Clinical trial NCT03139032
Conditions: Inflammatory Bowel Diseases Skin Extra-intestinal Manifestations
Sponsor: Arena Pharmaceuticals
Start date: 2017-07-17; Completion date: 2017-12-06
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this phase 2a, proof of concept, open-label clinical study is to evaluate the efficacy and safety of etrasimod (APD334) in inflammatory bowel disease patients with active skin extra-intestinal manifestations.

Detailed description:

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

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Trial Protocol: APD334-006
Study Title:
A Phase 2a, Proof of Concept, Open-label Study Evaluating the 
Efficacy and Safety of Etrasimod (APD334) in Inflammatory Bowel 
Disease Patients with active Skin Extra-intestinal Manifestations
Study Number:
APD334-006
Study Phase:
2a
Product Name:
Etrasimod (APD334)
EudraCT Number:
2016-003797-40
Indication:
Inflammatory Bowel Disease with active skin extra-intestinal 
manifestations
Investigators:
Multicenter
Sponsor:
Arena Pharmaceuticals, Inc.
6154 Nancy Ridge Drive
San Diego, California 92121
Sponsor Contact:
 MD
CMO Research and Development 
Arena Pharmaceuticals, Inc.
6154 Nancy Ridge Dr.
San Diego, CA 92121
Phone: 
email:
Date
Original Protocol:
20 October 2016
Amendment 01:
11 April 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.
NCT Number: NCT03139032
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


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PROTOCOL AMENDMENT SUMMARY
The following is a list of key changes of no substantial protocol clarifications to the 
APD334-006 Protocol Amendment 01 dated 11 April 2017.
Section(s) Amended
Description of Changes made
Synopsis
Deleted sentence 
“Diagnosis of active psoriasis, erythema nodosum or 
pyoderma gangrenosum by Investigator assessments. After 
the enrollment of 10 patients with active EIM, patients with 
active psoriasis due to anti TNF-alpha therapy can also be 
included.”
4.1 Study Population
Deleted sentence 
“Adult men and women, ages 18-80 years, who have mild, 
moderate or severe UC or CD with active skin extra-
intestinal manifestations including pyoderma gangrenosum, 
erythema nodosum or psoriasis. After the enrollment of 10 
patients with active EIM, also patients with psoriasis due to 
anti TNF-alpha treatment can be enrolled into the study”.   
Synopsis Sample Size
Changed “10-20 patients” to:
current: “Up to 20 patients (with up to 10 patients with anti 
TNF-alpha induced psoriasis)”
3.1 Overall Study Design 
and Plan
Study number corrected “APD334-003 is an open-label, …” 
to: 
current “APD334-006 is an open label, ….”
3.1 Overall Study Design 
and Plan
Changed “Between 10 to 20 IBD patients with acute 
psoriasis, pyoderma gangrenosum or erythema nodosum 
will be included in the study. In these patients, psoriasis 
cannot be triggered by anti-TNF-alpha. However, after the 
enrollment of 10 patients, IBD patients with psoriasis due to 
anti-TNF-alpha treatment can be included to the study” to:  
current “Up to 20 IBD patients with acute psoriasis, 
pyoderma gangrenosum or erythema nodosum (with up to 
10 patients with anti TNF-alpha induced psoriasis) will be 
included in the study”.


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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................8
LIST OF ABBREVIATIONS..................................................................................................16
1
INTRODUCTION ...........................................................................................................19
1.1
Background Information........................................................................................20
1.1.1
Rationale for Proposed Clinical Study.........................................................20
1.1.2
Summary of Preclinical Data.......................................................................21
1.1.3
Summary of Clinical Data ...........................................................................23
1.2
Ethics and Regulatory Considerations...................................................................26
2
STUDY OBJECTIVES....................................................................................................27
2.1
Objectives ..............................................................................................................27
3
INVESTIGATIONAL PLAN..........................................................................................28
3.1
Overall Study Design and Plan..............................................................................28
3.2
Study Duration and Dates......................................................................................28
4
STUDY POPULATION SELECTION ...........................................................................33
4.1
Study Population....................................................................................................33
4.2
Inclusion and Exclusion Criteria............................................................................33
5
STUDY TREATMENT(S)..............................................................................................34
5.4
Study Restrictions of Fluid and Food Intake prior drug screening........................34
5.5
Accountability........................................................................................................35
5.6
Investigational Product Retention at Study Site ....................................................35
6
STUDY PROCEDURES .................................................................................................36
6.1
Informed Consent...................................................................................................36
6.2
Medical History .....................................................................................................36
6.2.1
Prior Therapies.............................................................................................36
6.2.2
History of IBD .............................................................................................36
6.3
Physical and Neurological Examinations ..............................................................36
6.3.1
Physical Examination...................................................................................36
6.3.2
Neurological Examination ...........................................................................37
6.4
Vital Signs..............................................................................................................37


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6.6
Tuberculosis Screening and Chest X- ray..............................................................39
6.7
Pulmonary Function Testing..................................................................................39
6.11
Adverse Events Assessments.................................................................................43
6.11.1
Adverse Event Reporting.............................................................................44
6.11.1.1
Progressive Multifocal Leukoencephalopathy (PML).......................44
6.11.2
Serious Adverse Events and Expedited Reporting of Adverse Events........45
6.11.2.1
Patient and Patient-partner Pregnancy...............................................46
6.11.3
Assessment of Adverse Event Severity .......................................................46
6.11.4
Assessment of Adverse Event Relationship to Study Medication...............47
6.11.5
Assessment of Adverse Event Outcome......................................................47
6.11.6
Action Taken for Adverse Event .................................................................48
6.11.7
Action Taken for Study Drug ......................................................................48


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6.11.8
Follow-up of Adverse Events Present at Last Scheduled Study Visit.........48
6.13
Removal of Patients from the Trial or Study Drug................................................50
6.13.1
Handling of Withdrawals.............................................................................50
6.13.2
Replacements...............................................................................................50
8
DATA MANAGEMENT.................................................................................................56
8.1
Data Collection ......................................................................................................56
8.2
Data Coding ...........................................................................................................56
8.2.1
Adverse Events ............................................................................................56
8.2.2
Concomitant Medications and Non-drug Treatments..................................56
8.2.3
Medical History ...........................................................................................56
9
PLANNED STATISTICAL METHODS ........................................................................57
9.1
Hypotheses and Objectives....................................................................................57
9.1.1
Objectives ....................................................................................................57
9.1.1.1
Efficacy Objectives............................................................................57
9.1.1.2
Safety Objective.................................................................................57
9.1.2
Hypotheses...................................................................................................57
9.2
Sample Size and Power Calculations.....................................................................57
9.3
Analysis Populations..............................................................................................57
9.4
Demographics and Baseline Characteristics..........................................................57
9.5
Efficacy Endpoints.................................................................................................58
9.6
Statistical Methods.................................................................................................58
9.6.1
Efficacy Analysis.........................................................................................58
9.6.2
Subgroup Analyses ......................................................................................58
9.6.3
Interim Analysis...........................................................................................58


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9.7
Safety Analysis ......................................................................................................59
9.7.1
Adverse Events ............................................................................................59
9.7.2
Physical Examinations.................................................................................59
9.7.3
Concomitant Medication..............................................................................59
9.7.4
Vital Signs....................................................................................................59
9.7.5
Clinical Laboratory Values..........................................................................59
9.7.7
Lymphocyte counts......................................................................................60
10
REGULATORY REQUIREMENTS...............................................................................61
10.1
Pre-Study Documentation:.....................................................................................61
10.2
Investigator Obligations.........................................................................................61
10.3
Patient Confidentiality...........................................................................................61
10.4
Informed Consent...................................................................................................61
10.5
Institutional Review Board ....................................................................................62
11
PROTOCOL MANAGEMENT AND ADMINISTRATIVE CONSIDERATIONS......63
11.1
Study Documentation.............................................................................................63
11.2
Protocol Interpretation and Compliance................................................................63
11.3
Study Monitoring...................................................................................................63
12
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ...................................................64
13
REFERENCES ................................................................................................................66
PROTOCOL SIGNATURE PAGE .........................................................................................70


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LIST OF IN-TEXT TABLES
LIST OF APPENDICES
Appendix 1Progressive Multifocal Leukoencephalopathy (PML) Checklist ...................71


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SYNOPSIS
Name of Drug:
Etrasimod (APD334)
Indication
Inflammatory Bowel Disease (IBD) with active skin extra-intestinal 
manifestations (EIM) including Psoriasis, Erythema Nodosum (EN), 
and Pyoderma Gangrenosum (PG)
Sponsor:
Arena Pharmaceuticals, Inc.
154 Nancy Ridge Drive
San Diego, CA 92121
Name of Sponsor 
Contact
, MD
CMO Research and Development
Arena Pharmaceuticals, Inc.
6154 Nancy Ridge Dr.
San Diego, CA 92121
Phone: 
email: 
Name of Principal 
Investigator(s):
Multi-center
Medical Monitor:
, MD
Medical Monitor Arena
Arena Pharmaceuticals, Inc.
Gotthardstrasse 3
CH-6300 Zug
Phone: 
email: 
Test Product, Dose
and Mode of
Administration:

 etrasimod once daily (q.d.) for 12 weeks

Patients should be instructed to take their tablet on an empty 
stomach (after overnight fast) and to avoid eating for 1 hour 
after dosing. Patients should be advised not to crush, break, 
chew, or dissolve the tablet and to take study medication 
with an adequate amount of water.
Concurrent Control:
None. This is an open-label study.
Objectives:
The efficacy objective is to determine the treatment effect of 
etrasimod in Inflammatory Bowel Disease patients on the clinical 
improvement of active skin extra-intestinal manifestations. 
The safety objective is to determine the safety profile and 
tolerability of etrasimod.
Study Design
This is a phase 2a, proof-of-concept, multicenter, open-label, single-
arm study in 10-20 IBD patients with active skin extra-intestinal 
manifestations. 
All visits in the study are ambulatory visits. The screening period 


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will last up to 4 weeks and is followed by a 12-week treatment 
period.  During this treatment period patients will take one tablet of 
study medication once per day. The last dose is planned to be taken 
one day before the last treatment visit at week 12. A follow-up visit 
will take place 2 weeks after the end of treatment. 


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Study Site(s)
This study will be conducted in approximately 3 clinical centers.
Patient Population:
Inclusion Criteria
1. Men or women of age 18 to 80 years, inclusive.
2. Able to give signed informed consent and willing and able to 
comply with the study requirements.
3. Considered to be in stable health in the opinion of the 
investigator as determined by:
a.) A pre-study physical examination with no clinically 
significant abnormalities unrelated to IBD.
b.) Vital signs (VS) at screening: pulse rate ≥ 55 bpm, 
systolic blood pressure (SBP) ≥90, and diastolic blood 
pressure (DBP) ≥ 55 mmHg.
c.) Liver function tests (ALT/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.
e.) 12-lead electrocardiogram (ECG) showing no clinically 
significant abnormalities in the opinion of the 
investigator (for confirmation please refer to exclusion 
criteria # 22).
f.)
A chest x- ray showing no evidence of active pulmonary 
disease (a chest x-ray taken within the previous 12 
months from the screening visit may also be used).
g.) Ophthalmology evaluation (by an ophthalmologist) 
without evidence of macular edema, supported with 
OCT where available (dependent on site capability) no 
later than 3 months prior to screening.
4. Patients receiving stable treatment for IBD and EIM as defined 
in section 6.12.
5. Diagnosis of active psoriasis, erythema nodosum or pyoderma 
gangrenosum by Investigator assessments. 
6. Diagnosis of ulcerative colitis (UC) or Crohn’s disease (CD)
established prior to screening by clinical and endoscopic 
evidence.  
7. Eligible female patients 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.


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b.) non-lactating.
c.) 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 method 
are not acceptable methods of contraception.
d.) surgically sterile or 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. Acceptable methods of birth control are:
-
combined (estrogen and progestogen containing)
hormonal contraception associated with inhibition of 
ovulation)
o
oral
o
intravaginal
o
transdermal
-
progestogen-only hormonal contraception associated 
with inhibition of ovulation
o
oral
o
injectable
o
implantable
-
intrauterine device (IUD)
-
intrauterine hormone-releasing system (IUS)
patients should be consistently taking the hormonal 
contraceptive for at least 3 months [90 days] prior to 
screening);  
-
surgical sterility for at least 6 months prior to 
screening for tubal ligation performed 
laparoscopically, hysterectomy and/or bilateral 
oophorectomy; and/or postmenopausal (defined as at 
least 2 years without menses).
Contraceptive measures, such as Plan B (used after 
unprotected sex), are not acceptable methods of 
contraception for this study.
8. 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 


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least 30 days after last study medication 
administration as defined in 7 above. Please note that 
the use of condoms is an acceptable method of 
contraception for this study.
9. Eligible male and female patients must agree not to participate 
in a conception process (i.e. active attempt to become pregnant 
or to impregnate, sperm donation, in vitro fertilization) for 30 
days after the last dose of study drug.
Exclusion Criteria: 
1. Evidence of abdominal abscess or toxic megacolon at the 
screening visit.
2. Patients with history of extensive colitis or pancolitis of > 8 
years duration or left-sided colitis of > 12 years duration must 
have documented evidence that a surveillance colonoscopy was 
performed within 12 months of the initial screening visit (if not, 
the patient should undergo a colonoscopy in lieu of a flexible 
proctosigmoidoscopy during screening).
3. Previous extensive colonic resection (subtotal or total 
colectomy).
4. Current evidence of adenomatous colonic polyps that have not 
been removed.
5. Current evidence of colonic mucosal dysplasia.  
6. Ileostomy, colostomy, or known fixed symptomatic stenosis of 
the intestine or stoma.
7. Clinical significant infection as judged by the investigator in the 
previous 6 weeks before enrollment.
8. Evidence of or treatment for C. difficile infection within 60 days 
or other intestinal pathogen within 30 days prior to 
randomization.
9. Within 5 half-lives prior to randomization exposure to 
natalizumab or rituximab.
10. Within 30 days prior to randomization, treatment of underlying 
disease other than those specifically listed in Section 6.12.
11. Within 30 days or 5 half-lives (whichever is longer) prior to 
randomization receipt of any investigational agent.
12. Currently require or are anticipated to require surgical 
intervention for IBD during the study.
13. FEV1 or FVC < 80% of predicted values (i.e., abnormal).
14. Infection with the Hepatitis B or C virus.
15. Active or latent tuberculosis, regardless of treatment history, as 
evidenced by any of the following:


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a.
History of tuberculosis (that has not been successfully treated)
b. A positive diagnostic tuberculosis (TB) test within one 
month of randomization defined as a positive 
QuantiFERON® test or 2 successive indeterminate 
QuantiFERON tests
c.
Chest X-ray within 12 months of randomization in which 
active or latent pulmonary tuberculosis cannot be excluded.
16. Any known history of congenital or acquired immunodeficiency 
(e.g., common variable immunodeficiency, human 
immunodeficiency virus [HIV] infection [ELISA and Western 
blot] test result, organ transplantation).
17. Clinically significant extra-intestinal infection (e.g., pneumonia, 
pyelonephritis) within 30 days prior to randomization.
18. Recent history (within 6 months of screening visit) of cardio or 
cerebrovascular disease, ACS, MI, unstable angina, CVA, TIA 
at screening.
19. Any surgical procedure requiring general anesthesia within 30 
days prior to randomization or plans to undergo major surgery 
during the study period.
20. History of retinal macular edema.
21. History of or signs and symptoms of progressive multifocal 
leukoencephalopathy (PML) as assessed by the PML checklist.
22. History 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 and Class III anti-
arrhythmic agents, or baseline QTc ≥ 500 msec.
23. Infection requiring hospitalization or intravenous antimicrobial 
therapy, or opportunistic infection within 4 weeks of screening.
24. History of more than one episode of herpes zoster or any 
episode of disseminated zoster.
25. Without documented positive varicella zoster virus (VZV) IgG 
antibody status or who have completed VZV vaccination within 
30 days prior to randomization.
26. Receipt of live vaccine within 4 weeks prior to screening.
27. History of lymphoproliferative disorder, lymphoma, leukemia, 
myeloproliferative disorder, or multiple myeloma.
28. History of malignancy except for adequately treated basal cell 
skin cancer.
29. History of severe allergic or anaphylactic reactions requiring 
medical attention.
30. Current or recent history (within one year prior to 
randomization) of alcohol dependence or illicit drug use.
31. History of clinically significant leukopenia or lymphopenia at 
screening.
32. Active psychiatric problems that, in the investigator’s opinion, 


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may interfere with compliance with the study procedures.
33. History of any clinically significant medical condition that, in 
the investigator's opinion, would preclude participation in the 
study.
34. Use of moderate to strong inhibitors of CYP2C9.
35. History of severe renal or  hepatic impairment.
36. Inability to attend all the study visits or comply with study 
procedures.
37. Prior exposure of etrasimod.
Duration per 
Patient:
Up to 18 weeks total: 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.
Sample Size:
Up to 20 patients (with up to 10 patients with anti TNF-alpha 
induced psoriasis).
Efficacy Endpoints:
As this is a proof-of-concept study, all endpoints are exploratory.
-
UC endpoint: Change from baseline in stool frequency, 
rectal bleeding, PGA (Physicians Global Assessments) at 
weeks 1, 2, 4, 8 and 12.
-
CD endpoint: Change from baseline in disease activity score 
at week 1, 2, 4, 8 and 12.
-
Change from baseline in endoscopic improvement/histologic 
healing using endoscopy or flexible proctosigmoidoscopy. 
(Only if there are signs of inflammation at screening another 
evaluation will be performed at week 12). 
-
Change from baseline in level of fecal calprotectin at week 
4, 8 and 12.
-
Change from baseline in Physician Global Assessments for 
active skin extra-intestinal manifestations (PG, EN and 
psoriasis) at week 1, 2, 4, 8 and 12.
-
Change from baseline in Patients Global Assessments for 
active skin extra-intestinal manifestations (PG, EN and 
psoriasis) at week 1, 2, 4, 8 and 12.
-
Change from baseline in the Dermatology Life Quality 
Index (DLQI) score at week 1, 2, 4, 8 and 12.
-
Psoriasis endpoint only (all other endpoints are for all skin 
manifestations): Change from baseline in Psoriasis   


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Area and Severity Index (PASI) score at week 1, 2, 4, 8 and 
12.
-
Change from baseline in Inflammatory Bowel Disease 
Questionnaire (IBDQ) score at week 2, 4, 8 and 12.
-
Skin punch biopsies (from healthy skin and from target 
lesion) will be collected before treatment and at week 8 or 
12. Immunohistochemistry and other analyzing methods 
such as RT-PCR will be performed to evaluate immune cell 
infiltration, cytokine expression in the skin and other 
inflammatory parameters.
-
Change from baseline in C - reactive protein (CRP) at 
Weeks 1, 2, 4, 8 and 12.
-
Chang from baseline in leucocyte characterization.
-
Change from baseline in lymphocyte counts at Weeks 1, 2, 
4, 8 and 12.
Safety Assessments:
-
Clinical laboratory tests (chemistry, hematology and 
urinalysis)
-
Vital sign measurements
-
Physical examination 
-
12-lead electrocardiograms (ECGs)
-
Adverse event reporting
-
Concomitant medication
-
Lymphocyte counts
Statistical Analyses:
There is no formal sample size estimation for this proof-of-concept 
open label study. Sample size of 10 - 20 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
11 April 2017


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LIST OF ABBREVIATIONS
ACS
ADL
Acute Coronary Syndrome
Activities of Daily Living
ALB
albumin
ALK-P
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase (SGOT)
bpm
beats per minute
BUN
blood urea nitrogen
Ca
calcium
CBC
CD
complete blood count (test)
Crohn’s disease
CFR
Code of Federal Regulations
CGMP
Current Good Manufacturing Practice
CI
confidence interval
CIA
collagen-induced arthritis
Cl
chloride
CL/F
CMO
apparent oral clearance
contract manufacturing organization
CRF
CRP
case report form
C-reactive protein
CRO
D
DLQI
contract research organization
day
Dermatology Life Quality Index 
EAE
experimental autoimmune encephalomyelitis
ECG
electrocardiogram
ED50
EIM
median effective dose
Extra-intestinal Manifestation
ELISA
EN
EOS
EOT
enzyme-linked immunosorbent assay
Erythema Nodosum 
End of Study
End of Treatment
FDA
Food and Drug Administration
FEF25-75%
mean forced expiratory flow between 25 and to 75% of FVC
FEV1
FU
forced expiratory volume in the first second
follow-up 
FVC
forced vital capacity


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GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
Hb
hemoglobin
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
Hct
hematocrit
HCV
hepatitis C virus
HDPE
High-density polyethylene
HIV
human immunodeficiency virus
h
hour
HR
IBD
heart rate
Inflammatory Bowel Disease
IBDQ
Inflammatory Bowel Disease Questionnaire
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
kg
kilogram
LDH
lactate dehydrogenase
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
MI
milligram
Myocardial Infarction
mL
milliliter
mm
millimeter
mmHg
millimeters of mercury
MRSD
maximum recommended starting dose
Na
sodium
NOAEL
no observed adverse effect level
OCT
optical coherence tomography
OTC
over-the-counter
PA
Posteroanterior


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PASI
Psoriasis Area and Severity Index
PBL
peripheral blood lymphocyte
PFT
PG
PGA
pulmonary function test
Pyoderma Gangrenosum
Physicians Global Assessments
PI
Principal Investigator
PRO
patient reported outcome
PT
prothrombin time 
PTT
PV
partial thromboplastin time
Pharmacovigilance
RBC
RT-PCR
red blood cell (count)
real-time polymerase chain reaction
S1P(1-5)
sphingosine 1-phosphate (1-5) receptor
SAE
serious adverse event
SBP
systolic blood pressure
SD
standard deviation
sec
second
SOP(s)
standard operating procedure(s)
TEM
TIA
UC
ULN
VAS
T effector memory cells
Transient Ischemic Attack
Ulcerative Colitis
upper limit of normal
visual analogue scale
VS
VZV
vital signs
varicella zoster virus
WBC
white blood cell (count)
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 receptor 
(S1P) agonist.  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
Etrasimod is being developed to treat autoimmune diseases. Initial investigations will focus 
on Inflammatory Bowel Disease (IBD), which is a broad term that describes conditions with 
chronic or recurring immune response and inflammation of the gastrointestinal tract.2 There 
are two major types of IBD: Crohn’s disease (CD) and ulcerative colitis (UC). These are 
chronic remittent or progressive inflammatory conditions that may affect the entire 
gastrointestinal tract (CD) and the colonic mucosa (UC), and are associated with an increased 
risk for colon cancer.11  Collectively, patients with IBD suffer from a multitude of GI 
symptoms, including diarrhea, rectal bleeding and abdominal pain.
The causes of these IBDs are not completely understood, but 3 characteristics define their 
etiology: (1) genetic predisposition; (2) an altered, dysregulated immune response; and (3) an 
altered response to gut microorganisms.2 The triggering event for the activation of the 
immune response in IBD has yet to be identified, but possible factors related to this event 
include a pathogenic organism (as yet unidentified) or an inappropriate response to a 
normally innocuous microbial or other antigen (perhaps due to failure to downgrade the 
inflammatory response, and/or to repeated exposure to such antigen from an alteration in 
barrier function).2  Once the inflammation has been triggered, it may be difficult for the IBD 
patient’s immune system to turn off the response.3
The number of patients diagnosed with IBD has dramatically increased worldwide over the 
past 50 years.5 In 2014, The Crohn’s and Colitis Foundation of American estimated that 
approximately 1.6 million people are affected by IBD in the United States (US) alone,6 with 
as many as 70,000 new cases diagnosed in the US each year7. In Europe, an estimated 2.5 – 3 
million people are affected by IBD,8 and as many as 5 million may be affected worldwide.9
Universally, incidence rates for both Crohn’s disease and ulcerative colitis were highest 
among individuals between 20 and 40 years old. Thus, IBD affects individuals in the most 
healthy and productive years of life, resulting in long-term cost to the patient, health-care 
system and society.10
Treatment for patients with IBD is generally for symptomatic care (relief of symptoms) and 
mucosal healing and includes 5 major classes of medications: aminosalicylates (5-ASA), 
antibiotics, corticosteroids, immunomodulators, and biologic therapies. These drugs are 
generally prescribed in a “step-up” approach, with escalation of the medical regimen until a 
response is achieved.14


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A single ascending dose study (APD334-001) and a multiple ascending dose study (APD334-
002), conducted in healthy subjects, have demonstrated the lymphocyte lowering capabilities 
of etrasimod (see Section 1.1.3). 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. The availability of oral lymphocyte trafficking agents such 
as etrasimod would offer patients an additional, more convenient treatment for IBD.
1.1
Background Information
1.1.1
Rationale for Proposed Clinical Study
Inflammatory bowel diseases are associated with various extra-intestinal manifestations 
(EIMs). The prevalence of IBD patients with EIMs as co-morbidities varies from 25% to
40% depending on the clinical presentation.15. Specifically, IBD patients with EIMs could
have a negative impact on disease prognosis and quality of life, and in most cases their 
clinical course becomes independent of gut disease activity.
IBD patients with skin EIMs are common, occurring in 2% to 34% of the IBD population.15
Specifically, erythema nodosum and pyoderma gangrenosum are the most common skin 
manifestations of IBD, while psoriasis is the active dermatological comorbidity disease 
observed most often, affecting 7%-11% of the IBD population.16 IBD and these major skin 
EIMs in IBD share some common pathogenic mechanisms including neutrophil and 
lymphocyte infiltration.17 To this point, targeted immunosuppressive therapies have 
demonstrated efficacy in IBD patients with skin EIMs. For example, TNF-alpha inhibitors 
are known to reduce intestinal inflammation and induce clinical remission in IBD patients,
and are also known to reduce EIMs of IBD. However a small percentage of IBD patients 
taking TNF-alpha inhibitors experience de novo paradoxical psoriasis (reporting a rate 
ranging from 1.6 to 8.8%) despite beneficial intestinal effects while on treatment.18 The 
pathophysiology of the paradoxical disease is not understood, but the leading hypothesis is 
that decreased TNF-alpha induces the activation of autoreactive T cells and an increased 
interferon activity as well as other pro-inflammatory cytokines, such as IL-12, IL-17, IL-23. 
Recently, interferon-alpha (IFN-alpha) production by dermal plasmacytoid dendritic cells 
(DCs) has been identified as a key element in the early phase of psoriatic skin lesion 
induction. Plasmacytoid DCs, the natural IFN-alpha producing cells, have recently been 
shown to infiltrate the skin of patients with psoriasis and to produce IFN-alpha. IFN-alpha
induces the expression of CXCR3 on T cells, facilitating homing to the skin.19
It is clear that existing treatments for IBD, and IBD skin EIMs, including TNF-alpha 
inhibitors, have limitations and a need remains for therapies with sustained efficacy, 
improved safety, and convenient administration.20
Spingosine-1-phosphate (S1P) is a spingolipid required by lymphocytes to exit the lymphoid 
tissue and enter the bloodstream via a chemotactic gradient. Agonists of the S1P receptor-1 
(S1P1) block lymphocyte migration out of the lymph tissue through internalization of the 
receptor, resulting in a sequestration of lymphocytes.21 Recent clinical development of S1P1


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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 the treatment of multiple 
sclerosis.22 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.23 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.24 Importantly, a recent report demonstrating S1P4 agonists inhibit 
plasmacytoid dendritic cell activation and interferon-alpha production suggest a potential 
therapeutic role for S1P1/S1P4 agonists like etrasimod in paradoxical psoriasis.25
In addition to the potential anti-inflammatory benefits of systemic lymphocyte 
immunomodulation, S1P is known to exert anti-proliferative effects in human 
keratinocytes,26 and inhibits dendritic cell migration.27 Thus, the potential role of S1P 
receptor modulation in skin EIMs of IBD might involve both systemic and local epidermal 
mechanisms.
The aim of the proposed clinical studies is to evaluate the role of S1P modulation in the 
setting of IBD with skin EIMs. Next generation S1P modulators such as etrasimod with 
improved side effect profiles may represent a novel therapy for IBD patients with skin EIMs.
1.1.2
Summary of Preclinical Data


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1.2
Ethics and Regulatory Considerations  
The study will be conducted in compliance with the International Conference on 
Harmonisation (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 [IND]) 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 IRB/IEC and written approval from the Chair or 
designated deputy of the IRB/IEC is required before clinical activities of the study can 
commence.
The IRB/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 
volunteers
•
Changes increasing the risk to volunteers 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 volunteers or the conduct of 
the trial
Any changes to the protocol will be made by means of a formal written protocol amendment. 
All amendments will require IRB/IEC approval before implementation except when changes 
to the protocol are required immediately to eliminate hazards to the volunteer.


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2
STUDY OBJECTIVES
2.1
Objectives
The efficacy objectives will be to determine the effect of etrasimod in Inflammatory Bowel 
Disease patients on the clinical improvement of active skin extra-intestinal manifestations. 
The safety objective will be to determine the safety and tolerability of etrasimod.


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3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
APD334-006 is an open-label, phase 2, proof-of-concept single-arm study designed to 
evaluate the efficacy and safety of etrasimod in IBD patients with active skin extra-intestinal 
manifestations. 
Up to 20 IBD patients with acute psoriasis, pyoderma gangrenosum or erythema nodosum
(with up to 10 patients with anti TNF-alpha induced psoriasis) will be included in the study.
Patients will receive once daily (q.d.) 
 doses of etrasimod for 12 weeks. 
3.2
Study Duration and Dates
The total study participation/duration is approximately 18 weeks; up to 4 weeks for 
screening, followed by 12 weeks of dosing, and a follow-up visit 2 weeks after end of 
treatment.  
The schedule of procedures and visits for the study is provided in 


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4
STUDY POPULATION SELECTION
4.1
Study Population
Adult men and women, ages 18-80 years, who have mild, moderate or severe UC or CD with 
active skin extra-intestinal manifestations including pyoderma gangrenosum, erythema 
nodosum or psoriasis. 
Eligible patients must meet all entry criteria prior to being randomized to receive study
medication as outlined below. 
4.2
Inclusion and Exclusion Criteria
Each patient must meet the inclusion and exclusion criteria described in the synopsis to be 
enrolled in the study.


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5
STUDY TREATMENT(S)
5.4
Study Restrictions of Fluid and Food Intake prior drug screening
Consumption of foods and beverages containing the substances listed below will be 
prohibited as indicated. Exceptions may be permitted upon the joint agreement of Arena and 
the investigator, provided the safety of the patient and integrity of the study are not 
compromised.
Poppy seeds: Consumption of poppy seeds within 48 hours prior to drug screen may 
cause a positive drug screen. Patients who report that they have consumed poppy 
seeds within 48 hours of the screening visit should not be screened. They may return 
48 hours after the last poppy seed consumption for screening.  Poppy seeds should 


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not be eaten between screening and Week 0/Day 1 and throughout the inpatient 
period.
5.5
Accountability
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. Reasons for deviation from the expected 
dispensing regimen must also be recorded. Study medication will be reconciled by the Arena
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.
5.6
Investigational Product Retention at Study Site
At completion of the study, all study medication will be reconciled by the Arena monitor or 
contracted designee, and then returned at the direction of the Arena 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 (or 
contracted CRO) for approval of such action.


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6
STUDY PROCEDURES
6.1
Informed Consent
The investigator will obtain and document ICF for each patient screened for this study. All 
patients will be informed in writing 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 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 ICF should include all the elements as outlined in Section 4.8.10 of the ICH 
guideline for GCP (E6).
6.2
Medical History
At screening, a complete medical history, as well as a full history of IBD will be collected by 
patient interview. Concomitant medications, recent blood donations, illnesses, and 
participation in other investigational drug studies will also be recorded. A partial examination 
will be performed at check-in to update findings from screening and document any pre-
treatment AEs.
6.2.1
Prior Therapies
Prior therapies related to IBD and skin manifestations will be collected during screening.
6.2.2
History of IBD
A detailed history of IBD, including date of diagnosis, disease severity, hospitalizations, and
extra-intestinal manifestations will be collected during screening.
6.3
Physical and Neurological Examinations
6.3.1
Physical Examination
The physical examination 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 will be performed during screening and Week 12 by the investigator. A 
limited examination to assess clinically significant changes from the examination performed 
at screening will be completed during the Week 0/Day 1 visit. Height will only be obtained at 
screening.
The physical examination will also include visual acuity and dilated ophthalmoscopy (by an 
ophthalmologist) and with OCT (where available) at screening and Week 12 to rule out and 
monitor for any significant retinal disease, including macular edema. Retinal photos will be 
taken during the screening visit, Week 12 and any subsequent unscheduled ophthalmoscopy. 
Safety ECGs will also be performed as outlined in the schedule of procedures and visits 
 


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Clinically significant findings from the physical/neurological examination performed at 
screening will be recorded as medical history. Any new clinically significant findings from 
the time of screening through the first dose of study drug will be recorded as pre-treatment 
AEs. After the administration of the first dose of study drug, clinically significant findings 
will be recorded as AEs.
6.3.2
Neurological Examination
The neurological examination includes assessments of the neurological system (cranial 
nerves, motor and sensory function, coordination, and mental status), and will be performed 
during screening, Week 0/Day 1 (limited examination to assess clinically significant changes 
from the screening), and at Week 12 by the principal investigator or sub-investigator. In 
addition, monitoring for progressive multifocal leukoencephalopathy (PML), a potential 
adverse effect of S1P1 agonists, will be performed at each site visit (except for the Day -1 
) using a subjective PML checklist. 
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 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 may be referred to a neurologist for a full evaluation.  
Additional information on PML is provided in Section 6.11.1.1 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 that occurs at the same time point. Vital signs will be measured 
according to the time points in the schedule of procedures and visits
 


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6.6
Tuberculosis Screening and Chest X- ray
All patients will complete tuberculosis (TB) screening to determine eligibility. All patients 
who do not report a history of TB must complete a diagnostic TB test within 1 month prior to 
randomization and a chest X-ray within 12 months prior to randomization.
Patients will be excluded from the study if they have active or latent TB, regardless of 
treatment history, as evidenced by any of the following:
•
History of TB (that has not been acceptably treated and the treatment was 
successfully completed) 
•
A positive diagnostic TB test within 1 month of randomization defined as:
-
A positive QuantiFERON® test or 2 successive indeterminate QuantiFERON® 
tests 
-
Chest X-ray within 12 months of randomization in which active or latent 
pulmonary TB cannot be excluded
6.7
Pulmonary Function Testing
Pulmonary function testing (PFT) will be conducted using spirometry during screening and at 
Week 12 (and at the 2-week follow-up visit for patients not continuing on to the extension 
study). Spirometry will include measures of forced vital capacity (FVC), forced expiratory 
volume in the first second (FEV1) and mean forced expiratory flow between 25 and 75% of 
FVC (FEF25-75%). Since FVC and FEV are highly effort dependent, abnormal values or 
significant changes from baseline or the previous measurement should be verified with a 
repeat assessment.


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6.11
Adverse Events Assessments
Patients will be monitored from ICF signature to 2 weeks after the last dose of study drug for 
adverse reactions (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.


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6.11.1
Adverse Event Reporting
Patients will be instructed that they may report AEs 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. In the event that an AE is not resolved or stabilized by this time, the sponsor 
in consultation with the investigator will decide whether to continue to monitor the AE or
close-out the event in the database if no further follow-up is necessary.
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 adverse or 
unexpected events, signs and symptoms, will be fully recorded on the Adverse Event 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.
6.11.1.1
Progressive Multifocal Leukoencephalopathy (PML)
A patient with multiple sclerosis developed progressive multifocal leukoencephalopathy 
(PML) after nearly 8 months of treatment with another S1P1 agonist38, and enablement of the 
John Cunningham (JC) virus is therefore a potential adverse effect of this therapeutic class. 


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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 subinvestigator 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 Day -1) to probe for 
symptoms suggestive of PML. Any patients reporting signs and/or symptoms of PML will 
undergo objective testing and may be referred to a neurologist for a full evaluation.
A copy of the PML checklist is provided in Appendix 1.
6.11.2
Serious Adverse Events and Expedited Reporting of Adverse Events
A Serious Adverse Event (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 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) using the remote data capture (RDC) system 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:


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PPD Medical Affairs/Pharmacovigilance
PPD PVG Hotline:
PPD PVG Fax line:
In the event that RDC entry is not possible (e.g., system failure or access problems), the 
study site should complete the paper SAE report form and fax the form to PPD PVG within 
24 hours of awareness of the event. The RDC system should be updated as soon as it is 
available.
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 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.
6.11.2.1
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 IRB/IEC in the same manner as an SAE.
Pregnancies will be followed every trimester through the first well baby visit. For female 
partners whom become pregnant by male study patients during the course of the study, 
reasonable efforts will be made to collect information on the partner’s pregnancy through the 
first well baby visit as provided by the male study patient.
6.11.3
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 v4.0335 definitions,   
listed below:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.


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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 (ADL):
*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.
6.11.4
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, World Health Organization 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 
(dechallenge). Rechallenge 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.
6.11.5
Assessment of Adverse Event Outcome
Outcome of AEs will be defined according to ICH Topic E2B, ICH Guideline.
•
Recovered/Resolved
•
Recovered/Resolved with Sequelae


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•
Recovering/Resolving
•
Not Recovered/Not Resolved
•
Fatal
•
Unknown
6.11.6
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
6.11.7
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
6.11.8
Follow-up of Adverse Events Present at Last Scheduled Study Visit
Adverse events 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.


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6.13
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. 
The study may be terminated early if, in the opinion of the sponsor, investigator, or IRB/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
•
An adverse event
•
Lost to follow up
6.13.1
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.
6.13.2
Replacements
Patients who terminate early from the study will not be replaced.


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8
DATA MANAGEMENT
8.1
Data Collection
All data (ECGs, clinical laboratory data, and all other study-related data) will be collected 
according to the sponsor / CRO’s SOPs or according to study site standard if applicable.
8.2
Data Coding
8.2.1
Adverse Events
Adverse events will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA) and tabulated, including categorical information of interest such as 
onset and resolution times, time of onset relative to dose, severity at onset, maximum 
severity, causal relationship to study medication, and action taken. Whenever possible, a 
constellation of signs and symptoms should be recorded as a unifying diagnosis (e.g., self-
limited fever, runny nose, cough, and scratchy throat should be captured as an upper 
respiratory infection rather than by the individual signs and symptoms). AEs will be regarded 
as ‘pre-treatment’ if they occur between screening and the time of administration of the first 
dose of etrasimod. All other AEs that occur after the first dose of study medication will be 
considered to be ‘treatment-emergent’.
8.2.2
Concomitant Medications and Non-drug Treatments
Due to the variability in how medications are recorded, a standard naming convention is 
required 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.
8.2.3
Medical History
Medical history will be coded using the most current MedDRA-version.   


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9
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 statistical analysis plan, the changes will be listed along with an explanation as 
to why they occurred in the Clinical Study Report.
9.1
Hypotheses and Objectives
9.1.1
Objectives
9.1.1.1
Efficacy Objectives
The objectives will be to determine the effect of etrasimod in Inflammatory Bowel Disease 
patients on the clinical improvement of active skin extra-intestinal manifestations. 
9.1.1.2
Safety Objective
The safety objective will be to determine the safety profile and tolerability of etrasimod 
9.1.2
Hypotheses 
There are no formal hypothesis tests specified in this open-label study due to the lack of 
control treatment group.
9.2
Sample Size and Power Calculations
There is no formal sample size estimation for this proof-of-concept open-label study. Sample 
size of 10 - 20 subjects is reasonable to assess proof-of-concept of the efficacy of etrasimod 
in the target population. 
9.3
Analysis Populations
Efficacy endpoints will be analyzed in enrolled patients who have baseline and at least one 
post-baseline measure. 
Safety endpoints will be analyzed in enrolled patients who received at least one dose of study 
drug.
9.4
Demographics and Baseline Characteristics
All baseline patient characteristics of demographic data (age, height, weight, race), disease 
history, medical history (abnormalities only), physical examination (abnormalities only), and 
concomitant medications at study entry will be listed for all patients.


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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.
9.5
Efficacy Endpoints
Efficacy endpoints are outlined in the synopsis.
9.6
Statistical Methods
9.6.1
Efficacy Analysis
There are no inferential comparisons for study endpoints. Summary statistical analyses will 
be performed for all efficacy measures. For proportion based measures, N, frequencies, 
proportion and its 95% confidence interval (CI) will be produced. For continuous measure, 
N, mean, median, range, and SD will be produced for observed values, and additional 95% 
CI for change or percent change from baseline will be produced if applicable.
9.6.2
Subgroup Analyses
Efficacy endpoints will be analyzed on following patient populations. Certain subgroups may 
be combined when deemed clinically necessary.  
-
PG EIM
-
EN EIM
-
psoriasis EIM
-
psoriasis due to anti TNF-alpha treatment
Other subgroup analyses based on demographics (such as sex, age, race, etc.) may be 
performed when deemed appropriate.
9.6.3
Interim Analysis
No interim analyses are planned for this study.


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9.7
Safety Analysis
Safety and tolerability will be assessed by a review of all safety parameters including adverse 
experiences (AEs), laboratory safety parameters, vital signs, and ECG. Adverse experiences 
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.
9.7.1
Adverse Events
Adverse events 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. 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 Common Terminology Criteria for Adverse 
Events v4.0313 definitions). TEAEs will be classified according to system organ class. 
9.7.2
Physical Examinations
Physical examination results (abnormalities only) at each study visit will be listed.
9.7.3
Concomitant Medication
Pre-treatment and concomitant medication administered during the study will be listed. 
Concomitant medications will be coded using the WHODRUG Dictionary.
9.7.4
Vital Signs
Individual vital sign measurements will be summarized using descriptive statistics. Summary 
statistics will also be provided for change from baseline in vital sign measurements. Baseline
is defined as the last pre-dose measurement.
9.7.5
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 lab values. 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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9.7.7
Lymphocyte counts
Absolute lymphocyte counts at specified time points will be listed for each patient and will 
be summarized by dose level.  The relationship between clinical efficacy and lymphocyte 
count lowering will be assessed.


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10 REGULATORY REQUIREMENTS
10.1
Pre-Study Documentation:
The sponsor must receive the following documentation prior to initiation of the trial:
•
Protocol signature page signed and dated by the principal investigator (PI)
•
FDA form 1572 signed and dated by all PIs
•
Curriculum vitae of the PI and subinvestigators, updated within 2 years
•
Current medical licenses for the PI and all subinvestigators
•
Financial disclosure form signed by the PI and all subinvestigators listed on the FDA 
Form 1572 (USA only)
•
Copy of the IRB/IEC approval letter for the study and approved ICF
•
IRB/IEC Membership List
Additional country specific documentation may be required per international regulatory 
authorities.
10.2
Investigator Obligations
The PI is responsible for ensuring that all study site personnel, including subinvestigators and 
other study staff members, adhere to all country regulatory requirements and guidelines 
regarding clinical trials, including guidelines for GCP (including the archiving of essential 
documents), both during and after study completion. The PI will be responsible for the 
patient’s compliance to the study protocol. The PI is responsible for providing the sponsor an 
adequate final report shortly after he/she completes participation in the study, in accordance 
with ICH Guidelines E6, E2A, and E8.
10.3
Patient Confidentiality
All information obtained during the conduct of the study with respect to the patients’ 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.  
10.4
Informed Consent
According to the ICH guideline for GCP (E6), 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 


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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 
ICF should include all the elements as outlined in Section 4.8.10 of the ICH guideline for 
GCP (E6).
10.5
Institutional Review Board
This protocol and relevant supporting data are to be submitted to the appropriate IRB/IEC for 
review and approval before the study can be initiated. Amendments to the protocol will also 
be submitted to the IRB/IEC prior to implementation of the change. The sponsor must 
receive a letter documenting the IRB/IEC approval prior to initiation of the study. The PI is 
also responsible for informing the IRB/IEC of the progress of the study and for obtaining 
annual IRB/IEC renewal. The IRB 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 IRB/IEC in writing of any SAE or any unexpected AE according to ICH 
guidelines.


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11 PROTOCOL MANAGEMENT AND ADMINISTRATIVE 
CONSIDERATIONS
11.1
Study Documentation
The PI and study staff has 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 IRB/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 IRB/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 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.
11.2
Protocol Interpretation and Compliance
To ensure accurate interpretation and implementation of the study, the procedures and 
endpoints defined in the protocol will be carefully reviewed by the PI and his or her staff 
prior to the time of study initiation. The sponsor and PI will follow all reasonable means to 
resolve any differences of opinion of matters of eligibility, toxicity and other endpoints.  In 
the event that a resolution cannot be reached then one or both parties may seek to terminate 
the study following the provisions outlined in the Clinical Trials Agreement.
11.3
Study Monitoring
The sponsor or a contracted monitor will visit the study center periodically to monitor 
adherence to the protocol, compliance with ICH guidelines, adherence to applicable FDA 
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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12 PRINCIPAL INVESTIGATOR SIGNATURE PAGE
I agree to conduct the study as outlined in the protocol entitled “A Phase 2a, Proof of 
Concept, Open-label Study Evaluating the Efficacy and Safety of Etrasimod (APD334) in 
Inflammatory Bowel Disease Patients with active Skin Extra-intestinal Manifestations” in 
accordance with the guidelines 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 IRB/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 IRB/IEC.
•
Submission of any proposed change in the protocol to the IRB/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 IRB/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 IRB/IEC within 15 
calendar days of their disclosure.
•
Submission of timely progress reports to the IRB/IEC and sponsor at appropriate 
intervals on a schedule determined by the IRB/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. 


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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.
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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PROTOCOL SIGNATURE PAGE
Protocol Title: A Phase 2a, Proof of Concept, Open-label Study Evaluating the Efficacy and 
Safety of Etrasimod (APD334) in Inflammatory Bowel Disease Patients with active Skin 
Extra-intestinal Manifestations
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:
APD334-006
Arena Pharmaceuticals, Inc. Signatures:


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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.