summary of Clinical Data ........................................................................21
1.2
Ethics and Regulatory Considerations ................................................................23
2
STUDY OBJECTIVES................................................................................................25
2.1
Objectives..........................................................................................................25
3
INVESTIGATIONAL PLAN ......................................................................................26
3.1
Overall Study Design and Plan...........................................................................26
3.2
Study Duration and Dates...................................................................................27
4
STUDY POPULATION ..............................................................................................30
4.1
Inclusion and Exclusion Criteria ........................................................................30
4.1.1
Inclusion Criteria......................................................................................30
4.1.2
Exclusion criteria......................................................................................31
5
STUDY TREATMENT(S) ..........................................................................................34
5.1
Study Drug.........................................................................................................34
5.2
Dosage, Administration and Accountability .......................................................34
5.3
Investigational Product Retention at Study Site..................................................35
6
STUDY PROCEDURES .............................................................................................36
6.1
Informed Consent ..............................................................................................36
6.2
Medical History .................................................................................................36
6.3
Physical, Ophthalmological and Neurological Examinations..............................36
6.3.1
Physical Examination...............................................................................36
6.3.2
Ophthalmological Examination ................................................................36
6.3.3
Neurological Examination........................................................................36
6.4
Vital Signs .........................................................................................................37
6.6
Tuberculosis Screening ......................................................................................38


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
Page 3 of 67
6.8
Clinical Laboratory Tests...................................................................................38
6.8.1
List of Laboratory Parameters ..................................................................38
6.8.2
Virology...................................................................................................39
6.8.3
Urinalysis.................................................................................................40
6.8.4
Sample Collection ....................................................................................40
6.8.5
Blood Volume..........................................................................................40
6.9
Efficacy Assessments.........................................................................................40
6.9.1
Patient Global Assessment for Active Skin Manifestation Visual 
Analog Scale (VAS).................................................................................40
6.9.2
Physician Global Assessment for Active Skin Manifestations...................41
6.9.3
Dermatology Life Quality Index (DLQI) ..................................................41
6.9.4
C-reactive Protein (CRP)..........................................................................41
6.10
Other Exploratory Assessments..........................................................................41
6.10.1
Skin Punch Biopsies.................................................................................41
6.10.2
Imaging....................................................................................................41
6.10.3
Surface Area Evaluation...........................................................................41
6.11
Hematologic Assessments..................................................................................41
6.11.1
Complete Blood Count.............................................................................41
6.12
Adverse Events Assessments..............................................................................42
6.12.1
Adverse Event Reporting..........................................................................42
6.12.1.1
Progressive Multifocal Leukoencephalopathy (PML)......................43
6.12.2
Serious Adverse Events and Expedited Reporting of Adverse Events .......43
6.12.2.1
Patient and Patient-partner Pregnancy.............................................44
6.12.3
Assessment of Adverse Event Severity.....................................................45
6.12.4
Assessment of Adverse Event Relationship to Study Medication..............45
6.12.5
Assessment of Adverse Event Outcome....................................................46
6.12.6
Action Taken for Adverse Event...............................................................46
6.12.7
Action Taken for Study Drug ...................................................................46
6.12.8
Follow-up of Adverse Events Present at Last Scheduled Study Visit ........46
6.13
Concomitant Medications and Procedures..........................................................46
6.13.1
Permitted medications for the treatment of pyoderma gangrenosum 
and associated conditions .........................................................................47
6.13.2
Excluded Medications ..............................................................................47
6.14
Removal of Patients from the Trial or Study Drug..............................................47
6.14.1
Handling of Withdrawals..........................................................................48
6.14.2
Replacements ...........................................................................................48
6.15
Study and Site Discontinuation ..........................................................................48
7
DATA MANAGEMENT.............................................................................................50
7.1
Data Collection..................................................................................................50
7.2
Data Coding.......................................................................................................50
7.2.1
Adverse Events.........................................................................................50


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
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7.2.2
Concomitant Medications and Non-Drug Treatments ...............................50
7.2.3
Medical History........................................................................................50
8
PLANNED STATISTICAL METHODS .....................................................................51
8.1
Hypotheses and Objectives.................................................................................51
8.1.1
Objectives ................................................................................................51
8.1.1.1
Efficacy Objective ..........................................................................51
8.1.1.2
Safety Objective .............................................................................51
8.1.2
Hypotheses...............................................................................................51
8.2
Sample Size and Power Calculations..................................................................51
8.3
Analysis Populations..........................................................................................51
8.4
Demographics and Baseline Characteristics .......................................................51
8.5
Efficacy Endpoints.............................................................................................52
8.6
Statistical Methods.............................................................................................52
8.6.1
Efficacy Analysis .....................................................................................52
8.6.2
Subgroup Analyses...................................................................................52
8.7
Safety Analysis..................................................................................................53
8.7.1
Adverse Events.........................................................................................53
8.7.2
Physical Examinations..............................................................................53
8.7.3
Concomitant Medication ..........................................................................53
8.7.4
Vital Signs................................................................................................53
8.7.5
Clinical Laboratory Values.......................................................................53
9
REGULATORY REQUIREMENTS ...........................................................................55
9.1
Pre-Study Documentation ..................................................................................55
9.2
Investigator Obligations.....................................................................................55
9.3
Patient Confidentiality .......................................................................................55
9.4
Informed Consent ..............................................................................................55
9.5
Independent Ethics Committee (IEC) Human Research Ethics Committee 
(HREC)..............................................................................................................56
10
PROTOCOL MANAGEMENT AND ADMINISTRATIVE 
CONSIDERATIONS...................................................................................................57
10.1
Study Documentation.........................................................................................57
10.2
Protocol Interpretation and Compliance .............................................................57
10.3
Study Monitoring...............................................................................................57
11
PRINCIPAL INVESTIGATOR SIGNATURE PAGE .................................................58
12
REFERENCES............................................................................................................60
SPONSOR PROTOCOL SIGNATURE PAGE ...................................................................63
LIST OF IN-TEXT TABLES


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
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LIST OF APPENDICES
Appendix 1Progressive Multifocal Leukoencephalopathy (PML) Checklist ..................62
Appendix 2Physician Global Assessment for Active Skin Manifestations .....................63
Appendix 3Patients Global Assessment for Active Skin Disease VAS (Visual 
Analogue Scale)..........................................................................................64
Appendix 4Dermatology Life Quality Index (DLQI) form ............................................65


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
Page 6 of 67
SYNOPSIS
Name of Drug:
Etrasimod (APD334)
Indication
Pyoderma Gangrenosum (PG)
Sponsor:
Arena Pharmaceuticals, Inc.
154 Nancy Ridge Drive
San Diego, CA 92121, United States
Name of Sponsor 
Contact
Senior Director, Clinical Development
Arena Pharmaceuticals Development, GmbH
Gotthardstrasse 3
CH-6300 Zug, Switzerland
Tel: 
Mb: 
e-mail: 
Name of Principal 
Investigator(s):
Multicenter
Medical Monitor:
, MD
Medical Director Clinical Development
Arena Pharmaceuticals Development
Gotthardstrasse 3
CH-6300 Zug, Switzerland
Tel: 
Mb: 
Email: 
Test Product, Dose
and Mode of
Administration:
Etrasimod (APD334) 2mg tablets, once daily (q.d.) for 12 weeks.
Patients should be instructed to take their tablet as a first thing in the 
morning on an empty stomach). Patients should be advised not to 
crush, break, chew, or dissolve the tablet and to take study 
medication with water.
Concurrent Control:
No concurrent control
Background
Etrasimod is an orally available, selective, sphingosine 1-phosphate 
(S1P) receptor agonist. 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 which 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 circulation 1.
Agonists of the S1P1 receptor, such as etrasimod , block lymphocyte 


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
Page 7 of 67
migration out of the lymph tissue through internalization of the 
receptor, resulting in a sequestration of lymphocytes 1. Recent 
clinical development of S1P1 receptor agonists has demonstrated 
their effect on resulting lymphocyte sequestration, have potential for 
treating multiple autoimmune and chronic inflammatory diseases 
including multiple sclerosis, IBD and psoriasis.
Rationale for use of etrasimod in Treatment of Pyoderma 
Gangrenosum
Histopathology of ulcerative Pyoderma Gangrenosum (PG) is 
characterized by a dense dermal infiltrate composed mainly of 
neutrophils in biopsy from the central area of ulceration, and a 
mainly lymphocytic infiltrate with thrombosis of vessels and 
extravasated erythrocytes in biopsy from the border of the ulcer 2. In 
patients with ulcerative PG the number of T-lymphocytes are 
significantly higher at the wound edge compared to the wound bed. 
In contrast, neutrophils are significantly more numerous in the 
wound bed than the wound edge 3. This suggests that activated 
T-lymphocytes at the wound edge could promote ulcer formation. 
Further support for T-cell involvement in the disease comes from 
observations in PG patients that are characterized by an 
over-expression in the blood of the CD4+CCR5+ and CD4+CCR6+ 
and a down-regulation of CD4+CCR4+ counts with respect to 
healthy subjects 4.
In addition, a differentiated profile for etrasimod compared to other 
S1P modulators for the treatment of PG could arise from the 
hypothesis that S1P4 as well as S1P1 receptor agonism could aid in 
neutrophil trafficking 5.
Together, this evidence suggests that T-lymphocytes can play a role 
in PG and that reduction of lymphocytes by S1P1 modulators like 
etrasimod may represent a novel therapeutic approach in PG.
Objectives:
Efficacy
•
To evaluate the efficacy of etrasimod in patients with PG 
over a 12-week treatment period.
Safety
•
To assess the safety and tolerability of etrasimod in patients 
with PG over a 12-week treatment period.
Study Design
This is a Phase 2a, open label, proof-of-concept clinical study to 
assess the efficacy and safety of etrasimod in patients with PG.  The 
trial will include adult patients 18-80 years of age with active PG 
ulcers. 


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
Page 8 of 67
All visits in the study are ambulatory visits.  The screening period 
will last up to 4 weeks and will be followed by a 12-week treatment 
period.  During the treatment period, patients will need to take 
1 tablet of study medication once per day.  The last dose is planned 
to be taken one day before the end of the treatment period (Week 
12).  A follow-up visit will take place 2 weeks after the end of 
treatment. 
Screening Period(up to 4 weeks):
Each patient will be asked to visit the study site for screening 
assessments within 4 weeks prior to the planned start of the 
treatment (Day 1). 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.
 
 
 
Treatment Visits:
Baseline Visit (Day 1): Patients will return to the study site to 
receive the first dose of the study medication. Patients should be 
instructed to take their tablet as a first thing in the morning on an 
empty stomach.  Patients should be advised not to crush, break, 
chew, or dissolve the tablet and to take study medication with water.  
The patients will remain at the study site for at least 6 hours for 
safety evaluation (please refer to the 
 
 
 
Visits Week 2, Week 4, Week 8, and Week 12: Patients will return to 
the study site and all planned examinations as described in 
 
will be conducted.  Last dose of 
study medication is planned 1 day before the end of the treatment 
visit at Week 12.
Follow up Visit/End of Study Visit:
Visit Week 14, 2 weeks after end of treatment: Patients will return to 
the study site for the final visit, and final procedures will be 
performed per 


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
Page 9 of 67
Premature Discontinuation: All procedures planned for Week 12 
visit should be performed for all patients who discontinue the study 
prematurely. 
Study Site(s)
This study will be conducted in approximately 6 clinical centers.
Study population
Patients with PG who fulfill eligibility criteria.
Inclusion Criteria:
1. Male or female of age 18 to 80 years (inclusive) at the time of 
screening.
2. Able to provide a signed informed consent prior to any study 
related procedure being conducted and willing and able to 
comply with the study requirements.
3. Diagnosis of PG with active, non-healing ulcer.
4. Considered to be in stable health in the opinion of the 
investigator, as determined by:
a.) A screening physical examination with no clinically 
significant abnormalities unrelated to PG.
b.) Vital signs at screening: pulse rate ≥ 55 bpm, systolic blood 
pressure (SBP) ≥90 mmHg, and diastolic blood pressure 
(DBP) ≥55 mmHg. 
c.) Liver function tests (alanine aminotransferase 
[ALT]/aspartate aminotransferase [AST], bilirubin and 
alkaline phosphatase) < 2x the upper limit of normal (ULN).
d.) All other pre-study clinical laboratory findings within 
normal range, or if outside of the normal range are not 
deemed clinically significant in the opinion of the 
investigator with exemption to leucopenia and lymphopenia 
– please refer to exclusion criterion #24. 
e.) No clinical abnormalities noted in the12-lead 
electrocardiogram (ECG) in the opinion of the investigator 
(Refer also to exclusion criterion #13.
f.) No evidence of macular edema in an ophthalmology 
evaluation (performed by an ophthalmologist), supported 
with optical coherence tomography (OCT), where available 
(dependent on site capability) at screening.
5. Eligible male and female patients must agree not to participate 
in a conception process (i.e. active attempt to let female partner 
to become pregnant or to impregnate, sperm donation, oocyte 
donation, in vitro fertilization) for at least 30 days after the last 
dose of study drug.
Female patients who are sexually active with non-sterile male 
partner must be:
a.) non-pregnant (evidenced by a negative serum human 


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
Page 10 of 67
chorionic gonadotropin (hCG) pregnancy test at screening 
and a urine dipstick pregnancy test at Day 1)
b.) non-lactating
c.) one of the following:
-
either sexually abstinent (if this is the preferred and usual 
lifestyle of the individual). Periodic abstinence 
(calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), and lactational 
amenorrhoea methods are not acceptable 
-
or surgically sterile (surgical sterility prior to screening 
for at least 6 months for tubal ligation performed 
laparoscopically, hysterectomy and/or bilateral 
oophorectomy)
-
or postmenopausal (at least 2 years without menses)
-
or agree to continue to use an accepted method of birth 
control. Patients should be consistently using the 
hormonal contraceptive for at least 1 month (30 days)
prior to screening, during the study and for at least 
30 days after last study medication administration
Acceptable methods of birth control are:
-
combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation)
•
oral
•
intravaginal
•
transdermal
-
progestogen-only hormonal contraception associated 
with inhibition of ovulation
•
oral
•
injectable
•
implantable
-
intrauterine device (IUD)
-
intrauterine hormone-releasing system (IUS)
Contraceptive measures, such as Plan B (used after unprotected 
sex), are not acceptable methods of contraception for this study.
Eligible male patients will either be:
-
surgically sterile (i.e., vasectomy), for at least 3 months 
(90 days) prior to screening
or
-
when sexually active with a female partner, the partner 
must be either surgically sterile, postmenopausal, or 
agree to continue to use an accepted method of birth 
control during and for at least 30 days after last study 


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
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medication administration as defined above. Please 
note that the use of condoms alone or double barrier 
and use of spermicide are not an acceptable method of 
contraception for this study.
Exclusion criteria
1. Clinically significant infection (e.g., pneumonia, pyelonephritis) 
as judged by the investigator with an end date less than 6-weeks 
prior to treatment start (Day 1). In case of infection requiring 
hospitalization or intravenous antimicrobial therapy, or 
opportunistic infection, this infection must have ended at least 
8 weeks prior to Day 1.
2. Infection with hepatitis C virus anytime in the past; confirmed 
active infection with hepatitis B virus at screening.
3. History of severe renal or severe hepatic impairment.
4. Current active or latent tuberculosis (TB), regardless of 
treatment history or history of TB that has not been successfully 
treated
5. A positive diagnostic TB test at screening defined as a positive 
QuantiFERON® test or 2 successive indeterminate 
QuantiFERON® tests
6. Exposure to B-cell or T-cell targeted therapies (such as 
natalizumab, rituximab, abatacept) within 5 half-lives prior to 
Day 1.
7. Other immunosuppressive, immunomodulating or antineoplastic 
agents not listed in Section 6.13.1 or not meeting the stability 
time period for concomitant medications indicated as permitted 
in Section 6.13.
8. Receipt of any investigational agent within 30 days or 
5 half-lives (whichever is longer), prior to Day 1.
9. Use of moderate to strong inhibitors of CYP2C9 (e.g., 
amiodarone, felbamate, fluconazole, miconazole, piperine).
10. Abnormal forced expiratory volume (FEV1) or forced vital 
capacity (FVC) i.e., < 80% of predicted values at screening
11. Any known history of congenital or acquired immuno-
deficiency (e.g., common variable immunodeficiency, human 
immunodeficiency virus [HIV] infection [ELISA and Western 
blot] test result, organ transplantation).
12. Recent history (within 6 months of screening assessments) of 
cardio- or cerebrovascular disease, acute coronary syndrome
(ACS), myocardial infarction (MI), unstable angina, cerebro-
vascular accident, including transient ischemic attack (TIA).


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
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13. History or presence of cardiac arrhythmia, conduction system 
disease (including AV node dysfunction, 2nd or 3rd degree heart 
block, and sick sinus syndrome), or use of Class Ia or Class III 
anti arrhythmic agents, or baseline QTc ≥ 500 msec.
14. Congestive heart failure (NYHA III or NYHA IV)
15. Any surgical procedure requiring general anesthesia within 
30 days prior to Day 1 or plans to undergo major surgery during 
the study period.
16. History of retinal macular edema.
17. History of or signs and symptoms of progressive multifocal 
leukoencephalopathy (PML) as assessed by the PML checklist 
at screening.
18. History of more than one episode of herpes zoster or any 
episode of disseminated zoster.
19. Patients without documented positive varicella zoster virus 
(VZV) IgG-antibody status or patients who have not completed 
VZV vaccination within 6 weeks prior to Day 1.
20. Receipt of live vaccine within 6 weeks prior to Day 1.
21. History of lymphoproliferative disorder, lymphoma, leukemia, 
myeloproliferative disorder, or multiple myeloma.
22. History of malignancy except for adequately treated basal cell 
skin cancer and in situ carcinoma of the cervix of the uterus that 
have been completely excised with documented, clear margins.
23. History of severe allergic or anaphylactic reactions requiring 
medical attention.
24. Leukopenia or lymphopenia at screening.
25. Current or recent history (within 1 year prior to Day 1) of 
alcohol dependence or illicit drug use.
26. Active psychiatric problems that, in the investigator’s opinion, 
may interfere with compliance with the study procedures.
27. History of any other clinically significant medical condition 
that, in the investigator's opinion, would preclude patient from 
safe participation in the study.
28. Inability to attend all the study visits or comply with study 
procedures.
29. Prior exposure to etrasimod or prior participation in any study of 
etrasimod.
Duration of the 
Up to 18 weeks total: up to 4 weeks for screening, followed by a 


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
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Study (per Patient):
12-week treatment period and a follow-up visit 2 weeks after the 
end of treatment.
Sample Size:
Eight (8) patients
Efficacy Endpoints:
As this is a proof-of-concept study, all endpoints will be 
exploratory.
The efficacy endpoints will be as follows:
-
change from baseline (Day 1 pre-dose) to Week 12 in 
Physician Global Assessments for active skin manifestations.
Assessment of target lesion/ulceration
0: Total resolution of target ulcer with no signs of 
active PG 
1:
almost completely healed target ulcer with only 
minimal signs of active PG 
2: Evidence of target ulcer healing which involves at 
least 50% of ulcer/ulcer margin 
3:
Evidence of target ulcer healing which involves less 
than 50% of ulcer/ulcer margin 
4:
No evidence of target ulcer healing
-
change from baseline (Day 1 pre-dose) to Week 12 in Patient 
Global Assessments for active skin manifestations: visual 
analog scale (VAS) for assessment of severity of the disease
and severity of pain by patient.
-
change from baseline (Day 1 pre-dose) to Week 12 in 
Dermatology Life Quality Index (DLQI)
-
change from baseline (Day 1 pre-dose) to Week 12 in CRP 
levels
In addition, the following measures will be assessed as per 
 
-
Imaging (digital photos) of the target lesion.
-
Evaluation of the changes in surface area of target lesion.
-
Punch Biopsy (Histology)
Safety Assessments:
The following will be captured to assess the safety endpoints:
-
Adverse event reporting
-
Clinical laboratory test (including hematology, serum 
chemistry, coagulation and urinalysis) 
-
Physical and neurological examination
-
Vital sign measurement
-
12-lead ECG
Pharmacokinetic 
Assessments
Not planned.
Statistical Analyses:
There is no formal sample size estimation for this proof-of-concept 


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
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open label study. A sample size of 8 subjects is reasonable to assess 
proof-of-concept of the efficacy of etrasimod in the target 
population.
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.
Date
08 February 2017


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
Page 15 of 67
LIST OF ABBREVIATIONS
ACS
acute coronary syndrome
ADL
activities of daily living
AE
adverse event
ALK-P
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase (SGOT)
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
DLQI
Dermatology Life Quality Index
ECG
electrocardiogram
EIM
extra-intestinal manifestation
ELISA
enzyme-linked immunosorbent assay
EOS
end of study
EOT
end of treatment
FDA
Food and Drug Administration
FEV1
FU
forced expiratory volume in the first second
follow-up 
FVC
forced vital capacity
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HREC
human research ethics committee (AUS)
HIV
human immunodeficiency virus
HR
heart rate
ICH
International Conference on Harmonization
ICF
informed consent form
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board
INR
IUD
IUS
international normalized ratio
intrauterine device 
hormone-releasing system


Etrasimod (APD334)
Arena Pharmaceuticals, Inc.
Clinical Trial Protocol: APD334-011
08 February 2017
Confidential
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kg
kilogram
LDH
lactate dehydrogenase
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
NOAEL
no observed adverse effect level
OCT
optical coherence tomography
OTC
over-the-counter
PBL
peripheral blood lymphocyte
PFT
pulmonary function test
PG
pyoderma gangrenosum
PGA
Physicians Global Assessments
PI
Principal Investigator
PPD
A CRO responsible for SAE processing in this study
PPD PVG
A Pharmacovigilance department of PPD
PRO
patient reported outcome
PV
pharmacovigilance
q.d.
quaque die (once daily)
SAP
statistical analysis plan
S1P
sphingosine 1-phosphate receptor
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
TIA
transient ischemic attack
UC
ulcerative colitis
ULN
upper limit of normal
VAS
visual analogue scale
VS
vital signs
VZV
varicella zoster virus
WBC
white blood cell
WHO
World Health Organization 
WHODRUG
World Health Organization Drug Dictionary


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1
INTRODUCTION
Etrasimod (APD334) is an orally available, selective, sphingosine 1-phosphate (S1P)
receptor agonist.  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 which 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 circulation 1.
PG is considered to be a rare disorder associated with inflammation, mainly characterized 
by large skin ulcers 2, 3.  The ulcers are known to break down at a rapid rate and are 
painful, often turning necrotic 6.  Other inflammatory diseases such as inflammatory 
bowel disorder (IBD), ulcerative colitis (UC) and Bechet’s disease are indicated to share 
the same clinicopathophysiology 7.  PG was considered to have a parallel relationship 
with other underlying diseases (e.g., UC, IBD) with PG being the cutaneous manifestation
8, however this was refuted by Driesch 9 and published data support consideration of PG 
as an independent disease, irrespective of underlying disorders.
Based upon U.S. Department of Health and Human Services' National Institutes of
Health's Office of Rare Disease Research, the incidence of PG has been estimated that 
each year in the United States, 1 person per 100,000 people is affected 10. The incidence 
peak occurs between the ages of 20 to 50 years, with women being more often affected 
than men 11.
Diagnosis of PG is reliant on clinical signs, exclusion principle and supported by 
histopathology of the biopsy 11, 12.  The histopathology can differ dependent on the timing 
(early stage-mild to moderate perivascular lymphocytic infiltrate; late-stage necrosis with 
dense lymphocytic infiltration along with involvement of blood vessels) and site of 
biopsy6.  The diagnosis using clinical signs alone has been shown historically to lead to 
misdiagnoses as PG for at least 6 categories including vascular occlusive or venous 
disease, vasculitis, cancer, infectious disease, exogenous tissue injury and drug reactions
12, and support of exclusion and histopathology is recommended for diagnosis.
Treatment options
The best documented treatments are systemic corticosteroids and cyclosporin A. 
Combinations of steroids with cytotoxic drugs are used in resistant cases.
The 
combination of steroids with sulfa drugs or immunosuppressants has been used as steroid-
sparing modalities.  In some cases, anti-TNF therapy was reported to be beneficial which 
suggests that inhibition of TNF may help.
Gevokizumab is a potent IL-1 beta monoclonal antibody with unique allosteric 
modulating properties and has the potential to treat patients with a wide variety of 
inflammatory and other diseases. Gevokizumab binds strongly to interleukin-1 beta (IL-1 
beta), a pro-inflammatory cytokine, and modulates the cellular signaling events that 
produce inflammation. This agent was being developed as a potential treatment for PG 
but development was discontinued in 2016.


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In addition, results from studies for canakinumab, another anti IL-1β biologic, have been 
published for this drug 13.
 
 
Lymphocyte 
trafficking agents such as natalizumab and vedolizumab, both injectable or infused 
therapies, have demonstrated efficacy in IBD indications. More recently, ozanimod, an 
S1P1 oral receptor modulator, showed promising results in a Phase 2 study for UC 14.
The availability of lymphocyte trafficking agents such as etrasimod would offer patients 
an additional, oral treatment for PG.
1.1
Background Information
1.1.1
Rationale for Proposed Clinical Study
Agonists of the S1P1 receptor block lymphocyte migration out of the lymph tissue 
through internalization of the receptor, resulting in a sequestration of lymphocytes 15. 
Recent clinical development of S1P1 receptor agonists and the resulting lymphocyte 
sequestration have potential for treating multiple autoimmune and chronic inflammatory 
diseases including multiple sclerosis, IBD and psoriasis. Fingolimod was the first drug in
this class to be approved for the treatment of multiple sclerosis 16. More recently the S1P1
receptor agonist ponesimod was observed to reduce the severity of chronic plaque 
psoriasis after chronic oral administration in a Phase 2 randomized clinical trial 17. In this 
study, ponesimod was associated with dyspnea, elevated liver enzymes, bradycardia, 
headache and dizziness. Furthermore, S1P1 agonists (FTY720, SEW2871) have been 
observed to have an anti-inflammatory impact on the production of IL-12 family 
cytokines, indicating therapeutic potential for S1P treatment of several inflammatory 
diseases like psoriasis 18.
Importantly, a recent report demonstrating S1P4 agonists 
inhibition of plasmacytoid dendritic cell activation and interferon-alpha production 
suggest a potential therapeutic role for S1P1/S1P4 agonists like etrasimod in paradoxical 
psoriasis 19.
In addition to the potential anti-inflammatory benefits of systemic lymphocyte 
immunomodulation, S1P is known to exert anti-proliferative effects in human 
keratinocytes 20, and inhibits dendritic cell migration 21. Thus, the potential role of S1P 
receptor modulation in skin EIMs of IBD might involve both systemic and local 
epidermal mechanisms.
Histopathology of ulcerative PG is characterized by a dense dermal infiltrate composed 
mainly of neutrophils in biopsy from the central area of ulceration, and a mainly 
lymphocytic infiltrate with thrombosis of vessels and extravasated erythrocytes in biopsy 
from the border of the ulcer
2. 
In patients with ulcerative PG the number of 
T-lymphocytes are significantly higher at the wound edge compared to the wound bed. In 
contrast, neutrophils were significantly more numerous in the wound bed than the wound 
edge 3. This suggests that activated T-lymphocytes at the wound edge could promote
ulcer formation.  Further support for T-cell involvement in the disease comes from 
observations in PG patients that are characterized by an over-expression in the blood of 


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the CD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts with 
respect to healthy subjects 4.
In addition, a differentiated profile for etrasimod compared to other S1P modulators for 
the treatment of PG could arise from the hypothesis that S1P4 as well as S1P1 receptor 
modulation could aid in neutrophil trafficking 5.
Together, this evidence suggests that T-lymphocytes can play a role in PG and that 
reduction of lymphocytes by S1P1 receptor modulators like etrasimod may represent a 
novel therapeutic approach in PG.
The aim of the proposed clinical study is to evaluate the role of S1P modulation in the 
setting of active cutaneous PG. Next generation S1P modulators such as etrasimod with 
improved side effect profiles may represent a novel therapy for PG patients.
1.1.2
Summary of Preclinical Data
1.1.2.1
Pharmacology
1.1.2.2
Nonclinical Safety


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1.1.3
Summary of Clinical Data


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1.2
Ethics and Regulatory Considerations  
The study will be conducted in compliance with the International Conference on 
Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), Title 21 of the 
United States (US) Code of Federal Regulations (CFR) Part 50 (21CFR §50 (Protection 
of Human Subjects), 21 CFR §56 (Institutional Review Boards [IRB]), and 21 CFR §312
(Investigational New Drug) and applicable 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.
The IEC must be notified promptly by the investigator of the following:
•
Deviations from, or changes in, the protocol to eliminate immediate hazards to the 
trial participants
•
Changes increasing the risk to participants and/or affecting significantly the conduct 
of the trial
•
All AEs that meet the definition of a SAE if according to the local law and 
regulation
•
New information that may adversely affect the safety of the participants during the 
conduct of the trial.


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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 or when the changes involve only logistical or administrative aspects of the trial 
(for example, change of medical monitor, change in telephone number, etc.). 


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2
STUDY OBJECTIVES
2.1
Objectives
Efficacy
•
To evaluate the efficacy of etrasimod (APD334) in patients with PG over a 
12-week treatment period.
Safety
•
To assess the safety and tolerability of etrasimod (APD334) in patients with PG
over a 12-week treatment period.


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3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
This is a Phase 2a, open label, proof-of-concept clinical study to assess the efficacy and 
safety of etrasimod (APD334) in patients with PG.  The trial will include adult patients,
18-80 years of age with active PG ulcers. 
All visits in the study are ambulatory visits.  The screening period will last up to 4 weeks 
and will be followed by a 12-week treatment period.  During the treatment period, 
patients will need to take 1 tablet of study medication once per day.  The last dose is 
planned to be taken one day before the end of the treatment period at Week 12.  A 
follow-up visit will take place 2 weeks after the end of treatment. 
Figure 1
Study Design
The study will consist of the following periods:
Screening Period (up to 4 weeks before baseline visit): 
Each patient will be asked to visit the study site for screening assessments within 4 weeks 
prior to the planned start of the treatment (Day 1).  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.
 
Treatment Visits:
Baseline Visit (Day 1): Patients will return to the study site to receive the first dose of the 
study medication.  Patients should be instructed to take their tablet as a first thing in the 
morning on an empty stomach.  Patients should be advised not to crush, break, chew, or 
dissolve the tablet and to take study medication with  water.  The patients will remain at 
the study site for at least 6 hours for safety evaluation (please refer to the 
 
 
 
Visits Week 2, Week 4, Week 8, and Week 12: Patients will return to the study site and 
perform all planned examinations as described in 
 
  Last dose of study medication is planned 1 day before the end of the 
treatment visit at Week 12.  


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Follow up Visit/End of Study Visit:
Visit Week 14, 2 weeks after end of treatment: Patients will return to the study site for the 
final visit, and final procedures will be performed per 
 
Premature Discontinuation: All procedures planned for Week 12 visit should be 
performed for all patients that discontinue the study prematurely.
3.2
Study Duration and Dates
The study duration will be up to 18 weeks per patient.  This will include up to 4 weeks for 
screening, followed by a 12-week treatment period and a follow-up visit 2 weeks after the 
end of treatment.


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4
STUDY POPULATION
The study population will consist of eight (8) patients with PG 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.
4.1.1
Inclusion Criteria
1. Male or female of age 18 to 80 years (inclusive) at the time of screening.
2. Able to provide a signed informed consent prior to any study related procedure being 
conducted and willing and able to comply with the study requirements.
3. Diagnosis of PG with active, non-healing ulcer.
4. Considered to be in stable health in the opinion of the investigator as determined by:
a.) A screening physical examination with no clinically significant abnormalities 
unrelated to PG.
b.) Vital signs at screening: pulse rate ≥ 55 bpm, systolic blood pressure (SBP) 
≥90 mmHg, and diastolic blood pressure (DBP) ≥55 mmHg. 
c.) Liver function tests (alanine aminotransferase [ALT]/aspartate aminotransferase 
[AST], bilirubin and alkaline phosphatase) < 2x the upper limit of normal (ULN).
d.) All other pre-study clinical laboratory findings within normal range, or if outside 
of the normal range are not deemed clinically significant in the opinion of the 
investigator with exemption to leucopenia and lymphopenia – please refer to 
exclusion criterion #24. 
e.) No clinical abnormalities noted in the12-lead ECG in the opinion of the 
investigator (Refer also to exclusion criterion #13).
f.) No evidence of macular edema in an ophthalmology evaluation (performed by an 
ophthalmologist), supported with optical coherence tomography (OCT), where 
available (dependent on site capability) no later than 3 months prior to screening. 
5. Eligible male and female patients must agree not to participate in a conception 
process (i.e. active attempt to let female partner to become pregnant or to impregnate, 
sperm donation, oocyte donation, in vitro fertilization) for at least 30 days after the 
last dose of study drug.
Female patients who are sexually active with non-sterile male partner must be:
a.) non-pregnant (evidenced by a negative serum human chorionic gonadotropin 
(hCG) pregnancy test at screening and a urine dipstick pregnancy test at Day 1)
b.) non-lactating
c.) one of the following:
-
either sexually abstinent (if this is the preferred and usual lifestyle of the 
individual). Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), and lactational amenorrhoea
methods are not acceptable 


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-
or surgically sterile (surgical sterility prior to screening for at least 6 months 
for tubal ligation performed laparoscopically, hysterectomy and/or bilateral 
oophorectomy)
-
or postmenopausal (at least 2 years without menses)
-
or agree to continue to use an accepted method of birth control.  Patients 
should be consistently using the hormonal contraceptive for at least 1 month 
(30 days) prior to screening, during the study and for at least 30 days after last 
study medication administration  
Acceptable methods of birth control are:
-
combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation)
•
oral
•
intravaginal
•
transdermal
-
progestogen-only hormonal contraception associated with inhibition of 
ovulation
•
oral
•
injectable
•
implantable
-
intrauterine device (IUD)
-
intrauterine hormone-releasing system (IUS)
Contraceptive measures, such as Plan B (used after unprotected sex), are not acceptable
methods of contraception for this study.
Eligible male patients will either be:
-
surgically sterile (i.e., vasectomy), for at least 3 months (90 days) prior to 
screening
or
-
when sexually active with a female partner, the partner must be either 
surgically sterile, postmenopausal, or agree to continue to use an accepted 
method of birth control during and for at least 30 days after last study 
medication administration as defined in 7 above.  Please note that the use of 
condoms alone or double barrier and use of spermicide are not an acceptable 
method of contraception for this study.
4.1.2
Exclusion criteria
1. Clinically significant infection (e.g., pneumonia, pyelonephritis) as judged by the 
investigator with an end date less than 6-weeks prior to treatment start (Day 1).  In 
case of infection requiring hospitalization or intravenous antimicrobial therapy, or 
opportunistic infection, this infection must have ended at least 8 weeks prior to Day 1.


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2. Infection with hepatitis C virus anytime in the past; confirmed active infection with 
hepatitis B virus at screening.
3. History of severe renal or severe hepatic impairment.
4. Current active or latent tuberculosis (TB), regardless of treatment history or history of 
TB that has not been successfully treated
5. A positive diagnostic TB test at screening defined as a positive QuantiFERON® test 
or 2 successive indeterminate QuantiFERON® tests
6. Exposure to B-cell or T-cell targeted therapies (such as natalizumab, rituximab, 
abatacept) within 5 half-lives prior to Day 1.
7. Other immunosuppressive, immunomodulating or antineoplastic agents not listed in 
Section 6.13.1 or not meeting the stability time period for concomitant medications 
indicated as permitted in Section 6.13.
8. Receipt of any investigational agent within 30 days or 5 half-lives (whichever is 
longer), prior to Day 1.
9. Use of moderate to strong inhibitors of CYP2C9 (e.g., amiodarone, felbamate, 
fluconazole, miconazole, piperine).
10. Abnormal forced expiratory volume (FEV1) or forced vital capacity (FVC) i.e., < 80% 
of predicted values at screening.
11. Any known history of congenital or acquired immuno-deficiency (e.g., common 
variable immunodeficiency, human immunodeficiency virus [HIV] infection [ELISA 
and Western blot] test result, organ transplantation).
12. Recent history (within 6 months of screening assessments) of cardio- or 
cerebrovascular disease, acute coronary syndrome (ACS), myocardial infarction (MI), 
unstable angina, cerebro-vascular accident, including transient ischemic attack (TIA).
13. History or presence of cardiac arrhythmia, conduction system disease (including AV 
node dysfunction, 2nd or 3rd degree heart block, and sick sinus syndrome), or use of 
Class Ia or Class III anti arrhythmic agents, or baseline QTc ≥ 500 msec.
14. Congestive heart failure (NYHA III or NYHA IV).
15. Any surgical procedure requiring general anesthesia within 30 days prior to Day 1 or 
plans to undergo major surgery during the study period.
16. History of retinal macular edema.
17. History of or signs and symptoms of progressive multifocal leukoencephalopathy 
(PML) as assessed by the PML checklist at screening.
18. History of more than one episode of herpes zoster or any episode of disseminated 
zoster.
19. Patients without documented positive varicella zoster virus (VZV) IgG-antibody 
status or patients who have not completed VZV vaccination within 6 weeks prior to 
Day 1.
20. Receipt of live vaccine within 6 weeks prior to Day 1.


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21. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative 
disorder, or multiple myeloma.
22. History of malignancy except for adequately treated basal cell skin cancer and in situ 
carcinoma of the cervix of the uterus that have been completely excised with 
documented, clear margins.
23. History of severe allergic or anaphylactic reactions requiring medical attention.
24. Leukopenia or lymphopenia at screening; 
25. Current or recent history (within 1 year prior to Day 1) of alcohol dependence or
illicit drug use.
26. Active psychiatric problems that, in the investigator’s opinion, may interfere with 
compliance with the study procedures.
27. History of any other clinically significant medical condition that, in the investigator's 
opinion, would preclude patient from safe participation in the study.
28. Inability to attend all the study visits or comply with study procedures.
29. Prior exposure to etrasimod (APD334) or prior participation in any study of etrasimod 
(APD334).


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5
STUDY TREATMENT(S)
5.1
Study Drug
Etrasimod is an investigational product and will be provided by the Sponsor for the study.  
Etrasimod will be supplied as 2 mg immediate release tablets, packaged in high-density 
polyethylene bottles with child-resistant screw caps.  
 
 
 
Bottles should be stored at
°C (
ºF); excursions are permitted from 
°C to 
°C, until 
medication is dispensed.
5.2
Dosage, Administration and Accountability
Investigational product will be dispensed to the patients under the supervision of the 
investigator or his/her designee. Patients should be instructed to take their tablet as a 
first thing in the morning on an empty stomach.  Patients should be advised not to crush, 
break, chew, or dissolve the tablet and to take study medication with water.
Investigational product will be dispensed as follows:

1 bottle of 40 tablets at Day 1. Patient will be requested to bring the bottle back 
for drug accountability on Week 2; patient will return the bottle with all remaining 
tablets at Week 4.

1 bottle of 40 tablets at Week 4. Patient will return the bottle with all remaining 
tablets at Week 8.

1 bottle of 40 tablets at Week 8. Patient will return the bottle with all remaining 
tablets at Week 12.
The investigator will maintain accurate records of the receipt of all study medication. In 
addition, accurate records will be kept regarding when and how much study medication is 
dispensed and used by each patient in the study. 
Investigational product accountability will be performed by the site at Week 2, Week 4, 
Week 8 and Week 12.
Reasons for deviation from the expected dispensing regimen must also be recorded. 
Study medication will be reconciled by the Arena Pharmaceuticals monitor or contracted 
designee. The investigator agrees to provide sufficient access to study medication as
required for the reconciliation process to be completed in a timely fashion.


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5.3
Investigational Product Retention at Study Site
At completion of the study, all study medication will be reconciled by the Arena
Pharmaceuticals monitor or contracted designee, and then returned at the direction of the 
Arena Pharmaceuticals to be retained or destroyed according to applicable country
regulations. Prior to any action being taken with study medication after the study is 
completed, the investigator will contact Arena Pharmaceuticals (or contracted CRO) for 
approval of such action.


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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, that 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
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 
 
6.3
Physical, Ophthalmological and Neurological Examinations
6.3.1
Physical Examination
The examinations will be performed as outlined in 
 
 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.
6.3.2
Ophthalmological Examination
This examination will include visual acuity and dilated ophthalmoscopy (by an 
ophthalmologist) and with OCT (where available) to rule out and monitor for any 
significant retinal disease, including macular edema. Retinal photos will be taken. The 
examinations will be performed as outlined in 
6.3.3
Neurological Examination
The neurological examination includes assessments of the neurological system (cranial 
nerves, motor and sensory function, coordination, and mental status).  The examinations 
will be performed as outlined in 
In addition, 
monitoring for PML, a potential AE of S1P1 agonists, will be performed at each site visit 
using a subjective PML checklist (refer Section 
6.12.1.1). 
The investigator or sub-investigator will administer the subjective PML checklist during 
screening to exclude patients with positive responses from enrolling into the study. The 


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subjective PML checklist will also be administered at each site visit (except Day -1) to 
probe for symptoms suggestive of PML. Any patients reporting signs and/or symptoms 
of PML will undergo objective testing and must be referred to a neurologist for a full 
evaluation.  Additional information on PML is provided in Section 6.12.1.1 and a copy of 
the PML checklist is provided in Appendix 1.
6.4
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 
 


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6.6
Tuberculosis Screening
All patients will complete TB screening to determine eligibility. All patients must 
complete QuantiFERON® Test at screening.
Patients will be excluded from the study participation if they have active or latent TB, 
regardless of treatment history or a history of TB that has not been successfully treated. 
Patients will be also excluded from the study participation if they had a positive 
QuantiFERON® test or 2 successive indeterminate QuantiFERON® tests at screening. 
 
 
6.8
Clinical Laboratory Tests
The clinical laboratory tests will be performed as outlined in 
 
 
Tests will be performed in the local laboratory as per study site 
standard. 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.
6.8.1
List of Laboratory Parameters
Laboratory tests will include the following:
Serum Chemistry


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Albumin (ALB)
Alkaline phosphatase (ALK-P)
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)
FSH
Glucose
Lactate dehydrogenase (LDH)
Lipase
Magnesium
Phosphate 
Potassium (K)
Sodium (Na)
Total bilirubin 
Total cholesterol 
Total protein
Triglycerides
Hematology
Hematocrit (Hct)
Hemoglobin (Hb)
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
Prothrombin time (PT)
Activated partial thromboplastin time (PTT)
International Normalized Ratio (INR)
Additional tests
Serum human chorionic gonadotropin (hCG)
Follicle stimulating hormone (FSH)
HIV test
HBsAg
Anti- HCV
VZV IgG
QuantiFERON®
6.8.2
Virology
Evaluation of human immunodeficiency virus (HIV), hepatitis B (hepatitis B surface 
antigen), hepatitis C virus, and VZV IgG antibody will be performed at screening only.


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6.8.3
Urinalysis
Urinalysis will follow the local practice at the study site (as dip-stick).
Tests will be 
performed as outlined in 
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.
6.8.4
Sample Collection 
All blood and urine samples will be collected according to site standards.  Tests will be 
performed as outlined in 
 
6.8.5
Blood Volume
Total blood volume collected for CBC is up to 200 mL during the study.
6.9
Efficacy Assessments
All efficacy assessments are treated as exploratory, this being a proof of concept study.
6.9.1
Patient Global Assessment for Active Skin 
Manifestation Visual Analog Scale (VAS)
The patient global assessment for active skin manifestation is a tool to capture the disease 
and pain severity using a visual analogue to mark the patient’s score.  The assessment 
sheet asks the patient to rate their disease severity from “not severe” to “extremely 
severe” and pain levels from “no pain at all’ to “worst pain imaginable”.  This assessment 
sheet (Appendix 3) will be completed by the patient as per 
 
The assessment will be conducted at the study site during the patient’s scheduled visits.


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6.9.2
Physician Global Assessment for Active Skin 
Manifestations
The physician’s global assessment for active skin manifestations will record the number 
of ulcers, target lesion noted for endpoint evaluation, diameters of each target lesion and 
score of evaluation at each visit. The scores range from 0 (total resolution) to 4 (no 
evidence of healing) (Appendix 2).
This assessment sheet will be completed by the investigator after evaluating the patient’s 
disease as per 
6.9.3
Dermatology Life Quality Index (DLQI)
DLQI has been developed to use 10 simple questions to assess how much a patient’s life 
is affected through their skin problems (Appendix 4). This assessment sheet will be 
completed by the patient as per 
6.9.4
C-reactive Protein (CRP)
Elevation of CRP concentration have been observed in active PG and during subsequent 
relapses. 
High CRP levels have been also associated with poor prognosis of PG. 
Therefore CRP will be measured during the study to monitor potential correlation 
between the response to therapy and disease activity 29, 30. 
6.10
Other Exploratory Assessments
The following exploratory measures will also be assessed as per 
 
 
6.10.1
Skin Punch Biopsies
Histology data will be collected from the lesions via punch biopsies. Skin punch biopsies 
will be taken only if possible or necessary if deemed by investigator.
6.10.2
Imaging
Digital photos of the target lesion will be taken to document visual changes in the lesion.
6.10.3
Surface Area Evaluation
Evaluation of the changes in surface area of the target lesion will be done by the 
investigator.
6.11
Hematologic Assessments
6.11.1
Complete Blood Count
Blood samples for complete blood count (CBC) with differential and platelet count will 
be assessed. Tests will be performed as outlined in 


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If the absolute peripheral lymphocyte count has not recovered to at least 80% of the 
baseline value at the 2-week follow-up (week 14), the patient must return for weekly 
CBCs until the absolute peripheral lymphocyte count has returned to at least this value.
6.12
Adverse Events Assessments
Patients will be monitored from ICF signature to 2 weeks after the last dose of study drug
for AEs to the study drug and/or procedures.
AEs will be recorded and reported in accordance with ICH GCP and 21 CFR§312.32. 
The definitions of AEs and serious AEs (SAEs) will be as given in the ICH Topic E2A, 
ICH Guideline “Note for Guidance on Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting.”  The outcome of an AE will be defined according to 
ICH Topic E2B, ICH Guideline “Note for Guidance on Clinical Safety Data 
Management: Data Elements for Transmission of Individual Case Safety Reports.” The 
relationship to investigational product will be classified using the World Health 
Organization (WHO) criteria.
6.12.1
Adverse Event Reporting
Patients will be instructed to report all AEs, which can be reported at any time. AEs that 
occur from ICF signature until the time of administration of the first dose of etrasimod 
will be regarded as ‘pre-treatment’ and recorded as an AE. All events reported following 
study medication administration up to 30 days after the last medication intake will be 
presented as treatment emergent AEs (TEAEs).
Monitoring of ongoing AEs will be continued up to 2 weeks after study medication 
administration.
For this study, an AE is defined as: “Any untoward medical occurrence in a study patient
administered etrasimod which does not necessarily have to have a causal relationship with 
this treatment.” An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of 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 by asking the question: “Since 
you were last asked, have you felt unwell or different from usual in any way?”  Any 


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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.
6.12.1.1
Progressive Multifocal Leukoencephalopathy (PML)
A patient with multiple sclerosis developed PML after nearly 8 months of treatment with 
another S1P1 agonist 31, and enablement of the John Cunningham (JC) virus is therefore a 
potential adverse effect of this therapeutic class. Patients in this trial should therefore be 
monitored for any new onset or worsening of neurological signs and symptoms. Signs 
and symptoms associated with PML are diverse, progress over days to weeks, and include 
progressive weakness on one side of the body or clumsiness of limbs, disturbance of 
vision, and changes in thinking, memory, and orientation leading to confusion and 
personality changes. 
The progression of deficits usually leads to death or severe 
disability over weeks or months. If PML is suspected, withhold dosing and refer to a 
neurologist; if confirmed, discontinue dosing permanently.
The investigator or sub-investigator will administer the subjective PML checklist during 
screening to exclude patients with positive responses from enrolling into the study. The 
subjective PML checklist will be administered at each site visit (except D-1) to probe for 
symptoms suggestive of PML. Any patients reporting signs and/or symptoms of PML 
will undergo objective testing and must be referred to a neurologist for a full evaluation.
A copy of the PML checklist is provided in Appendix 1.
6.12.2
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
•
Important Medical Event
SAEs will be captured from the time of ICF signature to 30 days after the last dose of 
study drug, and will be monitored until resolution or stabilization.
An important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical 
judgment, it may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such a medical event 
includes allergic bronchospasm requiring intensive treatment in an emergency room or at 


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home, blood dyscrasias, or convulsions that do not result in in-patient hospitalization, or 
the development of drug dependency or drug abuse.
Elective hospitalization and/or surgery for clearly pre-existing conditions (for example a 
surgery that has been scheduled prior to the patient’s entry into the study) will not be 
reported as a SAE. All other hospitalizations, including elective hospitalizations for any 
condition that was not pre-existing, will be reported as a SAE.  
Any AE considered serious by the investigator or which meets SAE criteria must be 
reported to PPD Pharmacovigilance (PVG) within 24 hours from the time study site 
personnel first learn about the event. 
The following contact information is to be used for SAE reporting:
EMEA ASIA Safety Central Mailbox:
Or alternatively:
PPD Medical Affairs/Pharmacovigilance
PPD PVG Hotline:
(United Kingdom number) 
 
PPD PVG Fax line:
(United Kingdom number) 
A full description of every SAE will need to be provided to PPD PVG (this may be 
supported by source documentation such as laboratory reports or a discharge summary 
should the patient be hospitalized). 
Other safety issues as defined in ICH Topic E2A, 21 code of federal regulations 
(CFR) §312.32, and EU Eudralex Volume 10 also qualify for expedited reporting. In 
these situations, the process will be as detailed for SAEs above:
•
SAEs which could be associated with the trial procedures;
•
SAEs and AEs of special interest that could materially influence the benefit-risk 
assessment of a medicinal product, such as: a clinically important increase in the 
rate of a serious suspected adverse reaction over that listed in the investigator 
brochure.
6.12.2.1
Patient and Patient-partner Pregnancy
Patients who become pregnant during the study will be discontinued immediately. 
Although not considered an SAE or AE, pregnancies occurring during the period of study 
drug administration (Day 1 to Week 12) 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.


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6.12.3
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 32
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.
6.12.4
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.


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6.12.5
Assessment of Adverse Event Outcome
Outcome of AEs will be defined according to ICH Topic E2B, ICH Guideline.
•
Recovered/Resolved
•
Recovered/Resolved with Sequelae
•
Recovering/Resolving
•
Not Recovered/Not Resolved
•
Fatal
•
Unknown
6.12.6
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
6.12.7
Action Taken for Study Drug
Any action taken with study drug will be defined according to ICH Topic E2B, ICH
Guideline and documented in the CRF according to the following:
•
Drug Withdrawn
•
None (not changed)
•
Dose Interrupted
•
Unknown
•
Not Applicable
6.12.8
Follow-up of Adverse Events Present at Last 
Scheduled Study Visit
AEs present at the last study day (Week 12) that require follow-up or a repeat laboratory 
test will be followed-up according to the site’s standard practice for AE follow-up.
6.13
Concomitant Medications and Procedures
All medications (over the counter [OTC] and prescribed) that are taken by patients and all 
procedures that are performed during the screening period and during the study must be 
recorded in the case report form (CRF) with start date/time and stop date/time, if known.  
The following should be taken into account with regard to concomitant procedures:
•
Patients may not undergo major elective surgery while enrolled in this study.
•
Patients may not donate sperm, or oocytes during the study and for 30 days after 
the last dose of study drug.


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6.13.1
Permitted medications for the treatment of 
pyoderma gangrenosum and associated 
conditions
The following concomitant medication are allowed provided that the dose has been stable 
for at least 2 weeks prior to baseline and remain stable throughout the study: 
•
Oral corticosteroids (maximal allowed prednisone ≤20mg/day, or equivalent)
•
TNF-alpha inhibitor (etanercept, infliximab, adalimumab or other) 
•
Oral 5-ASA medication (for patients with ulcerative colitis)
•
Antidiarrheal treatment
•
OTC analgesics (paracetamol / acetaminophen, NSAIDs)
In addition, topical medication (other than excluded medication) that the patient is 
receiving at baseline should be continued, provided that these are stable for 2 weeks prior 
to baseline and should remain stable throughout the study.
Only non-sticking dressing of the wounds (e.g., jelonet and compression bandages) could 
be used throughout the study period. 
6.13.2
Excluded Medications
The following medications are excluded prior or during the study:
•
Exposure to B-cell or T-cell targeted therapies (such as natalizumab, rituximab, 
abatacept) within 5 half-lives prior to Day 1 
•
Other immunosuppressive, immunomodulating or antineoplastic agents or other 
monoclonal antibody / biologic not listed in the Permitted Medications within 5-
half-lives prior to Day 1 (small molecules) or 60 days prior to D1 (biologics). 
•
All live vaccines within 6 weeks prior to Day 1, during study treatment and for at 
least 6 months after the last dose of study drug
•
Moderate to strong inhibitors of CYP2C9 (e.g., amiodarone, felbamate, 
fluconazole, miconazole, piperine). within 5-half-lives prior to Day 1, during the 
study and for 2 weeks after the last intake of study medication
•
Other routes for systemic corticosteroids (IM and IV)
•
Class Ia or Class III anti-arrhythmic agents
•
Any other medication which in the opinion of the investigator would affect the 
suitability of the patient to continue in the study, interfere with interpretation of 
study results or affect compliance with the protocol requirements
•
Receipt of any investigational agent within 30 days or 5 half-lives (whichever is 
longer), prior to Day 1.
6.14
Removal of Patients from the Trial or Study Drug
Patients experiencing a significant infection (as judged by the investigator) will be 
discontinued from the study drug immediately.


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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.
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.
•
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 (<80%).
•
An AE.
•
Lost to follow up.
6.14.1
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 12 procedures.  If consented by the patient, effort will be made to 
conduct a follow-up visit within 2 weeks of discontinuation 
 if the patient has 
received at least 1 dose of the study drug.
6.14.2
Replacements
Patients who terminate early from the study will not be replaced.
6.15
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.
The Sponsor will notify the investigator 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:


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•
Excessively slow recruitment
•
Poor protocol adherence
•
Inaccurate or incomplete data recording
•
Non-compliance with the ICH guidelines for GCP


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7
DATA MANAGEMENT
7.1
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.
7.2
Data Coding
7.2.1
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’.
7.2.2
Concomitant Medications and Non-Drug 
Treatments
Due to the variability in how medications are recorded, a standard naming convention is 
required in order to tabulate this data effectively. A common method of standardization 
is to categorize medications by their Preferred Term. In order to do this, medications will 
be coded using the World Health Organization Drug Dictionary (WHO DD), Format C.
7.2.3
Medical History
Medical history will be coded using the most current MedDRA-version.


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8
PLANNED STATISTICAL METHODS
Details of the statistical analyses will be included in a separate statistical analysis plan 
(SAP) which will be finalized before database lock. If, after database lock, changes are 
made to the pre-specified SAP, the changes will be listed along with an explanation as to 
why they occurred in the Clinical Study Report.
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.
8.1
Hypotheses and Objectives
8.1.1
Objectives
8.1.1.1
Efficacy Objective
To evaluate the efficacy of etrasimod in patients with PG over a 12-week treatment 
period.
8.1.1.2
Safety Objective
To assess the safety and tolerability of etrasimod in patients with PG over a 12-week 
treatment period.
8.1.2
Hypotheses 
There are no formal hypothesis tests specified in this open-label study due to the lack of 
control treatment group.
8.2
Sample Size and Power Calculations
There is no formal sample size estimation for this proof-of-concept open label study.  A 
sample size of 8 subjects is reasonable to assess proof-of-concept of the efficacy of 
etrasimod in the target population.
8.3
Analysis Populations
Efficacy endpoints will be analyzed in enrolled patients who have baseline and at least 
1 post-baseline measure.
Safety endpoints will be analyzed in enrolled patients who received at least 1 dose of the
study drug.
8.4
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.


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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.
8.5
Efficacy Endpoints
As this is proof-of-concept study all endpoints will be exploratory. The efficacy 
endpoints will be as follows:
-
change from baseline (Day 1 pre-dose) to Week 12 in Physician Global 
Assessments for active skin manifestations.
Assessment of target lesion/ulceration
0:
Total resolution of target ulcer with no signs of active PG 
1: 
almost completely healed target ulcer with only minimal signs of active 
PG 
2: 
Evidence of target ulcer healing which involves at least 50% of 
ulcer/ulcer margin 
3: 
Evidence of target ulcer healing which involves less than 50% of 
ulcer/ulcer margin 
4: 
No evidence of target ulcer healing
-
change from baseline (Day 1 pre-dose) to Week 12 in Patient Global Assessments 
for active skin manifestations: Visual Analog Scale (VAS) for assessment of 
severity of the disease and severity of pain by patient.
-
change from baseline (Day 1 pre-dose) to Week 12 in Dermatology Life Quality 
Index (DLQI) (to measure how much a patient’s life is affected through their skin 
problems)
-
change from baseline (Day 1 pre-dose) to Week 12 in CRP levels
In addition, the following measures will be assessed as per Schedule of Procedures and 
Visits:
-
Imaging (digital photos) of the target lesion.
-
Evaluation of the changes in surface area of target lesion.
-
Skin punch biopsies (if performed).
8.6
Statistical Methods
8.6.1
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.
8.6.2
Subgroup Analyses
Not planned.


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8.7
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 last pre-dose
measurement. 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.
8.7.1
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’.
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 32). TEAEs will be classified according to system organ class. 
8.7.2
Physical Examinations
Physical examination results (abnormalities only) at each study visit will be listed.
8.7.3
Concomitant Medication
Pre-treatment and concomitant medication administered during the study will be listed. 
Concomitant medications will be coded using the WHO-DRUG Dictionary.
8.7.4
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.
8.7.5
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 last pre-
dose measurement. A clinically significant change from baseline may be recorded as an 
AE if deemed appropriate by the PI or sponsor.
 
 
 


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9
REGULATORY REQUIREMENTS
9.1
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 2 years
•
Current medical licenses for the PI and all sub-investigators
•
Financial disclosure form signed by the PI and all sub-investigators listed on the 
FDA Form 1572
•
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.
9.2
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.
9.3
Patient Confidentiality
All information obtained during the conduct of the study with respect to the patients’ state 
of health will be 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.  
9.4
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.


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9.5
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. 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.


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10 PROTOCOL MANAGEMENT AND ADMINISTRATIVE 
CONSIDERATIONS
10.1
Study Documentation
The PI and study staff have the responsibility of maintaining a comprehensive and 
centralized filing system containing all study-related documentation. These files must be 
available for inspection by the sponsor, representatives of the sponsor, the IEC, and 
regulatory authorities (i.e., FDA or international regulatory authorities) at any time, and 
should consist of the following elements:
•
Patient files, containing the completed case report forms (CRFs), 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 at least 2 years after marketing application approval, 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.
10.2
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.
10.3
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.


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11 PRINCIPAL INVESTIGATOR SIGNATURE PAGE
I agree to conduct the study as outlined in the protocol entitled “A Phase 2a, Open-label, 
Proof of Concept Study to Determine the Efficacy and Safety of Etrasimod (APD334) in 
Patients with Pyoderma Gangrenosum” in accordance with regulatory guidelines, ICH 
GCP Guidelines and the Declaration of Helsinki; and all applicable government 
regulations including Part 54: Financial Disclosure by Clinical Investigators.
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: Federal regulations 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.


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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 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 to the FDA or other 
legally constituted authority.
Principal Investigator
Date
Printed Name


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Clinical Trial Protocol: APD334-011
07 February 2017
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12 REFERENCES
1. Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery 
and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov
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2. Cohen, PR. Am J Clin Dermatol. Neutrophilic dermatoses: a review of current 
treatment options. Am J Clin Dermatol. 2009;10(5):301-12. 
3. Marzano AV et al.
Role of inflammatory cells, cytokines and matrix 
metalloproteinases in neutrophil-mediated skin diseases. Clinical and 
Experimental Immunology, 2010;162: 1–11.
4. Quaglino P, Fava P, Caproni M, et al.
Phenotypical characterization of 
circulating cell subsets in pyoderma gangrenosum patients: the experience of the 
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5. Allende ML, Bektas M, Lee BG, et al.
Sphingosine-1-phosphate lyase 
deficiency produces a pro-inflammatory response while impairing neutrophil 
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study of pyoderm gangrenosum. J Cut. Path; 1986;13: 323-330.
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challenges and solutions. Clin. Cos. Inv. Dermatol; 2015;8: 285-293.
8. Brunsting LA, Goeckerman
WH, O’Leary PA.  Pyoderm [ecthyma] 
gangrenosum; Clincial and experimental observations in five cases occurring in 
adults. Arch Dermatol Syph; 1930;22:655-680.
9. Von den Driesch P. Pyoderma gangrenosum: a report of 44 cases with follow-
up. Br. J. Dermatol; 1997;137(6):1000-5.
10. US Department of Health & Human Services National Institutes of Health 
https://rarediseases.info.nih.gov/diseases/7510/pyoderma-gangrenosum.
11. Wollina U.  Pyoderma Gangrenosum- a review. Orphanet Journal of Rare 
Diseases; 2007, 2:19.
12. Weenig RH, Davis MD, Dahl PR, et al. Skin ulcers misdiagnosed as pyoderm 
gangrenosum. N Engl J Med; 2002;347:1412-1418.
13. Kolios AG, Maul JT, Meier B, et al. Canakinumab in adults with steroid-
refractory pyoderma gangrenosum. Br J Dermatol; 2015 173: 1216-23.
14. Sandborn WJ, Feagan BG, Wolf DC et al.  Ozanimod Induction and 
Maintenance 
Treatment 
for 
Ulcerative 
Colitis. 
N 
Engl 
J 
Med;
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15. Brinkmann V, Davis MD, Heise CE et al. The immune modulator FTY720 
targets sphingosine 1-phosphate receptors. J Biol Chem; 2002; 277:21453-57.
16. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral 
fingolimod in relapsing multiple sclerosis. N Engl J Med.; 2010 Feb 4; 
362(5):387-401.
17. Vaclavkova A, Chimenti S, Arenberger P et al. Oral ponesimod in patients with 
chronic plaque psoriasis: a randomized, double-blind, placebo-controlled phase 2 
trial. Lancet; 2014; 384: 2036-45
18. Schaper K, Kietzmann M, Bäumer W. Sphingosine-1-phosphate differently 
regulates the cytokine production of IL-12, IL-23 and IL-27 in activated murine 
bone marrow derived dendritic cells. Mol Immunol.; 2014 May;59(1):10-8.  
19. Dillmann C, Ringel C, Ringleb J, et al. S1PR4 Signaling Attenuates ILT 7 
Internalization To Limit IFN-α Production by Human Plasmacytoid Dendritic 
Cells. J Immunol.; 2016 Feb 15;196(4):1579-90.
20. Schuppel M, Kurschner U, Kleuser U, et al. Sphingosine 1-phosphate restrains 
insulin-mediated keratinocyte proliferation via inhibition of Akt through the 
S1P2 receptor subtype. J Invest Dermatol 2008; 128:1747-56.
21. Reines I, Kietzmann M, Mischke R, et al. Topical application of sphingosine-1-
phosphate and FTY720 attenuate allergic contact dermatitis reaction through 
inhibition of dendritic cell migration. J Clin Invest Dermatol; 2009; 129:1954-
62.
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26. Gergely P, Nuesslein-Hildesheim B, Guerini D et al. The selective sphingosine 
1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and 
has species-specific effects on heart rate. Br J Pharmacol.;
2012 
Nov;167(5):1035-1047.
27. Brossard P, Derendorf H, Xu J et al.  Pharmacokinetics and pharmacodynamics 
of ponesimod, a selective S1P(1) receptor modulator, in the first-in-human 
study. Br J Clin Pharmacol; 2013; 76(6):888-96.


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28. Kovarik JM, Schmouder R, Barilla D et al. Multiple-dose FTY720: tolerability, 
pharmacokinetics, and lymphocyte responses in healthy subjects. 
J Clin 
Pharmacol; 2004 May;44(5):532-537.
29. Rowe IF, Deans AC.  Serum C-reactive protein measurement in pyoderma 
gangrenosum.  Dermatologica;1986;173(5):216-9.
30. Ye MJ, Ye JM.  Pyoderma Gangrenosum: A Review of Clinical Features and 
Outcomes of 23 Cases Requiring Inpatient Management.  Dermatol. Res. Prac.; 
2014;Vol. 2014-461467:7 pages.
31. http://www.fda.gov/drugs/drugsafety/ucm366529.htm. Accessed 27-April-2015.
32. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Publish 
Date: June 14, 2010. Accessed October 2010. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-4_QuickReference_5
x7.pdf


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SPONSOR PROTOCOL SIGNATURE PAGE
Protocol Title: A Phase 2a, Open-label, Proof of Concept Study to Determine the 
Efficacy and Safety of Etrasimod (APD334) in Patients with Pyoderma Gangrenosum.
This study will be conducted in accordance with the International Conference on 
Harmonization (ICH) guideline for Good Clinical Practice (GCP) (E6) and applicable 
Food and Drug Administration (FDA) guidelines.
Protocol Number:
APD334-011
Arena Pharmaceuticals, Inc. Signatures:


Etrasimod (APD334)
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Clinical Trial Protocol: APD334-011
07 February 2017
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Appendix 1
Progressive Multifocal Leukoencephalopathy (PML) 
Checklist
Symptoms
“Compared to how you 
usually feel, have you had a 
significant change in any of 
the following?”
If the answer is 
“yes”, obtain a 
description of the 
symptom(s) with 
examples.
Applicable Objective 
Test(s): Document 
results on PML 
Object Checklist
Yes
No
1) Have you been experiencing 
any persistent difficulty with 
your vision such as loss of 
vision or double vision? Have 
you been having trouble 
reading?
Test visual fields and 
ocular motility
2) Have you been experiencing 
any persistent difficulty 
speaking or having your speech 
understood by others?
Casual observation of 
speech output for 
dysarthria or aphasia. 
Ask patient to name a 
few objects and repeat 
a multipart phrase.
3) Have you been experiencing 
any persistent weakness in an 
arm or leg?
Test for pronator draft 
(Barre maneuver) 
and/or fixation on arm 
roll, Assess the ability 
to hop on either foot; 
foot and finger 
tapping. Test muscle 
strength.
4) Have you noticed yourself 
regularly bumping into things 
or having difficulty writing?
Ask for spontaneous 
writing sample and 
observe finger to nose, 
heel to shin, and 
tandem gait.
5) Have you regularly been 
experiencing difficulty 
understanding others?
Ability to follow serial 
commands
6) Have you had persistent 
problems with your memory or 
thinking?
Recall of 3 objects 
over 1 minute to 
distraction; ability to 
follow commands.
7) Have you been experiencing 
any persistent numbness or 
other loss of sensation?
Test sensation side to 
side with pinprock.
Version 1, 20 October 2016


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Clinical Trial Protocol: APD334-011
07 February 2017
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Appendix 2
Physician Global Assessment for Active Skin
Manifestations
Pyoderma Gangrenosum Patients
Patients Name: 
Study Subject Number: 
Number of Ulcers
Please indicate number of ulcers at indicated week
Week 
Number of Ulcers
Week 0
Week 1
Week 2
Week 4
Week 8
Week 12
Target Lesion / Ulceration of Pyoderma Gangrenosum
At the beginning of the study, the largest (or one of the largest) lesion is going to be designated “target 
lesion”. A digital photograph with a ruler next to the lesion has to be taken.
Place of target lesion: 
Week
Diameter of target 
Lesion / Ulceration in cm 
(longest distance)
Assessment of 
target Lesion / 
Ulceration
Date and Signature of 
Investigator
Week 0
Week 1
Week 2
Week 4
Week 8
Week 12
Assessment of target lesion / Ulceration
0: Total resolution of target ulcer with no signs of active PG
1: Almost completely healed target ulcer with only minimal signs of active PG
2: Evidence of target ulcer healing which involves at least 50% of ulcer/ulcer margin
3: Evidence of target ulcer healing which involves less than 50% of ulcer/ulcer margin
4: No evidence of target ulcer healing
Version 3.0 – 04 January 2017


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Clinical Trial Protocol: APD334-011
07 February 2017
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Appendix 3
Patients Global Assessment for Active Skin Disease 
VAS (Visual Analogue Scale)
Patient Name: 
-
Please judge the questions below regarding the past one week
-
Please note your answer with a vertical mark (I) on the line below
How do you rate the severity of your skin disease?
How severe is your pain?
(Visual Analogue Scale has to be exactly 10 cm in the print out.)
Version 1.0 – 09 November 2016


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Clinical Trial Protocol: APD334-011
07 February 2017
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Appendix 4
Dermatology Life Quality Index (DLQI) form


 
This is a representation of an electronic record that was signed electronically, and this 
page is the manifestation of the electronic signature. 
 
UserName:
Title:  Medical Director Safety / Pharmacovigilance 
Date: Wednesday, 08 February 2017, 10:34 AM   Pacific Daylight Time 
Meaning: Author Approval 
================================================
UserName:
Title:   
Date: Thursday, 09 February 2017, 12:08 AM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName:
Title:  VP, Clinical Development 
Date: Thursday, 09 February 2017, 02:59 AM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName:
Title:  Vice President, Regulatory Affairs and Quality  
Date: Thursday, 09 February 2017, 05:52 AM   Pacific Daylight Time 
Meaning: Approval 
================================================
UserName:
Title:  Biostatistician/SAS Programmer 
Date: Thursday, 09 February 2017, 06:51 AM   Pacific Daylight Time 
Meaning: Approval 
================================================